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PERCUTANEOUS CORONARY INTERVENTION REVIEW

FINAL DRAFT REPORT

JANUARY 2016

January 2016

Table of Contents

ABBREVIATIONS

EXECUTIVE SUMMARYDESCRIPTION OF PCIPURPOSE OF THE REVIEWREVIEW METHODOLOGYSTAKEHOLDER CONSULTATIONSUMMARY OF FINDINGS

CURRENT USAGE OF PCI IN AUSTRALIAEVIDENCE FOR THE EFFECTIVENESS AND SAFETY OF PCICLINICAL GUIDANCE ON PCIEVIDENCE FOR THE COST-EFFECTIVENESS OF PCI

CONCLUSIONS

1 BACKGROUND ON PCI1.1 DESCRIPTION OF PCI

1.1.1 INDICATIONS FOR PCI1.1.2 TREATMENT OPTIONS1.1.3 POPULATIONS OF RELEVANCE FOR THIS MBS REVIEW OF PCI1.1.4 INCIDENCE AND PREVALENCE OF CONDITIONS1.1.5 ACS CARE IN AUSTRALIA/NEW ZEALAND; SNAPSHOT STUDY

1.2 DESCRIPTION OF THE SERVICES UNDER REVIEW1.2.1 THE MBS ITEMS RELEVANT TO PCI

1.3 THE CLINICAL DECISION PATHWAY

2 REVIEW METHODOLOGY2.1 SECONDARY DATA ANALYSIS

2.1.1 THE RESEARCH QUESTIONS FOR THE MBS ANALYSIS2.1.2 THE RESEARCH QUESTIONS FOR THE NHMD ANALYSIS

2.2 GUIDELINE CONCORDANCE2.2.1 THE RESEARCH QUESTION FOR THE GUIDELINE CONCORDANCE ANALYSIS2.2.2 GUIDELINES SEARCH AND METHODS FOR GUIDELINE CONCORDANCE ANALYSIS

2.3 PICO CRITERIA FOR CLINICAL AND ECONOMIC LITERATURE SEARCHES2.4 SYSTEMATIC LITERATURE REVIEW FOR CLINICAL EVIDENCE

2.4.1 THE RESEARCH QUESTIONS FOR THE CLINICAL EVIDENCE REVIEW2.4.2 METHODS FOR THE CLINICAL EVIDENCE REVIEW

2.5 SYSTEMATIC LITERATURE REVIEW FOR ECONOMIC EVIDENCE2.5.1 THE RESEARCH QUESTIONS FOR THE ECONOMIC EVIDENCE REVIEW2.5.2 METHODS FOR THE ECONOMIC EVIDENCE REVIEW

3 SECONDARY DATA ANALYSIS3.1 MBS SERVICES AND EXPENDITURE FOR PCI

3.1.1 TOTAL SERVICES FOR ITEMS RELATING TO PCI3.1.2 GEOGRAPHIC AND TEMPORAL TRENDS3.1.3 AGE AND GENDER3.1.4 IN-HOSPITAL AND OUT-OF-HOSPITAL SERVICES FOR ITEMS RELATING TO PCI3.1.5 PCI SERVICES BY SPECIALTY TYPE3.1.6 CO-CLAIMING PATTERNS FOR MBS ITEMS RELATING TO PCI

3.2 NHMD DATA RELATING TO PCI

MBS Reviews – Percutaneous Coronary Intervention Review Report Page 2

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3.2.1 HOSPITAL SEPARATIONS FOR PCI3.2.2 CHARACTERISTICS OF PATIENTS UNDERGOING PCI3.2.3 HOSPITAL SEPARATIONS BY PRINCIPAL DIAGNOSIS

4 REVIEW OF GUIDELINES RELEVANT TO PCI4.1 STABLE ANGINA

4.1.1 EUROPEAN CPGS4.1.2 CPGS FROM THE UNITED STATES4.1.3 UNITED KINGDOM CPGS

4.2 NON-ST-SEGMENT ELEVATION ACUTE CORONARY SYNDROME4.2.1 AUSTRALIAN GUIDELINES4.2.2 EUROPEAN GUIDELINES4.2.3 CPGS FROM THE UNITED STATES4.2.4 UNITED KINGDOM CPGS

4.3 HIGH RISK BASED ON DIAGNOSTIC TESTING4.3.1 INVASIVE DIAGNOSTIC TESTING – FRACTIONAL FLOW RESERVE4.3.2 INVASIVE CORONARY ANGIOGRAPHY4.3.3 NON-INVASIVE DIAGNOSTIC TESTING

4.4 CONCORDANCE BETWEEN THE MBS DESCRIPTORS AND AUSTRALIAN AND INTERNATIONAL GUIDELINES

4.4.1 CHRONIC STABLE ANGINA4.4.2 DIAGNOSIS OF NSTE-ACS4.4.3 HIGH RISK BASED ON DIAGNOSTIC TESTING

5 REVIEW OF THE CLINICAL EVIDENCE FOR PCI5.1 EVIDENCE BASE

5.1.1 CHRONIC STABLE ANGINA5.1.2 DIAGNOSIS OF NSTE-ACS5.1.3 ASSESSMENT OF HIGH RISK BASED ON DIAGNOSTIC TESTING

5.2 EFFECTIVENESS AND SAFETY OF PCI5.2.1 CHRONIC STABLE ANGINA5.2.2 DIAGNOSIS OF NSTE-ACS5.2.3 ASSESSMENT OF HIGH RISK BASED ON DIAGNOSTIC TESTING

6 REVIEW OF THE ECONOMIC EVIDENCE FOR PCI6.1 EVIDENCE BASE6.2 CHRONIC STABLE ANGINA

6.2.1 PCI VERSUS OMT6.2.2 PCI VERSUS CABG

6.3 DIAGNOSIS OF NSTE-ACS6.3.1 TRIAL-BASED ANALYSES

6.4 HIGH RISK BASED ON DIAGNOSTIC TESTING6.4.1 TRIAL-BASED ANALYSES

7 FINDINGS AND CONCLUSIONS7.1 CURRENT USAGE OF PCI IN AUSTRALIA7.2 APPROPRIATENESS OF THE MBS ITEMS FOR SERVICE

7.2.1 STABLE ANGINA7.2.2 NSTE-ACS7.2.3 HIGH RISK BASED ON DIAGNOSTIC TESTING

7.3 EVIDENCE FOR THE EFFECTIVENESS AND SAFETY OF PCI7.4 EVIDENCE FOR THE COST-EFFECTIVENESS OF PCI


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7.5 CONCLUSIONS

APPENDIX 1 - REFERENCES

APPENDIX 2 - REVIEW WORKING GROUP MEMBERS

APPENDIX 3 - MBS INFORMATION

APPENDIX 4 - LITERATURE SEARCH

APPENDIX 5 - NHMRC TOOLS FOR ASSESSING THE EVIDENCE

APPENDIX 6 - ADDITIONAL ANALYSES OF SECONDARY DATAA-6.1 - USE OF A CORONARY PRESSURE WIREA-6.2 - CO-CLAIMING OF MBS ITEM 38306

APPENDIX 7 - CLINICAL PRACTICE GUIDELINE LEVELS OF EVIDENCE AND RECOMMENDATION GRADESA-7.1 NHFA/CSANZA-7.2 ESC/EACTSA-7.3 ACCF/AHA

APPENDIX 8 - STUDY QUALITY ASSESSMENTA-8.1 SYSTEMATIC REVIEWS

A-8.1.1 CHRONIC STABLE ANGINAA-8.1.2 DIAGNOSIS OF NSTE-ACSA-8.1.3 CONSIDERED AT HIGH RISK BASED ON DIAGNOSTIC TESTING

APPENDIX 9 - EARLY VS DELAYED INVASIVE STRATEGIES IN PATIENTS WITH NSTE-ACS


January 2016

TABLE OF TABLES

Table 1.1-1 Features used to stratify risk of adverse outcomes in patients with NTSE-ACSTable 1.1-2 Mortality in-hospital and at 6 months in low, intermediate and high-risk categories in

registry populations, according to the GRACE risk scoreTable 1.1-3 Characteristics of patients with confirmed ACS at discharge or likely ischaemic pain

treated with revascularisation, Australia and New Zealand SNAPSHOT studyTable 1.1-4 Care received by discharge diagnosis, for STEMI/LBBB and for STEMI/LBBB and

NSTEMITable 2.1-1 ACHI codes relevant to PCITable 2.3-1 Summary of PICO criteriaTable 2.4-1 Databases searched – clinical evidenceTable 2.4-2 Additional limits applied to the systematic literature searchTable 2.4-3 Summary of the process used to identify relevant systematic reviewsTable 2.5-1 Databases searched – economic evidenceTable 2.5-2 Summary of the process used to identify relevant economic analysesTable 3.1-1 Total services for PCI-related items, 2009-10 to 2013-14Table 3.1-2 Total benefits paid for PCI-related items, 2009-10 to 2013-14Table 3.1-3 Average fees charged and benefits paid for PCI items, 2013-14Table 3.1-4 PCI services by requesting specialty type, July 2009 to June 2014Table 3.1-5 Frequency of co-claiming between PCI items, 2013-14Table 3.1-6 Multiple billing of MBS item 38306, 2013-14Table 3.1-7 Frequency of co-claiming between PCI items and diagnostic radiology itemsTable 3.1-8 Frequency of co-claiming between PCI items and ultrasound itemsTable 3.1-9 Co-claiming data for MBS item 38306Table 3.2-1 ACHI codes relevant to PCITable 3.2-2 Number of separations for ACHI codes relating to PCI, 2009-10 to 2013-14Table 3.2-3 Total number of separations for PCI procedures (ACHI codes 38300-00 to 38318-01)

in private and public patients, 2009-10 to 2013-14Table 3.2-4 Common principal diagnoses associated with ACHI codes 38300-00 to 38318-01Table 3.2-5 Number of separations for ACHI code 38300-00 by diagnosis, 2009-10 to 2013-14Table 3.2-6 Number of separations for ACHI code 38303-00 by diagnosis, 2009-10 to 2013-14Table 3.2-7 Number of separations for ACHI code 38306-00 by diagnosis, 2009-10 to 2013-14Table 3.2-8 Number of separations for ACHI code 38306-01 by diagnosis, 2009-10 to 2013-14Table 3.2-9 Number of separations for ACHI code 38306-02 by diagnosis, 2009-10 to 2013-14Table 3.2-10 Number of separations for ACHI code 38309-00 by diagnosis, 2009-10 to 2013-14Table 3.2-11 Number of separations for ACHI code 38312-00 by diagnosis, 2009-10 to 2013-14Table 3.2-12 Number of separations for ACHI code 38312-01 by diagnosis, 2009-10 to 2013-14Table 3.2-13 Number of separations for ACHI code 38315-00 by diagnosis, 2009-10 to 2013-14Table 3.2-14 Number of separations for ACHI code 38318-00 by diagnosis, 2009-10 to 2013-14Table 3.2-15 Number of separations for ACHI code 38318-01 by diagnosis, 2009-10 to 2013-14Table 4.1-1 Summary of international CPGs – Stable angina/SCAD/SIHDTable 4.1-2 2014 ESC/EACTS indications for revascularisation (PCI or CABG) in patients with

stable angina or silent ischaemia (on OMT)Table 4.1-3 2014 ESC/EACTS recommendations for the type of revascularisation (PCI or CABG)

in patients with SCAD with suitable coronary anatomy and low predicted surgical mortality

Table 4.1-4 2014 ESC/EACTS recommendations for revascularisation in patients with diabetes and multivessel disease

Table 4.1-5 2014 ESC/EACTS recommendations for revascularisation in patients with moderate or severe CKD and multivessel CAD

Table 4.1-6 2014 ESC/EACTS recommendations for revascularisation in patients with chronic HF and systolic LV dysfunction (ejection fraction ≤35%)


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Table 4.1-7 2012 ACCF/AHA recommendations on revascularisation to improve survival in patients with stable angina/SIHD

Table 4.1-8 2012 ACCF/AHA recommendations on revascularisation to improve symptoms in patients with stable angina/SIHD with significant anatomic (≥50% Left Main or ≥70% Non–Left Main CAD) or physiological (FFR ≤0.80) coronary artery stenoses

Table 4.1-9 2014 ACC/AHA updated recommendations for CAD revascularisation to improve survival

Table 4.1-10 2011 NICE conclusions for revascularisation in patients with stable anginaTable 4.1-11 2007 SIGN recommendations for revascularisation in patients with stable anginaTable 4.2-1 Summary of Australian and international CPGs – NSTE-ACSTable 4.2-2 Summary of 2006 NHFA/CSANZ recommendations for patients with NSTE-ACSTable 4.2-3 2014 ESC/EACTS criteria for high risk with indication for invasive management in

patients with NSTE-ACSTable 4.2-4 2014 ESC/EACTS recommendations for invasive evaluation and revascularisation in

NSTE-ACSTable 4.2-5 2014 ESC/EACTS recommendation for revascularisation in patients with diabetes and

NSTE-ACSTable 4.2-6 2014 AHA/ACC clinical criteria associated with appropriate selection of early

invasive strategy or ischaemia-guided strategy in patients with NSTE-ACSTable 4.2-7 2014 AHA/ACC recommendations on early invasive strategies versus ischaemia-

guided strategy in patients with NSTE-ACSTable 4.2-8 2014 AHA/ACC recommendation on PCI in patients with NSTE-ACSTable 4.2-9 2014 AHA/ACC recommendation on revascularisation in NSTE-ACS with diabetes,

heart failure, multivessel CAD or CKDTable 4.2-10 2013 SIGN recommendations for revascularisation in patients with NSTE-ACSTable 4.2-11 2010 NICE recommendations for revascularisation in patients with NSTE-ACSTable 4.2-12 Risk assessment based on predicted 6-month mortality as used in the 2010 NICE

guidelineTable 4.3-1 Summary of relevant CPGs – patients assessed at high risk based on diagnostic testingTable 4.3-2 Recommendations for the use of FFR in patients with SCAD/SIHDTable 4.3-3 Summary of recommendations on coronary angiography in patients with stable

angina/SCAD/SIHDTable 4.3-4 Summary of recommendations on coronary angiography in patients with NSTE-ACSTable 4.3-5 Recommendations for the use of non-invasive diagnostic testing for risk assessment in

patients with stable angina/SIHDTable 5.1-1 Citation details for included systematic reviews of PCITable 5.1-2 Reasons for exclusion of additional systematic reviews of PCITable 5.1-3 Characteristics of included SR/MAs: chronic stable anginaTable 5.1-4 Studies included in the systematic reviews: chronic stable angina – PCI vs. medical

therapyTable 5.1-5 Extent of stent use and medical therapies in included RCTs: chronic stable angina –

PCI vs. medical therapyTable 5.1-6 Studies included in the systematic reviews: chronic stable angina – PCI vs. CABGTable 5.1-7 Characteristics of included SR/MAs: diagnosis of NSTE-ACS – routine vs. selective

invasive strategiesTable 5.1-8 Studies included in the systematic reviews: diagnosis of NSTE-ACS – routine vs.

selective invasive strategiesTable 5.1-9 Intervention and comparator definitions in the systematic reviews: diagnosis of NSTE-

ACS – routine vs. selective invasive strategiesTable 5.1-10 Medical therapies recommended in the selected RCTs: diagnosis of NSTE-ACS –

routine vs. selective invasive therapiesTable 5.1-11 Medical therapy use during the included RCTs: diagnosis of NSTE-ACS – routine vs.

selective invasive therapiesTable 5.1-12 Angiography and revascularisation in the included RCTs: diagnosis of NSTE-ACS –

routine vs. selective invasive therapies


January 2016

Table 5.1-13 Characteristics of included systematic reviews: high-risk based on diagnostic testing – PCI vs. medical therapy

Table 5.1-14 Studies included in systematic reviews: high risk based on diagnostic testing – PCI vs. medical therapy

Table 5.1-15 Definitions of ischaemia in the included RCTs: high risk based on diagnostic testing – PCI vs. medical therapy

Table 5.1-16 Medical therapies used in the most relevant RCTs: high risk based on diagnostic testing – PCI vs. medical therapy

Table 5.2-1 Results of included systematic reviews: chronic stable angina – PCI versus medical therapy

Table 5.2-2 Citation details for included RCTs: chronic stable angina – PCI vs. medical therapyTable 5.2-3 Characteristics and conclusions of the RCTs using OMT: chronic stable angina – PCI

vs. medical therapyTable 5.2-4 High-risk subgroup analyses in included RCTs: chronic stable angina – PCI vs.

medical therapyTable 5.2-5 Diabetes subgroup analyses in included RCTs: chronic stable angina – PCI vs.

medical therapyTable 5.2-6 Multivessel subgroup analyses in included RCTs: chronic stable angina – PCI vs.

medical therapyTable 5.2-7 Chronic kidney disease subgroup analyses in included RCTs: stable chronic angina –

PCI vs. medical therapyTable 5.2-8 Heart failure or known left ventricular dysfunction subgroup analyses in included

RCTs: chronic stable angina – PCI vs. medical therapyTable 5.2-9 Quality of life in included RCTs: chronic stable angina – PCI vs. medical therapyTable 5.2-10 Adverse events in included RCTs: chronic stable angina – PCI vs. medical therapyTable 5.2-11 Results of included systematic reviews: chronic stable angina – PCI versus CABGTable 5.2-12 Citation details for additional included RCTs: chronic stable angina – PCI vs. CABGTable 5.2-13 Characteristics and conclusions of the included RCTs: chronic stable angina – PCI vs.

CABGTable 5.2-14 Stent type subgroup analyses in the included RCTs: chronic stable angina – PCI vs.

CABGTable 5.2-15 Diabetes subgroup analyses in the included RCTs: chronic stable angina – PCI vs.

CABGTable 5.2-16 Chronic kidney disease subgroup analyses in the included RCTs: chronic stable angina

– PCI vs. CABGTable 5.2-17 Heart failure or known left ventricular dysfunction subgroup analyses in the included

RCTs: chronic stable angina – PCI vs. CABGTable 5.2-18 Quality of life in the included RCTs: chronic stable angina – PCI vs. CABGTable 5.2-19 Adverse events in the included RCTs: chronic stable angina – PCI vs. CABGTable 5.2-20 Results of the included systematic reviews: diagnosis of NSTE-ACS – routine vs.

selective invasive therapies (Hoenig 2010)Table 5.2-21 Results of the included systematic reviews: diagnosis of NSTE-ACS – routine vs.

selective invasive therapies (other reviews)Table 5.2-22 Citation details for included RCTs: diagnosis of NSTE-ACS – routine vs. selective

invasive therapiesTable 5.2-23 Characteristics of the included RCTs: diagnosis of NSTE-ACS – routine vs. selective

invasive therapiesTable 5.2-24 Type of revascularisation subgroup analyses in the included RCTs: diagnosis of

NSTE-ACS – routine vs. selective invasive therapiesTable 5.2-25 Multivessel subgroup analyses in the included RCTs: diagnosis of NSTE-ACS –

routine vs. selective invasive therapiesTable 5.2-26 Quality of life in the included RCTs: diagnosis of NSTE-ACS – routine vs. selective

invasive therapies (RITA 3)Table 5.2-27 Quality of life in the included RCTs: diagnosis of NSTE-ACS – routine vs. selective

invasive therapies (FRISC II)


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Table 5.2-28 Results of included systematic reviews: high risk based on diagnostic testing – PCI vs. medical therapy

Table 5.2-29 Citation details for included RCTs: high risk based on diagnostic testing – PCI vs. medical therapy

Table 5.2-30 Characteristics of the selected RCTs: high risk based on diagnostic testing – PCI vs. medical therapy

Table 5.2-31 Results of the included RCTs: high risk based on diagnostic testing – PCI vs. medical therapy

Table 5.2-32 Diabetes subgroup analyses in the included RCTs: high risk based on diagnostic testing – PCI vs. medical therapy

Table 5.2-33 Multivessel disease subgroups in the included RCTs: high risk based on diagnostic testing – PCI vs. medical therapy

Table 5.2-34 Adverse events in the included RCTs: high risk based on diagnostic testing – PCI vs. medical therapy

Table 6.1-1 Characteristics of included economic analysesTable 6.2-1 Results of the included economic analyses: chronic stable angina – PCI vs. medical

therapy (Zhang 2011)Table 6.2-2 Results of the included economic analyses: chronic stable angina – PCI vs. medical

therapy (Weintraub 2008)Table 6.2-3 Results of the included economic analyses: chronic stable angina – PCI vs. medical

therapy (Wijeysundera 2013)Table 6.2-4 Results of the included economic analyses: chronic stable angina – PCI vs. medical

therapy (Gada 2012)Table 6.2-5 Results of the included economic analyses: chronic stable angina – PCI vs. CABG

(Cohen 2014)Table 6.2-6 Results of the included economic analyses: chronic stable angina – PCI vs. CABG

(Magnuson 2013)Table 6.3-1 Results of the included economic analyses: diagnosis of NSTE-ACS – routine vs.

selective invasive strategy (Dijksman 2009)Table 6.3-2 Results of the included economic analyses: diagnosis of NSTE-ACS – routine vs.

selective invasive strategy (Henriksson 2008)Table 6.4-1 Results of the included economic analyses: high-risk based on diagnostic testing – PCI

+ OMT vs. OMT (Fearon 2013)

Table A-.2.1 Members of the RWG for the MBS Review of PCITable A-3.1 MBS items relating to PCITable A-3.2 Explanatory notes relating to PCITable A-3.3 Other relevant MBS itemsTable A-3.4 MBS items of interest in Group T8: Surgical operationsTable A-3.5 MBS items of interest in Group I3: Diagnostic radiologyTable A-3.6 MBS items of interest in Group I1: UltrasoundTable A-4.1 Search strategy for guideline evidenceTable A-4.2 Search strategy for clinical evidenceTable A-4.3 Search strategy for economic evidenceTable A-5.1 Designations of levels of evidence for interventional studiesTable A-6.1 Number of services for MBS item 38241, 2009-10 to 2013-14Table A-6.2 Benefits paid for MBS item 38241, 2009-10 to 2013-14Table A-6.3 Frequency of co-claiming between PCI items and MBS item 38241Table A-7.1 2006 NHFA/CSANZ guideline: Levels of evidence and grades of recommendationsTable A-9.1 Selected results of excluded SR/MAs: NSTE-ACS – early vs delayed invasive

strategies


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TABLE OF FIGURESFigure 1.1-1 Clinical conditions encompassed by acute coronary syndromeFigure 1.1-2 Populations that may receive PCI, indicating those of relevance to this ReviewFigure 1.1-3 Coronary heart disease prevalence, by age and sex, 2007-2008Figure 1.1-4 Rate of ACS events, by age and gender, in Australia, 2011Figure 1.1-5 Australian and New Zealand patients with an ACS discharge diagnosis, by ACS

subcategory, SNAPSHOT studyFigure 1.3-1 Clinical pathway for PCI showing the decisions leading to each of the relevant MBS

itemsFigure 3.1-1 Number of services per capita (100,000 population) for MBS items 38300 and 38303,

2013-14Figure 3.1-2 Number of services per capita (100,000 population) for MBS item 38306, 2013-14Figure 3.1-3 Total services for MBS item 38300 by age group and gender, 2013-2014Figure 3.1-4 Total services for MBS item 38303 by age group and gender, 2013-2014Figure 3.1-5 Total services for MBS item 38306 by age group and gender, 2013-2014Figure 3.1-6 Total services for MBS item 38309 by age group and gender, 2013-2014Figure 3.1-7 Total services for MBS item 38315 by age group and gender, 2013-2014Figure 3.1-8 Total services for MBS item 38312 by age group and gender, 2013-2014Figure 3.1-9 Total services for MBS item 38318 by age group and gender, 2013-2014Figure 3.1-10 Average out-of-pocket costs for MBS items 38300-38318 over five years, 2009-10 to

2013-14Figure 3.2-1 Number of separations for private and public patients, ACHI codes 38300-00 and

38303-00, 2013-14Figure 3.2-2 Number of separations for private and public patients, ACHI codes 38306-00, 38306-

01 and 38306-02, 2013-14Figure 3.2-3 Number of separations for private and public patients, ACHI codes 38309-00 and

38315-00, 2013-14Figure 3.2-4 Number of separations for private and public patients, ACHI codes 38312-00 and

38312-01, 2013-14Figure 3.2-5 Number of separations for private and public patients, ACHI codes 38318-00 and

38318-01, 2013-14Figure 3.2-6 Number of separations by age group, ACHI codes 38300-00 and 38303-00, 2013-14Figure 3.2-7 Number of separations by age group, ACHI codes 38306-00, 38306-01 and 38306-02,

2013-14Figure 3.2-8 Number of separations by age group, ACHI codes 38309-00 and 38315-00, 2013-14Figure 3.2-9 Number of separations by age group, ACHI codes 38312-00 and 38312-01, 2013-14Figure 3.2-10 Number of separations by age group, ACHI codes 38318-00 and 38318-01, 2013-14Figure 4.2-1 Treatment strategies for patients with NSTE-ACS, based on risk stratificationFigure 5.2-1 Forest plot of PCI versus OMT (including DECOPI): chronic stable angina – all-cause

mortalityFigure 5.2-2 Forest plot of PCI versus OMT (including DECOPI): chronic stable angina – cardiac

mortalityFigure 5.2-3 Forest plot of PCI versus OMT (including DECOPI): chronic stable angina – MIFigure 5.2-4 Forest plot of PCI versus OMT (including DECOPI): chronic stable angina – repeat

revascularisationFigure 5.2-5 Forest plot of routine invasive therapy versus selective invasive therapy (including

IES): NSTE-ACS – intermediate all-cause mortalityFigure 5.2-6 Forest plot of routine invasive therapy versus selective invasive therapy (including

IES): NSTE-ACS – intermediate MIFigure 5.2-7 Forest plot of routine invasive therapy versus selective invasive therapy (including

IES): NSTE-ACS – intermediate death/MIFigure 5.2-8 Forest plot of routine invasive therapy versus selective invasive therapy (including

OASIS-5): NSTE-ACS – early mortality


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Figure 5.2-9 Forest plot of routine invasive therapy versus selective invasive therapy (including IES and OASIS-5): NSTE-ACS – intermediate mortality

Figure 5.2-10 Forest plot of routine invasive therapy versus selective invasive therapy (including OASIS-5): NSTE-ACS – late mortality

Figure 5.2-11 Forest plot of routine invasive therapy versus selective invasive therapy (including OASIS-5): NSTE-ACS – early MI

Figure 5.2-12 Forest plot of routine invasive therapy versus selective invasive therapy (including IES and OASIS-5): NSTE-ACS – intermediate MI

Figure 5.2-13 Forest plot of routine invasive therapy versus selective invasive therapy (including OASIS-5): NSTE-ACS – late MI

Figure 5.2-14 Forest plot of routine invasive therapy versus selective invasive therapy (including OASIS-5): NSTE-ACS – early mortality/MI

Figure 5.2-15 Forest plot of routine invasive therapy versus selective invasive therapy (including IES and OASIS-5): NSTE-ACS – intermediate mortality/MI

Figure 5.2-16 Forest plot of routine invasive therapy versus selective invasive therapy (including OASIS-5): NSTE-ACS – late mortality/MI

Figure 5.2-17 Forest plot of routine invasive therapy versus selective invasive therapy (including OASIS-5): NSTE-ACS – bleeding

Figure 5.2-18 Forest plot of routine invasive therapy versus selective invasive therapy (including OASIS-5): NSTE-ACS – stroke

Figure A-6.1 Number of services per capita (100,000 population) for MBS item 38241, 2009-10 to 2013-14


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ABBREVIATIONS

Acronym Description

AATS American Association for Thoracic Surgery

ACC American College of Cardiology

ACCF American College of Cardiology Foundation

ACEI Angiotensin converting enzyme inhibitor

ACHI Australian Classification of Health Interventions

ACP American College of Physicians

ACS Acute coronary syndrome

AHA American Heart Association

AHRQ Agency for Healthcare Research and Quality

AIHW Australian Institute of Health and Welfare

AIIRA Angiotensin II receptor antagonist

APQLQ Angina Pectoris Quality of Life Questionnaire

ARR Absolute risk reduction

ARTS 1 Arterial Revascularization Therapies Study

BA Bayesian analysis

BARI 2D Bypass Angioplasty Revascularization Investigation 2 Diabetes

BMI Body mass index

BMS Bare metal stent

CABG Coronary artery bypass graft

CAD Coronary artery disease

CADTH Canadian Agency for Drugs and Technologies in Health

CAG Coronary angiography

CARDIa Coronary Artery Revascularization in Diabetes


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Acronym Description

CCS Canadian Cardiovascular Society

CFR Coronary flow reserve

CHD Coronary heart disease

CHF Congestive heart failure

CI Confidence interval/Credible interval

CKD Chronic kidney disease

CMFM Comprehensive Management Framework for the Medicare Benefits Schedule

CMR Cardiac magnetic resonance

COURAGE Clinical Outcomes Utilizing Revascularization and Aggressive DruG Evaluation

CPG Clinical practice guideline

CSANZ Cardiology Society of Australia and New Zealand

CTA Computed tomography angiography

CTCA Computed tomography coronary angiography

CTO Chronic total occlusion

CV Cardiovascular

DECOPI Desobstruction Coronaire en Post-Infarctus

DES Drug-eluting stent

DM Type 2 diabetes

DRG Diagnosis Related Group

EACTS European Association of Cardio-Thoracic Surgery

EAPCI European Association of Percutaneous Cardiovascular Interventions

ECG Electrocardiogram

EMSN Extended Medicare Safety Net

EQ-5D EuroQOL 5-Dimensional Classification


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Acronym Description

ERACI II Coronary Angioplasty With Stenting versus Coronary Bypass Surgery in Patients with Multiple-Vessel Disease

ESC European Society of Cardiology

ESR European Society of Cardiology

ETT Exercise treadmill testing

FAME 2 Fractional flow reserve versus Angiography for Multivessel Evaluation 2

FEM Fixed effects model

FFR Fractional flow reserve

FREEDOM Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease

FRISC II Framingham and Fast Revascularization During Instability in Coronary Artery Disease II

GDG Guideline Development Group

GDMT Guideline-directed medical therapy

GFR Glomerular filtration rate

GPIIb/IIIa Glycoprotein IIb/IIIa

GRACE Global Registry of Acute Coronary Events

HF Heart failure

HR Hazard ratio

HTA Health Technology Assessment

ICER Incremental cost-effectiveness ratio

ICTUS Invasive vs Conservative Treatment in Unstable Coronary Syndromes

ICU Intensive care unit

IES Italian Elderly Study

IHD Ischaemic heart disease

INSPIRE Adenosine Sestambi Post-Infarction Evaluation


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Acronym Description

IPD Individual patient data

IRR Incidence rate ratio

ISCHEMIA International Study of Comparative Health Effectiveness with Medical and Invasive Approaches

IVUS Intravascular ultrasound

JSAP Japanese Stable Angina Pectoris

LACAS Left anterior coronary artery stenosis

LAD Left anterior descending

LBBB Left bundle branch block

LE MANS Study of Unprotected Left Main Stenting Versus Bypass Surgery

LIMA Left internal mammary artery

LM Left main

LMWH Low molecular weight heparin

LOE Level of evidence

LV Left venticular

LVEF Left ventricular ejection fraction

LV PDS Left ventricular perfusion defect size

LYG Life-years gained

MA Meta-analysis

MACCE Major adverse cardiac and cerebrovascular events

MACE Major coronary adverse events

MBS Medicare Benefits Schedule

MD Mean difference

MI Myocardial infarction

MPI Myocardial perfusion imaging


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Acronym Description

MT Medical therapy

MV-C Multivessel disease – culprit vessel PCI

MV-M Multivessel disease – multivessel PCI

NA Not applicable

NE Not estimable

NHFA National Heart Foundation of Australia

NHMD National Hospital Morbidity Database

NHMRC National Health and Medical Research Council

NHS National Health Survey

NICE National Institute for Health and Care Excellence

NR Not reported

NSTE-ACS Non-ST-segment elevation acute coronary syndrome

NSTEMI Non-ST-segment elevation myocardial infarction

NYHA New York Heart Association

OAT Occluded Artery Trial

OBS Observational study

OCT Optical coherence tomography

OMT Optimal medical therapy

OP Off-pump

OR Odds ratio

PAD Peripheral artery disease

PASC Protocol Advisory Sub-Committee

PBS Pharmaceutical Benefits Scheme

PCI Percutaneous coronary intervention

PCNA Preventive Cardiovascular Nurses Association


January 2016

Acronym Description

PICO Population, Intervention, Comparator, Outcome

PRECOMBAT Premier of Randomized Comparison of Bypass Surgery versus Angioplasty Using Sirolimus-Eluting Stent in Patients with Left Main Coronary Artery Disease

PTCA Percutaneous transluminal coronary angioplasty

PTCR Percutaneous transluminal coronary revascularisation

PTCRA Percutaneous transluminal coronary rotational atherectomy

PTP Pre-test probability

QALY Quality-adjusted life-year

QoL Quality of life

RCT Randomised controlled trial

RD Risk difference

RE Risk estimate

REM Random effects model

RITA-3 Third Randomized Intervention Treatment of Angina

RR Relative risk

RWG Review Working Group

SAE Serious adverse events

SAQ Seattle Angina Questionnaire

SCAD Stable coronary artery disease

SCAG Selective coronary angiography

SCAI Society for Cardiovascular Angiography and Interventions

SD Standard deviation

SF-36 Short Form-36

SIGN Scottish Intercollegiate Guidelines Network

SIHD Stable ischaemic heart disease


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Acronym Description

SIMA Stenting to Internal Mammary Artery

SoS Stent or Surgery

SPECT Single-photon emission computed tomography

SR Systematic review

STEMI Segment elevation myocardial infarction

STS Society of Thoracic Surgeons

SV Single-vessel disease

SWISSI II Swiss Interventional Study on Silent Ischemia Type II

SYNTAX Synergy Between Percutaneous Coronary Intervention With TAXUS and Cardiac Surgery

TACTICS-TIMI 18

Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy-Thrombolysis in Myocardial Infarction 18

TIA Transient ischaemic attack

TGA Therapeutic Goods Administration

TMR TMR, transmyocardial revascularisation

TMT Treatment

TOSCA-2 Total Occlusion Study of Canada

UA Unstable angina

UFH Unfractionated heparin

UK United Kingdom

ULMCA Upper left main coronary artery

ULN Upper limit of normal

US United States

VT Ventricular tachycardia

WTP Willingness to pay


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EXECUTIVE SUMMARY

The Department of Health engaged HealthConsult Pty Ltd to undertake an evidence-based review of percutaneous coronary intervention (PCI) to ensure that the services on the Medicare Benefits Schedule (MBS) reflect contemporary evidence, improve health outcomes for patients and represent value for money. This Report presents the collection and analysis of evidence to inform assessment of the existing MBS items for PCI in this context. This project was commissioned as part of the Comprehensive Management Framework for the MBS.

The vast majority of MBS items are longstanding, with only a small proportion of services funded having undergone formal evidence-based assessment. MBS Reviews seek to ensure the Schedule reflects current clinical practice and contemporary evidence.

Description of PCI

PCI (commonly referred to as angioplasty) is a minimally invasive, non-surgical revascularisation technique performed to open narrowed or blocked coronary arteries and to restore arterial blood flow to the heart muscle.

PCI is performed using a catheter with a deflated balloon at its tip that is inserted into the femoral, radial, brachial or axillary arteries. Using fluoroscopy, the catheter is threaded through the blood vessels to the narrowed or blocked coronary artery. The balloon is inflated after the catheter has been placed within the narrowed area of the coronary artery. The inflation of the balloon disrupts and compresses the atherosclerotic plaque into the wall of the artery and makes a larger opening inside the artery for improved blood flow.

Balloon angioplasty is rarely the only procedure performed during PCI. The overwhelming majority of PCIs involve the implantation of one or more coronary stents, which are tiny, expandable metal coils that are deployed in the re-opened area of the artery to stabilise the disrupted plaque and also aid in reducing re-closure of the narrowed area in the six months after the procedure (restenosis). Another less common procedure performed during PCI is atherectomy, which removes the plaque burden within the artery using a cutting device, rotating burr or laser.

Purpose of the Review

All seven MBS items in Group T8 (Surgical operations); Subgroup 6 (Cardio-thoracic); Subheading 3 (Endovascular interventional procedures) of the MBS are included in this Review of PCI. The current descriptors and schedule fees for these items are provided in Appendix 3. These services relate to:

Angioplasty (MBS items 38300 and 38303) Stent insertion, including angioplasty (MBS item 38306) Rotational atherectomy, including angioplasty (MBS items 38309 and 38315) Rotational atherectomy, including angioplasty and stent insertion (MBS items 38312 and

38318)

The purpose of this Review is to evaluate whether PCI is a clinically necessary, safe and effective service. Given that the vast majority of PCIs involve coronary artery stent insertion, the key issues addressed in the evidence review relate to three specific populations where the safety, effectiveness and cost-effectiveness of PCI with stent insertion is uncertain or


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controversial: (i) patients with chronic stable angina; (ii) patients with a diagnosis of non-ST-segment elevation acute coronary syndrome (NSTE-ACS); and (iii) patients who are assessed at higher risk of coronary events following diagnostic testing (e.g. non-invasive imaging such as stress echocardiography or myocardial perfusion imaging, or invasive coronary angiography, with or without fractional flow reserve (FFR)).

The comparators depend on the population of interest (see Section 2.3) and may include a primary strategy of either (i) medical therapy alone, whereby the primary strategy comprises pharmacological therapy (i.e. medical management with antiplatelet therapy, lipid-lowering agents, etc.) with watchful waiting; or (ii) coronary artery bypass graft (CABG) surgery (combined with medical therapy). For the population of patients with a diagnosis of NSTE-ACS, the Review will compare a strategy of selective PCI (plus medical therapy) versus routine PCI (plus medical therapy), as both strategies are used in Australia and it is not clear which of these is superior.

Although PCI is also used in patients with a diagnosis of ST-segment elevation myocardial infarction (STEMI), this population was not included in the clinical and economic evidence review as the role of PCI in their management is well established.

This Review Report outlines the rationale behind conducting the review of the MBS items relevant to PCI and the process undertaken to identify and appraise the available information on the MBS items of interest.

Review methodology

The review methodology comprised the following components: consulting with key stakeholders; developing a review protocol, which outlined the detailed review methodology (including specifying the key clinical/research questions for the systematic review, preparing the clinical flowcharts); analysing secondary data sources (MBS and hospital separations data); an analysis of guideline concordance; conducting a systematic literature review for clinical and economic evidence and a de novo economic evaluation from the perspective of the Australian health care system; and undertaking an assessment and analysis of the evidence to draw conclusions in relation to the clinical/research questions.

The research methodology, including the clinical/research questions, is explained in detail in Section 2.

Stakeholder consultation

Stakeholder engagement is a pivotal part of the MBS Review process, particularly as feedback helps inform the final Review Report. During the review process, stakeholders were informed of the intention of the review of PCI, and were given the opportunity to comment on the review scope, the proposed methodology, and the draft Review Report. Relevant documents were released for public consultation and stakeholder comments were considered and incorporated prior to finalisation of the protocol and report.

As part of the MBS Review process, the Department established a Review Working Group (RWG). The RWG comprises nominated experts to provide clinical input and ensure the review reflects current Australian practice. Appendix 2 outlines the RWG members for this Review.


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Summary of findings

Current usage of PCI in Australia

An analysis of MBS data was undertaken to determine the current service profile for PCI (Section 3.1). This was supplemented with an analysis of hospital separations data from the National Hospital Morbidity Database (Section 3.2).

MBS item 38306 (angioplasty with the insertion of stent/s, one occluded site) is the most commonly used of the seven PCI items, accounting for $7,867,506 in benefits paid in the 2013-14 financial year and 23,746 services, which represents 92% of all PCI services.1 Due to the predominance of this item, many characteristics of overall PCI usage including age, gender, and geographical trends are similar to the individual usage of that item; however, no important differences were observed in any patient, geographic or temporal trends between MBS item 38306 and the other six PCI-related MBS items.

In addition to the analysis of MBS data, hospital separations data for both public and private patients were analysed using 11 Australian Classification of Health Interventions (ACHI) procedures codes (38300-00 to 38318-01). Importantly, the four additional ACHI procedures codes (compared with the seven MBS items) provided further information about the number of coronary arteries involved or the number of stents that were inserted during a particular procedure.

Both the number of MBS services undertaken and the number of hospital separations involving PCI have increased gradually over the five-year period from July 2009 to June 2014, with percentage growth over the time of 8.5% and 6.4%, respectively. While MBS expenditure has increased more rapidly (18.3%), this growth is likely to be largely attributable to several increases in MBS fees over that time. Out-of-pocket costs have remained relatively consistent over the same five-year period.

PCI is nearly always undertaken in patients aged 50 years or older, with the number of MBS services as well as hospital separations increasing with age and commonly peaking in one of two age groups: 65 to 69 years; or 70 to 74 years. The predominance of PCI usage in an older population is unsurprising given that the prevalence of coronary heart disease (CHD) and incidence of acute coronary events both increase with age. The MBS data that showed that around three-quarters of patients who underwent MBS-funded PCI procedures in 2013-14 were male, which is consistent with epidemiological data for CHD and acute coronary events.

According to MBS data from 2013-14, approximately 96% of PCI procedures were undertaken in-hospital and nearly all services (90%) were requested by cardiology specialists.

Based on 2013-14 Admitted Patient Care Data, the principal diagnosis for 43% of hospital separations in which PCI was undertaken was acute MI. Patients with a principal diagnosis of atherosclerotic heart disease or angina made up the majority of the remaining hospital separations, accounting for approximately 30% and 20%, respectively.

Evidence for the effectiveness and safety of PCI

The evidence base for the assessment of the effectiveness and safety of PCI was largely based on the findings of systematic reviews of randomised controlled trials (RCTs). Individual RCT

1 The average benefit paid per service is lower than the Schedule Fee due to the Multiple Operations Rule.


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results were used only to supplement this evidence where data on specific subgroups or outcomes of interest were lacking.

Overall, the identified Level I or Level II evidence does not support the use of PCI in terms of reducing rates of death or myocardial infarction (MI) in the following populations: (i) patients with chronic stable angina that is well controlled with optimal medical therapy (OMT); (ii) low- or intermediate-risk patients with a diagnosis of NSTE-ACS; and (iii) patients with stable coronary artery disease (CAD) who are assessed at higher risk of coronary events following diagnostic testing such as FFR. Reductions in other end-points such as subsequent MI, refractory angina and urgent revascularisation were found for particular populations and/or subgroups, as were associated harms. Key findings will be discussed in turn for each of the specific clinical questions.

(1)A. What is the evidence for the safety and effectiveness of PCI with stent insertion combined with medical therapy compared with medical therapy alone in patients with chronic stable angina?

The findings for this comparison were largely based on the conclusions of one health technology assessment conducted on behalf of the German Federal Ministry of Health (Gorenoi et al, 2010). This systematic review (Level I evidence) limited inclusion of studies to those that used what it defined as OMT. Individual RCTs (Level II evidence) were eligible for inclusion if beta-adrenergic receptor blockers, aspirin and statins were used in at least 80% of the included patients, and angiotensin converting enzyme inhibitors (ACEI) were used in at least 50% of the included patients. An additional RCT that met these criteria (DECOPI) was incorporated into the Gorenoi meta-analysis for the purpose of this MBS Review. As shown in Table ES.1, there was no significant difference between PCI and OMT for any of the efficacy outcomes assessed in this Review. Although not an outcome pre-specified in the PICO criteria for this Review, the Gorenoi review also found that the proportion of patients with angina attacks was lower after PCI at one and three years, but not at five years.

Table ES.1 Clinical evidence: chronic stable angina – PCI vs. OMT (Gorenoi et al, 2011 + update)

Population Outcome Studies (patients) Risk estimate(95% CI); p value

Stable angina All-cause mortality 4 (6270) RR 0.99 (0.85, 1.16); 0.94

Cardiac mortality 4 (6270) RR 1.08 (0.86, 1.36); 0.51

MI 4 (6270) RR 1.16 (1.00, 1.36); 0.06

Death/MI 3 (6058) RR 1.10 (0.98, 1.12); 0.10

Stroke 3 (6058) RR 1.09 (0.76, 1.56); 0.65

Death/MI/stroke 3 (3892) RR 1.09 (0.94, 1.28); 0.26Note: Included studies are BARI-2D, COURAGE, OAT and DECOPI.Abbreviations: CI, confidence interval; MI, myocardial infarction; OMT, optimal medical therapy, PCI, percutaneous coronary intervention; RR, relative risk.

Based on the results of RCTs that used OMT, these findings were consistent across different patient subgroups including those at high risk, and those with diabetes, multivessel disease, chronic kidney disease (CKD) and left ventricular dysfunction. PCI improved quality of life over the shorter term (≤12 months) but not over the longer term. Major haemorrhage occurred more frequently following PCI + OMT than OMT alone, but the underlying risk was low (0.7% vs. 0.1%; p=0.04).


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(1)B. What is the evidence for the safety and effectiveness of PCI with stent insertion combined with medical therapy compared with medical therapy alone in patients who are assessed at higher risk of coronary events following diagnostic testing?

The findings for this comparison were largely based on the conclusions of one recent systematic review with meta-analysis (SR/MA). This review (Gada et al, 2015) limited inclusion in their analysis to trials in which objective evidence of ischaemia (using non-invasive imaging or its invasive equivalent) was required. One of the three RCTs included in the Gada review was excluded from consideration from this MBS Review because no patients included in the PCI arm received stents; all patients received balloon angioplasty only. As shown in Table ES.2, there was no significant difference between PCI and OMT for all-cause mortality.

Table ES.2 Clinical evidence: high risk based on diagnostic testing – PCI vs. OMT (Gada et al, 2015)

Population Outcome Studies (patients) Risk estimate(95% CI); p value

Stable CAD and objective evidence of ischaemia using imaging (non-invasive or invasive)

All-cause mortality 2 (1356) HR 0.59 (0.29, 1.17); 0.13

Note: Included studies are the COURAGE nuclear sub-study and FAME 2.Abbreviations: CAD, coronary artery disease; CI, confidence interval; HR, hazard ratio; OMT, optimal medical therapy, PCI, percutaneous coronary intervention.

Of the two studies included in this analysis (COURAGE nuclear sub-study and FAME 2), neither showed an overall benefit in favour of PCI for death or MI. However, when separate time point analyses were conducted in the FAME 2 study, a significantly increased risk of MI was seen for PCI in the first 7 days (HR 9.01; 95% CI 1.13, 72.0; p=0.012). For > 7 days, a trend towards a decreased risk of MI was seen for PCI compared with medical therapy (HR 0.58; 95% CI 0.32, 1.05; p=0.07).2

There was no interaction seen between treatment type and multivessel or diabetes subgroups for the primary outcome death/MI/urgent revascularisation in the FAME 2 study. Also in the FAME 2 study, the rate of serious adverse events was similar between the PCI and medical therapy groups.

(2)A. What is the evidence for the safety and effectiveness of PCI with stent insertion combined with medical therapy compared with CABG combined with medical therapy in patients with chronic stable angina?

The findings for this comparison were largely based on the conclusions of two SR/MAs of RCTs (D’Ascenzo et al, 2014; Fanari et al, 2014). It should be noted that in the D’Ascenzo SR/MA, 100% of patients in the PCI arm of 14 out of the 20 included RCTs received stents, while in four studies, no patients received stents. In the remaining two studies, 54% and 68% of patients received stents. In the Fanari SR/MA, studies included patients who received PCI + drug-eluting stents (DES).

2 There was a significant benefit seen for PCI compared with medical therapy for the primary outcome in the FAME 2 study, death/MI/urgent revascularisation. As discussed in Section 5.2.3, revascularisation is not considered an appropriate outcome for the PCI versus medical therapy comparison.


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As shown in Table ES.3, there was no significant difference between PCI and CABG for death or MI (for both the overall population and the subgroup with multivessel disease) in the D’Ascenzo review, while there was a significantly increased risk of death and MI at 5 years associated with PCI + DES compared with CABG in patients with multivessel disease and the subgroup of patients with multivessel disease who have diabetes. There was a significantly lower risk of stroke for PCI compared with CABG at 30 days and study follow-up (which ranged from 1 to 5 years) for both the overall population and the subgroup with multivessel disease. The significantly lower risk of stroke was also seen for PCI + DES at 1, 2 and 5 years in the Fanari et al (2014) review.

Table ES.3 Clinical evidence: chronic stable angina – PCI vs. CABG

Population Outcome (analysis/subgroup) Studies (patients) Risk estimate(95% CI); p value

D’Ascenzo et al (2014) review - Stable angina

Death (overall population)Death (multivessel disease)

NRNR

OR 0.99 (0.77, 1.27)OR 1.11 (0.87, 1.43)

MI (overall population)MI (multivessel disease)

NRNR

OR 1.03 (0.77, 1.37)OR 1.00 (0.72, 1.39)

Stroke (30 days – overall population)Stroke (follow-up – overall population)Stroke (30 days – multivessel disease)Stroke (follow-up – multivessel disease)

NRNRNRNR

OR 0.36 (0.20, 0.62)OR 0.57 (0.41, 0.80)OR 0.34 (0.19, 0.61)OR 0.49 (0.25, 0.97)

Fanari et al review (2014) - Multivessel disease

Death – 1 yDeath – 2 yDeath – 5 yDeath – 5 y (diabetes)

6 (5123)4 (4498)3 (4202)3 (2854)

RR 1.02 (0.77, 1.36); NRRR 1.31 (0.83, 2.08); NRRR 1.30 (1.10, 1.54); NRRR 1.36 (1.11, 1.66); NR

MI – 1 yMI – 2 yMI – 5 yMI – 5 y (diabetes)

6 (5123)4 (4498)3 (4202)3 (2854)

RR 1.02 (0.77, 1.36); NRRR 1.21 (0.70, 2.11); NRRR 2.21 (1.75, 2.79); NRRR 2.01 (1.54, 2.62); NR

Target vessel revasc. – 1 y 6 (5123) RR 2.31 (1.80, 2.96); NR

Stroke – 1 yStroke – 2 yStroke – 5 yStroke – 5 y (diabetes)

6 (5123)4 (4498)3 (4202)3 (2854)

RR 0.35 (0.19, 0.62); NRRR 0.55 (0.35, 0.87); NRRR 0.60 (0.42, 0.86); NRRR0.59 (0.39, 0.89); NR

Note: Included studies are FREEDOM, Budriot 2011, PRECOMBAT, CARDIa, SYNTAX LM, SYNTAX, LE MANS, Seoul 2005, MASS II, Groningen 2002, Leipzig 2002, SoS, ARTS 1, AWESOME, ERACI II, SIMA, BARI, EAST, GABI and RITA. Statistically significant results are shown in bold. Abbreviations: CABG, coronary artery bypass graft; CI, confidence interval; MI, myocardial infarction; NR, not reported; OR, odds ratio; PCI, percutaneous coronary intervention; RR, relative risk.

Based on the results of the individual RCTs included in the D’Ascenzo et al (2014) review, there was no significant interaction between PCI and CABG and subgroups including renal insufficiency and left ventricular dysfunction. In the Fanari et al (2014) review, the risk of death and MI was significantly greater for patients with multivessel disease and diabetes who received PCI + DES compared with CABG; this review included data from the SYNTAX, FREEDOM and CARDIa trials. However, in other RCTs comparing results in diabetes and no diabetes subgroups, no interaction between treatment and diabetes was seen.

In the short term (≤1 month), quality of life was significantly greater in patients undergoing PCI compared with CABG. However, this difference did not persist into the longer term and in some cases, an improved quality of life was seen for CABG compared with PCI. Major


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bleeding tended to be greater following CABG than PCI; for example, in the CARDIa trial, TIMI major bleeding occurred in 1.2% of patients following PCI and 6.1% of patients following CABG (HR 0.19; 95% CI 0.06, 0.67; p=0.009). In the SYNTAX study, stent thrombosis occurred most commonly in the first month following PCI (2.0%), while graft occlusion most commonly occurred after 1 month (2.5%).

(2)B. What is the evidence for the safety and effectiveness of PCI with stent insertion combined with medical therapy compared with CABG combined with medical therapy in patients with a diagnosis of NSTE-ACS?

No Level I or Level II studies were identified that specifically compared the use of PCI with CABG in patients with NSTE-ACS. The TACTICS-TIMI 18 trial, which compared a routine invasive strategy (catheterisation in all patients with revascularisation with PCI ± stenting or CABG as appropriate) with a conservative strategy (medical therapy with revascularisation when clinically indicated) provides efficacy results by revascularisation status, and hence provides results for patients undergoing PCI only and CABG only. However, it is not appropriate to make comparisons between PCI and CABG in this study, as they may be subject to selection bias; the decision to revascularise, and the method used, was based on the clinical characteristics of the patient. Thus, patients were not randomised to medical therapy only, PCI or CABG so there may be substantial differences between the populations that underwent different procedures.

(2)C. What is the evidence for the safety and effectiveness of PCI with stent insertion combined with medical therapy compared with CABG combined with medical therapy in patients who are assessed at higher risk of coronary events following diagnostic testing?

No Level I or Level II studies were identified that specifically compared the use of PCI with CABG in patients assessed at higher risk of coronary events following diagnostic testing.

(3) What is the evidence for the safety and effectiveness of a selective PCI strategy compared with a routine PCI strategy in patients with a diagnosis of NSTE-ACS?

The findings for this comparison were largely based on a Cochrane Review conducted by Hoenig and colleagues (2010) for a number of reasons: (i) it limits inclusion of RCTs to those conducted during the ‘stent era’; (ii) it provides subgroup analyses of studies with and without GPIIb/IIIa use, as these treatments are considered to be important in contemporary clinical practice; (iii) it provides the most comprehensive list of outcomes, assessing both efficacy and safety; and (iv) where data are available, outcome results are presented at different time points: index (during initial hospitalisation), early (≤4 months), intermediate (6 – 12 months) and late (>12 months). The Hoenig review included data from up to five RCTs. One additional RCT (IES) was published after the Hoenig review. Data from the IES trial was incorporated into the Hoenig review meta-analysis where applicable for the purpose of this MBS Review.

It should be noted that the Hoenig review, and the remaining 10 reviews identified, all compared a routine/early invasive strategy with a selective invasive/conservative strategy. All strategies included revascularisation with either PCI or CABG depending on the clinicians choice; no SR or included RCT specifically looked at routine versus selective PCI.


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The results of the updated Hoenig et al (2010) SR/MA are presented in Table ES.4. There was no significant difference in death between the routine and selective invasive strategies at any of the time points examined, while a routine invasive strategy resulted in significantly fewer MIs at intermediate and late time points. Procedure-related MI and bleeding occurred significantly more frequently in the routine invasive strategy group than the selective invasive strategy group. Thus, while there was some benefit of a routine strategy in this population, there were also increased risks associated with the increased number of procedures.

Table ES.4 Clinical evidence: NSTE-ACS – routine invasive therapy vs. selective invasive therapy (Hoenig et al, 2010)

Outcome Overall -

Efficacy outcomes Studies (patients) RR (95% CI); p value

Index death3

Early deathIntermediate deathLate death

5 (7781)3 (4161)6 (8131)3 (5467)

RR 1.53 (0.98, 2.39); 0.06RR 1.11 (0.66, 1.88); 0.70RR 0.84 (0.62, 1.13); 0.25RR 0.90 (0.76, 1.08); 0.25

Index MIEarly MIIntermediate MILate MI

5 (7781)3 (4161)6 (8131)3 (5467)

RR 1.03 (0.52, 2.03); 0.93RR 0.64 (0.38, 1.06); 0.08RR 0.73 (0.62, 0.86); 0.0001RR 0.78 (0.67, 0.92); <0.001

Index death/MIEarly death/MIIntermediate death/MILate death/MI

4 (6618)2 (2351)5 (6931)3 (5467)

RR 1.14 (0.59, 2.21); 0.69RR 0.64 (0.45, 0.92); 0.015RR 0.78 (0.66, 0.92); 0.003RR 0.89 (0.73, 1.08); 0.23

Intermediate refractory angina 4 (7687) RR 0.67 (0.55, 0.83); <0.001

Intermediate rehospitalisation 4 (6008) RR 0.67 (0.61, 0.74); <0.001

Safety outcomes Studies (patients) RR (95% CI); p value

Procedure-related MI 3 (5467) RR 2.00 (1.53, 2.61); <0.001

Bleeding 3 (6487) RR 1.71 (1.27, 2.31); <0.001

Stroke 2 (4677) RR 0.89 (0.34, 2.31); 0.81Note: Included studies are IES, ICTUS, RITA 3, VINO, TACTICS-TIMI 18, FRISC II. Statistically significant results shown in bold. Abbreviations: CI, confidence interval; MI, myocardial infarction; NSTE-ACS, non-ST-segment-elevation acute coronary syndrome; RR, relative risk; SR, systematic review.

Two additional reviews assessed outcomes by risk subgroups. Based on analysis of individual patient data (IPD) from three RCTs (ICTUS, RITA 3 and FRISC II) Fox et al (2010) showed that, when categorised into low, moderate and high-risk categories, a routine invasive strategy provided a greater reduction in the composite outcome of cardiovascular (CV) death/MI compared with a selective invasive strategy for high-risk patients (RD –11.1%; 95% CI –18.4%, –3.8%), compared with moderate-risk (RD –3.8%; 95% CI –7.4%, –0.1%) and low-risk (RD –2.0%; 95% CI –4.1%, 0.1%) patients. Based on a subsequent analysis of the same studies, Alfredsson et al (2014) showed that high-risk and medium-risk men gained a benefit in the composite outcome of CV death/MI from the use of a routine compared with a selective invasive strategy (HR 0.56; 95% CI 0.41, 0.75 and HR 0.74; 95% CI 0.58, 0.96, respectively), while low-risk men, and low, medium and high-risk women did not.

While these results suggest that patients at high risk may significantly benefit from undergoing a routine invasive strategy compared with a selective invasive strategy, there are some important points to note: (i) the results are based on a post hoc analysis of IPD from 3 ‘Index’ end-points indicate follow up during the initial hospitalisation. ‘Early’ end-points indicate a follow up ≤4 months. ‘Intermediate’ end-points indicate a follow up ≥6 months, or ≤12 months. ‘Late’ end-points indicate a follow up ≥2years.


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selected trials, and (ii) the methods used to categorise patients into risk groups were not based on validated methods. Australian and International clinical practice guidelines (CPGs) recommend that an early invasive strategy should be used in patients considered to be at high risk of cardiac events. However, these recommendations relate to the timing of routine intervention (i.e. early versus late), rather than whether or not an invasive strategy should be carried out, and are based on a separate body of evidence to the one assessed as part of this Review (see Section 5.1.2).

With regards to patients with diabetes, O’Donoghue et al (2012) compared an invasive strategy with a conservative strategy in patients with and without diabetes, and found that MI was significantly reduced in patients with diabetes who receive an invasive strategy compared with a conservative strategy (RR 0.71; 95% CI 0.55, 0.92). Based on the results of two of the RCTs that were included in the Hoenig et al (2010) SR/MA, RITA-3 and FRISC II, quality of life was significantly improved in patients undergoing a routine invasive strategy compared with patients undergoing a selective invasive strategy up to 1 year follow-up.

(4)A. Supplementary question: What is the evidence for the safety and effectiveness of DES compared with bare metal stents (BMS) in patients with chronic stable angina?

One Level I study was identified that specifically compared the use of BMS with DES as part of a PCI strategy in patients with chronic stable angina. Trikalinos et al (2009) assessed the effect of PCI in patients with non-acute coronary disease using direct and indirect meta-analysis. As part of this assessment they separately compared BMS and DES with medical therapy, as well as comparing BMS with DES. There was no significant difference between BMS and medical therapy for the direct or indirect analyses. There were no trials directly comparing DES and medical therapy so only indirect comparisons were available for the outcomes of interest (all-cause mortality, MI and CABG). These indirect comparisons showed no difference between DES and medical therapy for all-cause mortality and MI, and a significantly reduced risk of CABG for DES compared with medical therapy.

It is important to note that the inclusion of trials in these analyses was not limited to those in which OMT was used, which may have biased the findings in favour of PCI. Finally, direct and indirect comparisons between DES and BMS were undertaken, showing no difference between the different types of stents for all-cause mortality and MI, and a significantly reduced risk of CABG for patients receiving DES compared with BMS for both the direct and indirect comparisons. In summary, the use of DES or BMS does not result in differences in all-cause mortality or MI, while DES appears to reduce the risk of requiring CABG compared with the use of BMS.


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Table ES.5 Stent type analysis: chronic stable angina – PCI vs. medical therapy (Trikalinos et al, 2009)

Comparison Outcome Studies (patients) Risk estimate(95% CI); p value

BMS vs. MT All-cause mortality (direct)All-cause mortality (direct and indirect)

3 (4518)52 (23,557)

RR 0.96 (0.79, 1.18)RR 0.90 (0.70, 1.16)

MI (direct)MI (direct and indirect)

4 (4619)55 (23,622)

RR 1.18 (0.97, 1.43)RR 1.24 (0.88, 1.75)

CABG (direct)CABG (direct and indirect)

2 (2267)52 (18,024)

RR 0.97 (0.63, 1.50)RR 1.04 (0.83, 1.29)

Repeat revasc. (direct)Repeat revasc. (direct and indirect)

3 (4518)13 (8809)

RR 0.78 (0.58, 1.05)RR 0.71 (0.58, 0.87)

DES vs. MT All-cause mortality (direct)All-cause mortality (direct and indirect)

0 (0)51 (23,557)

-RR 0.96 (0.60, 1.52)


0 (0)55 (23,622)

-RR 1.15 (0.73, 1.82)


0 (0)43 (18,201)

-RR 0.58 (0.38, 0.88)

DES vs. BMS All-cause mortality (direct)All-cause mortality (direct and indirect)

15 (7328)51 (23,557)

RR 1.09 (0.73, 1.63); NRRR 1.06 (0.71, 1.58); NR


14 (6303)55 (23,622)

RR 1.03 (0.79, 1.35); NRRR 0.93 (0.68, 1.26); NR


12 (4995)43 (18,201)

RR 0.56 (0.36, 0.88); NRRR 0.56 (0.39, 0.80); NR

Note: Statistically significant results are shown in bold. Abbreviations: BMS, bare metal stent; CABG, coronary artery bypass graft; CI, confidence interval; DES, drug-eluting stent; MI, myocardial infarction; MT, medical therapy; RR, relative risk.

One RCT comparing PCI + stent insertion with CABG indirectly compared the effect of different types of stents: BMS and DES. In the CARDIa trial (Kapur et al, 2010), which included patients with multivessel CAD and diabetes, PCI was initially conducted using BMS; however, DES were used once they became available. In order to minimise potential confounding in the comparison, patients receiving BMS were compared with patients who received CABG prior to the introduction of DES, while patients receiving DES were compared with patients who received CABG following the introduction of DES. As shown in Table ES.6, there was a higher (although not statistically significant) risk of death/MI/stroke in patients receiving BMS compared with patients receiving CABG, while there was no difference between patients receiving DES and CABG. There was also a significantly higher rate of major cardiac and cerebrovascular events (MACCE) in patients receiving BMS compared with CABG, and no significant difference between patients receiving DES compared with CABG.


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Table ES.6 Stent type subgroup analysis: chronic stable angina – PCI vs. CABG (CARDIa)

Outcome PopulationSubgroup

PCI + stentn (%)

CABGn (%)

Risk estimate(95% CI); p value

Subgroup p value

Death/MI/stroke BMSDES

13 (15.9)20 (11.6)

4 (5.7)22 (12.4)

HR 2.99 (0.97, 9.16); NRHR 0.93 (0.51, 1.71); NR

0.076

MACCE BMSDES

18 (22.0)31 (18.0)

5 (7.1)23 (12.9)

HR 3.42 (1.27, 9.22); NRHR 1.41 (0.82, 2.42); NR

0.131

Note: Statistically significant results shown in bold. Abbreviations: BMS, bare metal stent; CABG, coronary artery bypass graft; CI, confidence interval; DES, drug-eluting stent; HR, hazard ratio; MACCE, major cardiac and cerebrovascular events; MI, myocardial infarction; PCI, percutaneous coronary intervention.

(4)B. Supplementary question: What is the evidence for the safety and effectiveness of DES compared with BMS in patients with a diagnosis of NSTE-ACS?

No Level I or Level II studies were identified that specifically compared the use of BMS with DES as part of a PCI strategy in patients with a diagnosis of NSTE-ACS.

(4)C. Supplementary question: What is the evidence for the safety and effectiveness of DES compared with BMS in patients who are assessed at higher risk of coronary events following diagnostic testing?

No Level I or Level II studies were identified that specifically compared the use of BMS with DES as part of a PCI strategy in patients assessed at higher risk of coronary events following diagnostic testing.

Clinical guidance on PCI

A search was undertaken to identify Australian and international CPGs that relate to PCI in the three populations of interest. Current clinical guidance is summarised briefly below. Further details are presented in Section 4.1 (chronic stable angina), Section 4.2 (NSTE-ACS) and Section 4.3 (high risk on the basis of diagnostic testing).

Chronic stable anginaThere are no Australian CPGs available for this population. Based on an assessment of the international guidelines, factors such as risk stratification, the number of coronary arteries with stenosis (one-, two- or three-vessel disease) with and without involvement of proximal left anterior descending (LAD) and left main (LM) CAD play an important role in the decision-making on the choice of revascularisation. If the decision to revascularise is made, PCI or CABG is generally recommended for less complex CAD, while CABG is generally indicated for more complex CAD and where comorbidities exist. PCI is recommended in certain circumstances where the patient is not a candidate for CABG.

Diagnosis of NSTE-ACSAustralian guidelines emphasise the use of risk stratification in patients with NSTE-ACS to identify patients at high, intermediate or low risk of clinical events. Early coronary angiography (within 48 hours) and revascularisation is recommended for patients with NSTE-ACS and high-risk features (except in patients with severe comorbidities). The preferred revascularisation approach is not specified. Recent international guidelines from the United States and Europe use more complex risk stratification scores, but do not make firm recommendations about the preferred revascularisation strategy, acknowledging that management of NSTE-ACS depends on many factors including the patient’s condition, the


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presence of risk factors, comorbidities, and the extent and severity of the lesions as identified by coronary angiography.

High risk based on diagnostic testingAustralian guidelines do not contain recommendations on the use of FFR accompanying invasive coronary angiography in the risk stratification of patients who are being considered for revascularisation. However, recent international guidelines place emphasis on the documentation of ischaemia by non-invasive or invasive diagnostic tests prior to revascularisation. In cases where ischaemia is not documented using non-invasive diagnostic testing, FFR measurement is recommended for the identification of haemodynamically relevant coronary lesions. There is consensus in the international guidelines that FFR<0.80 is indicative of inducible ischaemia, and thus revascularisation is recommended in patients that meet this threshold. However, none of the guidelines made recommendations on the use of FFR for determining the type of revascularisation that is undertaken.

Evidence for the cost-effectiveness of PCI

The search for economic analyses identified nine studies that were relevant to the PICO criteria. None of the studies were conducted from an Australian healthcare perspective.

Four studies examined the cost-effectiveness of PCI added onto OMT in patients with stable angina or stable CAD. Two studies used data from the COURAGE RCT, and concluded that the addition of PCI to OMT is not cost-effective in patients with stable CAD, with ICERs in excess of $150,000/QALY. The findings of these studies are consistent with the findings of the clinical review based on Level I evidence that PCI is not more clinically effective than OMT alone. However, the remaining two studies, based on observational data, concluded that PCI is cost-effective.

The cost-effectiveness of CABG was compared with PCI in specific subgroups of patients with stable CAD (those with left main disease and three-vessel disease, and those with diabetes and multivessel disease) in two studies based on data from the SYNTAX and FREEDOM trials. These analyses showed that CABG was cost-effective, with ICERs of approximately US$16,000/QALY and US$8,000/QALY. This finding is in line with the assessment of clinical evidence in these subgroups, which showed overall improved clinical outcomes with CABG.

Two studies were identified that assessed the cost-effectiveness of a routine invasive strategy compared with a selective invasive strategy in patients with NSTE-ACS. These analyses were based on data from the ICTUS and RITA 3 trials and showed that a routine invasive strategy was unlikely to be cost-effective compared with a selective invasive strategy in the general NSTE-ACS population, although there was some indication that it may be cost-effective in patients at higher risk of cardiac events. These findings are in line with the clinical evidence that suggests that a routine invasive strategy does not provide clinical benefit over a selective invasive strategy in low- to intermediate-risk patients, while there may be some benefits in higher-risk patients.

One study, based on the FAME 2 trial, assessed the cost-effectiveness of PCI added to OMT in patients identified as being at high risk of cardiac events using diagnostic testing. The authors concluded that in patients with an FFR ≤ 0.80, PCI added to OMT was cost-effective, with an overall ICER of US$36,000/QALY. However, the robustness and usefulness of the results of this study are limited by the one-year time horizon, and the fact that utility weights


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were collected at one month, and extrapolated over the 12 month period. In addition, there was a substantial difference in utilities at baseline between the two groups. Thus, the uncertainty around the findings of this study, coupled with the lack of clear clinical benefit displayed in the FAME 2 trial, do not support the cost-effectiveness of PCI in this patient population.

No economic analyses were identified that specifically compared the cost-effectiveness of PCI with CABG in patients with a diagnosis of NSTE-ACS or those considered to be at high risk based on diagnostic testing.

Overall, the findings of the published economic analyses of PCI in each of the populations of interest should be interpreted while keeping in mind that there was no strong published clinical evidence to support the use of PCI in these specific populations.

Conclusions

(i) The identified Level I or Level II evidence does not support the use of PCI in terms of reducing rates of death or MI in patients with chronic stable angina that is well controlled with OMT. No Level I or II evidence was identified that assessed the effect of PCI in patients with chronic stable angina who are refractory to OMT.

(ii) The identified Level I or Level II evidence does not support the routine use of an invasive strategy in terms of reducing rates of death or MI in low- to intermediate- risk patients with a diagnosis of NSTE-ACS. However, there is some low quality evidence4 that suggests that death and MI may be reduced following a routine invasive strategy in high-risk patients with a diagnosis of NSTE-ACS. Australian and International CPGs note the existence of a body of evidence that supports the use of an early invasive strategy in intermediate- and high-risk patients with NSTE-ACS; however, this body of evidence was not assessed as part of this Review.

(iii) The identified Level I or Level II evidence does not support the use of PCI in terms of reducing rates of death and MI in patients with stable CAD on OMT who are assessed at higher risk of coronary events following diagnostic testing such as FFR.

(iv) Like many descriptors for MBS items, the item numbers that relate to angioplasty with or without stenting (items 38300, 38303 and 38306) do not provide details of the target population for PCI, or restrict the use of PCI to any particular population(s).

(v) It is unclear whether PCI services are being used in a broader patient population in Australia than is currently supported by the clinical evidence base.

4 This evidence is considered to be low quality because it is based a post hoc analysis of data from selected trials, and validated methods were not used to stratify patients into risk categories.


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1 BACKGROUND ON PCI

1.1 Description of PCI

Percutaneous coronary intervention (PCI) is a minimally invasive, non-surgical revascularisation technique performed to open narrowed or blocked coronary arteries and to restore arterial blood flow to the heart muscle. Narrowing or blockage of the coronary vessels is mainly caused by atherosclerosis, a disease in which plaque – composed of fat, calcium, cholesterol and other substances – is deposited into the internal wall of the blood vessel.

PCI (commonly referred to as angioplasty) is performed using a catheter with a deflated balloon at its tip that is inserted into the femoral, radial, brachial or axillary arteries. Using a special type of X-ray imaging called fluoroscopy, the catheter is threaded through the blood vessels to the narrowed or blocked coronary artery. The balloon is inflated after the catheter has been placed within the narrowed area of the coronary artery. The inflation of the balloon disrupts and compresses the atherosclerotic plaque into the wall of the artery and makes a larger opening inside the artery for improved blood flow.

Balloon angioplasty is rarely the only procedure performed during PCI. The overwhelming majority of PCIs involve the implantation of one or more coronary stents, which are tiny, expandable metal coils that are deployed in the re-opened area of the artery to stabilise the disrupted plaque and also aid in reducing re-closure of the narrowed area in the six months after the procedure (restenosis). There are three main types of stents: bare metal stents (BMS), drug-eluting stents (DES), and bio-absorbable stents. DES consists of the metal coil (stent), an anti-proliferative drug and a coating made of a polymer that holds the drug and controls its release rate (although there are now stents available that do not have the polymer). The drug inhibits the proliferation of smooth muscle cells which could otherwise result in restenosis (Schwartz et al, 1995). DES were originally developed to reduce the relatively high rate of reintervention (subsequent need for repeat angioplasty) associated with BMS. A comparison of BMS and DES is beyond the scope of this Review; however, there are numerous published systematic reviews that have compared their safety and efficacy (Greenhalgh et al, 2010; Mahmoudi et al, 2011; Bangalore et al, 2013, Kang et al, 2014; Palmerini et al, 2015).

Another less common procedure performed during PCI is atherectomy, which removes the plaque burden within the artery using a cutting device, rotating burr or laser.

1.1.1 Indications for PCI

Acute coronary syndromeAcute coronary syndrome (ACS) is a spectrum of life-threatening conditions that involve reduction of blood flow to the heart (ischaemia) that is sudden (Theroux et al, 1998). The key symptoms of ACS are chest pain, pressure, tightness, or heaviness, which may radiate to neck, jaw, shoulders, back, or one or both arms (ACCF/AHA, 2012). ACS is almost always associated with varying degrees of inflammatory rupture of an atherosclerotic plaque, with partial or complete occlusion by thrombosis of one or more arteries supplying blood to the heart muscle (Bassand et al, 2007; Anderson et al, 2007). Depending on the extent of the blockage and many other factors, patients who develop ACS may present with unstable angina (UA), or the critical manifestations of ACS; myocardial infarction (MI, commonly referred to as heart attack) or sudden cardiac death.


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Where the myocardial ischaemia is of short duration, myocardial cell damage and death (necrosis) may not occur. In that case, the clinical condition is UA (NICE, 2013). MI, on the other hand, is a result of myocardial necrosis. Cell rupture releases cardiac enzymes and markers such as creatine kinase-myocardial band (CK-MB) and troponin; elevated levels of these necrosis markers differentiate MI from UA (NICE, 2013).

MI can be classified into two clinical categories based on electrocardiography (ECG) findings, depending on whether the ST segment is elevated. In a normal ECG, the ST segment is a relatively flat line that sits between the QRS segment (the largest peak and trough in a normal ECG) and the T wave. Where the necrosis is limited to a small area of the myocardium, there is no impact on the ST segment, and the condition is classified as non-ST-segment elevation myocardial infarction (NSTEMI) (NICE, 2013). Where ischaemia is prolonged and necrosis is more extensive, usually due to complete occlusion, the ST segment is elevated above baseline, and this condition is classified as ST-segment elevation myocardial infarction (STEMI) (NICE, 2013).

Figure 1.1-1 depicts the spectrum of conditions encompassed by ACS and the typical ECG and myocardial marker findings. ACS can be regarded as a continuum of conditions, with the severity of the underlying pathophysiology determining the severity of the presentation, from UA to STEMI. The recognition of UA as a clinical entity emerged from prospective observation of symptoms preceding acute MI (Théroux et al, 1998). The myocardial ischaemia of UA can be attributed to one or a combination of pathophysiologies, the most common being non-occlusive thrombus on a fissured or eroded atherosclerotic plaque (Braunwald, 1998). Products of aggregating platelets are released into the coronary circulation, and continued thrombus formation can occur after the initial rupture for many months. NSTEMI and UA are frequently regarded as a single entity for treatment purposes, and are collectively referred to as non-ST-segment elevation ACS (NSTE-ACS; Bassand et al, 2007).

Figure 1.1-1 Clinical conditions encompassed by acute coronary syndrome

Abbreviations: CK-MB, creatine kinase-myocardial band; NSTE-ACS, non-ST-segment elevation acute coronary syndrome; STEMI, ST-segment elevation myocardial infarction.

CK-MB has traditionally been used as a marker of myocardial necrosis, but the introduction of the extremely sensitive troponin measurement (troponin T and troponin I) has allowed the detection of minimal damage (micro-infarcts) in the absence of elevation of other cardiac


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markers (SIGN, 2013). The concept of acute and chronic troponin elevation is now emerging, based on change from baseline, although the relevant magnitude of change that distinguish unstable angina from non-STEMI continue to be debated (NHFA/CSANZ, 2011; ESC, 2014).

Stable coronary artery diseasePatients with stable coronary artery disease (stable CAD), have stable angina or other stable ischaemic equivalents such as dyspnoea or arm pain with exertion. Stable CAD can be considered to be on a continuum of CAD severity that is less severe than ACS, where thrombosis dominates the clinical presentation. Stable CAD also includes post-ACS patients who have stabilised, and are often asymptomatic (ESC, 2013).

In patients with stable angina, symptoms such as substernal discomfort, heaviness, or pressure are usually brought on in a consistent manner by exertion, emotional stress, cold, or a heavy meal, although some residual symptoms may persist in the absence of these triggers. The condition is typically due to partial, substantial obstruction of coronary arteries that, at times of exertion, leads to demand ischaemia (Kones et al, 2010). Fixed areas of stenosis are created by lesions that reduce the diameter of the coronary arteries (Kones et al, 2010). These stable obstructions are in contrast to the sudden, discrete plaque events (rupture, erosion, or haemorrhage) of ACS.

An elevated ST segment may be observed in patients with stable angina, but only during an ischaemic event (e.g. during an exercise ECG test). If left untreated, patients are at risk of complications from CAD, including MI, heart failure, stroke and death (SIGN, 2007).

1.1.2 Treatment options

Treatment options for acute coronary syndrome

STEMIA completely blocked coronary artery is the usual cause of STEMI, and reperfusion is the primary goal. Where it can be delivered promptly by a qualified interventional cardiologist, PCI is the preferred intervention according to Australian and international guidelines; where this cannot be achieved, fibrinolytic therapy is recommended for patients without contraindications (NHFA/CSANZ, 2006; ACCF/AHA, 2013; ESC, 2012). In conjunction with these approaches, adjuvant therapy is also recommended (antiplatelet agents and anticoagulants).

Like PCI, coronary artery bypass graft (CABG) is a revascularisation technique (described below), but has a limited role in the acute phase of STEMI other than for cardiogenic shock and mechanical repair (NHFA/CSANZ, 2006). It may also be indicated for failed PCI, for coronary artery lesions not amenable to PCI, and for patients who are not candidates for PCI or fibrinolysis.

In light of the consistent clinical evidence supporting the use of PCI in patients with STEMI, this population is not included in the populations investigated in this MBS Review.

Non-ST-segment elevation acute coronary syndromeThe most frequent manifestation of ACS, NSTE-ACS, is a spectrum of unstable conditions characterised by ischaemic recurrences and complications that can lead to death or MI in the short and long term. Long-term mortality and morbidity rates are not unlike those of STEMI


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patients (ESC, 2014). Assessment of the risk of clinical events is recommended as soon as possible after presentation to allow for timely treatment.

Pharmacological interventions aim to inhibit thrombosis and address the cardiac oxygen demand/supply imbalance; these include anti-ischaemic agents, antiplatelet agents and anticoagulants (note, fibrinolytic agents are not used for NSTE-ACS). Anti-ischaemic therapy decreases the oxygen demand of the heart by lowering heart rate, or increases the oxygen supply by vasodilation. These include β blockers and nitrates5. Antiplatelet therapy is critical for all NSTE-ACS patients, as platelet activation and subsequent aggregation propagates thrombosis. Antiplatelet agents include aspirin, which is highly recommended for all patients, and some may also receive a P2Y12 receptor inhibitor (e.g. clopidogrel), or glycoprotein IIb/IIIa receptor inhibitors, although they are now avoided if possible (NHFA/CSANZ, 2011). Anticoagulants are also used to inhibit thrombin-induced conversion of fibrinogen to fibrin. Thrombin inhibitors include fondaparinux, bivalirudin, low molecular weight heparin and unfractionated heparin (NHFA/CSANZ, 2011).

Invasive strategies to achieve revascularisation include PCI and CABG. While PCI attempts to restore the blood flow of the native coronary vasculature, CABG is an open surgical procedure in which un-diseased vasculature is grafted to the mid-coronary vessel beyond the culprit lesion or lesions. This approach also protects against the consequences of further proximal disease.

The Australian ACS guidelines (NHFA/CSANZ, 2006) recommend that NSTE-ACS patients are evaluated for risk of short-term adverse outcomes, by the presence of clinical features that are stratified into high, intermediate or low-risk categories. The presence of one of these features places a patient presenting with symptoms consistent with ACS into that risk category (Table 1.1-1), which then guides the management strategy.

Table 1.1-1 Features used to stratify risk of adverse outcomes in patients with NTSE-ACS

Features by risk classification

High-risk featuresPresentation with clinical features consistent with ACS and any of the following high-risk features:

Repetitive or prolonged (> 10 minutes) ongoing chest pain or discomfort

Elevated level of at least one cardiac biomarker (troponin or creatine kinase-MB isoenzyme)

Persistent or dynamic electrocardiographic changes of ST-segment depression ≥0.5 mm or new T-wave inversion ≥2 mm

Transient ST-segment elevation (≥ 0.5 mm) in more than two contiguous leads

Haemodynamic compromise – systolic blood pressure

< 90 mmHg, cool peripheries, diaphoresis, Killip Class >I, and/or new-onset mitral regurgitation

Sustained ventricular tachycardia

Syncope

Left ventricular systolic dysfunction (left ventricular ejection fraction <0.40)

Prior percutaneous coronary intervention within 6 months or prior coronary artery bypass surgery

Presence of known diabetes (with typical symptoms of ACS)

Chronic kidney disease (estimated glomerular filtration rate < 60 mL/minute) (with typical symptoms of ACS)

Intermediate-risk featuresPresentation with clinical features consistent with ACS and any of the following intermediate-risk features AND NOT meeting the criteria for high-risk ACS:

5 International guidelines also recommend vasodilation with calcium channel blockers under some circumstances (ESC, 2014, ACCF/AHA 2012).


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Features by risk classificationChest pain or discomfort within the past 48 hours that occurred at rest, or was repetitive or prolonged (but currently resolved)

Age >65 years

Known coronary heart disease – prior myocardial infarction with left ventricular ejection fraction ≥ 0.40, or known coronary lesion more than 50% stenosed

No high-risk changes on electrocardiography (see above)

Two or more of the following risk factors: known hypertension, family history, active smoking or hyperlipidaemia

Presence of known diabetes (with atypical symptoms of ACS)

Chronic kidney disease (estimated glomerular filtration rate < 60 mL/minute) (with atypical symptoms of ACS)

Prior aspirin use

Low-risk featuresPresentation with clinical features consistent with an acute coronary syndrome without intermediate-risk or high-risk features. This includes onset of anginal symptoms within the last month, or worsening in severity or frequency of angina, or lowering of anginal thresholdSource: NHFA/CSANZ (2006) Box 8, p S20Abbreviations: ACS, acute coronary syndrome.

Patients designated high risk are recommended to undergo both aggressive medical management and invasive therapy, except patients with severe comorbidities. The type of revascularisation is not specified by the Australian ACS guidelines, and the only recommendation around timing is that coronary angiography should occur within 48 hours (NHFA/CSANZ, 2006), which is referred to as early invasive therapy. The relevant recommendations from Australian and international guidelines are provided in Section 4.

The Thrombolysis in Myocardial Infarction (TIMI) risk score is a simple scoring system from 0 to 7 based on the following seven factors; age over 65 years, more than three coronary risk factors, prior angiographic coronary obstruction, ST-segment deviation, more than two angina events within 24 hours, use of aspirin within 7 days, and elevated levels of cardiac biomarkers. The Australian ACS guidelines describe the TIMI risk score as a useful tool, particularly where hospital resources are limited; patients with a score of greater than three can undergo additional risk stratification to determine whether to proceed with early invasive management (NHFA/CSANZ, 2006). However, the TIMI score itself is not considered in the main NHFA/CSANZ clinical paradigm.

Subsequent to publication of the Australian ACS guidelines in 2006, a more complex model was developed and validated to evaluate early risk (in-hospital) of acute coronary events in ACS, developed from the Global Registry of Acute Coronary Events (GRACE) database6 (Pieper et al, 2009). This tool takes into account predictors of bleeding risk (e.g. creatinine levels) in addition to other clinical data such as ECG findings and cardiac enzyme levels. The GRACE risk score, which ranges from 0 to 258 points, provides more discriminative accuracy than TIMI (ESC, 2011). International evidence-based clinical practice guidelines (CPGs) for NSTE-ACS incorporate specific GRACE score thresholds, along with other risk criteria similar to those in the Australian ACS guideline, into their clinical management pathways to inform decisions about which patients are appropriate for invasive intervention (AHA/ACC, 2014; ESC, 2014).

The 2011 addendum to the Australian ACS guidelines (NHFA/CSANZ, 2011) acknowledges a role for the GRACE risk score in the individualisation of pharmacotherapies for NTSE-

6 The GRACE tool was originally developed to assess mortality risk at 6 months post-discharge (Eagle et al, 2004).


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ACS, but no specific advice is provided for how these scores should be integrated with the original clinical paradigm regarding the decision whether to proceed with invasive therapy (NHFA/CSANZ, 2006).

Table 1.1-2 shows the GRACE scores stratified by the level of risk (high, intermediate and low), and the mortality risk rates for each of these profiles while in-hospital or once discharged from hospital up to 6 months.

Table 1.1-2 Mortality in-hospital and at 6 months in low, intermediate and high-risk categories in registry populations, according to the GRACE risk score

Risk category (tertile) GRACE risk score In-hospital death (%)Low ≤108 <1

Intermediate 109–140 1–3

High >140 >3

Risk category (tertile) GRACE risk score Post-discharge to 6-months death (%)Low ≤88 <3

Intermediate 89–118 3-8

High >118 >8Source: ESC (2011), Table 5, pp3010Abbreviations: GRACE, Global Registry of Acute Coronary Events.

As mentioned above, the type of revascularisation (PCI or CABG) that should be used in NSTE-ACS patients is not specified by the Australian ACS guidelines. The more recent international guidelines do not make firm recommendations either, stating the choice of preferred approach (PCI or CABG) depends on many factors including the patient’s condition, the presence of risk features, comorbidities, and the extent and severity of the lesions as identified by coronary angiography (ESC, 2011).

Some patients undergo invasive evaluation (angiography), followed by extemporaneous revascularisation with PCI where single-vessel disease is discovered (AHA/ACC, 2014). For those with multivessel disease, PCI may be performed on either the culprit lesion or multiple vessels. While it is not recommended to perform PCI on vessels other than culprit lesions for STEMI, there is less agreement on whether non-culprit lesions should undergo intervention at the time of culprit-lesion PCI for NSTE-ACS. In general, the more complex and widespread the disease, the more likely CABG will be chosen (AHA/ACC, 2014).

Treatment options for stable anginaUnlike patients with UA who usually require more urgent or immediate management, stable angina is often predictable in severity and is initially managed in the primary care setting prior to specialist referral. The symptoms of stable angina are typically relieved within minutes by rest or glyceryl trinitrate. Management options for patients diagnosed with stable angina include lifestyle advice, medical management (pharmaceutical therapy) and revascularisation using percutaneous or surgical techniques. Revascularisation in patients with stable angina aims to provide symptom relief where optimal medical therapy is not effective and/or to improve the prognosis of patients assessed to have a high risk of a cardiac event (ESC, 2013). Risk assessment tools, such as the SYNTAX score, may be useful when making revascularisation decisions (ESC, 2013; ACCF/AHA, 2012). In addition, clinical features such as comorbid chronic conditions also influence the decision regarding the use of PCI.


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1.1.3 Populations of relevance for this MBS Review of PCI

As discussed above in Section 1.1.2, prompt revascularisation with PCI in STEMI patients is consistently recommended by CPGs. However, the clinical evidence for the value of PCI in patients with stable angina and NSTE-ACS remains less well-defined. Consequently, as shown in Figure 1.1-2, the populations of relevance to this MBS Review are ACS patients with NSTE-ACS or chronic stable angina. While this figure depicts a clear separation between acute and stable conditions, ACS and stable CAD are essentially on a continuum and cannot always be regarded as discreet diagnoses.

In addition to these populations, which are defined by clinical assessment, this Review also includes patients identified by diagnostic testing as having myocardial ischaemia and who are assessed at higher risk of coronary events. These objective tests include non-invasive imaging such as stress echocardiography or myocardial perfusion imaging, or invasive diagnostic testing, specifically fractional flow reserve (FFR). This population is referred to as objective ischaemia, and includes patients with stable angina, no ischaemic symptoms (silent myocardial ischaemia), or other stable CAD syndromes (e.g. dyspnoea). Patients with unstable angina can also have silent myocardial ischaemia (Cox, 2003), and would fall into the objective ischaemia group.7 Therefore, while Figure 1.1-2 shows objective ischaemia as a subset of stable CAD patients, in the clinical setting the objective ischaemia group overlaps with the unstable angina patients in the ACS population.

Figure 1.1-2 Populations that may receive PCI, indicating those of relevance to this Review

Abbreviations: ACS, acute coronary syndrome; CAD, coronary artery disease; FFR, fractional flow reserve; MBS, Medical Benefits Scheme; STEMI, ST-segment-elevation myocardial infarction; NSTE-ACS, Non-ST-segment elevation acute coronary syndrome; NSTEMI, non-ST-segment elevation myocardial infarction.Note: MBS Review populations are indicated with shading. Some overlap may occur between low-risk unstable angina and stable CAD. Relative sizes of populations not related to sizes of graphics.a Objective ischaemia refers to patients at higher risk of coronary events following diagnostic testing (e.g. non-invasive imaging such as stress echocardiography or myocardial perfusion imaging, or invasive diagnostic testing, specifically FFR). This population may include stable CAD patients without angina (i.e. dyspnoea, arm pain with exertion, silent myocardial disease).

1.1.4 Incidence and prevalence of conditions

ACS and stable angina are collectively referred to as coronary heart disease (CHD). CHD is another term for CAD or ischaemic heart disease, and is the most common form of cardiovascular disease. According to the Australian Institute of Health and Welfare (AIHW),

7 As covered in the clinical review section of this Report (Section 5), the definition of objective ischaemia is used in a number of trials where patient selection is first limited to those with stable CAD followed by testing for objective evidence of myocardial ischaemia i.e. unstable angina patients would be excluded from those objective ischaemia populations.


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CHD accounted for 15% (21,513) of all deaths in 2011 (AIHW, 2014a). There have been large declines in this rate over recent decades, as a result of improved diagnosis and treatment and improved risk factor behaviours, but it remains the single leading cause of death in Australia (AIHW, 2014a).

Based on the self-reporting National Health Survey (NHS), it was estimated that around 3% of Australians (around 685,000 people) had CHD in 2007-2008 (AIHW, 2011), which declined to 585,900 in 2011-12 (AIHW, 2014a). As shown in Figure 1.1-3, the prevalence of CHD increases markedly with age and is more prevalent in males than females; after adjusting for age, 4% of males and 2% of females were estimated to have CHD in 2007-2008 (AIHW, 2011).

Figure 1.1-3 Coronary heart disease prevalence, by age and sex, 2007-2008

Source: AIHW (2011) Figure 4.1, p58

No reliable national or jurisdictional data sources exist for measuring the incidence of acute coronary events in Australia. The AIHW has reported approximations of the incidence of acute coronary events (acute MI and UA) based on unlinked hospitalisation data from the AIHW National Hospital Morbidity Database (NHMD) and deaths data from the AIHW National Mortality Database (AIHW, 2014b). In 2011, the number of acute coronary events in Australians over the age of 25 was estimated at 69,900 (427 per 100,000 population).

Incidence rates for major coronary events increase with age in both males and females (Figure 1.1-4). As seen for the prevalence of CHD, gender differences in the incidence of acute coronary events are marked, with the overall rate after adjusting for age being twice as high in males than females in 2011 (584 per 100,000 population versus 284 per 100,000 population, respectively) and almost two-thirds (63%) of the total number of acute coronary events in 2011 were in males (AIHW, 2014b).


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Figure 1.1-4 Rate of ACS events, by age and gender, in Australia, 2011

Source: Based on data reported in AIHW (2014b), Table E1, p48Note: The source reports rate of heart attacks, which includes both acute MI (STEMI and NSTEMI) and UA (i.e. ACS), and is also referred to as acute coronary events.

1.1.5 ACS care in Australia/New Zealand; SNAPSHOT study

The proportion of ACS patients that are diagnosed with either STEMI, NSTEMI or unstable angina was investigated in the SNAPSHOT study conducted in 286 Australian and New Zealand Hospitals. Over a two-week period in May 2012, consecutive first admissions of patients presenting with suspected or confirmed ACS were tracked for their duration of acute care, including hospital transfers. Patient characteristics were reported by diagnosis at discharge.

Of the 4,398 patients with suspected or confirmed ACS entered into the study, 2,365 had a final diagnosis of ACS or an uncertain diagnosis (in the absence of definitive ECG changes and/or biomarker elevation) but who were revascularised with PCI or CABG. For simplicity, this group is referred to here as the ACS group. Two additional final diagnosis groups, ‘unlikely ischaemic chest pain’ and ‘other diagnosis’, are not discussed here.

Figure 1.1-5 shows the proportion of the ACS group by diagnostic subcategory. Around 18% of the 2,365 patients in the ACS group had a final diagnosis of STEMI/left bundle branch block8 (LBBB), while around half of the remaining patients were designated NSTEMI (42.9%) and the other half, unstable angina/uncertain but revascularised (39.3%).

8 An atypical ECG presentation that deserves prompt management in patients with signs and symptoms of ongoing myocardial infarction.


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Figure 1.1-5 Australian and New Zealand patients with an ACS discharge diagnosis, by ACS subcategory, SNAPSHOT study

Source: Chew (2013), Table 3, p 4 (study also reports characteristics of two other diagnostic groups at discharge: unlikely ischaemic chest pain and ‘other diagnosis’, which included secondary myonecrosis).Abbreviations: NSTEMI, non-ST-segment elevation myocardial infarction; STEMI, ST-segment elevation myocardial infarction; UA, unstable angina.* Includes patients with diagnosis of left bundle branch block.** Includes patients with uncertain diagnosis who were revascularised.

Patient characteristics are shown for each of the three categories of the ACS group (Table 1.1-3). Mean age is highest for NSTEMI (71.2 years, SD 13.2) and lowest for STEMI/LBBB (65.6 years, SD 14.4). The gender imbalance is apparent in all groups, but more marked for STEMI/LBBB (28.3% female). The median GRACE risk score is similar for STEM/LBBB and NSTEMI (140 and 137 respectively), and is lower for unstable angina/revascularised patients (115). Diabetes is more common in NSTEMI and unstable angina/revascularised (around 30%) but less common in STEMI/LBBB patients (around 20%).

Table 1.1-3 Characteristics of patients with confirmed ACS at discharge or likely ischaemic pain treated with revascularisation, Australia and New Zealand SNAPSHOT study

Characteristic STEMI/LBBB(n = 421)

NSTEMI(n = 1015)

Unstable angina/ uncertain but

revasculariseda

(n = 929)Age in years, mean (SD) 65.6 (14.4) 71.2 (13.2) 68.1 (12.9)

Female 119 (28.3%) 376 (37.0%) 343 (36.9%)

Median creatinine level, μmol/L (25th–75th percentile)

89 (73–106) 89 (74–113) 86 (71–106)

Killip Class II–IV at presentation 81 (19.2%) 206 (20.3%) 78 (8.4%)

Presentation with cardiac arrest 35 (8.3%) 12 (1.2%) 4 (0.4%)

Median GRACE risk score(25th–75th percentile)

140 (118–165) 137 (114–159) 115 (96–136)

Diabetes 83 (19.7%) 314 (30.9%) 289 (31.1%)

Hypertension 229 (54.4%) 699 (68.9%) 677 (72.9%)

Dyslipidaemia 192 (45.6%) 588 (57.9%) 618 (66.5%)

Current smoker 130 (30.9%) 175 (17.2%) 134 (14.4%)

Prior myocardial infarction 75 (17.8%) 345 (34.0%) 335 (36.1%)

Prior PCI 48 (11.4%) 184 (18.1%) 308 (33.2%)

Prior CABG 21 (5.0%) 135 (13.3%) 133 (14.3%)

Prior atrial fibrillation 31 (7.4%) 174 (17.1%) 126 (13.6%)


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Characteristic STEMI/LBBB(n = 421)

NSTEMI(n = 1015)

Unstable angina/ uncertain but

revasculariseda

(n = 929)Known PAD 22 (5.2%) 91 (9.0%) 67 (7.2%)

Prior TIA or CVA 23 (5.5%) 144 (14.2%) 108 (11.6%)

Prior admission for major bleeding or transfusion

10 (2.4%) 26 (2.6%) 20 (2.2%)

Active cancer limiting life expectancy 8 (1.9%) 27 (2.7%) 21 (2.3%)

Cognitive impairment or dementia 11 (2.6%) 42 (4.1%) 27 (2.9%)

Nursing home resident 13 (3.1%) 33 (3.3%) 28 (3.0%)Source: Adapted from Chew et al (2013), Table 3, p 4 (study also reports characteristics of two other diagnostic groups at discharge: unlikely ischaemic chest pain and ‘other diagnosis’, which included secondary myonecrosis).Abbreviations: CABG, coronary artery bypass graft; CVA, cerebrovascular accident; ECG, electrocardiograph; GRACE, Global Registry of Acute Coronary Events; LBBB, left bundle branch block; NSTEMI, non-ST-segment elevation myocardial infarction; PAD, peripheral artery disease; PCI, percutaneous coronary intervention; SD, standard deviation; STEMI, ST-segment elevation myocardial infarction; TIA, transient ischaemic attack.a Uncertain diagnosis in the absence of definitive ECG changes and/or biomarker elevation, but patients revascularised with PCI or CABG.

Of the 4,398 patients presenting with suspected or confirmed ACS, 59% presented to hospitals capable of providing primary PCI, and only 1.4% presented to hospitals unable to provide STEMI reperfusion therapy. Around a quarter of patients needed to be transferred to at least one other hospital.

Table 1.1-4 reports the care received by the 421 patients with a discharge diagnosis of STEMI/LBBB; 106 (25.2%) received fibrinolytic therapy, 163 (38.7%) received primary PCI and 152 (36.1%) received no perfusion therapy. Data are also shown combined for patients with a discharge diagnosis of STEMI/LBBB or NSTEMI; at 42.5%, the proportion of patients receiving PCI is similar to that for STEMI/LBBB. CABG is performed relatively infrequently (8.1%).

Table 1.1-4 Care received by discharge diagnosis, for STEMI/LBBB and for STEMI/LBBB and NSTEMI

Care received STEMI/LBBB Care received STEMI/LBBB and NSTEMITotal patients 421 Total patients 1436

Fibrinolytic therapy 106 (25.2%) Coronary angiography 1019 (71.0%)

Primary PCI 163 (38.7%) PCI 610 (42.5%)

No perfusion therapy 152 (36.1) CABG 116 (8.1%)Source: Chew (2013), p3Abbreviations: CABG, coronary artery bypass graft; LBBB, left bundle branch block; NSTEMI, non-STEMI; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction.

1.2 Description of the services under review

1.2.1 The MBS items relevant to PCI

All seven MBS items in Group T8 (Surgical operations); Subgroup 6 (Cardio-thoracic); Subheading 3 (Endovascular interventional procedures) of the MBS are included in this Review of PCI. The current descriptors and schedule fees for these items are provided in Appendix 3 (Table A-3.1). These services relate to:

Angioplasty (MBS items 38300 and 38303) Stent insertion, including angioplasty (MBS item 38306) Rotational atherectomy, including angioplasty (MBS items 38309 and 38315)


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Rotational atherectomy, including angioplasty and stent insertion (MBS items 38312 and 38318)

MBS items 38300, 38303 and 38306 are not restricted to percutaneous intervention, and can be used for angioplasty accessed via an open approach.

MBS items co-claimed with the PCI MBS itemsThere are currently a number of items on the MBS that relate to diagnostic coronary angiography and radiological services, and catheter guidance during angioplasty. The descriptors for all seven relevant MBS items specifically exclude these services, which can be co-claimed through separate MBS items in Group T8 – surgical operations, Group I3 –diagnostic radiology, and Group I1 – ultrasound (shown in Appendix 3). Included in these is MBS item 38241 for the measurement of FFR, often used during a catheterisation (i.e. coronary angiogram) to assist in determining the significance of an intermediate coronary narrowing (30-70% diameter stenosis). The technique involves placing a pressure-transducing wire across the narrowing, and after a brief infusion of a coronary vasodilator, measuring the pressure change in the coronary artery. The measurement of FFR has been shown to be useful in determining whether or not to perform PCI on intermediate blockages (ACCH/AHA, 2011). The item descriptor for 38241 restricts the use of a coronary pressure wire to cases where previous stress testing has either not been performed or the results are inconclusive.

Other costsAlthough the MBS provides funding for services associated with coronary artery stent insertion, the cost of the stent itself is covered by private health insurers (for private patients) or the public hospital system (for public patients). Various coronary artery stents (BMS and DES) are available on the Prostheses List, with benefits payable for DES higher than that of BMS.

1.3 The clinical decision pathway

A clinical decision pathway for MBS items relating to PCI is presented in Figure 1.3-1. Angioplasty without stent insertion is claimed using MBS item 38300 (for one occluded coronary artery) or item 38303 (for more than one occluded coronary artery). Angioplasty performed with rotational atherectomy (without stent insertion) is claimed using MBS item 38309 (for one occluded coronary artery) or item 38315 (for more than one occluded coronary artery). According to Explanatory Note T8.42, percutaneous transluminal coronary rotational atherectomy is suitable for revascularisation of complex and heavily calcified coronary artery stenoses in patients for whom coronary artery bypass graft surgery is contraindicated. A coronary artery lesion is considered to be complex when the lesion is a chronic total occlusion, located at an ostial site, angulated, tortuous or greater than 1 cm in length.

However, the vast majority of interventions are performed with coronary stent insertion (as shown in the MBS data presented in Section 3 of this Review), as they prevent recoil, abrupt closure and late restenosis (Serruys et al, 1994; Fischman et al, 1994). Angioplasty performed with the insertion of a stent (or stents) is claimed using MBS item 38306 for each occluded site. Explanatory Note T8.63 states that it is not appropriate to bill item 38306 multiple times for the insertion of more than one stent at the same occlusional site in the same artery; however, it would be appropriate to claim this item multiple times for insertion of stents into the same artery at different occlusional sites or into another artery or occlusional site. Angioplasty performed with rotational atherectomy and stent insertion is claimed using MBS


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item 38312 (for one occluded coronary artery) or 38318 (for more than one occluded coronary artery).

Figure 1.3-1 Clinical pathway for PCI showing the decisions leading to each of the relevant MBS items

Source: MBS Review Final Protocol, Percutaneous coronary interventions, Figure 1, p11Abbreviations: CABG, coronary artery bypass graft, PCI, percutaneous coronary intervention.


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2 REVIEW METHODOLOGY

The review methodology involved an analysis of secondary data (e.g. MBS claims, hospital separations), a guideline concordance analysis, a systematic literature review of clinical and economic evidence, and a de novo economic evaluation from the perspective of the Australian health care system. This section presents the research questions and the methodology for each of these review components.

2.1 Secondary data analysis

Data from Medicare Australia and the NHMD were analysed to determine whether the existing MBS item numbers for PCI services are appropriate.

2.1.1 The research questions for the MBS analysis

MBS data relates to private medical services (provided in- or out-of-hospital), where the services are provided to patients regardless of whether or not they have private health cover. MBS in-hospital services are mainly provided in private hospitals and day surgery clinics, but patients can elect to be treated as a private patient in a public hospital.

MBS data were analysed by patient gender, age group, patterns of use and discipline of provider requesting the test for the seven relevant MBS items (see Appendix 3 for item descriptors). In particular, the MBS data were examined to address the following questions:

(1) What is the profile of claiming relating to MBS items for PCI?

a. Are there any temporal or geographic trends associated with usage of these items?

b. What are the characteristics of patients undergoing PCI (e.g. gender, age)?

c. Are the MBS claims data consistent with trends in the incidence/prevalence of conditions/diseases being addressed by the service?

d. What is the profile of service providers for PCI?

e. What MBS items related to coronary angiography or radiography are being claimed on the same occasion as MBS items related to PCI?

(2) What is the profile of benefits relating to MBS items for PCI?

a. Have patient out-of-pocket costs risen over time for PCI services?

Results of the analysis of the MBS data are presented in Section 3.

2.1.2 The research questions for the NHMD analysis

The NHMD is compiled by the AIHW from data supplied by the state and territory health authorities. It is a collection of electronic confidentialised summary records for separations (that is, episodes of care) in public and private hospitals in Australia. The data available within the NHMD includes patient’s principal diagnosis, the associated Diagnosis Related Group (DRG) and the procedure they underwent during the separation (i.e. Australian Classification of Health Interventions (ACHI) code).


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The research questions addressed in the analysis of the NHMD data were:

(1) What are the characteristics of the service profile under the relevant ACHI codes?

a. the number of separations where PCIs were performed by year?

b. the principal diagnosis profile of patients for whom PCIs were performed?

c. the age profile of patients for whom PCIs were performed?

d. the profile of PCI procedures by health sector (public/private)?

(2) Are the relevant ACHI code profiles different to the analysis of MBS items?

The ACHI codes relevant to PCI are shown in Table 2.1-1.

Table 2.1-1 ACHI codes relevant to PCI

ACHI code Descriptor38300-00 Percutaneous transluminal balloon angioplasty of 1 coronary artery

38303-00 Percutaneous transluminal balloon angioplasty of ≥2 coronary arteries

38306-00 Percutaneous insertion of 1 transluminal stent into single coronary artery

38306-01 Percutaneous insertion of ≥2 transluminal stents into single coronary artery

38306-02 Percutaneous insertion of ≥2 transluminal stents into multiple coronary arteries

38309-00 PTCRA, 1 artery

38312-00 PTCRA, 1 artery with insertion of 1 stent

38312-01 PTCRA, 1 artery with insertion of ≥2 stents

38315-00 PTCRA, multiple arteries

38318-00 PTCRA, multiple arteries with insertion of 1 stent

38318-01 PTCRA, multiple arteries with insertion of ≥2 stentsSource: Australian Institute of Health and Welfare, accessed 20 June 2014Abbreviations: PTCRA, percutaneous transluminal coronary rotational atherectomy.

2.2 Guideline concordance

2.2.1 The research question for the guideline concordance analysis

The clinical/research question addressed as part of the Review using guideline concordance is as follows:

(1) Is the descriptor for the MBS item number/service under review consistent with evidence-based (or in the absence of evidence, consensus-based) recommendations provided in relevant clinical practice guidelines?

2.2.2 Guidelines search and methods for guideline concordance analysis

Searches of guideline databases and relevant discipline websites were undertaken to locate any existing guidelines relevant to PCI services. The search strategies used on EMBASE.com (EMBASE and Medline) and the Cochrane Library are shown in Appendix 4, Table A-4.2 and were conducted on 29 June 2015. Searches were also performed on 6 July 2015 on the following organisation websites: Guidelines International Network (G-I-N); the National Guidelines Clearinghouse, and the National Health and Medical Research Council (NHMRC), the National Institute for Health and Care Excellence (NICE), the Scottish Intercollegiate Guidelines Network (SIGN), and the Canadian Agency for Drugs and Technologies in Health (CADTH).


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In addition, the websites of the following associations and societies were searched for relevant guidelines:

National Heart Foundation Cardiac Society of Australia and New Zealand.

Analysis of the seven relevant MBS item numbers was undertaken relative to ‘best practice’ as recommended in relevant Australian CPGs or guidelines in comparable health systems overseas. Relevant CPGs relating to PCI are presented in Section 4.

2.3 PICO criteria for clinical and economic literature searches

The PICO (Population, Intervention, Comparator, Outcomes) criteria were used to develop well-defined questions for the search of published literature. This involved focusing the questions on four elements:

(1) the target population for the intervention;

(2) the intervention being considered;

(3) the comparator for the existing MBS service (where relevant); and

(4) the clinical outcomes that are most relevant.

Given that the vast majority of PCIs involve coronary artery stent insertion, the key issues addressed in the literature review relate to specific populations where the safety, effectiveness and cost-effectiveness of PCI with stent insertion is uncertain or controversial. The review of the scientific literature focused on the three population groups below:

(1) patients with chronic stable angina;

(2) patients with a diagnosis of NSTE-ACS; and

(3) patients who are assessed at higher risk of coronary events following diagnostic testing (e.g. non-invasive imaging such as stress echocardiography or myocardial perfusion imaging, or invasive diagnostic testing, specifically FFR).

Although PCI is also used in patients with a diagnosis of STEMI, this population was not included in the clinical and economic evidence review as the role of PCI in their management is well established.

The PICO criteria were determined on the basis of information provided in the literature, as well as clinical advice. The PICO criteria for the review of PCI are shown in Table 2.3-1.

Table 2.3-1 Summary of PICO criteria

Population Intervention Comparator Outcomes1) Patients with chronic stable angina

Subgroups: multivessel disease diabetes chronic kidney disease

(CKD) heart failure or known

left ventricular dysfunction/reduced ejection fraction

PCI with stent insertion (DES or BMS), combined with medical therapy

Medical therapy alone

orCABG, combined with medical therapy

Clinical effectiveness cardiac and all-cause mortality MI stroke reintervention/ revascularisation restenosis QoL

Safety complications/ adverse events bleeding

Cost implications cost


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Population Intervention Comparator Outcomes cost-effectiveness

(2) Patients with a diagnosis of NSTE-ACS

Subgroups: multivessel disease diabetes

Selective PCI with stent insertion (DES or BMS), combined with medical therapy

Routine PCI with stent insertion (DES or BMS), combined with medical therapy

As above

PCI (selective or routine) with stent insertion (DES or BMS), combined with medical therapy

CABG, combined with medical therapy

As above

(3) Patients who are assessed at higher risk of coronary events following diagnostic testing (e.g. non-invasive imaging such as stress echocardiography or myocardial perfusion imaging, or invasive diagnostic testing, specifically FFR)

Subgroups: multivessel disease diabetes

PCI with stent insertion (DES or BMS), combined with medical therapy

Medical therapy alone

orCABG, combined with medical therapy

As above

Source: MBS Review Final Protocol, Percutaneous coronary interventions, Table 1, p14Abbreviations: BMS, bare metal stent; CABG, coronary artery bypass graft; DES, drug-eluting stent; FFR, fractional flow reserve; MI, myocardial infarction; NSTE-ACS, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; QoL, quality of life; PICO, population, intervention, comparator, outcomes.

2.4 Systematic literature review for clinical evidence

2.4.1 The research questions for the clinical evidence review

The key research questions for the clinical evidence review are:

(1) What is the evidence for the safety and effectiveness of PCI with stent insertion combined with medical therapy compared with medical therapy alone in the relevant populations (patient groups 1 and 3)?

(2) What is the evidence for the safety and effectiveness of PCI with stent insertion combined with medical therapy compared with CABG combined with medical therapy in the relevant populations (patient groups 1, 2 and 3)?

(3) What is the evidence for the safety and effectiveness of a selective PCI strategy compared with a routine PCI strategy in the relevant populations (patient group 2 only)? For the purposes of this Review, a selective strategy refers to medical therapy combined with careful clinical assessment and testing, with selective use of PCI in high-risk individuals. A routine strategy involves early revascularisation in patients without clinical contraindication.

(4) Supplementary question: What is the evidence for the safety and effectiveness of DES compared with BMS in the relevant populations undergoing PCI (patient groups 1, 2 and 3)?

As described above in Section 2.3, the three populations of interest are as follows:

(1) Patients with chronic stable angina.

(2) Patients with a diagnosis of NSTE-ACS.


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(3) Patients who are assessed at higher risk of coronary events following diagnostic testing (e.g. non-invasive imaging such as stress echocardiography or myocardial perfusion imaging, or invasive diagnostic testing, specifically FFR).

Within each of the three population groups defined in the PICO (Section 2.3, Table 2.3-1), various subgroups of particular interest are specified. Where available, data were extracted for these subgroups, with a preference for analyses that were pre-specified rather than post hoc.

The comparators depend on the population of interest (Section 2.3, Table 2.3-1) and may include a primary strategy of either (i) medical therapy alone, whereby the primary strategy comprises pharmacological therapy (i.e. medical management with antiplatelet therapy, lipid-lowering agents, etc.) with watchful waiting; or (ii) CABG (combined with medical therapy). Distinction was made in analysing studies between those that incorporate optimal medical therapy (appropriate dosing and titration of pharmacological therapies) and those that do not. When drawing conclusions, the results of individual studies that incorporate optimal medical therapy have been given more weight, as have any published systematic reviews that only include studies with optimal medical therapy.

2.4.2 Methods for the clinical evidence review

The following section outlines the methods used to identify relevant data for the review of clinical evidence. This includes a description of the literature search strategy and the criteria used to define the inclusion/exclusion of studies.

Search strategyA comprehensive search of peer-reviewed scientific literature was conducted to identify studies that provide clinical evidence relating to the safety and effectiveness of PCI with stent insertion in the defined populations of interest. Electronic databases were searched for original research papers describing (i) systematic reviews and meta-analyses; and (ii) randomised controlled trials (RCTs) as shown in Table 2.4-1. The search of embase.com and the Cochrane Library was restricted by date (from 2007) and was searched up to 29 June 2015. The specific search terms used to identify relevant literature are outlined in Appendix 4.

Databases maintained by Health Technology Assessment (HTA) agencies were also searched to identify relevant literature and existing HTAs of PCI with stent insertion in the populations of interest. In addition, the reference lists of relevant systematic reviews, selected narrative reviews, evidence-based treatment guidelines and primary articles were also examined to identify additional relevant studies.

Table 2.4-1 Databases searched – clinical evidence

Database Search periodembase.com (EMBASE and Medline) 1 January 2007 to 29 June 2015

The Cochrane Library (includes Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects, Health Technology Assessment)

1 January 2007 to 29 June 2015

Relevant HTA websites and databases a 1 January 2007 to 6 July 2015a The following HTA websites were searched: Agency for Healthcare Research and Quality (AHRQ) at AHRQ; Canadian Agency for Drugs and Technologies in Health (CADTH) at CADTH Reports; National Institute for Health and Care Excellence (NICE) at NICE, UK.

The Review Protocol specified additional limits that were applied to the systematic literature search. These are outlined in Table 2.4-2.


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Table 2.4-2 Additional limits applied to the systematic literature search

Limit Inclusion criteriaPublication types Full text, peer-reviewed studies in humans.

Exclude narrative reviews, editorials, letters, conference abstracts, non-clinical studies.

Study types Select and report only the most recent, good quality literature. Use a hierarchical step-wise method to select studies according to study design – as determined by the NHMRC Levels of evidence hierarchy (Appendix 5).If there are no systematic reviews of Level II studies available, then select Level II studies alone. Should these be unavailable then select systematic reviews of non-randomised comparative and/or cohort studies. If these are not available, then select non-randomised comparative studies.Exclude non-comparative studies (case series and case reports).

Language English language only.

Search period 2007 to present. Restrict search to capture contemporary evidence using second-generation stents. However, should there be limited data available during this period, extend the search back in five-year increments until sufficient data are sourced.

Abbreviations: NHMRC, National Health and Medical Research Council.

Eligibility criteria for studiesThe literature search outlined above identified 234 citations. Application of the following exclusion criteria resulted in identification of 47 relevant systematic reviews.

The exclusion criteria were as follows:

Not a systematic review – excludes narrative reviews, other study types and other publication types including letters, editorials and commentaries.

Wrong intervention – excludes systematic reviews that do not assess PCI, or an intervention that includes PCI.

Wrong comparator – excludes systematic reviews that do not compare PCI, or an intervention including PCI, with either CABG or medical therapy.

Wrong population – excludes systematic reviews that do not assess PCI in one of the selected populations of interest: chronic stable angina, NSTE-ACS or patients at high risk of coronary events based on diagnostic testing. Populations that are broader but encompass these populations have been included.

Wrong outcomes – excludes systematic reviews that do not assess one of the outcomes outlined in Section 2.4.1.

Not in English – excludes systematic reviews not published in English that do not include at least some information (e.g. a summary) in English.

Duplicate data – excludes systematic reviews that report data already reported in a previous publication, or conference abstracts that have subsequently been published.

Superseded – excludes systematic reviews that have been updated.

The exclusion of citations from the searches is presented in Table 2.4-3.


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Table 2.4-3 Summary of the process used to identify relevant systematic reviewsDescription embase.com

29 June 2015Cochrane Library

30 June 2015Number of citations retrieved by search 212 22Number of duplicate citations removed 3 10Total number of citations screened 209 12Number of citations excluded in title/abstract review:

Not a systematic reviewWrong interventionWrong comparator

Wrong populationWrong outcomesNot in English

676516501

171000

Total citations excluded at title/abstract review 154 9Citations screened by full text review 55 3Citations excluded in full text review:

Not a systematic reviewWrong intervention

Wrong comparatorWrong populationWrong outcomesDuplicate data

Superseded

4511071

0000000

Total citations excluded at full text review 19 0Included citations from each database 36 3Manually identified citations 9Total included citations 48

Evidence appraisalThe levels of evidence hierarchy developed by the NHMRC (Appendix 5) were used to select studies according to study design. The evidence base was appraised in accordance with the five-component body of evidence matrix recommended by the NHMRC (2009), which considers the evidence base (in terms of quantity, level and quality), the consistency of results, the potential clinical impact, and the generalisability and applicability of the evidence.

The quality of included clinical studies was assessed using a study-specific quality assessment checklist adapted from the NHMRC (NHMRC, 2000). The quality assessment checklists for each included study are presented in Appendix 8.

2.5 Systematic literature review for economic evidence

2.5.1 The research questions for the economic evidence review

The key research questions for the economic evidence review are:

(1) What is the evidence for the cost-effectiveness of PCI with stent insertion combined with medical therapy compared with medical therapy alone in the target populations (patient groups 1 and 3)?

(2) What is the evidence for the cost-effectiveness of PCI with stent insertion combined with medical therapy compared with CABG combined with medical therapy in the target populations (patient groups 1, 2 and 3)?

(3) What is the evidence for the cost-effectiveness of selective PCI with stent insertion combined with medical therapy compared with routine PCI with stent insertion combined with medical therapy in the target populations (patient group 2 only)?


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As described above for the clinical evidence review (Section 2.4.2), the three populations of interest are as follows:

(1) Patients with chronic stable angina.

(2) Patients with a diagnosis of NSTE-ACS.

(3) Patients who are assessed at higher risk of coronary events following diagnostic testing (e.g. non-invasive imaging such as stress echocardiography or myocardial perfusion imaging, or invasive diagnostic testing, specifically FFR).

Within each of the three population groups defined in the PICO (Section 2.3, Table 2.3-1), various subgroups of particular interest are specified. Where available, data were extracted for these subgroups. As for the clinical evidence search, the comparators depend on the population of interest (Section 2.3, Table 2.3-1) and may include a primary strategy of either (i) medical therapy alone, whereby the primary strategy comprises pharmacological therapy (i.e. medical management with antiplatelet therapy, lipid-lowering agents, etc.) with watchful waiting; or (ii) CABG (combined with medical therapy).

In addition, published economic analyses that compare different types of stents were included in the economic evidence review but a full systematic review of the evidence for BMS versus DES was not undertaken.

2.5.2 Methods for the economic evidence review

The following section outlines the methods used to identify relevant data for the review of economic evidence. This includes a description of the literature search strategy and the criteria used to define the inclusion/exclusion of studies.

Search strategyA comprehensive search of peer-reviewed scientific literature was conducted to identify studies that provide economic evidence relating to the cost-effectiveness of PCI with stent insertion in the defined populations of interest. Electronic databases were searched for original research papers describing (i) economic evaluations (cost-effectiveness, cost-utility, cost-benefit and cost-minimisation analyses), or (ii) costing studies, that evaluated PCI compared with one of the comparators listed in Table 2.3-1.

Table 2.5-1 shows the databases searched and the dates the searches were performed. The specific search terms used to identify relevant literature are outlined in Appendix 4. Databases maintained by HTA agencies were also searched to identify relevant literature and existing HTAs of PCI with stent insertion in the populations of interest. In addition, the reference lists of relevant systematic reviews, selected narrative reviews, evidence-based treatment guidelines, and primary articles identified in the search for clinical evidence were also examined to identify additional relevant economic evaluations and costing studies.


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Table 2.5-1 Databases searched – economic evidence

Database Search periodembase.com (EMBASE and Medline) 1 January 2007 to 29 June 2015

The Cochrane Library (NHS Economic Evaluation Database) 1 January 2007 to 29 June 2015

Relevant HTA websites and databases a 1 January 2007 to 6 July 2015a The following HTA websites were searched: Agency for Healthcare Research and Quality (AHRQ) at AHRQ; Canadian Agency for Drugs and Technologies in Health (CADTH) at CADTH Reports; National Institute for Health and Care Excellence (NICE) at NICE, UK.

Eligibility criteriaThe literature search outlined above identified 371 citations. Application of pre-defined exclusion criteria resulted in identification of 11 relevant cost-effectiveness analyses.

The exclusion criteria were as follows:

Not an economic analysis – excludes narrative reviews, other study types and other publication types including letters, editorials and commentaries.

Wrong intervention – excludes economic analyses that do not assess PCI, or an intervention that includes PCI.

Wrong comparator – excludes economic analyses that do not compare PCI, or an intervention including PCI, with either CABG or medical therapy.

Wrong population – excludes economic analyses that do not assess PCI in one of the selected populations of interest: chronic stable angina, diagnosis of NSTE-ACS or patients at high risk of coronary events based on diagnostic testing. Populations that are broader but encompass these populations have been included.

Not in English – excludes economic analyses not published in English that do not include at least some information (e.g. a summary) in English.

Duplicate data – excludes economic analyses that report data already reported in a previous publication, or conference abstracts that have subsequently been published.

The exclusion of citations from the searches is presented in Table 2.5-2.


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Table 2.5-2 Summary of the process used to identify relevant economic analysesDescription embase.com

29 June 2015Cochrane Library30 June 2015

Number of citations retrieved by search 362 9Number of duplicate citations removed 9Total number of citations screened 353 9Number of citations excluded in title/abstract review:

Not an economic evaluation/costing studyWrong interventionWrong comparator

Wrong populationNot in English

247

71

8

9

0

3

1

1

0

0

Total citations excluded at title/abstract review 335 5Citations screened by full text review 18 4Citations excluded in full text review:

Not an economic evaluation/costing studyWrong intervention

Wrong comparatorWrong populationConference abstract only

Superseded

1

1

0

0

13

0

0

0

0

0

0

0

Total citations excluded at full text review 15 0Included citations from each database 3 4Manually identified citations 4Total included citations 11


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3 SECONDARY DATA ANALYSIS

This section presents an analysis of the available secondary data that describes the use of PCI in Australia. An analysis of MBS data was undertaken to determine the current service profile for PCI. This was supplemented with an analysis of hospital separations data from the NHMD.

3.1 MBS services and expenditure for PCI

This section focuses on the seven MBS items that relate to PCI. Two of those items describe angioplasty without atherectomy or stenting (MBS items 38300 and 38303). Four items describe rotational atherectomy with balloon angioplasty, including two that involve stenting (MBS items 38312 and 38318) and two that do not (MBS items 38309 and 38315). Finally, one of the seven relevant MBS items describes a procedure involving the insertion of stent/s into one occlusional site, including associated balloon dilation of the coronary artery (MBS item 38306).

The full item descriptors and fees for the seven in-scope MBS items are provided in Appendix 3. Data relating to an additional relevant MBS item (38241, use of a coronary pressure wire during selective coronary angiography) is presented in Appendix 6.

3.1.1 Total services for items relating to PCI

Table 3.1-1 shows the total services for each of the seven relevant MBS items from 2009-10 to 2013-14. The number of services for each item in 2013-14 is also shown as a proportion of all services in that financial year, with the relative proportions indicating that MBS item 38306 is the most commonly used item, accounting for 92% of all services. Due to the predominance of this item, the overall growth of PCI-related services over the five-year period to 2013-14 of 8.5% is similar to the growth of MBS item 38306 (6.7%). Five-year growth for three of the included items was greater than 60%; however, these were low-use items with less than 50 services per item in 2013-14.

Table 3.1-1 Total services for PCI-related items, 2009-10 to 2013-14

Description MBS item

2009-10 2010-11 2011-12 2012-13 2013-14 Total % of total,

2013-14a

Five-year

growth

Angioplasty, 1 occluded artery

38300 1,122 1,241 1,315 1,370 1,437 6,485 5.6% 28.1%

Angioplasty, >1 occluded artery

38303 156 170 194 206 216 942 0.8% 38.5%

Angioplasty with the insertion of stent/s, 1 occluded site

38306 22,248 23,180 23,614 23,548 23,746 116,336 92.2% 6.7%

Angioplasty, rotational atherectomy, 1 occluded artery

38309 21 16 20 20 38 115 0.1% 81.0%

Angioplasty, rotational atherectomy and stent/s, 1 occluded artery

38312 169 142 177 247 269 1,004 1.0% 59.2%

Angioplasty, rotational atherectomy, >1 occluded artery

38315 5 4 3 6 10 28 0.0% 100.0%


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2009-10 2010-11 2011-12 2012-13 2013-14 Total % of total,

2013-14a

Five-year

growth

Angioplasty, rotational atherectomy and stent/s, >1 occluded artery

38318 28 36 28 42 46 180 0.2% 64.3%

- Total 23,749 24,789 25,351 25,439 25,762 125,090 100% 8.5%Source: Department of Health, Medical Benefits Division, Medicare Financing & Listings Branch, MBS Analytics Section. Data received 10 July 2015.Note: These data are determined by the date the service was provided, not the date the service was processed by Medicare Australia.Abbreviations: MBS, Medicare Benefits Schedule; PCI, percutaneous coronary intervention.a Proportion of total services for all included items.

Table 3.1-2 shows the total benefits paid for each of the seven PCI items over the same five financial years.9 Between 2009-10 and 2013-14, MBS item 38306 accounted for between 92% and 94% of total expenditure on PCI services. Across all items, the five-year growth in expenditure was greater than the five-year growth in service number. It should be noted that the MBS fee for all seven items increased annually from November 2009 until the most recent fee increase in November 2012.

Table 3.1-2 Total benefits paid for PCI-related items, 2009-10 to 2013-14


2009-10 2010-11 2011-12 2012-13 2013-14 Five-year growth

Angioplasty, 1 occluded artery

38300 $222,387 $238,010 $278,581 $270,672 $329,084 48.0%

Angioplasty, >1 occluded artery

38303 $34,965 $45,172 $51,792 $52,460 $65,103 86.2%

Angioplasty with the insertion of stent/s, 1 occluded site

38306 $6,829,084 $6,940,764 $7,699,324 $7,520,392 $7,867,506 15.2%

Angioplasty, rotational atherectomy, 1 occluded artery

38309 $9,947 $9,307 $12,252 $12,820 $23,248 133.7%

Angioplasty, rotational atherectomy and stent/s, 1 occluded artery

38312 $131,444 $103,095 $150,051 $205,231 $231,477 76.1%

Angioplasty, rotational atherectomy, >1 occluded artery

38315 $4,290 $2,617 $1,772 $4,279 $8,392 95.6%

Angioplasty, rotational atherectomy and stent/s, >1 occluded artery

38318 $25,562 $38,164 $33,600 $43,916 $61,923 142.2%

- Total $7,257,679 $7,377,129 $8,227,371 $8,109,770 $8,586,733 18.3%Source: Department of Health, Medical Benefits Division, Medicare Financing & Listings Branch, MBS Analytics Section. Data received 10 July 2015.Note: These data are determined by the date the service was processed by Medicare Australia, not the date the service was provided.Abbreviations: MBS, Medicare Benefits Schedule; PCI, percutaneous coronary intervention.

3.1.2 Geographic and temporal trends

AngioplastyFigure 3.1-1 shows the number of services per capita for MBS items 38300 and 38303 for transluminal balloon angioplasty of one and more than one coronary artery, respectively. The service described by these two items is transluminal balloon angioplasty without rotational 9 The average benefit paid per service is shown in Table 3.1-3 and is lower than the Schedule Fee due to the Multiple Operations Rule.


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atherectomy or stenting. The highest per capita usage was in New South Wales, Western Australia and Tasmania, while the lowest usage was in the Northern Territory.

Figure 3.1-1 Number of services per capita (100,000 population) for MBS items 38300 and 38303, 2013-14

Source: Department of Human Services, Medicare Australia Statistics. Accessed 07 July 2015Note: These data are determined by the date the service was processed by Medicare Australia, not the date the service was provided. Services per capita (i.e. per 100,000 population) is calculated by dividing the number of services processed in a month by the number of people enrolled in Medicare at the end of that month.Abbreviations: MBS, Medicare Benefits Schedule.

Angioplasty with the insertion of stent/sFigure 3.1-2 shows the number of services per capita for the highest-use PCI item, 38306. Per capita usage was highest in New South Wales, Victoria and Western Australia, where over 100 services per 100,000 population were undertaken. Those three states also had the highest per capita usage across the five-year period up to 2013-14 (data not presented). Usage of MBS item 38306 was substantially lower in the Northern Territory than any other state or territory with only 22 services per 100,000 population.


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Figure 3.1-2 Number of services per capita (100,000 population) for MBS item 38306, 2013-14

Source: Department of Human Services, Medicare Australia Statistics. Accessed 07 July 2015Note: These data are determined by the date the service was processed by Medicare Australia, not the date the service was provided. Services per capita (i.e. per 100,000 population) is calculated by dividing the number of services processed in a month by the number of people enrolled in Medicare at the end of that month.Abbreviations: MBS, Medicare Benefits Schedule.

Per capita usage for the remaining PCI items (MBS items 38309, 38312, 38315, 38318) was very low at ≤1 per 100,000 population nationally and in each state and territory in 2013-14. The very low usage of those items in 2013-14 was representative of the preceding four years, in which the national usage for each of the items was never higher than 1 per 100,000 population. As such, the per capita usage of MBS items 38309 to 38318 is not depicted.

3.1.3 Age and gender

AngioplastyAs discussed previously, two MBS items relate to transluminal balloon angioplasty without rotational atherectomy or stenting, with the difference between the items being the number of arteries involved. Data presented in Table 3.1-1 demonstrate that procedures involving one artery are more common, making up 87% of balloon angioplasty services (without rotational atherectomy or stenting) over the five-year period from 2009-10 to 2013-14. While the total number of services increased steadily from 2009-10 to 2013-14, neither age nor gender appeared to vary during that period. Therefore, the following data analyses are restricted to the most recent financial year for which data were available (July 2013 to June 2014).

Figure 3.1-3 shows the age and gender distribution of services for MBS item 38300. Males accounted for 78% of procedures involving a single coronary artery, with males aged between 55 and 84 years accounting for 65% of the total services for this procedure. Across both genders, there was limited usage of MBS item 38300 in patients aged <50 years (4% of total usage) or ≥85 years (5% of total usage).

The equivalent data for MBS item 38303 is presented in Figure 3.1-4. As expected, due to the similarity between the two items, the demographics of patients claiming MBS item 38303 are similar to those described above. Males accounted for 81% of total procedures involving more than one artery and over three-quarters of the total services were undertaken in males aged


January 2016

≥50 years. While 41 (19%) out of 219 total procedures involved female patients, the youngest female patients who underwent angioplasty in multiple coronary arteries were in the 55-59 years age category. In contrast, 22 males (12% of all males) underwent PCI of multiple coronary arteries while they were under 55 years of age.

Figure 3.1-3 Total services for MBS item 38300 by age group and gender, 2013-2014

Source: Department of Health, Medical Benefits Division, Medicare Financing & Listings Branch, MBS Analytics Section. Data received 13 July 2015.Note: These data are determined by the date the service was processed by Medicare Australia, not the date the service was provided.Abbreviations: MBS, Medicare Benefits Schedule.




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Angioplasty with the insertion of stent/sAs discussed in Section 3.1.1, over 90% of all PCI services involved MBS item 38306, which represented approximately 24,000 services in the 2013-14 financial year. Over three-quarters (78%) of patients who underwent PCI with item 38306 were male, with this higher use being observed across all age groups. Male usage peaked in the 65-69 years age group, with a slightly later peak in females, at 70-74 years of age.



Angioplasty and rotational atherectomy, no stent/sThe two MBS items involving angioplasty and rotational atherectomy without insertion of stent/s were the least used of the seven PCI items. In 2013-14, only 39 services were processed for MBS item 38309 (one coronary artery) and only nine for MBS item 38315 (more than one coronary artery). Across both items, only one patient was less than 60 years of age and 37 (77%) were male.


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Angioplasty with rotational atherectomy and the insertion of stent/sLike all other PCI items, MBS items 38312 and 38318 were mostly claimed by male patients, who made up 69% and 87% of claims, respectively. Total usage of MBS item 38312 peaked in the 70-74 years age group, although the highest use among females was in those aged between 80 and 84 years. For MBS item 38318, 96% of services were undertaken in patients aged ≥50 years, with the majority being male.


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The age and gender profiles shown in this section largely align with the epidemiological data discussed in Section 1.1.4. The National Health Survey (AIHW, 2011) indicated that CHD is more prevalent in males,10 which is consistent with the higher number of PCI-related MBS services undertaken in males than females in 2013-14. Similarly, the incidence rate for acute coronary events was higher in males than females, with age-adjusted, unlinked hospitalisation 10 In 2007-08, 4% of males and 2% of females were estimated to have CHD (AIHW, 2011).


January 2016

data from the NHMD showing that in 2011 almost two-thirds of the total events occurred in males (AIHW, 2014b). Again, this is relatively consistent with PCI services funded through the MBS, with males accounting for approximately 75% of procedures in the 2011-12 financial year.11

A marked increase in the prevalence of CHD with increasing age was also reported in the National Health Survey, with the highest prevalence in people aged 85 years or older (AIHW, 2011). While the use of PCI tended to increase with age, a peak in PCI services was generally observed in patients aged between 60 and 74 years, followed by a gradual decline thereafter. This may indicate a reluctance to undertake PCI in older patients or a need for more invasive procedures such as CABG.

3.1.4 In-hospital and out-of-hospital services for items relating to PCI

Across most PCI items, out-of-hospital procedures made up between 2-5% of procedures undertaken in 2013-14. The one exception was MBS item 38315, where 20% of procedures were conducted out-of-hospital in 2013-14. However, it should be noted that 20% corresponds to only two services and additionally this appeared to be an anomaly. Of the 18 services for MBS item 38315 conducted in the previous four years, none were undertaken out-of-hospital.

Table 3.1-3 also shows the average out-of-pocket costs for the seven PCI items in 2013-14. Out-of-pocket costs (calculated as ‘average fees charged per service’ minus ‘average benefits paid per service’) were lowest for the two angioplasty items that do not involve atherectomy or stenting (MBS items 38300 and 38303) and highest for MBS item 38318, which involves atherectomy in more than one coronary artery and insertion of one or more stents. Out-of-pocket costs did not increase noticeably for any of the items over a five-year period from 2009-10 to 2013-14, as shown in Figure 3.1-10. The overall percentage growth during the five-year period was 2.7%, ranging from -23% (-$167) for MBS item 38315 to 11% ($27) for MBS item 38303.

Table 3.1-3 Average fees charged and benefits paid for PCI items, 2013-14

MBS item 38300 38303 38306 38309 38312 38315 38318Number of services 1,437 216 23,746 38 269 10 46

In-hospital (%) 97.2 96.8 95.8 94.7 97.8 80.0 95.7

Out-of-hospital (%) 2.8 3.2 4.2 5.3 2.2 20.0 4.3

Average fee charged per service $410.80 $582.58 $609.11 $1,030.34 $1,493.55 $1,508.53 $2,106.98

Average benefits paid per service

$214.37 $308.14 $324.33 $594.97 $845.93 $961.78 $1,193.84

Average out-of-pocket costsa $196.42 $274.44 $284.78 $435.37 $647.62 $546.75 $913.14Source: Department of Health, Medical Benefits Division, Medicare Financing & Listings Branch, MBS Analytics Section. Data received 10 July 2015.Note: These data are determined by the date the service was provided, not the date the service was processed by Medicare Australia.Abbreviations: PCI, percutaneous coronary intervention.a The average out-of-pocket cost is equal to ‘average fees charged per service’ minus ‘average benefits paid per service’.

11 Department of Health, Medical Benefits Division, Medicare Financing & Listings Branch, MBS Analytics Section. Data received 13 July 2015.


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Figure 3.1-10 Average out-of-pocket costs for MBS items 38300-38318 over five years, 2009-10 to 2013-14

Source: Department of Health, Medical Benefits Division, Medicare Financing & Listings Branch, MBS Analytics Section. Data received 10 July 2015.Note: These data are determined by the date the service was provided, not the date the service was processed by Medicare Australia.Abbreviations: MBS, Medicare Benefits Schedule.

3.1.5 PCI services by specialty type

During the five-year period from 2009-10 to 2013-14, the vast majority of PCI procedures were undertaken by cardiology specialists. Across the seven PCI items, 90% of services were undertaken by cardiology specialists during that period, with internal medicine and nuclear medicine specialists making up most of the remaining services (6% and 4%, respectively). Other specialties made up only 0.2% of total services, most of which were surgery or respiratory and sleep specialists. Table 3.1-4 shows service provider information for each of the PCI items separately.

Table 3.1-4 PCI services by requesting specialty type, July 2009 to June 2014

Specialty type (%) 38300 38303 38306 38309 38312 38315 38318Cardiology 91.6 94.5 89.5 90.7 87.2 91.7 85.6

Internal medicine 5.6 3.8 6.1 4.2 6.8 4.2 9.8

Nuclear medicine 2.3 0.5 4.2 1.7 5.8 4.2 4.6

Other 0.6 1.1 0.2 3.4 0.1 0.0 0.0Source: Department of Health, Medical Benefits Division, Medicare Financing & Listings Branch, MBS Analytics Section. Data received 10 July 2015.Note: These data are determined by the date the service was processed by Medicare Australia, not the date the service was provided.Abbreviations: PCI, percutaneous coronary intervention.

3.1.6 Co-claiming patterns for MBS items relating to PCI

This section presents data showing the frequency of co-claiming among the seven PCI items and also between each PCI item and associated diagnostic radiology and ultrasound items. Data are presented for one financial year, July 2013 to June 2014. It was relatively rare for more than one PCI service to be undertaken on the same occasion. In part, this is likely to be due to a restriction on this type of co-claiming in explanatory note T8.42, which prohibits the claiming of more than one of MBS items 38309, 38312, 38315 and 38318 in a single patient episode. These restricted co-claiming combinations are shown in grey in Table 3.1-5.


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There were a small number of cases in which MBS items 38300 and 38303 were claimed by the same patient on the same day. It is unclear whether this is appropriate as the descriptor for MBS item 38303 specifies angioplasty of more than one coronary artery with no upper limit on the number of arteries. However, it is possible that a patient could return to the operating theatre on the same day as the original procedure for further surgery due to post-operative complications.

In 2013-14, MBS item 38306 (angioplasty with the insertion of stent/s) was undertaken in combination with another PCI service on 429 occasions (same patient, same day). While this made up only a small proportion (2.7%) of the total occasions on which that high-use service was undertaken, it often made up a considerable proportion of total occasions for the other PCI services. In 2013-14, MBS items 38306 and 38300 were billed together on 302 occasions (same patient, same day), which represented 2% of all occasions where item 38306 was billed and 25% of all occasions where item 38300 was billed.12

MBS item 38306 was the only PCI item that was often billed multiple times on one occasion (same patient, same day). In 2013-14, approximately 24,000 services were provided under MBS item 38306; however, these services were undertaken on only 15,971 separate occasions, 26% of which included two or more services (see Table 3.1-5).

Table 3.1-5 Frequency of co-claiming between PCI items, 2013-14

MBS item38300

(N=1,188)n (%)

38303(N=168)n (%)

38306(N=15,971)

n (%)

38309(N=30)n (%)

38312(N=244)n (%)

38315(N=9)n (%)

38318(N=41)n (%)

38300 1 (0.1) 3 (1.8) 302 (1.9) 0 10 (4.1) 0 2 (4.9)

38303 3 (0.3) 3 (1.8) 27 (0.2) 0 0 0 0

38306 302 (25.4) 27 (16.1) 4,131 (25.9) 1 (3.3) 95 (38.9) 0 4 (9.8)

38309 0 0 1 (0.0) 0 0 0 1 (2.4)

38312 10 (0.8) 0 95 (0.6) 0 0 0 1 (2.4)

38315 0 0 0 0 0 0 0

38318 2 (0.2) 0 4 (0.0) 1 (3.3) 1 (0.4) 0 0

Total 318 (26.8) 33 (19.6) 4,560 (28.6) 2 (6.7) 106 (43.4) 0 8 (19.5)Source: Department of Health, Medical Benefits Division, Medicare Financing & Listings Branch, MBS Analytics Section. Data received 13 July 2015.Note 1: These data are determined by the date the service was provided, not the date the service was processed by Medicare Australia.Note 2: N in the header row refers to the number of occurrences of each PCI number (same patient, same day).Note 3: MBS item 38306 is often billed multiple times on the same occasion. Where this is the case, the table includes only one tally towards the frequency of co-claiming (e.g. in the following billing sequence: 38300, 38306, 38306, 38306; MBS item 38306 is counted once, not three times).Note 4: Co-claiming of the items shown in grey shading is restricted according to explanatory note T8.42.Abbreviations: MBS, Medicare Benefits Schedule; PCI, percutaneous coronary intervention.

Table 3.1-6 provides further detail about multiple billing of MBS item 38306. Nearly three-quarters of all occurrences of MBS item 38306 included only one service for that item. However, multiple billing was not uncommon, with two, three and four services being undertaken on approximately 20%, 5% and 1% of occasions, respectively. The highest number of services for MBS item 38306 in the same patient on the same day was ten; however, as shown in Table 3.1-6, it was rare for MBS item 38306 to be billed five or more times on the same occasion. A detailed description of co-claiming in such instances, including the use of diagnostic radiology and ultrasound services, is provided in Appendix 6. 12 The 302 billing sequences each included one service of MBS item 38300. MBS item 38306 was billed once on 207 of those occasions; twice on 72 occasions; three times on 15 occasions; four times on six occasions; and six times on two occasions.


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Table 3.1-6 Multiple billing of MBS item 38306, 2013-14

Number of services (same patient, same day) Occasions, n (%) Total number of services,

MBS item 383061 11,840 (74.1) 11,840

2 3,138 (19.7) 6,276

3 768 (4.8) 2,304

4 171 (1.1) 684

5 48 (0.3) 240

6 2 (0.0) 12

7 1 (0.0) 7

8 2 (0.0) 16

9 0 (0.0) 0

10 1 (0.0) 10

Total 15,971 (100.0) 21,389Source: Department of Health, Medical Benefits Division, Medicare Financing & Listings Branch, MBS Analytics Section. Data received 13 July 2015.Note: These data are determined by the date the service was provided, not the date the service was processed by Medicare Australia.

Table 3.1-7 and Table 3.1-8 list a variety of MBS-funded imaging services that are regularly undertaken on the same day as PCI. The following MBS items were examined in this analysis of co-claiming: MBS items 38215 to 38240; 38243 to 38246; 55005 to 55855; 59903 to 59973; and 61109 to 61110. These items fall into two broad categories: diagnostic radiology; and ultrasound (see Appendix 3 for the full item descriptors).

Co-claiming data are presented as the number of occasions on which each of the diagnostic radiology or ultrasound items occurred in the same patient and on the same day as a PCI item during 2013-14. These data are also shown as a proportion of total occurrences of each PCI item. The two most frequently co-claimed imaging items were MBS item 59925 (selective coronary arteriography and angiocardiography) and MBS item 38246 (selective coronary angiography), which were both claimed on 65% of the total occasions (N=17,651) on which at least one of the PCI items were claimed.

It should be noted that the tables below are limited to diagnostic radiology and ultrasound items that were undertaken on ≥1% of occasions (same patient, same day) on which at least one of the PCI items occurred. Any imaging items that occurred less frequently are not shown.

Table 3.1-7 Frequency of co-claiming between PCI items and diagnostic radiology items

MBS item38300

(N=1,188)n (%)

38303(N=168)n (%)

38306(N=15,971)

n (%)

38309(N=30)n (%)

38312(N=244)n (%)

38315(N=9)n (%)

38318(N=41)n (%)

59925 696 (58.6) 103 (61.3) 10,535 (66.0) 6 (20.0) 99 (40.6) 6 (66.7) 15 (36.6)

38246 674 (56.7) 96 (57.1) 10,670 (66.8) 3 (10.0) 107 (43.9) 0 5 (12.2)

59912 445 (37.5) 56 (33.3) 5,123 (32.1) 20 (66.7) 119 (48.8) 2 (22.2) 21 (51.2)

38243 326 (27.4) 36 (21.4) 4,014 (25.1) 16 (53.3) 101 (41.4) 3 (33.3) 21 (51.2)

38218 119 (10.0) 14 (8.3) 1,294 (8.1) 2 (6.7) 16 (6.6) 2 (22.2) 1 (2.4)

38240 68 (5.7) 12 (7.1) 540 (3.4) 2 (6.7) 9 (3.7) 0 0

61109 35 (3.0) 5 (3.0) 356 (2.2) 3 (10.0) 10 (4.1) 0 3 (7.3)

38215 30 (2.5) 6 (3.6) 414 (2.6) 0 2 (0.8) 0 0

59972 23 (1.9) 1 (0.6) 292 (1.8) 0 3 (1.2) 1 (11.1) 0


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MBS item38300

(N=1,188)n (%)

38303(N=168)n (%)

38306(N=15,971)

n (%)

38309(N=30)n (%)

38312(N=244)n (%)

38315(N=9)n (%)

38318(N=41)n (%)

59903 1 (0.1) 0 5 (0.0) 0 0 0 1 (2.4)

59973 6 (0.5) 0 49 (0.3) 0 0 0 1 (2.4)Source: Department of Health, Medical Benefits Division, Medicare Financing & Listings Branch, MBS Analytics Section. Data received 10 July 2015.Note: N in the header row refers to the number of occurrences of each PCI number (same patient, same day).Abbreviations: MBS, Medicare Benefits Schedule; PCI, percutaneous coronary intervention.

Table 3.1-8 Frequency of co-claiming between PCI items and ultrasound items

MBS item38300

(N=1,188)n (%)

38303(N=168)n (%)

38306(N=15,971)

n (%)

38309(N=30)n (%)

38312(N=244)n (%)

38315(N=9)n (%)

38318(N=41)n (%)

55113 74 (6.2) 4 (2.4) 802 (5.0) 0 5 (2.0) 0 1 (2.4)

55054 5 (0.4) 2 (1.2) 74 (0.5) 0 1 (0.4) 0 0

55118 4 (0.3) 0 14 (0.1) 1 (3.3) 1 (0.4) 0 0Source: Department of Health, Medical Benefits Division, Medicare Financing & Listings Branch, MBS Analytics Section. Data received 10 July 2015.Note: N in the header row refers to the number of occurrences of each PCI number (same patient, same day).Abbreviations: MBS, Medicare Benefits Schedule; PCI, percutaneous coronary intervention.

The frequency of co-claiming shown above indicates that, on some occasions, more than one diagnostic radiology or ultrasound service is used. As such, an in-depth exploration of co-claiming patterns has been undertaken for the highest-use PCI service, MBS item 38306.

As in Table 3.1-9, the most common ‘same patient, same day’ combination was item 38306 together with item 38246 (selective coronary angiography prior to any coronary interventional procedure) and item 59925 (selective coronary arteriography and angiocardiography). It is unclear whether co-claiming of the latter two items is appropriate due to the overlap between the item descriptors. However, using this ‘same day’ co-claiming data it is not possible to ascertain whether the same provider is undertaking the two services; it may be the case that a non-interventional cardiologist first undertakes the service relating to MBS item 59925, while an interventional cardiologist undertakes the service relating to MBS item 38246 at the time of the PCI procedure (MBS item 38306). Nonetheless, a question remains regarding whether a patient should undergo two invasive coronary angiography procedures in one day.

It should be noted that Table 3.1-9 does not provide an exhaustive list of co-claimed services. Combinations of items that accounted for <1% of total occurrences are not presented. In addition, only the aforementioned diagnostic radiology and ultrasound items were considered to be in-scope for this analysis of co-claiming. As such, the co-claiming combinations listed in Table 3.1-9 do not include other MBS items that are commonly billed with PCI services, such as:

MBS item 110 – referred consultation with consultant physician; MBS item 116 – subsequent attendance with consultant physician; MBS item 13882 – ventilatory support in an Intensive Care Unit; MBS item 51303 – assistance at an operation; MBS item 65070 – erythrocyte count, haematocrit, haemoglobin, calculations or

measurement of red cell index or indices, platelet count, leucocyte count and manual or instrument generated differential count;


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MBS item 66500 – quantitation in serum, plasma, urine or other body fluid (except amniotic fluid); or

MBS item 73930 – initiation of a patient episode by collection of a specimen.

Table 3.1-9 Co-claiming data for MBS item 38306

Trigger item Item combination co-claimedOccasions

n (%)38306 38246, 59925 5,140 (32.2)

38306 [2] 38246, 59925 1,349 (8.4)

38306 38243, 59912 1,275 (8.0)

38306 38246, 59912 1,145 (7.2)

38306 [2] 38243, 59912 405 (2.5)

38306 38243, 59925 384 (2.4)

38306 [3] 38246, 59925 327 (2.0)

38306 38246, 55113, 59925 314 (2.0)

38306 38246 290 (1.8)

38306 [2] 38246, 59912 288 (1.8)

38306 38241, 38246, 59925 285 (1.8)

38306 38218, 59925 258 (1.6)

38306 38240, 59925 227 (1.4)

38306 38218, 38243, 59912, 59925 200 (1.3)

38306 Othera 4,084 (25.6)

Total - 15,971Source: Department of Health, Medical Benefits Division, Medicare Financing & Listings Branch, MBS Analytics Section. Data received 13 July 2015.Note: Numbers shown in square brackets indicate multiple billing of the preceding MBS item.a This included 38 occasions on which MBS item 38306 was claimed without any diagnostic radiology or ultrasound item.

3.2 NHMD data relating to PCI

This section examines NHMD hospital separations data from July 2009 to June 2014, inclusive. The 11 relevant ACHI procedure codes through which hospital separations were examined are shown in Table 3.2-1. Importantly, the four additional ACHI procedures codes (compared with the seven MBS items in Section 3.1) provide additional information about the number of coronary arteries involved or the number of stents that were inserted during a particular procedure.

Table 3.2-1 ACHI codes relevant to PCI

ACHI code Descriptor38300-00 Percutaneous transluminal balloon angioplasty of 1 coronary artery

38303-00 Percutaneous transluminal balloon angioplasty of ≥2 coronary arteries

38306-00 Percutaneous insertion of 1 transluminal stent into single coronary artery38306-01 Percutaneous insertion of ≥2 transluminal stents into single coronary artery38306-02 Percutaneous insertion of ≥2 transluminal stents into multiple coronary arteries

38309-00 PTCRA, 1 artery

38312-00 PTCRA, 1 artery with insertion of 1 stent38312-01 PTCRA, 1 artery with insertion of ≥2 stents

38315-00 PTCRA, multiple arteries

38318-00 PTCRA, multiple arteries with insertion of 1 stent38318-01 PTCRA, multiple arteries with insertion of ≥2 stents


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Abbreviations: ACHI, Australian Classification of Health Interventions; PTCRA, percutaneous transluminal coronary rotational atherectomy.

3.2.1 Hospital separations for PCI

Table 3.2-2 shows the number of separations for each of the 11 ACHI codes over a five-year period from July 2009 to June 2014. The data indicate that, in most instances, the number of separations has remained relatively stable or undergone marginal growth over time. The vast majority of PCI-related hospital separations involved stenting, with over 90% of PCI-related separations including one of the following ACHI codes: 38306-00, 38306-01, 38306-02, 38312-00, 38312-01, 38318-00 or 38318-01.

Table 3.2-2 Number of separations for ACHI codes relating to PCI, 2009-10 to 2013-14

ACHI code 2009-10 2010-11 2011-12 2012-13 2013-14 Growth (%)38300-00 1,953 2,104 2,077 2,144 2,635 34.9

38303-00 379 393 336 363 396 4.5

38306-00 23,618 25,034 25,316 25,446 25,487 7.938306-01 6,717 6,755 6,634 6,606 6,537 -2.738306-02 4,347 4,222 4,200 3,965 3,986 -8.3

38309-00 42 51 54 50 62 47.6

38312-00 105 110 123 218 273 160.038312-01 56 66 101 130 179 219.6

38315-00 6 6 6 9 6 0.0

38318-00 7 14 12 11 6 -14.338318-01 14 18 32 37 55 292.9

Total 37,244 38,773 38,891 38,979 39,622 6.4Source: Admitted Patient Care Data, 2009-10 to 2013-14.Abbreviations: ACHI, Australian Classification of Health Interventions; PCI, percutaneous coronary intervention.

3.2.2 Characteristics of patients undergoing PCI

Hospital separations by patient typeIn recent years, public patients have accounted for just over half of the total hospital separations in which a PCI procedure (ACHI codes 38300-00 to 38318-01) was undertaken (see Table 3.2-3). From July 2009 to June 2014, inclusive, the proportion of separations involving public patients was consistently between 55% and 56% of total separations.

Table 3.2-3 Total number of separations for PCI procedures (ACHI codes 38300-00 to 38318-01) in private and public patients, 2009-10 to 2013-14

Separations 2009-10 2010-11 2011-12 2012-13 2013-14 TotalPrivate, n (%) 16,437 (44.1) 17,225 (44.4) 17,411 (44.8) 17,153 (44.0) 17,461 (44.1) 85,687 (44.3)

Public, n (%) 20,807 (55.9) 21,548 (55.9) 21,480 (55.2) 21,826 (55.2) 22,161 (55.9) 107,822 (55.7)Source: Admitted Patient Care Data, 2009-10 to 2013-14.

The relative proportions of private and public patients are shown for each of the 11 relevant ACHI codes in Figure 3.2-1 to Figure 3.2-5. As per the overall data, most procedures were undertaken slightly more often in public patients, based on separations that occurred in the 2013-14 financial year. Private patients outnumbered public patients in some procedure types, including percutaneous insertion of ≥2 transluminal stents into multiple coronary arteries (ACHI code 38306-02). The remaining procedures that were undertaken in more private than


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public patients were low-use procedures and any differences in patient type, therefore, amounted to very few hospital separations.

Figure 3.2-1 Number of separations for private and public patients, ACHI codes 38300-00 and 38303-00, 2013-14

Source: Admitted Patient Care Data, 2009-10 to 2013-14.Abbreviations: ACHI, Australian Classification of Health Interventions.

Figure 3.2-2 Number of separations for private and public patients, ACHI codes 38306-00, 38306-01 and 38306-02, 2013-14



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Hospital separations by ageFigure 3.2-6 to Figure 3.2-10 show the age profile of patients who underwent in-hospital PCI procedures (ACHI codes 38300-00 to 38318-01) during the 2013-14 financial year. Overall, >90% of separations were in patients aged 50 years or older, while 70% were in patients aged 60 years or older. Data for each of the 11 ACHI codes showed that the number of hospital separations generally peaked in one of two age groups: 65 to 69 years; or 70 to 74 years. Importantly, the age distributions shown here are very similar to those observed in the MBS data, despite the fact that MBS data include only private patients. This indicates that there is no apparent difference in the usage of PCI, based on age, regardless of whether patients are public or private. As discussed in Section 3.1.3, the age profile from the MBS and NHMD data are consistent with epidemiological evidence shown in Section 1.1.4.

The data also show that procedures involving a single coronary artery and, where applicable, a single stent were more common than procedures involving multiple arteries and multiple stents. The one exception was ACHI code 38318-01 (rotational atherectomy in multiple arteries and the insertion of two or more stents), which was undertaken during a greater number of hospital separations than ACHI code 38318-00 (rotational atherectomy in multiple arteries with the insertion of one stent).


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Figure 3.2-6 Number of separations by age group, ACHI codes 38300-00 and 38303-00, 2013-14


Figure 3.2-7 Number of separations by age group, ACHI codes 38306-00, 38306-01 and 38306-02, 2013-14



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3.2.3 Hospital separations by principal diagnosis

The NHMD data were examined to determine the most common principal diagnoses for PCI undertaken using ACHI procedure codes 38300-00 to 38318-01. Principal diagnoses were classified according to the Australian Modification of the International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10-AM). Nearly 95% of PCI-related hospital separations that occurred in 2013-14 were associated with one of the principal diagnoses listed in Table 3.2-4.

Table 3.2-4 Common principal diagnoses associated with ACHI codes 38300-00 to 38318-01

Diagnosis code DescriptionI20.0I20.1I20.8I20.9

Unstable anginaAngina pectoris with documented spasmOther forms of angina pectorisAngina pectoris, unspecified

I21.0I21.1I21.2I21.3I21.4I21.9

Acute transmural myocardial infarction of anterior wallAcute transmural myocardial infarction of inferior wallAcute transmural myocardial infarction of other sitesAcute transmural myocardial infarction of unspecified siteAcute subendocardial myocardial infarctionAcute myocardial infarction, unspecified

125.11125.12125.13

Atherosclerotic heart disease, of native coronary arteryAtherosclerotic heart disease, of autologous bypass graftAtherosclerotic heart disease, of nonautologous bypass graft

Source: Separation statistics by principal diagnosis (ICD−10−AM 7th edition), Australia, 2011−12 to 2012−13; AIHW National Hospital Morbidity Database.Abbreviations: ACHI, Australian Classification of Health Interventions.

For the purposes of the following analyses, some diagnosis codes were grouped into broader categories. For example, all of the codes beginning I21 were categorised as ‘acute myocardial infarction’ because further differentiation according to the site of myocardial infarction is not


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relevant to this Review. In other cases, it was preferable to retain additional information such as type of angina.

Table 3.2-5 to Table 3.2-15 show the number and proportion of separations that related to the aforementioned diagnoses or diagnostic categories, for each of the 11 relevant ACHI codes, over a five-year period from 2009-10 to 2013-14.

Table 3.2-5 Number of separations for ACHI code 38300-00 by diagnosis, 2009-10 to 2013-14

Diagnosis code(s)

Principal diagnosis

2009-10n (%)

2010-11n (%)

2011-12n (%)

2012-13n (%)

2013-14n (%)

Five-year growth

I20.0 Unstable angina 281 (14.5) 274 (13.1) 218 (10.6) 237 (11.1) 275 (10.5) -2.1%I20.1, I20.8, I20.9

Angina, other typesa

339 (17.5) 375 (17.9) 332 (16.1) 286 (13.4) 355 (13.5) 4.7%

I21.1, 121.2, 121.3, 121.4, 121.9

Acute myocardial infarction

744 (38.3) 812 (38.7) 734 (35.6) 771 (36.2) 947 (36.1) 27.3%

I25.11Atherosclerotic heart disease, native coronary artery

427 (22.0) 462 (22.0) 597 (28.9) 632 (29.7) 828 (31.5) 93.9%

I25.12, I25.13

Atherosclerotic heart disease, of bypass graftb

23 (1.2) 20 (1.0) 27 (1.3) 24 (1.1) 25 (1.0) 8.7%

Total - 1,814 (93.5) 1,943 (92.7) 1,908 (92.5) 1,950 (91.5) 2,430 (92.5) 34.0%Source: Admitted Patient Care Data, 2009-10 to 2013-14.Abbreviations: ACHI, Australian Classification of Health Interventions.a Includes angina pectoris with documented spasm (I20.1); other forms of angina pectoris (I20.8); and angina pectoris, unspecified (I20.9).b Includes autologous bypass graft (I25.12); and nonautologous bypass graft (I25.13).

Table 3.2-6 Number of separations for ACHI code 38303-00 by diagnosis, 2009-10 to 2013-14Diagnosis code(s)

Principal diagnosis

2009-10n (%)

2010-11n (%)

2011-12n (%)

2012-13n (%)

2013-14n (%)

I20.0 Unstable angina 46 (12.2) 55 (14.0) 45 (13.4) 43 (11.9) 39 (9.9)I20.1, I20.8, I20.9


49 (13.0) 54 (13.7) 45 (13.4) 43 (11.9) 49 (12.4)

I21.1, 121.2, 121.3, 121.4, 121.9


167 (44.2) 153 (38.9) 117 (34.8) 139 (38.4) 144 (36.5)


85 (22.2) 94 (23.9) 86 (25.6) 104 (28.7) 131 (33.2)

I25.12, I25.13


2 (0.5) 3 (0.8) 5 (1.5) 1 (0.3) 4 (1.0)

Total - 349 (92.3) 359 (91.3) 298 (88.7) 330 (91.2) 367 (92.9)Source: Admitted Patient Care Data, 2009-10 to 2013-14.Abbreviations: ACHI, Australian Classification of Health Interventions.a Includes angina pectoris with documented spasm (I20.1); other forms of angina pectoris (I20.8); and angina pectoris, unspecified (I20.9).b Includes autologous bypass graft (I25.12); and nonautologous bypass graft (I25.13).


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Diagnosis code(s)

Principal diagnosis

2009-10n (%)

2010-11n (%)

2011-12n (%)

2012-13n (%)

2013-14n (%)

Five-year growth

I20.0 Unstable angina 3,537 (15.1) 3,159 (12.7) 2,959 (11.8) 2,765 (11.0) 2,605 (10.4) -26.4%I20.1, I20.8, I20.9


3,670 (15.7) 3,462 (14.0) 3,238 (12.9) 2,859 (11.4) 2,584 (10.3) -29.6%

I21.1, 121.2, 121.3, 121.4, 121.9


10,392 (44.5)

11,169 (45.0)

11,187 (44.7)

11,476 (45.6)

11,365 (45.2)

9.4%


4,590 (19.6) 5,776 (23.3) 6,308 (25.2) 6,607 (26.2) 7,115 (28.3) 55.0%

I25.12, I25.13


140 (0.6) 180 (0.7) 182 (0.7) 185 (0.7) 170 (0.7) 21.4%

Total - 22,329 (95.5)

23,746 (95.8)

23,874 (95.3)

23,892 (94.9)

23,839 (94.7)

6.8%

Source: Admitted Patient Care Data, 2009-10 to 2013-14.Abbreviations: ACHI, Australian Classification of Health Interventions.a Includes angina pectoris with documented spasm (I20.1); other forms of angina pectoris (I20.8); and angina pectoris, unspecified (I20.9).b Includes autologous bypass graft (I25.12); and nonautologous bypass graft (I25.13).


Diagnosis code(s)

Principal diagnosis

2009-10n (%)

2010-11n (%)

2011-12n (%)

2012-13n (%)

2013-14n (%)

Five-year growth



1,140 (17.1) 1,060 (15.7) 956 (14.5) 874 (13.3) 783 (12.0) -31.3%

I21.1, 121.2, 121.3, 121.4, 121.9


2,821 (42.3) 2,733 (40.6) 2,829 (42.9) 2,832 (43.1) 2,847 (43.8) 0.9%


1,427 (21.4) 1,734 (25.8) 1,688 (25.6) 1,803 (27.4) 1,866 (28.7) 30.8%

I25.12, I25.13


50 (0.7) 50 (0.7) 53 (0.8) 48 (0.7) 50 (0.8) 0.0%

Total - 6,401 (95.9) 6,432 (95.5) 6,305 (95.5) 6,253 (95.2) 6,171 (94.8) -3.6%Source: Admitted Patient Care Data, 2009-10 to 2013-14.Abbreviations: ACHI, Australian Classification of Health Interventions.a Includes angina pectoris with documented spasm (I20.1); other forms of angina pectoris (I20.8); and angina pectoris, unspecified (I20.9).b Includes autologous bypass graft (I25.12); and nonautologous bypass graft (I25.13).


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Diagnosis code(s)

Principal diagnosis

2009-10n (%)

2010-11n (%)

2011-12n (%)

2012-13n (%)

2013-14n (%)

Five-year growth



837 (19.3) 727 (17.3) 652 (15.6) 588 (14.9) 505 (12.7) -39.7%

I21.1, 121.2, 121.3, 121.4, 121.9


1,404 (32.4) 1,402 (33.3) 1,404 (33.6) 1,347 (34.1) 1,444 (36.3) 2.8%


1,168 (26.9) 1,246 (29.6) 1,343 (32.1) 1,304 (33.0) 1,389 (34.9) 18.9%

I25.12, I25.13


43 (1.0) 34 (0.8) 28 (0.7) 31 (0.8) 26 (0.7) -39.5%

Total - 4,131 (95.3) 3,995 (95.0) 3,951 (94.5) 3,736 (94.5) 3,767 (94.8) -8.8%Source: Admitted Patient Care Data, 2009-10 to 2013-14.Abbreviations: ACHI, Australian Classification of Health Interventions.a Includes angina pectoris with documented spasm (I20.1); other forms of angina pectoris (I20.8); and angina pectoris, unspecified (I20.9).b Includes autologous bypass graft (I25.12); and nonautologous bypass graft (I25.13).


Principal diagnosis

2009-10n (%)

2010-11n (%)

2011-12n (%)

2012-13n (%)

2013-14n (%)



6 (14.3) 5 (10.0) 12 (22.2) 10 (20.0) 11 (17.7)

I21.1, 121.2, 121.3, 121.4, 121.9


19 (45.2) 9 (18.0) 11 (20.4) 8 (16.0) 7 (11.3)


8 (19.0) 25 (50.0) 25 (46.3) 21 (42.0) 29 (46.8)

I25.12, I25.13


0 0 0 2 (4.0) 4 (6.5)



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Diagnosis code(s)

Principal diagnosis

2009-10n (%)

2010-11n (%)

2011-12n (%)

2012-13n (%)

2013-14n (%)



22 (21.0) 26 (23.9) 25 (20.3) 38 (17.4) 47 (17.2)

I21.1, 121.2, 121.3, 121.4, 121.9


51 (48.6) 19 (17.4) 22 (17.9) 62 (28.4) 54 (19.8)


22 (21.0) 47 (43.1) 56 (45.5) 79 (36.2) 131 (48.0)

I25.12, I25.13


0 0 0 2 (0.9) 2 (0.7)



Principal diagnosis

2009-10n (%)

2010-11n (%)

2011-12n (%)

2012-13n (%)

2013-14n (%)



13 (23.2) 11 (16.7) 15 (15.0) 23 (17.7) 29 (16.4)

I21.1, 121.2, 121.3, 121.4, 121.9


17 (30.4) 17 (25.8) 27 (27.0) 32 (24.6) 42 (23.7)


17 (30.4) 27 (40.9) 43 (43.0) 58 (44.6) 81 (45.8)

I25.12, I25.13


0 0 0 0 2 (1.1)



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Diagnosis code(s)

Principal diagnosis

2009-10n (%)

2010-11n (%)

2011-12n (%)

2012-13n (%)

2013-14n (%)

I20.0 Unstable angina 0 0 1 (16.7) 1 (11.1) 2 (33.3)I20.1, I20.8, I20.9


3 (50.0) 3 (50.0) 0 1 (11.1) 1 (16.7)

I21.1, 121.2, 121.3, 121.4, 121.9


1 (16.7) 0 1 (16.7) 2 (22.2) 1 (16.7)


1 (16.7) 2 (33.3) 3 (50.0) 5 (55.6) 1 (16.7)

I25.12, I25.13


0 0 0 0 0



Principal diagnosis

2009-10n (%)

2010-11n (%)

2011-12n (%)

2012-13n (%)

2013-14n (%)

I20.0 Unstable angina 0 1 (7.1) 2 (16.7) 0 1 (16.7)I20.1, I20.8, I20.9


1 (14.3) 4 (28.6) 2 (16.7) 0 1 (16.7)

I21.1, 121.2, 121.3, 121.4, 121.9


3 (42.9) 2 (14.3) 3 (25.0) 5 (45.5) 1 (16.7)


2 (28.6) 3 (21.4) 5 (41.7) 4 (36.4) 3 (50.0)

I25.12, I25.13


0 1 (7.1) 0 0 0



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Diagnosis code(s)

Principal diagnosis

2009-10n (%)

2010-11n (%)

2011-12n (%)

2012-13n (%)

2013-14n (%)



3 (21.4) 3 (16.7) 7 (21.9) 10 (27.0) 8 (14.5)

I21.1, 121.2, 121.3, 121.4, 121.9


2 (14.3) 4 (22.2) 7 (21.9) 8 (21.6) 13 (23.6)


2 (14.3) 7 (38.9) 9 (28.1) 14 (37.8) 26 (47.3)

I25.12, I25.13


0 1 (5.6) 0 0 0


Based on combined data for the 11 ACHI codes in 2013-14, weighted averages were calculated to determine the most frequent principal diagnoses that led to PCI. Any variation between these weighted averages and the results shown in the tables above is likely to result from the small number of separations associated with some ACHI codes rather than a true difference in underlying conditions that led to different PCI procedures.

Acute myocardial infarction was the principal diagnosis in approximately 43% of separations, ranging from 11% (ACHI code 38309-00) to 45% (ACHI code 38318-00). The relative proportion of hospital separations for STEMI and NSTEMI patients cannot be determined on the basis of the principal diagnosis codes available. Atherosclerotic heart disease in a native coronary artery accounted for 30% of total separations (range 17% to 50%), while atherosclerosis of coronary artery bypass graft(s) was the principal diagnosis in less than 1% of separations. Unstable angina and other types of angina13 each accounted for 10-11% of principal diagnoses in 2013-14. Other types of angina may include patients with stable CAD.

13 Includes ‘angina pectoris with documented spasm’, ‘other forms of angina pectoris’, and ‘angina pectoris, unspecified’.


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4 REVIEW OF GUIDELINES RELEVANT TO PCI

This section presents the results of the literature search for CPGs and the guideline concordance analysis conducted for PCI. There was one Australian guideline for the management of ACS published jointly by the National Heart Foundation of Australia (NHFA) and the Cardiology Society of Australia and New Zealand (CSANZ). This guideline was published in 2006, and was followed by two addenda in 2007 and 2011. However, there were no Australian guidelines identified on the management of stable angina.

4.1 Stable angina

Six evidence-based CPGs published from 2007 onwards were identified with recommendations for revascularisation by PCI in patients with stable angina. These guidelines were developed by various international organisations (see Table 4.1-1). There were no Australian guidelines identified for the management of stable angina. Of note was the adoption of the term stable coronary artery disease (SCAD) and stable ischaemic heart disease (SIHD) by some of the international guidelines. These terms include the stable angina population as well as a wider population of patients with ischaemia and stenosis.

Table 4.1-1 Summary of international CPGs – Stable angina/SCAD/SIHD

ID Title of guideline Method AffiliationEuropeESC/EACTS 2014

2014 ESC/EACTS Guidelines on myocardial revascularization. The Task Force on Myocardial Revascularization of the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery.

Based on assessment of best available evidence

European Society of Cardiology (ESC)/ European Association for Cardio-Thoracic Surgery (EACTS).Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI).

ESC 2013 2013 ESC guidelines on the management of stable coronary artery disease. The Task Force on the management of stable coronary artery disease of the European Society of Cardiology.


European Society of Cardiology (ESC)

United StatesACC/AHA 2014 2014

ACC/AHA/AATS/PCNA/SCAI/STS Focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease.


American College of Cardiology (ACC)/American Heart Association (AHA) Task Force on practice guidelines, and the American Association for Thoracic Surgery (AATS), Preventive Cardiovascular Nurses Association (PCNA), Society for Cardiovascular Angiography and Interventions (SCAI), and Society of Thoracic Surgeons (STS)

ACCF/AHA 2012

2012 ACCF/AHA/ACP/AATS/ PCNA/SCAI/STS Guideline for the diagnosis and management of patients with stable ischemic heart disease.


American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) Task Force on practice guidelines, and the American College of Physicians (ACP), American Association for Thoracic Surgery (AATS), Preventive Cardiovascular Nurses Association (PCNA), Society for Cardiovascular Angiography and Interventions (SCAI), and Society of Thoracic Surgeons (STS)


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ID Title of guideline Method AffiliationUnited StatesACCF/AHA 2012

2012 ACCF/AHA/ACP/AATS/ PCNA/SCAI/STS Guideline for the diagnosis and management of patients with stable ischemic heart disease: Executive summary.

Based on the 2012 ACCF/AHA guideline

As above

United KingdomNICE 2011 Management of stable angina.

NICE clinical guideline 126. Last modified December 2012.


National Institute for Health and Care Excellence (NICE)

SIGN 2007 Management of stable angina. A national clinical guideline. February 2007.


Scottish Intercollegiate Guidelines Network (SIGN)

Abbreviations: CPG, clinical practice guideline; SCAD, stable coronary artery disease; SIHD, stable ischaemic heart disease.

4.1.1 European CPGs

ESC/EACTS 2014The European Society of Cardiology (ESC) and the European Association of Cardio-thoracic Surgery (EACS) released new guidelines on myocardial revascularisation in 2014. The 2014 guidelines update the previous 2010 guideline version (not shown in the table above). In addition, it provides a systematic review of all RCTs performed since 1980 comparing different strategies of revascularisation, including CABG, PCI (with DES) and balloon angioplasty. The guideline also covers the selection of patients requiring revascularisation as well as the methods recommended in patients with SCAD14 and ACS (NSTE-ACS and STEMIs). It also largely focuses on revascularisation modalities in patients with various comorbidities, especially diabetes mellitus, chronic kidney disease and heart failure, as well as procedural aspects of CABG, PCI and adjunctive medical therapy.

Of note, the term ‘stable angina pectoris’ has been replaced in the 2014 ESC guideline with the much broader term, SCAD, to include both symptomatic and asymptomatic patients with a previous or present history of confirmed or suspected SCAD.

The guideline warns that although the recommendations are based on individual RCTs and meta-analyses, the extrapolation of their results to routine clinical practice has its limitations. The guideline notes that the majority of RCTs included mainly male patients who were relatively young, had preserved left ventricular function, and had not previously undergone revascularisation. Patients were highly selected, as randomisation was usually performed following delineation of coronary anatomy by angiography without routine assessment of ischaemia. There was a high rate of cross-over, where all the RCTs compared treatment strategies that allowed subsequent revascularisation when patients deteriorated on medical therapy. Further, several of the new recommendations are based on various conclusions of the SYNTAX trial, where the main hypothesis of non-inferiority of PCI versus CABG was not achieved and patients were not pre-stratified with the SYNTAX scale before being randomised.

14 The ESC/EACTS guideline defines SCAD as ‘coronary heart disease generally characterised by episodes of reversible myocardial demand/supply mismatch related to ischaemia or hypoxia, which are usually inducible by exercise, emotion or other stress and reproducible, but, which may also be occurring spontaneously. Such episodes of ischaemia/hypoxia are commonly associated with transient chest discomfort (angina pectoris). SCAD also includes the stabilised, often asymptomatic phases that follow an ACS’.


January 2016

Revascularisation for stable coronary artery diseaseThe 2014 ESC/EACTS guideline emphasises that patients with SCAD must receive guideline-recommended medical treatment prior to revascularisation. Revascularisation and medical therapy are viewed as complementary rather than competitive treatment strategies. Table 4.1-2 presents the clinical indications where revascularisation (CABG or PCI) is recommended. The guideline notes that despite the multitude of studies that have compared the two revascularisation strategies, neither PCI nor CABG alone can provide a solution for the entire spectrum of SCAD patients who need revascularisation.

With respect to the selection of SCAD patients who require revascularisation, emphasis is placed on the documentation of ischaemia. If non-invasive proof of ischaemia is not available in stable patients, identification of haemodynamically relevant coronary lesions with FFR measurement is recommended. For prognostic reasons, revascularisation is recommended for left main stenoses, proximal left anterior descending (LAD) stenoses, and stenoses in two or triple-vessel disease with impaired left ventricular function. The guideline also recommends revascularisation for any other stenosis causing ischaemia of 10% or more of the left ventricle. In addition, revascularisation is also recommended for all stenoses that cause ischaemia and symptoms that cannot be relieved by medical therapy.

Table 4.1-2 2014 ESC/EACTS indications for revascularisation (PCI or CABG) in patients with stable angina or silent ischaemia (on OMT)

Benefit Recommendations Class of recommendation

LOE Studies

Prognosis Revascularisation to improve prognosis is indicated for patients with significant (>50%a diameter stenosis) left main coronary artery stenosis.

I A Yusuf et al (1994), Bittl et al (2013), APPROACH (2001)

Prognosis Revascularisation to improve prognosis is indicated for patients with any proximal LAD stenosis (>50%a diameter stenosis).

I A MASS II, Yusuf et al (1994), APPROACH (2001), Smith et al (2006)

Prognosis Revascularisation to improve prognosis is indicated for patients with two-vessel or three-vessel disease with stenosis >50%a with impaired LV function (LVEF <40%a).

I A Frye et al (2009), MASS II, Yusuf et al (1994), Velazquez et al (2011), Hannan

et al (2012), APPROACH (2001), Hannan et al (2008), Caracciolo et al

(1995), BARI 2D (2009), Passamani et al (1985), Jones et al (1996), Baker et al

(1994)

Prognosis Revascularisation to improve prognosis is indicated for patients with large area of ischaemia (>10% LV).

I B De Bruyne et al (2012), Boden et al (2007), Hachamovitch et al (2011),

COURAGE (2008), Hachamovitch et al (2003), ACIP (1997)

Prognosis Revascularisation to improve prognosis is indicated for patients with single remaining patent (i.e. unobstructed) coronary artery with stenosis >50%a.

I C -

Symptom Revascularisation to improve symptoms is indicated for patients with any coronary stenosis (>50%a diameter stenosis) in the presence of limiting angina or angina equivalent, unresponsive to medical therapy.

I A De Bruyne et al (2012), Pursnani et al (2012), Bangalore et al (2013), Yusuf et al (1994), Katritsis et al (2005), Schomig

et al (2008), Trikalinos et al (2009), Thomas et al (2013)

Source: ESC/EACTS (2014), p18. Refer to Appendix 5 for definitions of the Class of recommendation and Level of evidence.Abbreviations: CABG, coronary artery bypass graft; EACTS, European Association For Cardio-Thoracic Surgery; ESC, European Society of Cardiology; FFR, fractional flow reserve; LAD, left anterior descending (coronary artery); LOE, Level of evidence; LV, left ventricular; LVEF, left ventricular ejection fraction; OMT, optimal medical therapy; PCI, percutaneous coronary intervention.a With documented ischaemia or FFR ≤ 0.80 for diameter stenosis <90%.


January 2016

Proximal left anterior descending coronary artery diseaseTable 4.1-3 presents recommendations for the type of revascularisation (CABG or PCI) in patients with SCAD with suitable coronary anatomy for both procedures and low predicted surgical mortality.

In patients with involvement of the proximal LAD coronary artery, the ESC/EACTS review of the evidence showed benefits for both CABG and PCI without differences in mortality, myocardial infarction, or stroke. However, PCI was associated with a greater need for revascularisation during follow-up. Therefore, PCI is now equally recommended as CABG for the treatment of proximal LAD alone, as well as in the context of a two-vessel disease (Table 4.1-3). The guideline noted that most studies were performed before the introduction of the new-generation DES.

Left main coronary artery diseaseRegarding revascularisation of lesions of the left main coronary artery, the ESC/EACTS review of the evidence suggests that the both CABG and PCI exhibit similar rates of total mortality, cardiovascular mortality, and myocardial infarction. Moreover, although CABG increased stroke risk, PCI was associated with a greater need for revascularisation during follow-up. Longer-term results indicate that the evidence in favour of CABG is more robust.

As presented in Table 4.1-3, PCI is not recommended for left main CAD with a very complex coronary artery anatomy (SYNTAX15 score >32). However, PCI and CABG are equally recommended for the treatment of left main CAD with a low anatomical complexity (SYNTAX score ≤22). In patients with moderate anatomic complexity (SYNTAX score 23-32), CABG is probably recommended in preference to PCI.

Three-vessel coronary artery diseasePCI and CABG are equally recommended for the treatment of three-vessel disease with a low anatomical complexity (SYNTAX score ≤22). However, the guideline recognises the greater evidence supporting CABG in patients with three-vessel disease and a low SYNTAX score. PCI is discouraged in three-vessel CAD with more complex anatomies (SYNTAX score >22) (Table 4.1-3).

15 The SYNTAX score is a measure of the anatomical severity of CAD and has been arbitrary classified as low (SYNTAX score 0-22), intermediate (SYNTAX score 23-32), and high severity (SYNTAX score >32), to produce three approximately similar-sized groups. The SYNTAX is also mentioned in the American guidelines (ACCF/AHA 2012) as reasonable tools to guide the decision-making of the revascularisation modality in patients with stable ischaemic heart disease (SIHD).


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Table 4.1-3 2014 ESC/EACTS recommendations for the type of revascularisation (PCI or CABG) in patients with SCAD with suitable coronary anatomy and low predicted surgical mortality

Recommendations according to extent of CAD

Class of recommendation

LOE Class of recommendation

LOE Studies

One- or two-vessel disease with or without proximal LAD

CABG PCI

One- or two-vessel disease without proximal LAD stenosis

IIb C I C -

One-vessel disease with proximal LAD stenosis

I A I A Jeremias et al (2012), Yusuf et al (1994), Kapoor et al (2008), Aziz et al (2007), Blazek et al

(2013), Thiele et al (2009)

Two-vessel disease with proximal LAD stenosis

I B I C Yusuf et al (1994), APPROACH (2001), Hannan

et al (2008)

Left main CAD CABG PCILeft main disease with a SYNTAX score ≤ 22

I B I B SYNTAX (2013) ,Bittle et al (2013), Capodanno et al

(2011)

Left main disease with a SYNTAX score 23-32

I B IIa B SYNTAX (2013)

Left main disease with a SYNTAX score >32

I B III B SYNTAX (2013)

Three-vessel disease CABG PCIThree-vessel disease with a SYNTAX score ≤ 22

I A I B SYNTAX (2013), Serruys et al (2009), Farkouh et al

(2012), SYNTAX (2014)

Three-vessel disease with a SYNTAX score 23-32

I A III B As above

Three-vessel disease with a SYNTAX score >32

I A III B As above

Source: ESC/EACTS (2014), p21. Refer to Appendix 5 for definitions of the Class of recommendation and Level of evidence.Abbreviations: CABG, coronary artery bypass graft; CAD, coronary artery disease; EACTS, European Association For Cardio-Thoracic Surgery; ESC, European Society of Cardiology; LAD, left anterior descending (coronary artery); LOE, Level of evidence; PCI, percutaneous coronary intervention; SCAD, stable coronary artery disease; SYNTAX, Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery.NOTE: SYNTAX score is a measure of the anatomical severity of CAD and has been arbitrary classified as low (SYNTAX score 0-22), intermediate (SYNTAX score 23-32), and high severity (SYNTAX score >32), to produce three approximately similar-sized groups.

Revascularisation in patients with diabetesThe 2014 ESC/EACTS guideline recommends revascularisation in patients with diabetes with documented ischaemia, or symptoms of angina in the presence of angiography-defined SCAD. Diabetic patients undergoing revascularisation, either with CABG or PCI, are at greater risk for kidney injury than patients without diabetes. Regarding the type of revascularisation (CABG or PCI), CABG is clearly recommended over PCI in stable diabetic patients with multivessel disease with an acceptable surgical risk. PCI is recommended as an alternative to CABG in patients with less severe disease (with SYNTAX score ≤22).


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Table 4.1-4 2014 ESC/EACTS recommendations for revascularisation in patients with diabetes and multivessel disease

Clinical indication Class of recommendation LOE Studies

DiabetesIn stable patients with multivessel CAD and/or evidence of ischaemia, revascularisation is indicated in order to reduce cardiac adverse events.

I B Frye et al (2009), MASS II

In patients with stable multivessel CAD and an acceptable surgical risk, CABG is recommended over PCI.

I A Hlatky et al (2009), Farkouh et al (2012), Verma et al (2013)

In patients with stable multivessel CAD and SYNTAX score ≤22, PCI should be considered as alternative to CABG.

IIa B SYNTAX, Hakeem et al (2013)

New-generation DES are recommended over BMS. I A Stettler et al (2008), Bangalore et al (2012)

Source: ESC/EACTS (2014), p35. Refer to Appendix 5 for definitions of the Class of recommendation and Level of evidence.Abbreviations: BMS, bare metal stent; CABG, coronary artery bypass graft; CAD, coronary artery disease; DES, drug-eluting stent; EACTS, European Association For Cardio-Thoracic Surgery; ESC, European Society of Cardiology; LOE, Level of evidence; PCI, percutaneous coronary intervention; SCAD, stable coronary artery disease; SYNTAX, Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery.

Revascularisation in patients with chronic kidney diseaseThe 2014 ESC/EACTS guideline recommendations for revascularisation in patients with moderate or severe CKD and multivessel CAD are shown in Table 4.1-5.

Table 4.1-5 2014 ESC/EACTS recommendations for revascularisation in patients with moderate or severe CKD and multivessel CAD

Recommendation Class of recommendation

LOE Studies

CKDCABG should be considered over PCI in patients with multivessel CAD and symptoms/ischaemia whose surgical risk profile is acceptable and life expectancy is beyond one year.

IIa B SYNTAX (2013), Chang et al (2012), Fox et al (2010), Yan et al

(2011), Zheng et al (2013)

PCI should be considered over CABG in patients with multivessel CAD and symptoms/ischaemia whose surgical risk profile is high or life expectancy is less than one year.

IIa B Fox et al (2010), Yan et al (2011),

New-generation DES are recommended over BMS. I B Tsai et al (2011), Shenoy et al (2010)Source: ESC/EACTS (2014), p36. Refer to Appendix 5 for definitions of the Class of recommendation and Level of evidence.Abbreviations: CABG, coronary artery bypass graft; CAD, coronary artery disease; CKD, chronic kidney disease; EACTS, European Association For Cardio-Thoracic Surgery; ESC, European Society of Cardiology; LOE, Level of evidence; PCI, percutaneous coronary intervention.

Heart failureThe 2014 ESC/EACTS guideline recommends that revascularisation by PCI should be considered in patients with significant myocardial viability (see Table 4.1-6).There are no other recommendations in this population that are specific to revascularisation by PCI.


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Table 4.1-6 2014 ESC/EACTS recommendations for revascularisation in patients with chronic HF and systolic LV dysfunction (ejection fraction ≤35%)

Recommendations Class of recommendation LOE References

Myocardial revascularisation should be considered in the presence ofviable myocardium

IIa B Allman et al (2002)

PCI may be considered if anatomy is suitable, in the presence of viable myocardium, and surgery is not indicated.

IIb C -

Source: ESC/EACTS (2014), p29. Refer to Appendix 5 for definitions of the Class of recommendation and Level of evidence.Abbreviations: EACTS, European Association For Cardio-Thoracic Surgery; ESC, European Society of Cardiology; LOE, Level of evidence; HF, heart failure; LV, left ventricular; PCI, percutaneous coronary intervention.

In summary, as compared with the previous 2010 edition, PCI now assumes a similar Class and Level of evidence as CABG in patients with proximal LAD disease, simple left main disease (SYNTAX score <22) and simple three-vessel disease (SYNTAX score <22). Conversely, PCI was downgraded among patients with complex three-vessel disease (SYNTAX score >22) and left main disease (SYNTAX score >32). Based on the results of the FREEDOM trial (mentioned in Section 5.1.1), CABG is now the favoured revascularisation therapy among diabetic patients with multivessel CAD and acceptable surgical risk.

4.1.2 CPGs from the United States

ACCF/AHA 2012The 2012 American College of Cardiology Foundation (ACCF)/American Heart Association (AHA) guideline for the diagnosis and management of patients with SIHD is the most current US-based guideline on stable angina/SIHD. The guideline is intended for management of adult patients with stable known or suspected ischaemic heart disease, including new-onset chest pain (i.e. low-risk UA), and adult patients with stable pain syndromes. The recommendations update those of the 2011 ACCF/AHA/SCAI guideline for PCI use in SIHD (Levine et al, 2011).

Table 4.1-7 and Table 4.1-8 summarise the 2012 ACCF/AHA recommendations on the use of PCI (and CABG) to improve survival and/or to relieve symptoms, respectively. The recommendations are predominantly based on studies of patients with symptomatic SIHD and should be interpreted in this context.

Table 4.1-7 2012 ACCF/AHA recommendations on revascularisation to improve survival in patients with stable angina/SIHD

Recommendations Class of recommendation LOE

Unprotected left main CAD revascularisationCABG to improve survival is recommended for patients with significant (≥50% diameter stenosis) left main coronary artery stenosis.

I B

PCI to improve survival is reasonable as an alternative to CABG in selected stable patients with significant (≥50% diameter stenosis) unprotected left main CAD with (i) anatomic conditions associated with a low risk of PCI procedural complications and a high likelihood of good long-term outcome (e.g. low SYNTAX scorea ≤22, ostial or trunk left main CAD) and (ii) clinical characteristics that predict a significantly increased risk of adverse surgical outcomes (e.g. STS-predicted risk of operative mortality ≥5%)b.

IIa B

PCI to improve survival is reasonable in patients with UA/NSTEMI when an unprotected left main coronary artery is the culprit lesion and the patient in not a candidate for CABG.

IIa B

Unprotected left main CAD revascularisation


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PCI to improve survival may be reasonable as an alternative to CABG in selected stable patients with significant (≥50% diameter stenosis) unprotected left main CAD with (i) anatomic conditions associated with a low to intermediate risk of PCI procedural complications and an intermediate to high likelihood of good long-term outcome (e.g. low-intermediate SYNTAX score <33, bifurcation left main CAD) and (ii) clinical characteristics that predict an increased risk of adverse surgical outcomes (e.g. moderate-severe chronic obstructive pulmonary disease, disability from previous stroke, or previous cardiac surgery; STS-predicted risk of operative mortality >2%)b.

IIb B

PCI to improve survival should not be performed in stable patients with significant (≥50% diameter stenosis) unprotected left main CAD who have unfavourable anatomy for PCI and who are good candidates for CABG.

III (Harm) B

Non-left main CAD revascularisationd

Three-vessel disease with or without proximal LAD artery diseaseCABG to improve survival is beneficial in patients with significant (≥70% diameter) stenoses in three major coronary arteries (with or without involvement of the proximal LAD artery).

I B

It is reasonable to choose CABG over PCI to improve survival in patients with complex three-vessel CAD (e.g. SYNTAX score >22), with or without involvement of the proximal LAD artery who are good candidates for CABG.

IIa B

The usefulness of PCI to improve survival is uncertain in patients with three-vessel CAD (with or without involvement of the proximal LAD artery).

IIb B

Two-vessel disease with proximal LAD artery diseaseCABG to improve survival is beneficial in patients with significant (≥70% diameter) stenoses in the proximal LAD artery plus one other major coronary artery.

I B

The usefulness of PCI to improve survival is uncertain in patients with two-vessel CAD (with involvement of the proximal LAD artery).

IIb B

Two-vessel disease without proximal LAD artery diseaseCABG to improve survival is reasonable in patients with significant (≥70% diameter) stenoses in two major coronary arteries with severe or extensive myocardial ischemia (e.g. high-risk criteria on stress testing, abnormal intracoronary hemodynamic evaluation, or >20% perfusion defect by myocardial perfusion stress imaging) or target vessels supplying a large area of viable myocardium.

IIa B

The usefulness of PCI to improve survival is uncertain in patients with two-vessel CAD (without involvement of the proximal LAD artery).

IIb B

One-vessel proximal LAD artery diseaseCABG with a LIMA graft to improve survival is reasonable in patients with significant (≥70% diameter) stenosis in the proximal LAD artery and evidence of extensive ischemia.

IIa B

The usefulness of PCI to improve survival is uncertain in patients with one-vessel proximal LAD disease.

IIb B

One-vessel disease without proximal LAD artery involvementCABG or PCI should not be performed with the primary intent to improve survival in patients with one-vessel disease without proximal LAD artery involvement.

III (Harm) B

LV dysfunctionCABG to improve survival is reasonable in patients with mild-moderate LV systolic dysfunction (ejection fraction 35%-50%) and significant (≥70% diameter stenosis) multivessel CAD or proximal LAD coronary artery stenosis, when viable myocardium is present in the region of intended revascularisation.

IIa B

CABG might be considered with the primary or sole intent of improving survival in patients with SIHD with severe LV systolic dysfunction (ejection fraction <35%) whether or not viable myocardium is present.

IIb B

Survivors of sudden cardiac death with presumed ischaemia-mediated VTCABG or PCI to improve survival is beneficial in survivors of sudden cardiac death with presumed ischaemia-mediated ventricular tachycardia caused by significant (≥70% diameter) stenosis in a major coronary artery.

I CABG: BPCI: C


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Multivessel CAD and diabetesCABG is probably recommended in preference to PCI to improve survival in patients with multivessel CAD and diabetes mellitus, particularly if a LIMA graft can be anastomosed to the LAD artery.

IIa B

Previous CABGThe usefulness of CABG or PCI to improve survival is uncertain in patients with previous CABG and extensive anterior wall ischemia on noninvasive testing.

IIb B

No anatomic or physiologic criteria for revascularisationCABG or PCI should not be performed with the primary or sole intent to improve survival in patients with SIHD with one or more coronary stenoses that are not anatomically or functionally significant (e.g. <70% diameter non-left main coronary artery stenosis, FFR >0.80c, no or only mild ischemia on noninvasive testing), involve only the left circumflex or right coronary artery, or subtend only a small area of viable myocardium.

III (Harm) B

Source: ACCF/AHA (2012), Executive Summary, p2582. Refer to Appendix 5 for definitions of the Class of recommendation and Level of evidence.Abbreviations: ACCF, American College of Cardiology Foundation; AHA, American Heart Association; CABG, coronary artery bypass graft; CAD, coronary artery disease; FFR, fractional flow reserve; LAD, left anterior descending; LIMA: left internal mammary artery; LOE, Level of evidence; LV, left ventricular; NSTEMI, non–ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; SIHD, stable ischaemic heart disease; STS, Society of Thoracic Surgeons; SYNTAX, Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery; UA, unstable angina.a SYNTAX score is a measure of the anatomical severity of CAD and has been arbitrary classified as low (SYNTAX score 0-22), intermediate (SYNTAX score 23-32), and high severity (SYNTAX score >32), to produce three approximately similar-sized groups. b The STS risk model predicts the risk of operative mortality and morbidity of adult cardiac surgery on the basis of patient demographic and clinical variables. c FFR refers to the measurement that involves determining the ratio between the maximum achievable blood flow in a diseased coronary artery and the theoretical maximum flow in a normal coronary artery. An FFR of 1.0 is widely accepted as normal. An FFR of <0.75-0.80 is generally considered to be associated with myocardial ischaemia. d This category includes three-vessel disease (with or without proximal LAD artery involvement), two-vessel disease (with or without proximal LAD artery involvement), one-vessel disease (with or without proximal LAD artery involvement).

Table 4.1-8 2012 ACCF/AHA recommendations on revascularisation to improve symptoms in patients with stable angina/SIHD with significant anatomic (≥50% Left Main or ≥70% Non–Left Main CAD) or physiological (FFR ≤0.80) coronary artery stenoses

RecommendationsClass of recommendation

LOE

CABG or PCI to improve symptoms is beneficial in patients with one or more significant (≥70% diameter) coronary artery stenoses amenable to revascularisation and unacceptable angina despite GDMT.

I A

CABG or PCI to improve symptoms is reasonable in patients with one or more significant (≥70% diameter) coronary artery stenoses amenable to revascularisation and unacceptable angina for whom GDMT cannot be implemented because of medication considerations, adverse effects, or patient preferences.

IIa C

PCI to improve symptoms is reasonable in patients with previous CABG, one or more significant (≥70% diameter) coronary artery stenoses associated with ischaemia, and unacceptable angina despite GDMT.

IIa C

It is reasonable to choose CABG over PCI to improve symptoms in patients with complex three-vessel CAD (e.g. SYNTAX score >22), with or without involvement of the proximal LAD artery, who are good candidates for CABG.

IIa B

CABG to improve symptoms might be reasonable for patients with previous CABG, one or more significant (≥70% diameter) coronary artery stenoses not amenable to PCI, and unacceptable angina despite GDMT.

IIb C

CABG or PCI to improve symptoms should not be performed in patients who do not meet the anatomical (≥50% diameter left main or ≥70% non-left main stenosis diameter) or physiological (e.g. abnormal FFR ≤0.80) criteria for revascularisation.

III (Harm) C

Source: ACCF/AHA (2012), Executive Summary, p2584. Refer to Appendix 5 for definitions of the Class of recommendation and Level of evidence.Abbreviations: ACCF, American College of Cardiology Foundation; AHA, American Heart Association; CABG, coronary artery bypass graft; CAD, coronary artery disease; FFR, fractional flow reserve; GDMT, guideline-directed medical therapy; LAD, left anterior


January 2016

descending; LOE, Level of evidence; PCI; percutaneous coronary intervention; SYNTAX, Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery; TMR, transmyocardial revascularisation.

ACC/AHA 2014 Focused UpdateA Focused Update of the 2012 ACCF/AHA guideline was released in 2014. This Update includes a new section specifically addressing the role of coronary angiography for the diagnosis of CAD in patients with suspected SIHD, and includes several new or updated recommendations for treatment options, as well as CAD revascularisation. Of relevance to this MBS Review, the Update offers a modified recommendation (previously Class II, now Class I) for CABG in preference to PCI to improve survival in patients with diabetes mellitus and multivessel CAD. This modification of the recommendation was based on the results of the FREEDOM trial, where the primary outcome (a composite of death, non-fatal myocardial infarction, or nonfatal stroke) was reported to occur more frequently in the PCI group. On the basis of this evidence, the Update notes that in most patients with diabetes mellitus and complex multivessel disease, CABG appears to be associated with lower risk of mortality than PCI.

Table 4.1-9 2014 ACC/AHA updated recommendations for CAD revascularisation to improve survival

2012 Recommendation 2014 Focused Update Recommendations Comments

Non-left main CAD revascularisationClass IIa; LOE: BCABG is probably recommended in preference to PCI to improve survival in patients with multivessel CAD and diabetes mellitus, particularly if a LIMA graft can be anastomosed to the LAD artery.

Class I; LOE: BCABG is generally recommended in preference to PCI to improve survival in patients with diabetes mellitus and multivessel CAD for which revascularisation is likely to improve survival (three-vessel CAD or complex two-vessel CAD involving the proximal LAD), particularly if a LIMA graft can be anastomosed to the LAD artery, provided the patient is a good candidate for surgery.

Modified recommendation (Class of Recommendation changed from IIa to I)

Source: ACC/AHA (2014), Focused Update, Table 4, p1757. Refer to Appendix 5 for definitions of the Class of recommendation and Level of evidence.Abbreviations: ACC, American College of Cardiology; AHA, American Heart Association; CABG, coronary artery bypass graft; CAD, coronary artery disease; LAD, left anterior descending; LIMA; left internal mammary artery; LOE, Level of evidence; PCI; percutaneous coronary intervention.

4.1.3 United Kingdom CPGs

NICE 2011The NICE 2011 guidance for the management of patients with stable angina highlights the importance of optimising medical therapy before considering revascularisation (PCI or CABG). For those patients who remain symptomatic after optimal medical therapy, the guidelines suggest that a review of the diagnosis together with a review of anatomical and/or functional tests is needed before offering revascularisation with CABG or PCI. Therefore, revascularisation is recommended for symptomatic relief in patients with stable angina and in whom medical therapy fails.

There is also a clear recommendation about the preference of CABG to PCI and vice versa. Patients with lesions not suitable for PCI or who have multivessel disease and are aged 65 years and older and/or who have diabetes should be considered for CABG. However, when either procedure would be appropriate, the risks and benefits of PCI and CABG for those with anatomically less complex disease should be explained to the patient. If no preference is expressed, PCI may be offered in preference to CABG based on evidence that suggests that PCI may be a more cost-effective solution.


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Table 4.1-10 2011 NICE conclusions for revascularisation in patients with stable angina

Conclusions The GDG concluded that the main indication for revascularisation in patients with stable angina is relief of symptoms.

Patients with symptoms that are not satisfactorily controlled with OMT should be offered coronary angiography to assess the coronary anatomy and feasibility of myocardial revascularisation.

The relative risks and benefits of CABG and PCI should be considered in individual patients with stable angina, taking account of the severity and complexity of the person's coronary disease and other relevant clinical factors and comorbidities. If only one revascularisation strategy is clinically and angiographically feasible the patient should be offered CABG or PCI as appropriate.

Patients who have multivessel disease and are aged 65 years and older and/or who have diabetes and also those with lesions not suitable for PCI, should be considered for CABG.

For patients whose symptoms are not satisfactorily controlled by OMT and who are with anatomically complex three-vessel disease, with or without involvement of the left main stem, and for people with multivessel disease who have diabetes or are aged >65 years, clinicians should take account of the potential survival advantage of CABG over PCI when advising patients about the appropriate revascularisation strategy.

When either procedure would be appropriate, the risks and benefits of PCI and CABG for those with anatomically less complex disease should be explained to help the patient make an informed choice of treatment. If the person does not express a preference, PCI may be offered in preference to CABG based on the evidence that suggests that PCI may be a more cost-effective procedure.

Source: NICE (2011)Abbreviations: CABG, coronary artery bypass graft; GDG, Guideline Development Group; OMT, optimal medical therapy; PCI; percutaneous coronary intervention.

The Guideline Development Group recognised the limitations in the evidence base and this is demonstrated in a number of clear research recommendations that have been made in order to inform future updates of the guideline. They acknowledged that clinical trials in people with stable angina (COURAGE, BARI-2D, MASS II) have not shown survival benefit from revascularisation compared with medical therapy.

SIGN 2007The Scottish Intercollegiate Guidelines Network (SIGN) published recommendations for the management of stable angina in 2007, with a focus on the principles of assessment, diagnosis, pharmacotherapy, and the role of the patient with stable angina. There were no recent updates to the guideline since its release. Table 4.1-11 presents the recommendations for revascularisation in patients with stable angina.


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Table 4.1-11 2007 SIGN recommendations for revascularisation in patients with stable angina

Grades of Recommendation

Recommendations LOE

- Revascularisation is recommended for prognostic and symptomatic benefit in patients with the following anatomy: significant LMS disease (>50% stenosis), or proximal three-vessel disease, or two-vessel disease involving the proximal LAD.The benefit is greatest in patients with left ventricular dysfunction and/or evidence of reversible ischaemia at low or moderate workloads on exercise testing.

4(Based on the 2004 ACC/AHA guideline update for CABG)

- The following groups of patients may receive symptomatic benefit (but not prognostic advantage) from surgical revascularisation: those with single-vessel disease not involving the LAD those with two-vessel disease not involving the LAD.

1++

1+

Choice of revascularisation technique

✓Recommended best practice based on the clinical experience of the GDG

CABG and PCI are both appropriate options for the alleviation of anginal symptoms.

-

Revascularisation to relieve anginaA Patients who have been assessed and are anticipated to receive symptomatic

relief from revascularisation should be offered either CABG or PCI.-

Revascularisation to improve long-term prognosisA Patients with significant LMS disease should undergo CABG. -

A Patients with triple-vessel disease should be considered for CABG to improve prognosis, but where unsuitable be offered PCI.

-

A Patients with single- or double-vessel disease, where OMT fails to control angina symptoms, should be offered PCI or where unsuitable, considered for CABG.

-

Source: SIGN (2007), Management of stable angina; pp12-14. Refer to Notes 1 and 2 below for definitions of the Grades of recommendation and Level of evidence.Abbreviations: AHA, American Heart Association; ACC, American College of Cardiology; CABG, coronary artery bypass graft; GDG, Guideline Development Group; LAD, left anterior descending; LMS, left main stem; LOE, Level of evidence; OMT, optimal medical therapy PCI; percutaneous coronary intervention; SIGN, Scottish Intercollegiate Guidelines Network.Note 1: Levels of evidence – 1++ = High quality meta-analyses, systematic reviews of randomised controlled trials (RCTs), or RCTs with a very low risk of bias; 1+ = Well conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias; 4 = Expert opinion.Note 2: Grades of recommendation – A = At least one meta-analysis, systematic review of RCTs, or RCT rated as 1++ and directly applicable to the target population; or a body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results

4.2 Non-ST-segment elevation acute coronary syndrome

Five evidence-based CPGs published from 2007 onwards were identified with recommendations for revascularisation by PCI in patients with NSTE-ACS. These guidelines were developed by Australian and international organisations (Table 4.2-1). The use of the term NSTE-ACS in these guidelines was in reference to UA and NSTEMI patients.

The only European guideline included in the Review for this population is the ESC/EACTS 2014 guideline on myocardial revascularisation. Recommendations from the ESC 2011 guideline on the management of ACS in patients presenting without persistent ST-segment elevation have not been included because they have been superseded by the 2014 guideline. An updated version of the ESC 2011 guideline was published in September 2015, but was not included in this Review because it was published after the literature search cut-off date (July 2015). However, the relevant recommendations in the ESC 2015 guideline have been checked against the recommendations included in this Review from the ESC/EACTS 2014 guideline and, other than slight differences in wording, they are consistent.


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Table 4.2-1 Summary of Australian and international CPGs – NSTE-ACS

ID Title Method AffiliationAustralianNHFA/CSANZ 2006

Guidelines for the management of acute coronary syndromes 2006

Based on consensus and assessment of existing Australian and international CPGs and evidence

National Heart Foundation of Australia (NHFA)Cardiac Society of Australia and New Zealand (CSANZ)

NHFA/CSANZ2007 Addendum

2007 addendum to the National Heart Foundation of Australia/ Cardiac Society of Australia and New Zealand Guidelines for the management of acute coronary syndromes 2006


NHFA/CSANZ

NHFA/CSANZ2011 Addendum

2011 addendum to the National Heart Foundation of Australia/ Cardiac Society of Australia and New Zealand Guidelines for the management of acute coronary syndromes 2006


NHFA/CSANZ

EuropeESC/EACTS 2014

2014 ESC/EACTS Guidelines on myocardial revascularization


European Society of Cardiology/(ESC)European Association for Cardio-Thoracic Surgery (EACTS)

United StatesAHA/ACC 2014 2014 AHA/ACC Guideline for the

management of patients with non–ST-elevation acute coronary syndromes. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines


American Heart Association (AHA)American College of Cardiology (ACC)

AHA/ACC 2014 2014 AHA/ACC Guideline for the management of patients with non-ST-elevation acute coronary syndromes: Executive Summary: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines

Based on 2014 AHA/ACC guideline

AHA/ACC

United KingdomSIGN 2013 Acute coronary syndromes Based on assessment of best

available evidenceScottish Intercollegiate Guidelines Network (SIGN)

NICE 2010 The early management of unstable angina and non-ST-segment-elevation myocardial infarction



Abbreviations: CPG, clinical practice guideline; NSTE-ACS, non-ST-segment elevation acute coronary syndrome.

4.2.1 Australian guidelines

NHFA/CSANZ 2006, Addenda 2007, 2011The current Australian guideline for the management of both STEMI and NSTE-ACS has been developed jointly by the National Heart Foundation of Australia (NHFA) and the Cardiac Society of Australia and New Zealand (CSANZ). A summary of the recommendations for the management of patients with NSTE-ACS (which includes UA and NSTEMI) are presented in Table 4.2-2. It should be noted that the guidelines are based on the best information available up to September 2005, and therefore may not reflect current Australian clinical practice.


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Two addenda supplementing the recommendations outlined in the 2006 NHFA/CSANZ guideline were published in 2007 and 2011, respectively. Both addenda considered new evidence providing additional information to be considered in the choice of therapies in the management of ACS. The 2007 addendum considered evidence published since 2007 and gives updated recommendations for antithrombin therapy for acute STEMI, antithrombin therapy for acute NSTE-ACS, and antiplatelet therapy for NSTE-ACS. The 2011 addendum considers evidence published since 2007 and gives updated recommendations for: serum troponin measurement; choice of reperfusion therapy for STEMI; antithrombotic therapy for STEMI; antithrombotic therapy for NSTE-ACS; bleeding risk in ACS; oxygen therapy for patients with ACS; and system factors. There were no new recommendations made relating to revascularisation or the use of PCI in NSTE-ACS.

Table 4.2-2 Summary of 2006 NHFA/CSANZ recommendations for patients with NSTE-ACS

Recommendations LOE Grade of recommendation

High-risk NSTE-ACSHigh-risk patients with NSTE-ACS should be treated with aggressive medical management (including aspirina, clopidogrel, unfractionated heparin or subcutaneous enoxaparin, intravenous tirofiban or eptifibatide and a β-blocker), and arrangements should be made for coronary angiography and revascularisation, except in those with severe comorbidities.

I A

Early coronary angiography (within 48 hours) and revascularisation are recommended in patients with NSTE-ACS and high-risk features.

- A

Intermediate-risk NSTE-ACSIntermediate-risk patients with NSTE-ACS should undergo an accelerated diagnostic evaluation and further assessment to allow reclassification as low or high risk.

III B

Low-risk NSTE-ACSLow-risk patients with NSTE-ACS, after an appropriate period of observation and assessment, may be discharged on upgraded medical therapy for outpatient follow-up.

- -

Source: NHFA/CSANZ (2006), pS22. Refer to Appendix 5 for definitions of the Class of recommendation and Level of evidence.Abbreviations: LOE, Level of evidence; NSTE-ACS, non-ST-segment elevation acute coronary syndromes.a All patients with NSTE-ACS should be given aspirin, unless contraindicated (Grade of recommendation: A)

NHFA/CSANZ recommend that all patients with NSTE-ACS should have their risk stratified to direct management decisions. Features associated with high-risk, intermediate-risk and low-risk NSTE-ACS, as specified by the 2006 NHFA/CSANZ guideline, were shown in Section 1 (Table 1.1-1). In addition to those features, pain or ischaemia refractory to medical therapy, and high-risk features on early exercise testing, can also identify patients suitable for early invasive therapy. The guideline also acknowledges the TIMI risk score as a validated and valuable measure of early risk in NSTE-ACS, however, no recommendations were made based on the TIMI risk score.

Figure 4.2-1 presents the 2006 NHFA/CSANZ treatment strategies for patients with NSTE-ACS based on the risk stratification criteria. Although NHFA/CSANZ strongly recommend early coronary angiography (within 48 hours) and revascularisation in patients with NSTE-ACS and high-risk features (except in patients with severe comorbidities), the choice of revascularisation (PCI or CABG) is not specified in the guidelines.


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Figure 4.2-1 Treatment strategies for patients with NSTE-ACS, based on risk stratification

Source: NHFA/CSANZ (2006), Box 10, pS21Abbreviations: NSTE-ACS, non-ST-segment elevation acute coronary syndrome.

DiabetesThe CPG states that in patients with NSTE-ACS, diabetes is an independent risk factor for adverse cardiac events (Level I evidence), and should be regarded as a high-risk feature in patients who present with typical symptoms of ACS. According to the guideline, people with diabetes have an increased risk similar to that of patients with an elevated troponin level or ST-segment deviation. No specific recommendations for the choice of revascularisation were made by the guideline in regards to this population.

Chronic kidney diseaseThe CPG supports the use of either an early invasive strategy or established pharmacotherapies in the management of patients with CKD who present with an ACS (Grade of recommendation: B). However, where relevant (e.g. with β-blockers), titration of such agents should be performed cautiously to avoid drug accumulation in the context of renal clearance.

Multivessel diseaseThere were no specific recommendations made in the NHFA/CSANZ guideline in relation to patients with multivessel disease and NSTE-ACS.

4.2.2 European guidelines

ESC/EACTS 2014The 2014 ESC/EACTS guideline emphasises early stratification to identify patients whose prognosis would be improved by an invasive approach16. Details on risk stratification to help identify patients at high risk are shown in Table 4.2-3. The guideline also emphasises the importance of also identifying patients at low risk, in whom invasive and medical treatments provide little benefit or may even cause harm. Therefore risk stratification is pivotal in the decision-making process for the management of patients with NSTE-ACS.

16 Invasive approach or invasive strategy is understood to be invasive angiography followed by revascularisation depending on anatomical and functional findings.


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Table 4.2-3 2014 ESC/EACTS criteria for high risk with indication for invasive management in patients with NSTE-ACS

Primary criteria1. Relevant rise or fall in troponin

2. Dynamic ST- or T-wave changes (symptomatic or silent)

3. GRACE score >140

Secondary criteria4. Diabetes mellitus

5. Renal insufficiency (eGFR <60 ml/min/1.73 m2)

6. Reduced LV function (LVEF <40%)

7. Early postinfarction angina

8. Recent PCI

9. Prior CABG

10. Intermediate to high GRACE risk scoreSource: ESC/EACTS (2014), Table 7, p22Abbreviations: CABG, coronary artery bypass graft; EACTS, European Association for Cardio-Thoracic Surgery; ESC, European Society of Cardiology; eGFR, estimated glomerular filtration rate; GRACE, Global Registry of Acute Coronary Events; LV, left ventricular; LVEF, left ventricular ejection fraction; NSTE-ACS, non-ST-segment elevation acute coronary syndrome; PCI, percutaneous coronary intervention.

As mentioned in Section 1.1.2, the GRACE and the TIMI risk scores are two of the several risk scores that are used to predict short- or mid-term risk of ischaemic events. According to the ESC/EACTS guideline, the GRACE risk score (see Section 1.1.2, Table 1.1-2) provides the most accurate stratification of risk both on admission and at discharge due to its good discriminative power. The TIMI risk score (using only six variables in an additive scoring system) is simpler to use, but its discriminative accuracy is considered to be inferior to that of the GRACE risk score.

Table 4.2-4 presents the 2014 ESC/EACTS guideline recommendations for invasive evaluation and revascularisation in NSTE-ACS. The guideline acknowledges that there are no specific RCTs comparing PCI with CABG in patients with NSTE-ACS; in all trials that compared an early invasive with a late strategy, or an invasive with a medical management strategy, the decision on whether to perform CABG or PCI was left to the investigator’s discretion.

The ESC/EACTS guideline emphasises that the timing of angiography and revascularisation should be based on patient risk profile. Patients at very high risk should be considered for urgent coronary angiography (that is performed in less than 2 hours). In patients at high risk, with at least one primary high-risk criterion, an early invasive strategy within 24 hours appears to be the reasonable timescale. In lower-risk subsets, with a GRACE risk score of <140 but with at least one secondary high-risk criterion (Table 4.2-3), the invasive evaluation can be delayed without increased risk but should be performed during the same hospital stay, preferably within 72 hours of admission. In other low-risk patients without recurrent symptoms, a non-invasive assessment of inducible ischaemia should be performed before hospital discharge.

Subsequent to the literature search for this Review, ESC published a guideline on the management of ACS in patients presenting without persistent ST-segment elevation.17 The only difference in recommendations between the 2014 and 2015 guidelines was related to the use of DES. In the 2015 guideline, ESC recommends that DES be used for patients in whom a

17 Eur Heart J. 2016 Jan 14;37(3):267-315. doi: 10.1093/eurheartj/ehv320. Epub 2015 Aug 29.


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short dual antiplatelet therapy duration (30 days) is planned because of an increased bleeding risk.

Table 4.2-4 2014 ESC/EACTS recommendations for invasive evaluation and revascularisation in NSTE-ACS

Recommendations Class of recommendation

LOE Studies

Urgent coronary angiography (<2 hours) is recommended in patients at very high ischaemic risk (refractory angina, with associated heart failure, cardiogenic shock, life-threatening ventricular arrhythmias, or haemodynamic instability).

I C -

An early invasive strategy (<24 hours) is recommended in patients with at least one primary high-risk criterion (Table 4.2-3).

I A Katritsis et al (2011), Mehta et al (2009)

An invasive strategy (<72 hours after first presentation) is indicated in patients with at least one high-risk criterion (Table 4.2-3) or recurrent symptoms.

I A 2011 ESC guideline

Non-invasive documentation of inducible ischaemia is recommended in low-risk patients without recurrent symptoms before deciding on invasive evaluation.

I A 2011 ESC guideline, Amsterdam et al (2002), Nyman et al (1993)

It is recommended to base the revascularisation strategy (ad hoc culprit-lesion PCI/multivessel PCI/CABG) on the clinical status and comorbidities as well as the disease severity, i.e. distribution and angiographic lesion characteristics (e.g. SYNTAX score), according to the local Heart Team protocol.

I C -

New-generation DES are indicated for percutaneous treatment of significant coronary lesions in ACS patients.

I A Bangalore et al (2012), Stefanini et al (2013), Bengalore et al (2013), Kaiser et al (2010),

Greenhalgh et al (2010), Kirtane et al (2009), TAXUS-IV (2005)

Source: ESC/EACTS (2014), p23. Refer to Appendix 5 for definitions of the Class of recommendation and Level of evidence.Abbreviations: ACS, acute coronary syndrome; CABG, coronary artery bypass graft; DES, drug-eluting stent; EACTS, European Association for Cardio-Thoracic Surgery; ESC, European Society of Cardiology; LOE, Level of evidence; NSTE-ACS, non-ST-segment elevation acute coronary syndrome; PCI, percutaneous coronary intervention; SYNTAX, Synergy between percutaneous coronary intervention with TAXUS.

Multivessel diseaseAs stated above, the 2014 ESC/EACTS guideline made no specific recommendations on the choice of revascularisation in patients with NSTE-ACS. Furthermore, there are no specific recommendations in patients with multivessel disease and NSTE-ACS. However, the guideline reflects that in stabilised patients with NSTE-ACS, ‘the choice of revascularisation modality can be made in analogy to patients with SCAD. In approximately one-third of patients, angiography will reveal single-vessel disease, allowing ad hoc PCI in most cases. Multivessel disease will be present in another 50%. Here the decision is more complex and the choice has to be made between culprit-lesion PCI, multivessel PCI, CABG, or a combined (hybrid) revascularisation. The revascularisation strategy in patients with multivessel CAD should be determined early by the Heart Team and based on the patient’s clinical status, as well as the severity and distribution of the CAD and the characteristics of the lesion. The SYNTAX score has proved to be strongly predictive of death, myocardial infarction and target vessel revascularisation’.

The guideline further reflects that, ‘culprit-lesion PCI is usually the first choice in most patients with NSTE-ACS and multivessel disease; however, there are no prospective studies


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comparing culprit-lesion PCI with early CABG. In stabilised patients with multivessel disease and a high SYNTAX score (>22), particularly when there is no clearly identified culprit lesion, a strategy of urgent CABG should be preferred. The strategy of multivessel PCI for suitable significant stenoses—rather than PCI limited to the culprit lesion—has not been evaluated in an appropriate, randomised fashion’.

DiabetesTable 4.2-5 presents the 2014 ESC/EACTS recommendation for revascularisation in patients with diabetes and NSTE-ACS. The guideline does not specify the type of revascularisation in this patient population.

Table 4.2-5 2014 ESC/EACTS recommendation for revascularisation in patients with diabetes and NSTE-ACS


LOE

In patients with NSTE-ACS, an early invasive strategy is recommended over noninvasive management

I A

Source: ESC/EACTS (2014), p35. Refer to Appendix 5 for definitions of the Class of recommendation and Level of evidence.Abbreviations: EACTS, European Association for Cardio-Thoracic Surgery; ESC, European Society of Cardiology; LOE, Level of evidence; NSTE-ACS, non-ST-segment elevation acute coronary syndrome.

Type of stentThe ESC/EACTS 2014 guideline states that the safety and efficacy of DES has not been prospectively tested in a specific population of patients with NSTE-ACS, but this subset comprises up to 50% of patients included in most stent trials, particularly those with an all-comer design. The guideline claims that there is no particular safety concern in NSTE-ACS as new-generation DES have shown superior safety and efficacy in both SCAD and STEMI patients. Accordingly, new-generation DES are preferred over BMS as the default option.18

4.2.3 CPGs from the United States

AHA/ACC 2014The 2014 AHA/ACC CPG on NSTE-ACS is a full revision of the previous 2007 ACCF/AHA guideline for the management of patients with UA and NSTEMI, and the 2012 focused update. The 2014 recommendations also update those of a 2011 guideline for PCI use in UA/NSTEMI from the ACCF/AHA and the Society for Cardiovascular Angiography and Interventions (SCAI; authored by Levine et al, 2011).

According to the 2014 AHA/ACC guideline, patients with NSTE-ACS can be divided into four risk groups on the basis of their initial clinical presentation (see Table 4.2-6). The guideline recognises the TIMI and GRACE scores as useful tools for assigning risk to patients with NSTE-ACS, and the importance of risk stratification in identifying patients who are most likely to benefit from subsequent revascularisation. The guideline acknowledges that patients with NSTE-ACS and who are not in the very high-risk group and do not have findings that portend a high risk for adverse outcomes, are not likely to receive the same degree of benefit from routine revascularisation offered to high-risk patients.

18 The ESC 2015 guideline includes a more specific recommendation about DES, with DES recommended for patients in whom a short dual antiplatelet therapy duration (30 days) is planned because of an increased bleeding risk.


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Table 4.2-6 2014 AHA/ACC clinical criteria associated with appropriate selection of early invasive strategy or ischaemia-guided strategy in patients with NSTE-ACS

Time frame to revascularisation Clinical criteriaImmediate invasive (within 2 hours)

Refractory angina

Signs or symptoms of HF or new or worsening mitral regurgitation

Hemodynamic instability

Recurrent angina or ischaemia at rest or with low-level activities despite intensive medical therapy

Sustained VT or VF

Ischaemia-guided strategy Low-risk score (e.g. TIMI [0 or 1], GRACE [<109])

Low-risk troponin-negative female patients

Patient or clinician preference in the absence of high-risk features

Early invasive (within 24 hours) None of the above, but GRACE risk score >140

Temporal change in Troponin

New or presumably new ST depression

Delayed invasive (within 25-72 hours)

None of the above but diabetes mellitus

Renal insufficiency (GFR <60 mL/min/1.73 m²)

Reduced LV systolic function (EF <0.40)

Early postinfarction angina

PCI within 6 months

Prior CABG

GRACE risk score 109-140; TIMI score ≥2Source: AHA/ACC (2014), Executive summary, Table 8, pp26-27Abbreviations: ACC, American College of Cardiology; AHA, American Heart Association; CABG, coronary artery bypass graft; EF, ejection fraction; GFR, glomerular filtration rate; GRACE, Global Registry of Acute Coronary Events; HF, heart failure; LV, left venticular; NSTE-ACS, non-ST-segment elevation acute coronary syndrome; PCI, percutaneous coronary intervention; TIMI, Thrombolysis In Myocardial Infarction; VF, ventricular fibrillation; VT, ventricular tachycardia.

The choice between an immediate, early or delayed invasive strategy is multifactorial. Table 4.2-7 presents the recommendations on early invasive19 versus ischaemia-guided strategy in patients with NSTE-ACS.

Table 4.2-7 2014 AHA/ACC recommendations on early invasive strategies versus ischaemia-guided strategy in patients with NSTE-ACS


LOE

Early invasive and ischaemia-guided strategies

An urgent/immediate invasive strategy (diagnostic angiography with intent to perform revascularisation if appropriate based on coronary anatomy) is indicated in patients (men and women) with NSTE-ACS who have refractory angina or hemodynamic or electrical instability (without serious comorbidities or contraindications to such procedures).

I A

An early invasive strategy (diagnostic angiography with intent to perform revascularisation if appropriate based on coronary anatomy) is indicated in initially stabilised patients with NSTE-ACS (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events.

I B

It is reasonable to choose an early invasive strategy (within 24 hours of admission) over a delayed invasive strategy (within 25 to 72 hours) for initially stabilised high-risk patients with NSTE-ACS. For those not at high/intermediate risk, a delayed invasive approach is reasonable.

IIa B

19 The 2014 AHA/ACC guideline clearly defines early invasive strategy in their recommendations as diagnostic angiography with intent to perform revascularisation if appropriate based on coronary anatomy.


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LOE

Early invasive and ischaemia-guided strategies

In initially stabilised patients, an ischemia-guided strategy may be considered for patients with NSTE-ACS (without serious comorbidities or contraindications to this approach) who have an elevated risk for clinical events.

IIb B

An early invasive strategy (i.e., diagnostic angiography with intent to perform revascularisation) is not recommended in patients with:

a. Extensive comorbidities (e.g., hepatic, renal, pulmonary failure, cancer), in whom the risks of revascularisation and comorbid conditions are likely to outweigh the benefits of revascularisation.

III (No benefit) C

b. Acute chest pain and a low likelihood of ACS (LOE: C) who are troponin-negative, especially women (LOE: B).

III (No benefit) C/B

Source: AHA/ACC (2014), Executive summary, Table 8, p26. Refer to Appendix 5 for definitions of the Class of recommendation and Level of evidence.Abbreviations: ACC, American College of Cardiology; ACS, acute coronary syndrome; AHA, American Heart Association; LOE, Level of evidence; NSTE-ACS, non-ST-segment elevation coronary artery syndrome.

Table 4.2-8 presents the recommendation that specifically relates to revascularisation by PCI in patients with NSTE-ACS. The AHA/ACC guideline also contains a number of recommendations relating to medical therapy in patients undergoing PCI (not shown).

The decision to proceed with PCI in NSTE-ACS is not always clear cut and can be complex. The AHA/ACC guideline makes the following statement concerning the decision process: ‘the general indications for coronary angiography and revascularisation should be tempered by individual patient characteristics and preferences (a patient-centred approach)’.

Table 4.2-8 2014 AHA/ACC recommendation on PCI in patients with NSTE-ACS


LOE Studies

PCI – general considerationsA strategy of multivessel PCI, in contrast to culprit lesion−only PCI, may be reasonable in patients undergoing coronary revascularisation as part of treatment for NSTE-ACS.

IIb B OASIS-5 (2007)VANQWISH (1998)Savonitto et al (2012)

Source: AHA/ACC (2014), Executive Summary; p27. Refer to Appendix 5 for definitions of the Class of recommendation and Level of evidence.Abbreviations: ACC, American College of Cardiology; AHA, American Heart Association; LOE, Level of evidence; NSTE-ACS, non-ST-segment elevation acute coronary syndrome; PCI, percutaneous coronary intervention.

Diabetes, multivessel disease, chronic kidney diseaseTable 4.2-9 presents the AHA/ACC recommendation on revascularisation in patients with diabetes, heart failure, multivessel disease or CKD.


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Table 4.2-9 2014 AHA/ACC recommendation on revascularisation in NSTE-ACS with diabetes, heart failure, multivessel CAD or CKD

Recommendation Class of recommendation

LOE

Medical treatment in the acute phase of NSTE-ACS and decisions to perform stress testing, angiography, and revascularisation should be similar in patients with and without diabetes mellitus.

I A

It is reasonable to choose CABG over PCI in older patientsa with NSTE-ACS who are appropriate candidates, particularly those with diabetes mellitus or complex three-vessel CAD (e.g. SYNTAX score >22), with or without involvement of the proximal left anterior descending artery, to reduce cardiovascular disease events and readmission and to improve survival.

IIa B

Patients with a history of HF and NSTE-ACS should be treated according to the same riskstratification guidelines and recommendations for patients without HF.

I B

Selection of a specific revascularisation strategy should be based on the degree, severity, and extent of CAD; associated cardiac lesions; the extent of LV dysfunction; and the history of prior revascularisation procedures

I B

An invasive strategy is reasonable in patients with mild (stage 2) and moderate (stage 3) CKD.

IIa B

Source: AHA/ACC (2014), Executive Summary; pp34-35. Refer to Appendix 5 for definitions of the Class of recommendation and Level of evidence.Abbreviations: ACC, American College of Cardiology; AHA, American Heart Association; CABG, coronary artery bypass graft; CAD, coronary artery disease; CKD, chronic kidney disease; HF, heart failure; LOE, Level of evidence; LV, left ventricular; NSTE-ACS, non-ST-segment elevation acute coronary syndrome; PCI, percutaneous coronary intervention; SYNTAX, SYNergy between PCI with TAXUS and cardiac surgery.a Those ≥75 years of age.

4.2.4 United Kingdom CPGs

SIGN 2013SIGN published an updated guideline on the management of ACS (STEMI and NSTE-ACS) in 2013. The guideline provides recommendations based on current evidence for best practice in revascularisation in patients with NSTE-ACS. According to the guideline, findings from trials indicated that routine coronary angiography and revascularisation (that is, an invasive approach) reduced the rates of MI when compared with a conservative approach; similar benefits were observed for overall mortality in some of the trials. On the basis of the evidence, the guideline recommends that a routine invasive approach is indicated only in patients at medium to high risk or early recurrent cardiovascular events. The guideline warns that these findings are limited by significant heterogeneity between the included trials and the high rate of cross-over from a conservative to an invasive strategy in most of the trials, thus making it difficult to disentangle the potential benefits of an early invasive strategy.

Table 4.2-10 2013 SIGN recommendations for revascularisation in patients with NSTE-ACS

Recommendations Grades of Recommendation

LOE

Patients with NSTE-ACS at medium or high risk of early recurrent cardiovascular events should undergo early coronary angiography and revascularisation.

Ba -

Source: SIGN (2013), p19Abbreviations: LOE, Level of evidence; NSTE-ACS, non-ST-segment elevation acute coronary syndromes; SIGN, Scottish Intercollegiate Guidelines Network.a Grades of recommendation – B = A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results; or extrapolated evidence from studies rated as 1++ or 1+.

NICE 2010The 2010 NICE guideline addresses the early management of UA and NSTEMI once a firm diagnosis has been made and before discharge from hospital. The guideline recommends that


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patients with an intermediate risk (GRACE20 scores 88–100, representing a 6-month mortality > 3.0%) or higher should be triaged for an invasive strategy, with coronary angiography performed within 96 hours with follow-on PCI or CABG as appropriate. Medically stabilised lower-risk patients (e.g. GRACE score < 88, as per the NICE guidelines) may be discharged with planned outpatient angiography, as clinically appropriate. Table 4.2-11 presents the recommendations for revascularisation in patients with NSTE-ACS. The guideline does not make any specific recommendations in regards to the choice of revascularisation (PCI or CABG) in patients with NSTE-ACS. Further, there were no recommendations for revascularisation in patients with diabetes or multivessel disease.

Table 4.2-11 2010 NICE recommendations for revascularisation in patients with NSTE-ACS

Recommendations All patients are formally assessed on individual basis to determine the risk of future adverse cardiovascular events using

an established risk scoring system that predicts 6-month mortality (for example, GRACE). Use predicted 6-month mortality to categorise the risk of future adverse cardiovascular events. For patients with intermediate to higher risk of adverse cardiovascular events (predicted 6-month mortality >3.0%),

coronary angiography (with follow-on PCI if indicated) should be offered within 96 hours of first admission to hospital, and if they have no contraindications to angiography (such as active bleeding or comorbidity). Angiography should be performed as soon as possible for patients who are clinically unstable or at high ischaemic risk.

For patients with a low risk of adverse cardiovascular events (predicted 6-month mortality 3.0% or less), conservative management should be offered without early coronary angiography.

For patients with a low risk of adverse cardiovascular events (predicted 6-month mortality 3.0% or less), coronary angiography (with follow-on PCI if indicated) should be offered if ischaemia is subsequently experienced.

When advising patients about the choice of revascularisation strategy (PCI or CABG), take account of coronary angiographic findings, comorbidities, and the benefits and risks of each intervention.

When the role of revascularisation or the revascularisation strategy is unclear, resolve this by discussion involving an interventional cardiologist, cardiac surgeon and other healthcare professionals relevant to the needs of the patient. Discuss the choice of revascularisation strategy with the patient.

Source: NICE (2010)Abbreviations: CABG, coronary artery bypass graft; GRACE, Global Registry of Acute Coronary Events; NICE, National Institute for Health and Care Excellence; NSTE-ACS, non-ST-segment elevation acute coronary syndromes; PCI, percutaneous coronary intervention.

According to the 2010 NICE guideline, as soon as the diagnosis of UA or NSTEMI is made, and aspirin and antithrombin therapy have been offered, assessment of individual risk21 of future adverse cardiovascular events is performed using an established risk scoring system that predicts 6-month mortality (for example, GRACE) (see Table 4.2-12).

Table 4.2-12 Risk assessment based on predicted 6-month mortality as used in the 2010 NICE guideline

Predicted 6-month mortality Risk of future adverse cardiovascular events1.5% or below Lowest

>1.5% to 3.0% Low

>3.0% to 6.0% Intermediate

>6.0% to 9.0% over 9.0% High

Over 9.0% HighestSource: NICE (2010)Abbreviations: NICE, National Institute for Health and Care Excellence; NSTE-ACS, non-ST-segment elevation acute coronary syndromes.

20 The Global Registry of Acute Coronary Events (GRACE) risk score is a validated risk stratification tool which has incremental prognostic value for risk stratification compared with clinical assessment or troponin testing alone (Corcoran et al, 2015)21 Risk assessment also includes a full clinical history (including age, previous MI and previous PCI or CABG); a physical examination (including measurement of blood pressure and heart rate), resting ECG (looking particularly for dynamic or unstable patterns that indicate myocardial ischaemia), and blood tests (such as troponin I or T, creatinine, glucose and haemoglobin).


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4.3 High risk based on diagnostic testing

This section provides a summary of recommendations that relate specifically to the use of diagnostic testing for risk stratification in patients who are being considered for revascularisation. Eight relevant CPGs were identified, one of which is Australian (Table 4.3-1).

Table 4.3-1 Summary of relevant CPGs – patients assessed at high risk based on diagnostic testing

ID Title of guideline Method AffiliationAustraliaNHFA/CSANZ 2006

Guidelines for the management of acute coronary syndromes 2006


National Heart Foundation of Australia (NHFA)Cardiac Society of Australia and New Zealand (CSANZ)

EuropeESC/EACTS 2014

2014 ESC/EACTS Guidelines on myocardial revascularization. The Task Force on Myocardial Revascularization of the European Society of Cardiology and the European Association for Cardio-Thoracic Surgery


European Society of Cardiology (ESC), European Association for Cardio-Thoracic Surgery (EACTS).Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI)

ESC 2013 2013 ESC guidelines on the management of stable coronary artery disease. The Task Force on the management of stable coronary artery disease of the European Society of Cardiology


European Society of Cardiology (ESC)

United StatesAHA/ACC 2014 2014 AHA/ACC Guideline for the

management of patients with non–ST-elevation acute coronary syndromes. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines


American Heart Association (AHA)American College of Cardiology (ACC)

ACCF/AHA 2012

2012 ACCF/AHA/ACP/AATS/ PCNA/SCAI/STS Guideline for the diagnosis and management of patients with stable ischemic heart disease


American College of Cardiology Foundation (ACCF), American Heart Association (AHA), American College of Physicians (ACP), American Association for Thoracic Surgery (AATS), Preventive Cardiovascular Nurses Association (PCNA), Society for Cardiovascular Angiography and Interventions (SCAI), and Society of Thoracic Surgeons (STS)

ACCF/AHA 2012

2012 ACCF/AHA/ACP/AATS/ PCNA/SCAI/STS Guideline for the diagnosis and management of patients with stable ischemic heart disease: Executive summary

Based on the 2012 ACCF/AHA guideline

As above

ACCF/AHA/ SCAI 2011

2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions


American College of Cardiology Foundation (ACCF), American Heart Association (AHA), Society for Cardiovascular Angiography and Interventions (SCAI)


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ID Title of guideline Method AffiliationUnited KingdomNICE 2011 Management of stable angina. NICE

clinical guideline 126. Last modified December 2012.



NICE 2010 The early management of unstable angina and non-ST-segment-elevation myocardial infarction.NICE clinical guideline 94Last modified November 2013



Abbreviations: CPG, clinical practice guideline.

4.3.1 Invasive diagnostic testing – Fractional flow reserve

FFR assesses the hemodynamic significance of angiographically ‘intermediate’ or ‘indeterminant’ lesions and allows one to decide when PCI may be beneficial or safely deferred. Two international CPGs were identified that provide recommendations for the use of FFR in patients with SCAD/SIHD. The recommendations from the international CPGs are summarised in Table 4.3-2. No Australian CPGs were identified that provide specific guidance relating to FFR.

The 2013 ESC guidelines on the management of SCAD emphasises the role of FFR in helping the decision on when to revascularise in many uncertain clinical conditions. One such condition is multivessel disease. In these patients, FFR measurement may change the strategy of revascularisation (PCI versus CABG) and the extent of revascularisation according to the functional assessment of stenoses in critical coronary locations. FFR is also useful in the decision-making for revascularisation in left main stenosis, a lesion site that is of major prognostic importance and often determines the type of treatment.

The 2012 ACCF/AHA guideline emphasises that revascularisation is indicated in patients with SIHD based on the assessment of FFR (refer to Table 4.1-8 where FFR is used in deciding when revascularisation in indicated to improve symptoms in patients with SIHD). Thus, the guideline recommendations for revascularisation are for “significant” coronary stenoses with FFR ≤0.80. In the situation where FFR measurements are above 0.80, revascularisation (CABG or PCI) to improve prognosis or symptoms should not be performed.


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Table 4.3-2 Recommendations for the use of FFR in patients with SCAD/SIHD

Ref ID Recommendations Class of recommendation LOE

EuropeESC2013

FFR is recommended to identify hemodynamically relevant coronary lesion(s) when evidence of ischaemia is not available.

I A

Revascularisation of stenoses with FFR <0.80 is recommended in patients with angina symptoms or a positive stress test.

I B

IVUS or OCTa may be considered to characterise lesions. IIb B

IVUS or OCTa may be considered to improve stent deployment. IIb B

Revascularisation of an angiographically intermediate stenosis without related ischaemia or without FFR <0.80 is not recommended.

III B

United StatesACCF/AHA2012

Revascularisation (CABG or PCI) should not be performed with the primary or sole intent to improve survival in patients with SIHD with one or more coronary stenoses that are not anatomically or functionally significant (e.g. <70% diameter non–left main coronary artery stenosis, FFR >0.80, no or only mild ischaemia on non-invasive testing), involve only the left circumflex or right coronary artery, or subtend only a small area of viable myocardium.

IIIHarm

C

Revascularisation (CABG or PCI) to improve symptoms should not be performed in patients who do not meet anatomic (≥50% diameter left main or ≥70% non–left main stenosis diameter) or physiological (e.g. abnormal FFR) criteria for revascularisation.

IIIHarm

C

ACCF/AHA/SCAI 2011

FFR is reasonable to assess angiographic intermediatecoronary lesions (50% to 70% diameter stenosis) and can be useful for guiding revascularisation decisions in patients with SIHD.

IIa A

Source: ESC (2013), Table 31, p 2986; ACCF/AHA (2012), Executive Summary, pe417. Refer to Appendix 5 for definitions of the Class of recommendation and Level of evidence.Abbreviations: ACCF, American College of Cardiology Foundation; AHA, American Heart Association; CABG, coronary artery bypass graft; ESC, European Society of Cardiology; FFR, fractional flow reserve; IVUS, intravascular ultrasound; LOE, Level of evidence; OCT, optical coherence tomography; PCI, percutaneous coronary intervention; SCAD, stable coronary artery disease; SIHD, stable ischaemic heart disease.a IVUS and OCT are techniques that allow more accurate assessment of the luminal narrowing and characterisation of plaques. However, their value in clinical practice is not yet established.

4.3.2 Invasive coronary angiography

Invasive coronary angiography has been regarded as the reference standard for the detection and assessment of the severity of CAD. Three CPGs were identified that provide recommendations relating to the use of coronary angiography in patients with SCAD/SIHD who are candidates for coronary revascularisation (Table 4.3-3).

The 2014 ACC/AHA Focused Update of the Guideline for the diagnosis and management of patients with SIHD states that in the majority of patients with suspected SIHD, non-invasive stress testing for diagnosis and risk stratification is the appropriate initial study. Importantly, coronary angiography is appropriate only when the information derived from the procedure will significantly influence patient management and if the risks and benefits of the procedure have been carefully considered and understood by the patient. Coronary angiography to assess coronary anatomy for revascularisation is appropriate only when it is determined beforehand that the patient is amenable to, and a candidate for, percutaneous or surgical revascularisation. In patients with abnormal, non-invasive stress testing for whom a diagnosis of CAD remains in doubt, many clinicians proceed to diagnostic coronary angiography.


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Table 4.3-3 Summary of recommendations on coronary angiography in patients with stable angina/SCAD/SIHD

Ref ID Recommendations Class of recommendatio

nLOE

EuropeESC2013

ICA (with FFR when necessary) is recommended for patients with mild or no symptoms with medical treatment in whom non-invasive risk stratification indicates a high event risk and revascularisation is considered for improvement of prognosis.

I C

If coronary CTA is available for event risk stratification, possible overestimation of stenosis severity should be considered in segments with severe calcification, especially in patients at high intermediate PTP. Additional stress imaging may be necessary before referring a patient with few/no symptoms to ICA.

IIa C

United StatesACC/AHA Focused Update 2014

Coronary angiography is useful in patients with presumed SIHD who have unacceptable ischemic symptoms despite GDMT and who are amenable to, and candidates for, coronary revascularisation.

I C

Coronary angiography is reasonable to define the extent and severity of CAD in patients with suspected SIHD whose clinical characteristics and results of non-invasive testing (exclusive of stress testing) indicate a high likelihood of severe IHD and who are amenable to, and candidates for, coronary revascularisation.

IIa C

Coronary angiography is reasonable in patients with suspected symptomatic SIHD who cannot undergo diagnostic stress testing, or have indeterminate or non-diagnostic stress tests, when there is a high likelihood that the findings will result in important changes to therapy.

IIa C

Coronary angiography might be considered in patients with stress test results of acceptable quality that do not suggest the presence of CAD when clinical suspicion of CAD remains high and there is a high likelihood that the findings will result in important changes to therapy.

IIb C

ACCF/AHA2012

Coronary angiography for risk assessment is not recommended in patients with SIHD who elect not to undergo revascularisation or who are not candidates for revascularisation because of comorbidities or individual preferences.

III B

United KingdomNICE2010

Offer coronary angiography to guide treatment strategy for people with stable angina whose symptoms are not satisfactorily controlled with OMT. Additional noninvasive or invasive functional testing may be required to evaluate angiographic findings and guide treatment decisions.

- -

After discussion with people whose symptoms are satisfactorily controlled with OMT, consider coronary angiography when:

functional testing indicates extensive ischaemia or noninvasive anatomical testing indicates the likelihood of left main stem or proximal three-vessel disease; and

revascularisation is acceptable and appropriate.

- -

Sources: ACC/AHA Focused Update (2014), p1753; ACCF/AHA (2012), Executive Summary, p2578; ESC (2013), Table 20, p2972; NICE (2010). Refer to Appendix 5 for definitions of the Class of recommendation and Level of evidence.Abbreviations: ACC, American College of Cardiology; ACCF, American College of Cardiology Foundation; AHA, American Heart Association; CAD, coronary artery disease; CCS 3, Canadian Cardiovascular Society Class 3; CTA, computed tomography angiography; ESR, European Society of Cardiology; FFR, fractional flow reserve; GDMT, guideline-directed medical therapy; ICA, invasive coronary angiography; IHD, ischaemic heart disease; LOE, Level of evidence; NICE, National Institute for Health and Care Excellence; OMT, optimal medical therapy; PTP, pre-test probability; SCAD, stable coronary artery disease; SIHD, stable ischaemic heart disease.

Three CPGs were identified that provide recommendations relating to the use of coronary angiography in patients with NSTE-ACS who are candidates for coronary revascularisation (Table 4.3-4). One of these guidelines is Australian, jointly developed by the NHFA and CSANZ.


January 2016

Table 4.3-4 Summary of recommendations on coronary angiography in patients with NSTE-ACS

Ref ID Recommendations Class/Grade of recommendatio

nLOE

AustraliaNHFA/CSANZ2006

Early coronary angiography (within 48 hours) and revascularisation is recommended in patients with NSTE-ACS and high-risk features, except in patients with severe comorbidities.

A -

United StatesAHA/ACC2014

An urgent/immediate invasive strategy (diagnostic angiography with intent to perform revascularisation if appropriate based on coronary anatomy) is indicated in patients (men and women) with NSTE-ACS who have refractory angina or hemodynamic or electrical instability (without serious comorbidities or contraindications to such procedures).

I A

An early invasive strategy (diagnostic angiography with intent to perform revascularisation if appropriate based on coronary anatomy) is indicated in initially stabilised patients with NSTE-ACS (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events.

I B

United KingdomNICE2010

Perform angiography as soon as possible for patients who are clinically unstable or at high ischaemic risk.

- -

Coronary angiography should be offered (with follow-on PCI if indicated) within 96 hours of first admission to hospital to patients who have an intermediate or higher risk of adverse cardiovascular events (predicted 6-month mortality above 3.0%) if they have no contraindications to angiography (such as active bleeding or comorbidity).

- -

Coronary angiography (with follow-on PCI if indicated) should be offered to patients initially assessed to be at low risk of adverse cardiovascular events (predicted 6-month mortality 3.0% or less) if ischaemia is subsequently experienced or is demonstrated by ischaemia testing.

- -

Sources: AHA/ACC (2014), pe168; NHFA/CSANZ (2006), pS22; NICE (2010). Refer to Appendix 5 for definitions of the Class or Grade of recommendation and Level of evidence.Abbreviations: ACC, American College of Cardiology; AHA, American Heart Association; CSANZ, Cardiac Society of Australia and New Zealand; NHFA, National Heart Foundation of Australia; NICE, National Institute for Health and Care Excellence; NSTE-ACS, non-ST-elevation acute coronary syndrome; LOE, Level of evidence; PCI, percutaneous coronary intervention.

4.3.3 Non-invasive diagnostic testing

Recommendations that specifically relate to non-invasive diagnostic testing for risk assessment in patients who are being considered for revascularisation are shown in Table 4.3-5.


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Table 4.3-5 Recommendations for the use of non-invasive diagnostic testing for risk assessment in patients with stable angina/SIHD

ID Recommendations Class of recommendation LOE

United StatesACCF/AHA2012

Either exercise or pharmacological stress with imaging (nuclear MPI, echocardiography, or CMR) is recommended for risk assessment in patients with SIHD who are being considered for revascularisation of known coronary stenosis of unclear physiological significance.

I B

United KingdomNICE 2011 After discussion with people whose symptoms are satisfactorily controlled

with OMT, consider a functional or non-invasive anatomical test to identify people who might gain a survival benefit from surgery. Functional or anatomical test results may already be available from diagnostic assessment.

- -

After discussion with people whose symptoms are satisfactorily controlled with OMT, consider coronary angiography when:

functional testing indicates extensive ischaemia or noninvasive anatomical testing indicates the likelihood of left main stem or proximal three-vessel disease; and

revascularisation is acceptable and appropriate.

- -

Source: ACCF/AHA (2012), p2577. Refer to Appendix 5 for definitions of the Class of recommendation and Level of evidence.Abbreviations: ACCF, American College of Cardiology Foundation; AHA, American Heart Association; CMR, cardiac magnetic resonance; LOE, Level of evidence; MPI, myocardial perfusion imaging; OMT, optimal medical therapy; SIHD, stable ischaemic heart disease.

The NICE 2011 guidance for the management of patients with stable angina states that in the sub-study of COURAGE, which included patients who had myocardial perfusion single photon emission computed tomography (SPECT), PCI was shown to be more effective in treating ischaemia than optimal drug treatment, and in multivariate analyses, reduction of ischaemia was associated with greater event-free survival. It should be noted that this data described by NICE is from a publication excluded from consideration in this Review (Shaw et al, 2008; see Section 5.2.2) and is based on a non-randomised comparison. In addition, the greater event-free survival seen in patients with a ≥5% reduction in ischaemia compared with patients with a < 5% reduction in ischaemia was present for the unadjusted analysis only; when the analysis was adjusted for treatment arm the result was no longer statistically significant, and adjustment for other variables was not included in the analysis. The authors note that ‘Although when taken out of context, the sub-study results suggest that subjects randomised to PCI + OMT would have a lower risk for death or MI than those randomised to OMT alone, we know that this was not found in the main COURAGE trial results. This suggests that the sample in this nonrandomised sub-study is selected and deviates from the overall COURAGE population.’

Thus, the NICE 2011 guideline notes that it is unclear whether ‘people on optimal drug treatment who have evidence of inducible ischaemia on non-invasive functional testing should routinely have coronary angiography and revascularisation. This question is particularly relevant for people who have responded adequately (for example Canadian Cardiovascular Class 1 or 2) to optimal drug treatment and in whom, based on symptoms alone, revascularisation is not indicated.’ The guidelines recommend that a randomised trial be conducted of interventional management versus continued OMT in this population, with all-cause mortality and cardiovascular mortality as the primary endpoints.


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4.4 Concordance between the MBS descriptors and Australian and International guidelines

The descriptors for three of the seven MBS items 38300, 38303 and 38306 (angioplasty ± stenting) do not provide details of the target population for PCI, or restrict the use of PCI to any particular population(s). The only guidance on patient selection that is provided in the item descriptors (and the associated Explanatory Notes) relates to the atherectomy items (38309, 38312, 38315 and 38318), which are suitable for revascularisation of complex and heavily calcified coronary artery stenoses in patients for whom CABG surgery is contraindicated. A coronary artery lesion is considered to be complex when the lesion is a chronic total occlusion, located at an ostial site, angulated, tortuous or greater than 1 cm in length.22

This Review focused on specific populations where the value of PCI with stent insertion is uncertain or controversial. Australian and international clinical guidance regarding revascularisation is summarised below for each of the populations of interest. The role of PCI in the management of patients with STEMI is well established, and as such, this population was not specifically addressed in the MBS Review.

Based on the findings from the CPGs, and the unrestricted indications for angioplasty ± stenting items on the MBS, it is possible that PCI may be used in a broader patient population than is supported by recommendations arising from the clinical evidence base. However, there is no evidence available to confirm whether this is the case.

4.4.1 Chronic stable angina

There are no Australian CPGs available for this population. Based on an assessment of the international guidelines, factors such as risk stratification (e.g. the SYNTAX score), the number of coronary arteries with stenosis (one-, two- or three-vessel disease) with and without involvement of proximal LAD, and left main CAD play an important role in the decision-making on the choice of revascularisation. If the decision to revascularise is made, PCI or CABG is generally recommended for less complex CAD, while CABG is generally indicated for more complex CAD and where comorbidities exist. PCI is recommended in certain circumstances where the patient is not a candidate for CABG.

4.4.2 Diagnosis of NSTE-ACS

The 2006 NHFA/CSANZ guideline emphasises the use of risk stratification in patients with NSTE-ACS to identify patients at high, intermediate or low risk of clinical events. Early coronary angiography (within 48 hours) and revascularisation is recommended for patients with NSTE-ACS and high-risk features (except in patients with severe comorbidities). The preferred revascularisation approach is not specified. Recent international guidelines (AHA/ACC, 2014; ESC/EACTS, 2014) use more complex risk stratification scores, but do not make firm recommendations about the preferred revascularisation strategy, acknowledging that management of NSTE-ACS depends on many factors including the patient’s condition, the presence of risk factors, comorbidities, and the extent and severity of the lesions as identified by coronary angiography.

22 Explanatory Note T8.42


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4.4.3 High risk based on diagnostic testing

NHFA/CSANZ (2006) made no recommendation on the use of FFR in the risk stratification of patients who are being considered for revascularisation. However, recent international guidelines place emphasis on the documentation of ischaemia by non-invasive or invasive diagnostic tests prior to revascularisation. In cases where ischaemia is not documented using non-invasive diagnostic testing, FFR measurement is recommended for the identification of haemodynamically relevant coronary lesions. There is consensus in the international guidelines that FFR<0.80 is indicative of inducible ischaemia, and thus revascularisation is recommended in patients that meet this threshold. However, none of the guidelines made recommendations on the use of FFR for determining the revascularisation approach. None of the MBS item descriptors incorporate FFR measurements as a factor in determining appropriateness for PCI. However, the descriptor for MBS item 38241, which relates to FFR measurement, specifies that it is to be used to determine whether revascularisation should be performed, in circumstances where previous stress testing has either not been performed or the results are inconclusive.


January 2016

5 REVIEW OF THE CLINICAL EVIDENCE FOR PCI

This section presents the results of the systematic literature review on PCI in relation to the clinical research questions. Section 5.1 presents a description of the identified evidence base, while Section 5.2 presents the results of the identified studies.

5.1 Evidence base

A list of the included systematic reviews is provided in Table 5.1-1. The large number of systematic reviews identified highlights the intense interest in the use of PCI; of particular note, 15 systematic reviews have been published in the last 18 months alone. Details of the characteristics of the systematic reviews and the studies they include are summarised in Section 5.1.1 (chronic stable angina population), Section 5.1.2 (NSTE-ACS population) and Section 5.1.3 (high risk based on diagnostic testing population). A list of subsequently excluded systematic reviews is also provided in Table 5.1-2, including the reasons for exclusion.

In order to contain the scope of the review, the literature search was confined to search terms describing the three specific populations of interest: (i) patients with chronic stable angina, (ii) patients with a diagnosis of NSTE-ACS, and (iii) patients identified as being at high risk via diagnostic testing. During the course of the review, however, it became clear that no studies had specifically assessed the population with chronic stable angina; systematic reviews aiming to assess stable angina had included studies with a broader CAD population and had compared their results to reviews also assessing this broader population. As such, while systematic reviews assessing PCI in populations with CAD were identified from the reference lists of systematic reviews assessing stable angina, more recent systematic reviews in the CAD population were not systematically identified. The most recent and comprehensive of these, a network meta-analysis by Windecker et al (2014), was assessed and found to provide no strong evidence to change any of the conclusions drawn from the evidence review. As such, an additional search to identify all recent systematic reviews in a CAD population was not conducted.

Table 5.1-1 Citation details for included systematic reviews of PCI

Ref ID Citation

Chronic stable anginaD’Ascenzo 2014 D'Ascenzo, F., U. Barbero, et al. (2014) "Percutaneous coronary intervention versus coronary artery

bypass graft for stable angina: meta-regression of randomized trials." Contemporary Clinical Trials 38: 51-58.

Fanari 2014 Fanari, Z., S. A. Weiss, et al. (2014). "Short, Intermediate and long term outcomes of CABG vs. PCI with DES in Patients With Multivessel Coronary Artery Disease. Meta-Analysis of Six Randomized Controlled Trials." Eur J Cardiovasc Med 3(1): 382-389.

Qi 2014 Qi, X., M. Xu, et al. (2014). "Comparing mortality and myocardial infarction between coronary artery bypass grafting and drug eluting stenting in patients with diabetes mellitus and multivessel coronary artery disease: A meta-analysis." Archives of Medical Science 10(3): 411-418.

Takagi 2014 Takagi, H., T. Watanabe, et al. (2014). "A review with meta-analysis of observational studies for survival following off-pump coronary artery bypass versus drug-eluting stent implantation." Interactive Cardiovascular and Thoracic Surgery 18(6): 807-813.

Bangalore 2013 Bangalore, S., S. Pursnani, et al. (2013). "Percutaneous coronary intervention versus optimal medical therapy for prevention of spontaneous myocardial infarction in subjects with stable ischemic heart disease." Circulation 127(7): 769-781.


January 2016

Ref ID CitationMorrone 2013 Morrone, D., A. Horne, et al. (2013). "Bayesian meta-analysis of percutaneous coronary

intervention compared to optimal medical therapy in stable ischemic heart disease patients." European Heart Journal 34: 176.

Chronic stable anginaThomas 2013 Thomas, S., R. Gokhale, et al. (2013). "A Meta-analysis of Randomized Controlled Trials

Comparing Percutaneous Coronary Intervention With Medical Therapy in Stable Angina Pectoris." Canadian Journal of Cardiology 29(4): 472-482.

Pursnani 2012 Pursnani, S., F. Korley, et al. (2012). "Percutaneous coronary intervention versus optimal medical therapy in stable coronary artery disease: a systematic review and meta-analysis of randomized clinical trials." Circ Cardiovasc Interv 5(4): 476-490.

Stergiopoulos 2012 Stergiopoulos, K. and D. L. Brown (2012). "Initial coronary stent implantation with medical therapy vs medical therapy alone for stable coronary artery disease: Meta-analysis of randomized controlled trials." Archives of Internal Medicine 172(4): 312-319.

Gorenoi 2011 Gorenoi, V., M. P. Schönermark, et al. (2011) Percutaneous coronary intervention with optimal medical therapy vs. optimal medical therapy alone for patients with stable angina pectoris. Accessed from the University of York website.

Wijeysundera 2010 Wijeysundera, H. C., B. K. Nallamothu, et al. (2010). "Meta-analysis: effects of percutaneous coronary intervention versus medical therapy on angina relief." Ann Intern Med 152(6): 370-379.

Jeremias 2009 Jeremias, A., S. Kaul, et al. (2009). "The impact of revascularization on mortality in patients with nonacute coronary artery disease." Am J Med 122(2): 152-161.

Trikalinos 2009 Trikalinos, T. A., A. A. Alsheikh-Ali, et al. (2009). "Percutaneous coronary interventions for non-acute coronary artery disease: a quantitative 20-year synopsis and a network meta-analysis." Lancet 373(9667): 911-918.

Schömig 2008 Schömig, A., J. Mehilli, et al. (2008). "A meta-analysis of 17 randomized trials of a percutaneous coronary intervention-based strategy in patients with stable coronary artery disease." J Am Coll Cardiol 52(11): 894-904.

Ioannidis 2007 Ioannidis, J. P. and D. G. Katritsis (2007). "Percutaneous coronary intervention for late reperfusion after myocardial infarction in stable patients." Am Heart J 154(6): 1065-1071.

Diagnosis of NSTE-ACSAlfredsson 2014 Alfredsson, J., T. Clayton, et al. (2014). "Impact of an invasive strategy on 5 years outcome in men

and women with non-ST-segment elevation acute coronary syndromes." American Heart Journal 168(4): 522-529.

Angeli 2014 Angeli, F., P. Verdecchia, et al. (2014). "Early invasive versus selectively invasive strategy in patients with non-ST-segment elevation acute coronary syndrome: Impact of age." Catheterization and Cardiovascular Interventions 83(5): 686-701.

Damman 2012a Damman, P., T. Clayton, et al. (2012). "Effects of age on long-term outcomes after a routine invasive or selective invasive strategy in patients presenting with non-ST segment elevation acute coronary syndromes: A collaborative analysis of individual data from the FRISC II - ICTUS - RITA-3 (FIR) trials." Heart 98(3): 207-213.

O'Donoghue 2012 O'Donoghue, M. L., A. Vaidya, et al. (2012). "An invasive or conservative strategy in patients with diabetes mellitus and non-ST-segment elevation acute coronary syndromes: A collaborative meta-analysis of randomized trials." Journal of the American College of Cardiology 60(2): 106-111.

Swahn 2012 Swahn, E., J. Alfredsson, et al. (2012). "Early invasive compared with a selective invasive strategy in women with non-ST-elevation acute coronary syndromes: A substudy of the OASIS 5 trial and a meta-analysis of previous randomized trials." European Heart Journal 33(1): 51-60.

Fox 2010 Fox, K. A. A., T. C. Clayton, et al. (2010). "Long-Term Outcome of a Routine Versus Selective Invasive Strategy in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome. A Meta-Analysis of Individual Patient Data." Journal of the American College of Cardiology 55(22): 2435-2445.

Hoenig 2010 Hoenig, M. R., C. N. Aroney, et al. (2010). "Early invasive versus conservative strategies for unstable angina and non-ST elevation myocardial infarction in the stent era." Cochrane Database of Systematic Reviews: CD004815.

Charytan 2009 Charytan, D. M., L. Wallentin, et al. (2009). "Early angiography in patients with chronic kidney disease: A collaborative systematic review." Clinical Journal of the American Society of Nephrology 4(6): 1032-1043.


January 2016

Ref ID CitationO'Donoghue 2008 O'Donoghue, M., W. E. Boden, et al. (2008). "Early invasive vs conservative treatment strategies in

women and men with unstable angina and non-ST-segment elevation myocardial infarction: A meta-analysis." JAMA - Journal of the American Medical Association 300(1): 71-80.

Qayuum 2008 Qayyum, R., M. R. Khalid, et al. (2008). "Systematic review: Comparing routine and selective invasive strategies for the acute coronary syndrome." Annals of Internal Medicine 148(3): 186-196.

Tarantini 2007 Tarantini, G., R. Razzolini, et al. (2007). "Patient risk profile and benefit from an invasive approach in the initial management of non-ST-segment elevation acute coronary syndrome." Journal of Cardiovascular Medicine 8(10): 799-802.

High risk based on diagnostic testingGada 2015 Gada, H., A. J. Kirtane, et al. (2015). "Meta-analysis of trials on mortality after percutaneous

coronary intervention compared with medical therapy in patients with stable coronary heart disease and objective evidence of myocardial ischemia." American Journal of Cardiology 115(9): 1194-1199.

Stergiopoulos 2014 Stergiopoulos, K., W. E. Boden, et al. (2014). "Percutaneous coronary intervention outcomes in patients with stable obstructive coronary artery disease and myocardial ischemia: A collaborativemeta-analysis of contemporary randomized clinical trials." JAMA Internal Medicine 174(2): 232-240.

Table 5.1-2 Reasons for exclusion of additional systematic reviews of PCI

Ref ID Citation Reason for exclusionLee 2010 Lee, M. S., T. Yang, et al. (2010). "Meta-analysis of studies comparing

coronary artery bypass grafting with drug-eluting stenting in patients with diabetes mellitus and multivessel coronary artery disease." Am J Cardiol 105(11): 1540-1544.

Wrong study type. Systematic review of observational studies; no indication if adjusted results used.

Diagnosis of NSTE-ACSJang 2015 Jang, J. S., H. Y. Jin, et al. (2015). "Meta-Analysis of Multivessel Versus

Culprit-Only Percutaneous Coronary Intervention in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome and Multivessel Coronary Disease." American Journal of Cardiology 115: 1027-1032.

Wrong comparison. Multivessel vs. culprit-only PCI.

Milasinovic 2015 Milasinovic, D., A. Milosevic, et al. (2015). "Timing of invasive strategy in NSTE-ACS patients and effect on clinical outcomes: A systematic review and meta-analysis of randomized controlled trials." Atherosclerosis 241(1): 48-54.

Wrong comparison. Compares early vs. late PCI

Jiang 2014 Jiang, M., J. L. Mao, et al. (2014). "Timing of early angiography in non-ST elevation acute coronary syndrome." Journal of Invasive Cardiology 26(2): 47-54.


Li 2014 Li, Y. Q., N. Liu, et al. (2014). "Outcomes in patients with non-ST-elevation acute coronary syndrome randomly assigned to invasive versus conservative treatment strategies: a meta-analysis." Clinics (São Paulo, Brazil) 69(6): 398-404.

Wrong study type. Systematic review of predominantly observational studies

Nairooz 2014 Nairooz, R., P. Sardar, et al. (2014). "Improved angiographic outcomes with delayed stenting compared with immediate stenting for acute myocardial infarction. Evidence from a meta-analysis." Circulation 130: A13101.


Jang 2013 Jang, J. S., H. Y. Jin, et al. (2013). "Invasive versus conservative strategies in patients with non-st-elevation acute coronary syndrome: An updated meta-analysis." European Heart Journal 34: 1004.

Conference abstract

Navarese 2013a Navarese, E. P., F. Andreotti, et al. (2013). "Optimal timing of coronary invasive strategy in non-ST elevation acute coronary syndromes: A comprehensive meta-analysis of current evidence." European Heart Journal 34: 69.


Navarese 2013b Navarese, E. P., P. A. Gurbel, et al. (2013). "Optimal timing of coronary invasive strategy in non-ST-segment elevation acute coronary syndromes: A systematic review and meta-analysis." Annals of Internal Medicine 158(4): 261-270.



January 2016

Ref ID Citation Reason for exclusionRajpurohit 2013a Rajpurohit, N., C. Farritor, et al. (2013). "Early versus delayed

percutaneous coronary intervention for high risk patients with non ST elevation-acute coronary syndrome: A meta-analysis." Journal of the American College of Cardiology 62(18): B255.


Diagnosis of NSTE-ACSRajpurohit 2013b Rajpurohit, N., N. Garg, et al. (2013). "Early versus delayed percutaneous

coronary intervention for patients with non-ST segment elevation acute coronary syndrome: A meta-analysis of randomized controlled clinical trials." Catheterization and Cardiovascular Interventions 81(2): 223-231.


Santarella 2013 Santarella, L., E. Agushi, et al. (2013). "Routine invasive strategy is of most benefit in trials that did not specify positive cardiac biomarker status as an inclusion criterion: A meta-analysis." European Heart Journal 34: 412.

Conference abstract

Damman 2012b Damman, P., N. van Geloven, et al. (2012). "Timing of angiography with a routine invasive strategy and long-term outcomes in non-ST-segment elevation acute coronary syndrome: a collaborative analysis of individual patient data from the FRISC II (Fragmin and Fast Revascularization During Instability in Coronary Artery Disease), ICTUS (Invasive Versus Conservative Treatment in Unstable Coronary Syndromes), and RITA-3 (Intervention Versus Conservative Treatment Strategy in Patients With Unstable Angina or Non-ST Elevation Myocardial Infarction) Trials." JACC Cardiovasc Interv 5(2): 191-199.


Woudstra 2012 Woudstra, P., P. Damman, et al. (2012). "Routine invasive versus selective invasive strategy and long-term outcomes in patients with reduced renal function presenting with non-ST segment elevation acute coronary syndrome." Journal of the American College of Cardiology 59(13): E392.

Conference abstract

Katritsis 2011 Katritsis, D. G., G. C. M. Siontis, et al. (2011). "Optimal timing of coronary angiography and potential intervention in non-ST-elevation acute coronary syndromes." European Heart Journal 32(1): 32-40.


Stavrakis 2011 Stavrakis, S., J. A. Stoner, et al. (2011). "Impact on short- and long-term mortality of invasive vs. conservative strategy in non-ST elevation acute coronary syndromes: A meta-analysis." European Heart Journal 32: 657.

Conference abstract

Zixiang 2011 Zixiang, Y., M. Yitong, et al. (2011). "Short-term and long-term outcome of early invasive therapy in patients with non-ST-segment elevation acute coronary syndrome: A meta-analysis." Heart 97: A110.

Conference abstract

High risk based on diagnostic testingNascimento 2015 Nascimento, B. R., A. F. L. Belfort, et al. (2015). "Meta-analysis of

deferral versus performance of coronary intervention based on coronary pressure-derived fractional flow reserve." American Journal of Cardiology 115(3): 385-391.

Wrong study type. Systematic review of predominantly observational studies

Johnson 2014 Johnson, N. P., G. G. Toth, et al. (2014). "Prognostic value of fractional flow reserve: Linking physiologic severity to clinical outcomes." Journal of the American College of Cardiology 64(16): 1641-1654.

Wrong comparison. Low FFR vs. high FFR

Kirtane 2013 Kirtane, A. J., H. Gada, et al. (2013). "Percutaneous coronary intervention is associated with lower mortality compared with optimal medical therapy in patients with stable ischemic heart disease and objective evidence of ischemia or abnormal fractional flow reserve: A meta-analysis of randomized controlled trials." Journal of the American College of Cardiology 62(18): B255.

Conference abstract

Abbreviations: FFR, fractional flow reserve; NSTE-ACS, non-ST-segment elevation acute coronary syndrome; PCI, percutaneous coronary intervention.


The literature search identified 15 meta-analyses based on systematic reviews of evidence (SR/MAs) that assessed the use of PCI in patients with stable angina, or a broader group of


January 2016

patients that included those with stable angina. The main characteristics and quality of these studies are summarised in Table 5.1-3. Studies were classified according to the NHMRC Levels of evidence hierarchy (see Appendix 5). The majority of included SR/MAs were considered to be of fair to good methodological quality, while the included RCTs were generally considered to be of fair methodological quality.

Eleven reviews were SR/MAs of RCTs only comparing PCI with medical therapy; only four of these specifically aimed to compare PCI with optimal medical therapy (OMT). OMT was defined in two of the reviews. In the review by Gorenoi et al (2011), which was a health technology assessment conducted on behalf of the German Federal Ministry of Health, individual RCTs were eligible for inclusion if beta-adrenergic receptor blockers, aspirin and statins were used in at least 80% of the included patients, and angiotensin converting enzyme inhibitors (ACEI) were used in at least 50% of the included patients. The reviews by Pursnani et al (2012) and Bangalore et al (2013) defined OMT as a medical regimen consisting of at least an antiplatelet, antianginal and lipid-lowering therapy. The study by Morrone et al (2013) is published as a conference abstract only and OMT was not defined.

While PCI was the intervention of interest in all studies, not all patients who underwent PCI had stents implanted. Only one study, by Stergiopoulos and Brown (2012), required that included studies used stents in at least 50% of patients. In the RCTs included in the SR/MAs, stent implantation ranged from 0% to 100%.

Four reviews compared the use of PCI with CABG: two were SR/MAs of RCTs (D’Ascenzo et al, 2014; Fanari et al, 2014), one was a SR/MA of RCTs and observational studies (Qi et al, 2014), and one was a SR/MA of observational studies only (Takagi et al, 2014). The SR/MAs that included observational studies (which represent Level III evidence) were only included due to the small amount of evidence based on SR/MA of RCTs.


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Table 5.1-3 Characteristics of included SR/MAs: chronic stable angina

Study IDSR quality [included study quality]

Studies (patients) Population Intervention Comparator Outcomes

HTA

Gorenoi 2011Good [good]

7 SRs/3 RCTs (NR) Stable angina pectoris PCI + OMT OMT Use of beta-adrenergic receptor

blockers, aspirin and statins in about 80% of the included patients and use of ACEIs in 50% of the included patients.

All-cause mortalityMIStrokeHeart failureAnginaRepeat revascularisationQuality of lifeComposite endpoints

SR/MA – Level I

D’Ascenzo 2014Fair [fair]

20 RCTs (12,844) Stable angina Included patients with a mix of

multivessel, single vessel and unprotected left main and CAD

PCI No restriction on proportion

of stent use Four included studies had 0%

stent use and 14 included studies had 100% stent use

CABG Included a mix of on-pump and

off-pump, and arterial graft use ranged from 37% to 100%

All-cause mortalityMIRepeat revascularisationStroke

Fanari 2014Fair [unknown]

6 RCTs (up to 5123) Multivessel CAD PCI + DES CABG All –cause mortalityMITarget vessel revascularisationStroke

Bangalore 2013Good [fair]

12 RCTs (37,548 py) Stable CAD Excluded trials that enrolled

patients within a week of ACS

PCI Subgroup analysis performed

for stent trials (≥ 50% stenting) and non-stent trials (< 50% stenting)

OMT At least an antiplatelet,

antianginal and lipid-lowering agent

All-cause mortalityCV mortalityAll MISpontaneous nonprocedural MIProcedural MI

Morrone 2013Abstract onlyPoor [unknown]

17 RCTs (NR) Stable IHD PCI No restriction on proportion

of stent use

OMT Not defined

All-cause mortality/MIAll-cause mortalityRepeat revascularisationAngina


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SR/MA – Level I

Thomas 2013Good [high]23

10 RCTs (6752) Stable angina pectoris PCI No restriction on proportion

of stent use Two included studies had 0%

stent use One included study had 100%

stent use

Medical therapy All-cause mortalityCV mortalityMIFreedom from angina

Pursnani 2012Good [fair]

12 RCTs (7182) Stable CAD Five studies included patients

with angina (mainly CCS Class I OR II)

PCI Majority of studies included

angioplasty without stenting Only four RCTs had stenting

in > 50% of patients

OMT A medical regimen consisting of

at least an antiplatelet, antianginal and lipid-lowering therapy.

All-cause mortalityCV mortalityNon-fatal MIRepeat revascularisationFreedom from angina

Stergiopoulos 2012Fair [fair]

8 RCTs (7229) Stable CAD Five studies included patients

with angina

PCI Stent use had to exceed 50% Two included RCTs had

100% stent use

Medical therapy All-cause mortalityNon-fatal MIUnplanned revascularisationPersistent angina

Wijeysundera 2010Good [fair]

14 RCTs (7818) Stable CAD CCS angina (Class 0 or 1) ranged

from 12% to 100%

PCI No restriction on proportion

of stent use Four included studies had 0%

stent use One included study had 100%

stent use

Medical therapy Freedom from angina

Jeremias 2009Fair [unknown]

28 RCTs (13,121) Non-acute CAD Surgical revascularisation PCI in 17 RCTs, CABG in 6

studies and either in 5 studies

Medical therapy All-cause mortalityNon-fatal MI

SR/MA – Level I

23 Quality of body of evidence rated using GRADE as high for mortality, CV death, non-fatal MI and repeat revascularisation; quality of body of evidence for angina relief rated low. MBS Reviews – Percutaneous Coronary Intervention Review Report Page 117

January 2016



Trikalinos 2009Poor24 [unknown]

61 RCTs (25,338) Non-acute CAD PCI Including PTCA, BMS and

DES

Other PCI or medical therapy All-cause mortalityMI

Schömig 2008Fair [unknown]

17 RCTs (7513) Stable CAD PCI No restriction on proportion

of stent use Seven included studies had

0% stent use One included study had 100%

stent use

Medical therapy All-cause mortalityCV mortalityNon-fatal MI

Ioannidis 2007Good [fair]

6 RCTs25 (2617) Stable patients with an occluded artery

Late PCI ≥ 1 day to 45 days from onset

of symptoms

Medical therapy All-cause mortalityMIDeath/MICongestive heart failureChange in LVEF

SR/MA – Level I/III

Qi 2014Poor [unknown]

2 RCTs/8 OBSs (5264)

Diabetic patients with multivessel CAD Included patients with stable

(46%) and unstable (25%) angina

PCI + DES CABG All-cause mortalityMIMACCE26

SR/MA – Level III

Takagi 2014Fair [unknown]

10 OBSs (NR) Any CAD PCI + DES Off-pump CABG All-cause mortality

Note: Quality assessment forms for each SR/MA available in Appendix 8. Abbreviations: ACEI, angiotensin converting enzyme inhibitors; ACS, acute coronary syndrome; BMS, bare metal stent; CABG, coronary artery bypass graft; CCS, Canadian Cardiovascular Society; CV, cardiovascular; DES, drug-eluting stent; HTA, health technology assessment; IHD, ischaemic heart disease; LVEF, left ventricular ejection fraction; MA, meta-analysis; MACCE, major adverse cardiac and cerebrovascular events; MI, myocardial infarction; NR, not reported; OBS, observational study; OMT, optimal medical therapy; PCI, percutaneous coronary intervention; PTCA, percutaneous transluminal coronary angioplasty; py, patient years; RCT, randomised controlled trial; SR, systematic review.

24 Comprehensive network meta-analysis combining direct and indirect comparisons. Given a poor quality rating due to lack of individual included study characteristics and results, and lack of individual study quality assessment. 25 6 RCTs and one sub-study. 26 Defined as a composite of all-cause mortality, cerebrovascular accident, myocardial infarction or repeat revascularisation.


January 2016

Table 5.1-4 lists the RCTs included in the SR/MAs comparing PCI with medical therapy to show the extent of overlap. There was a substantial overlap between the RCTs included in SR/MAs that assessed PCI versus medical therapy.

Table 5.1-5 presents the proportion of patients that received OMT as defined in the review by Gorenoi et al (2011). Gorenoi’s definition of OMT included beta-adrenergic receptor blockers, aspirin, statins and ACEIs. RCTs were only included in their analysis if β-blockers, aspirin and statins were used by at least 80% of patients in the medical therapy arm, and ACE inhibitors were used by at least 50% of patients in the medical therapy arm. As can be seen in Table 5.1-5, six studies met this criteria: DECOPI, INSPIRE, COURAGE, OAT, BARI-2D and TOSCA-2. However, the review by Gorenoi included only three RCTs in the analysis: COURAGE, OAT and BARI-2D. While TOSCA-2 was excluded from further analysis by Gorenoi et al (2011) because it is a sub-study of OAT, it is unclear why the other two studies were also excluded. This will be examined further in Section 5.2.1. As shown in Table 5.1-5, similar types and rates of medical therapy were used by patients in both the PCI and medical therapy arms of these RCTs.

Table 5.1-6 lists the RCTs and observational studies included in the SR/MAs comparing PCI with CABG to show the extent of overlap. The two SR/MAs assessing RCTs only for PCI versus CABG (D’Ascenzo et al, 2014; Fanari et al, 2014) included a total of 22 RCTs of which only five were common to both. Of the two SR/MAs assessing PCI versus CABG that included observational studies (Qi et al, 2014; Takagi et al, 2014), there was overlap between only two observational studies.


January 2016

Table 5.1-4 Studies included in the systematic reviews: chronic stable angina – PCI vs. medical therapy27

Study ID Year Type of medical therapy

Gorenoi 2011

HTA – SR/RCT

Bangalore 2013

SR/MA – RCT only

Thomas 2013

SR/MA – RCT only

Pursnani 2012

SR/MA – RCT only

Stergiopoulos 2012

SR/MA – RCT only

Wijeysundera 2010SR/MA – RCT only

Jeremias 2009

SR/MA – RCT only

Trikalinos 2009

SR/MA – RCT only

Schömig 2008

SR/MA – RCT only

Ioannidis 2007

SR/MA – RCT only

SR Year of search

Wijeysundera 2010 2009 -

Jeremias 2009 2008 -

Trikalinos 2009 2008 -

Schömig 2008 2007 -

Ioannidis 2007 2007 -

Bucher 2000 1998 -

RCT Final enrolment

BARI 2D 2005 Optimal pharm.

OAT 2005 Optimal pharm.

TOSCA-2 2005 Optimal pharm.

COURAGE 2004 Optimal pharm.

JSAP 2004 Pharm.

INSPIRE 2002 Intensive pharm.

DECOPI 2001 Standard pharm.

Hambrecht 2004 2001 Pharm.

Silva 2005 2001 Conservative

MASS II 2000 Optimal pharm. 28

TIME 2000 Optimal pharm.

DEFER 1998 Pharm. 28

TOAT 1999 Optimal pharm.

27 Morrone 2013 (abstract only) excluded from this table because it does not list the individual included studies. MBS Reviews – Percutaneous Coronary Intervention Review Report Page 120

January 2016

Study ID Year Type of medical therapy

Gorenoi 2011

HTA – SR/RCT

Bangalore 2013

SR/MA – RCT only

Thomas 2013

SR/MA – RCT only

Pursnani 2012

SR/MA – RCT only

Stergiopoulos 2012

SR/MA – RCT only

Wijeysundera 2010SR/MA – RCT only

Jeremias 2009

SR/MA – RCT only

Trikalinos 2009

SR/MA – RCT only

Schömig 2008

SR/MA – RCT only

Ioannidis 2007

SR/MA – RCT only

RCT Final enrolment

ALKK 1997 Pharm. 28

SWISSI II 1997 Intensive pharm.

AVERT 1996 Pharm. 28

Dakik 1998 1996 Intensive pharm. 28

RITA 2 1996 Conservative

DANAMI 1994 Conservative

ACIP 1993 Anti-anginal

Horie 1998 1992 Pharm.

TOMIIS 1992 Pharm.

TOPS 1992 Pharm.

MASS 1991 Pharm.

ACME 1 1990 Pharm.

ACME 2 1990 Pharm.

Sievers 1993 NR NR Source: Adapted from Gorenoi et al (2011). Abbreviations: HTA, health technology assessment; MA, meta-analysis; NR, not reported; Pharm., pharmacological; RCT, randomised controlled trial; SR, systematic review.

28 Study results are only included in the sensitivity analysis. MBS Reviews – Percutaneous Coronary Intervention Review Report Page 121

January 2016

Table 5.1-5 Extent of stent use and medical therapies in included RCTs: chronic stable angina – PCI vs. medical therapy

RCT ID Final year of enrolment

Stent use%

β-blockerPCI%

β-blockerMedical

%

AspirinPCI%

AspirinMedical

%

StatinPCI%

StatinMedical

%

ACEIPCI%

ACEIMedical

%

OMT29

BARI 2D 2005 91 84 88 94 94 95 95 91 92

OAT 2005 87 86 89 97 94 80 82 80 80

TOSCA-230 2005 99 89 94 99 97 84 86 87 90

COURAGE 2004 94 85 89 96 95 86 89 58 60

INSPIRE 2002 39 86 93 95 100 77 84 57 77

DECOPI 2001 80 81 81 83 83 82 82 58 58

Not OMT31

JSAP 2004 76 44 52 92 91 49 45 22 14

Hambrecht 2001 100 86 88 98 98 80 72 88 74

Silva 2005 2001 100 100 83 100 100 39 25 100 100

MASS II 2000 72 61 68 80 80 73 68 30 29

TIME 2000 86 82 72 85 82 25 22 23 35

TOAT 1999 100 84 82 NR NR NR NR 100 100

DEFER 1998 46 62 71 92 92 37 37 NR NR

ALKK 1997 17 74 75 100 100 NR NR NR NR

SWISSI II 1997 0 37 91 98 98 33 28 35 46

AVERT 1996 39 69 62 89 82 69 93 8 9

Dakik 1996 32 84 82 100 100 53 45 NR NR

RITA 2 1996 9 68 65 87 87 13 12 9 11

DANAMI 1994 0 20 40 100 100 NR NR NR NR

29 Includes studies that meet Gorenoi’s definition of OMT; i.e. beta-adrenergic receptor blockers, aspirin and statins were used in at least 80% of the included patients, and ACE inhibitors were used in at least 50% of the included patients.30 Sub-study of OAT. 31 Includes studies that do not meet Gorenoi’s definition of OMT.MBS Reviews – Percutaneous Coronary Intervention Review Report Page 122

January 2016

RCT ID Final year of enrolment

Stent use%

β-blockerPCI%

β-blockerMedical

%

AspirinPCI%

AspirinMedical

%

StatinPCI%

StatinMedical

%

ACEIPCI%

ACEIMedical

%

Not OMT32

ACIP 1993 0 NR NR 88 90 NR NR NR NR

Horie 1992 29 27 28 64 67 NR NR 11 23

TOMIIS 1992 0 62 82 100 100 NR NR 79 94

TOPS 1992 0 37 37 100 100 NR NR NR NR

MASS 1991 0 52 46 75 78 42 36 30 25

ACME 1990 0 39 42 91 83 NR NR NR NR

Sievers 1993 NR 0 NR NR NR NR NR NR NR NRSource: Adapted from Gorenoi et al (2011): Table 12, p 51 and patient characteristics from other included SR/MAs. Abbreviations: ACEI, angiotensin converting enzyme inhibitor; PCI, percutaneous coronary intervention; RCT, randomised controlled trial.

Table 5.1-6 Studies included in the systematic reviews: chronic stable angina – PCI vs. CABG

Study ID Publication year/ Study type

SR/MA – RCT onlyD’Ascenzo 2014

SR/MA – RCT onlyFanari 2014

SR/MA – RCT/OBSQi 2014

SR/MA – OBS onlyTakagi 2014

RCT Publication year

FREEDOM 2012

Budriot 2011

PRECOMBAT 2011

Banning 2010 2010

CARDIa 2010

SYNTAX LM 2010

SYNTAX 2009

Le Mans 2008

Seoul 2005

MASS II 2004

32 Includes studies that do not meet Gorenoi’s definition of OMT.MBS Reviews – Percutaneous Coronary Intervention Review Report Page 123

January 2016






OBS Study type

Groningen 2002

Leipzig 2002

SoS 2002

ARTS 1 2001

AWESOME 2001

ERACI II 2001

SIMA 2000

BARI33 1996

EAST32 1994

GABI32 1994

RITA32 1993

VA CARDS34 Unknown

CARE 2013 Registry

Yi 2013 Retrospective cohort

Dohi 2012 Prospective cohort

Kim 2012 Registry

Yi 2012a Prospective cohort

Yi 2012b Retrospective cohort

Onuma 2011 Non-randomised trial

Shimizu 2010 Retrospective cohort -

Yamagata 2010 Registry

Dominguez-Franco 2009 Retrospective cohort

Qiao 2009 Cohort study

33 No stents inserted in this trial. 34 The correct citation for this study could not be identified from the publication. The citation provided appears to be from a retrospective cohort study. MBS Reviews – Percutaneous Coronary Intervention Review Report Page 124

January 2016






OBS Study type

Tarantini 2009 Registry

Yan 2009 Prospective cohort

Briguori 2007 Registry

Lee 2007 Registry

Moshkovitz 2005 Retrospective cohort Abbreviations: MA, meta-analysis; OBS, observational study; RCT, randomised control trial; SR, systematic review.


January 2016


Eleven Level I studies were identified that assessed the efficacy of a routine invasive strategy compared with a selective invasive strategy in patients with NSTE-ACS. A summary of the characteristics of these studies is provided in Table 5.1-7. The studies comprised two different types of meta-analyses: eight SR/MAs, and three meta-analyses based on individual patient data (IPD) from selected RCTs (IPD/MAs). Table 5.1-8 presents the RCTs included in each of the SR/MAs and IPD/MAs. No Level I studies were identified that compared PCI with CABG in this patient population.

None of the included Level I studies specifically assessed the effect of PCI; all studies examined an ‘invasive strategy’, which involved angiography, followed by revascularisation by either PCI (± stent insertion) or CABG where indicated. No Level I study provided efficacy and/or safety data stratified by type of intervention undertaken (i.e. results are not reported separately for PCI and CABG). Furthermore, the intervention and comparator arms were labelled slightly differently in different Level I studies; intervention strategies were labelled as either routine invasive, early invasive or invasive, while comparator strategies were labelled as selective invasive, conservative or initially conservative management. As shown in Table 5.1-9, the different labels essentially described the same interventions and comparators: angiography in all patients and angiography only in patients for whom it is clinically indicated, respectively.

The recommended medical therapies in the most relevant RCTs (see Section 5.2.2) are summarised in Table 5.1-10. The therapies used in trials are generally similar with the exception of GPIIb/IIIa receptor antagonists which were only routinely recommended in the IES, ICTUS, TACTICS-TIMI 18 and FRISC II trials, and the use of dalteparin (a low molecular weight heparin) in the FRISC II trial. In the FRISC II trial, patients were initially randomised to routine or selective invasive therapy, and then randomised to either dalteparin or placebo. Actual medical therapy use during the trial is available for the IES, TACTICS-TIMI 18 and FRISC II studies, and is shown in Table 5.1-11.

As shown in Table 5.1-12, the majority of patients who underwent revascularisation following angiography in the most relevant RCTs had PCI, rather than CABG.

While initially being considered for inclusion for this population, nine Level I studies were subsequently excluded from this Review because they compared an early invasive strategy with a delayed invasive strategy; that is, all patients were to undergo an invasive strategy, with the difference between groups being the timing of the intervention (see Table 5.1-2). These Level I studies included a different set of RCTs to the routine versus selective Level I studies described above, and these studies were specifically excluded from those reviews. An exception is the study by Damman et al (2012b), which used IPD data from the routine invasive strategy arm of the FRISC II, ICTUS and RITA 3 trials, and performed an IPD/MA to determine the effect of early (within 2 days) versus delayed (3-5 days) angiography. While not formally included in this MBS Review, for interest only, a selection of the results of these excluded Level I studies are tabulated in Appendix 9.

Finally, five conference abstracts which reported on studies comparing a routine (early) invasive strategy with a selective (conservative) invasive strategy have also been excluded due to the large amount of evidence available from fully published SR/MAs and IPD/MAs, and the fact that the abstracts contain minimal methodological information and interpretation of data (see Table 5.1-2).


January 2016

Table 5.1-7 Characteristics of included SR/MAs: diagnosis of NSTE-ACS – routine vs. selective invasive strategies


Studies (patients) Population Intervention35 Comparator34 Outcomes

SR/MA

Angeli 2014Fair [unknown]

9 RCTs (9400) NSTE-ACS Diabetes prevalence

subgroups

Early invasive strategy Initial conservative management All-cause death/MI (primary)All-cause deathMIRehospitalisation

O’Donoghue 2012Fair [unknown]

9 RCTs (9904) NSTE-ACS Diabetes subgroups

Invasive strategy Conservative strategy 12-month death/MI/ rehospitalisation with ACS12-month death/MI12-month death12-month non-fatal MI12-month rehospitalisation with ACS

Swahn 2012Fair [unknown]

5 RCTs (7871) NSTE-ACS Gender subgroups

Early invasive strategy Selective invasive strategy Death/MI

Hoenig 2010Good [good]36

5 RCTs (7818) NSTE-ACS GPIIb/IIIa subgroups Gender subgroups

Early invasive strategy Conservative strategy Primary outcomesAll-cause deathMIDeath/MIRefractory anginaSecondary outcomesRehospitalisation for ACSComplications of angiography or revascularisation (i.e. bleeding, procedure-related MI or stroke)

35 Detailed definitions of the interventions and comparators for each study are provided in Table 5.1-9. 36 Two trials that included treatment with glycoprotein IIb/IIIa receptor antagonist use considered good quality. Two remaining trials fair (2) and poor (1) quality. MBS Reviews – Percutaneous Coronary Intervention Review Report Page 127

January 2016


Studies (patients) Population Intervention Comparator34 Outcomes

Charyton 2009Good [fair]

5 RCTs (1453) NSTE-ACS and CKD Early invasive strategy Conservative strategy 1-year death (primary)In-hospital deathIn-hospital MIIn-hospital death/MI1-year MI1-year death/MI1-year rehospitalisation

O’Donoghue 2008Fair [unknown]

8 RCTs (10,150) NSTE-ACS Gender subgroups

Early invasive strategy Conservative strategy Death/MI/ rehospitalisation with ACSDeath/MIRevascularisationPCICABG

Qayuum 2008Good [fair]

10 RCTs (10,648) NSTE-ACS Routine invasive strategy Selective invasive strategy DeathNon-fatal MIDeath/MI

Tarantini 2007Fair [unknown]

8 RCTs (10,412) NSTE-ACS Routine invasive strategy Conservative strategy All-cause mortalityDeath/MI

IPD/MA

Alfredsson 2014-

3 RCTs (5467) NSTE-ACS Gender subgroups

Routine invasive strategy Selective invasive strategy 5-year CV death/MI (primary)5-year CV death5-year MI

Damman 2012a-

3 RCTs (5467) NSTE-ACS Age subgroups


Fox 2010-

3 RCTs (5467) NSTE-ACS Risk subgroups


Note: Quality assessment forms for each SR/MA available in Appendix 8. Abbreviations: ACS, acute coronary syndrome; CABG, coronary artery bypass graft; CKD, chronic kidney disease; CV, cardiovascular; GPIIb/IIIa, glycoprotein IIb/IIIa receptor antagonists; IPD/MA, individual patient data meta-analysis; MI, myocardial infarction; NSTE-ACS, non-ST-segment elevation acute coronary syndrome; RCT, randomised controlled trial; SR/MA, systematic review meta-analysis; UA, unstable angina


January 2016

Table 5.1-8 Studies included in the systematic reviews: diagnosis of NSTE-ACS – routine vs. selective invasive strategies

RCT ID Publication year

Angeli 201437

SR/MA- RCT only

O’Donoghue 2012

SR/MA- RCT only

Swahn 2012

SR/MA- RCT only

Hoenig 201038

SR/MA- RCT only

Charytan 2009

SR/MA- RCT only

O’Donoghue 2008

SR/MA- RCT only

Qayyum 2008

SR/MA- RCT only

Tarantini 2007

SR/MA- RCT only

Alfredsson 2014

IPD/MA– RCT only

Damman 2012a

IPD/MA– RCT only

Fox 2010IPD/MA– RCT only

IES 2012

OASIS-5 sub-study 2012

Eisenberg 2005

ICTUS 2005

RITA 3 2002

VINO 2002

TACTICS-TIMI 18 2001

TRUCS 2000

FRISC II 1999

MATE 1998

VANQWISH 1998

TIMI 3B 1994 Abbreviations: ACS, acute coronary syndrome; IPD, individual patient data; MA, meta-analysis; NSTE-ACS, non-ST-segment-elevation acute coronary syndrome; RCT, randomised controlled trial; SR, systematic review.

37 Excluded studies that were considered non-contemporary (i.e. low use of dual oral antiplatelet therapy and stenting, or use of antifibrinolytic agents).38 Included only studies conducted during the ‘stent era’. The stent era is not defined. MBS Reviews – Percutaneous Coronary Intervention Review Report Page 129

January 2016

Table 5.1-9 Intervention and comparator definitions in the systematic reviews: diagnosis of NSTE-ACS – routine vs. selective invasive strategies

Study ID Intervention definition Comparator definition

SR/MA

Angeli 2004 Early invasive strategyCoronary angiography performed within 4 days from hospitalisation or randomisation.

Initially conservative managementEarly conventional medical therapy or selective invasive management if indicated by refractory or recurrent symptoms or inducible ischaemia (ischaemia-driven or symptom driven angiography).

O’Donoghue 2012

Invasive strategyRoutine coronary angiography in all patients followed by PCI or CABG if deemed appropriate.

Conservative strategyA primary strategy of pharmacological management and subsequent selective coronary angiography reserved for those patients with recurrent symptoms of unprovoked ischaemia or objective evidence of inducible ischaemic on non-invasive testing.

Swahn 2012 Early invasive strategyThe referral of all patients with NSTE-ACS for coronary angiography, followed by revascularisation if suitable.

Selective invasive strategyInitial pharmacological treatment followed by coronary angiography (and subsequent revascularisation if suitable) only in patients with symptoms of ischaemia or severe signs of ischaemia on non-invasive stress testing.

Hoenig 2010 Routine invasive strategyRoutine angiography with or without revascularisation in all patients. This was carried out in all eligible patients unless they had contraindications to angiography.

Conservative strategyAngiography with or without revascularisation only in eligible patients with evidence of cardiac ischaemia e.g. recurrent ischaemia, dynamic ECG changes or a positive stress test.

Charytan 2009 Routine invasive strategyRoutine, pre-discharge coronary angiography followed by revascularisation when appropriate.

Selective invasive strategyCoronary angiography in patients with inducible ischaemia or recurrent, spontaneous ischaemia.

O’Donoghue 2008

Early invasive strategyReferral of all patients with NSTE-ACS for coronary angiography followed by revascularisation if deemed appropriate.

Conservative strategyA conservative treatment strategy was defined as a primary strategy of pharmacological management and subsequent coronary angiography reserved only for those patients with recurrent symptoms of unprovoked ischaemia or objective evidence of inducible ischemia on non-invasive testing.

Qayyum 2008 Routine invasive strategyPatients with NSTE-ACS routinely had coronary angiography and revascularisation if appropriate.

Selective invasive strategyPatients with NSTE-ACS received aggressive pharmacologic therapy and coronary angiography, and if appropriate, revascularisation was performed only in the presence of cardiac ischaemia refractory to medical treatment or inducible by provocative testing.

Tarantini 2007 Routine invasiveThe referral of all patients with NSTE-ACS after initial medical treatment to coronary angiography, and if indicated, revascularisation in most, or all, patients with a suitable coronary anatomy who had no contraindications.

Conservative strategyAn approach whereby patients were treated with pharmacological therapy and underwent coronary angiography and revascularisation only if there was evidence of recurrent ischaemia (e.g. recurrent infarction, angina at rest, dynamic ST changes on ECG or definitive inducible ischaemia on provocative testing).

IPD/MA

Alfredsson 2014 Routine invasiveRoutine early coronary angiography with subsequent PCI or CABG, if feasible.

Selective invasiveInitial pharmacological stabilisation and an invasive approach if a patient had symptoms of ischaemia despite medical treatment, haemodynamic instability, or signs of ischaemia on a stress test


January 2016

Study ID Intervention definition Comparator definition

IPD/MA

Damman 2012 Routine invasiveEarly coronary angiography with subsequent revascularisation, if appropriate, within 7 days.

Selective invasiveInitial medical treatment with coronary angiography and revascularisation only in the case or refractory angina despite OMT (or haemodynamic or rhythmic instability in the ICTUS trial).

Fox 2010 Routine invasiveEarly coronary angiography. The decision to proceed to percutaneous or surgical revascularisation was based on angiographic findings.

Selective invasiveInitial medical treatment with coronary angiography and revascularisation only for refractory or an accelerating pattern of angina despite OMT (or haemodynamic or rhythmic instability in the ICTUS trial).

Abbreviations: ACS, acute coronary syndrome; CABG, coronary artery bypass graft; ECG, electrocardiogram; IPD, individual patient data; MA, meta-analysis; NSTE-ACS, non-ST-segment elevation acute coronary syndrome; OMT, optimal medical therapy; PCI, percutaneous coronary intervention; SR, systematic review.

Table 5.1-10 Medical therapies recommended in the selected RCTs: diagnosis of NSTE-ACS – routine vs. selective invasive therapies

Trial Treatment Admission

IES Aspirin All patients: 325 mg po (admission); 75-100 mg (follow-up)

Clopidogrel All patients: 300 mg (admission); 75 mg (follow-up)

Enoxaprin All patients: iv bolus of 3000 U, followed by sc administration of 75 U/kg (max 6000 U) bid for 3-5 days. Latest dose ≥ 8 hours prior to angiography No further UFH/enoxparin post-angiography except for patients laying in bed (50 U od)

Fondaparinux

All patients: 2.5 mg sc od during the entire hospital stay, particularly in patients treated conservatively

UFH All undergoing angiography: 2500 iv bolus, then start infusion of 7U/kg/hr nomogram-adjusted to a target aPTT of 50-70 seconds up to 30 mins prior to angiography

GPIIa/IIIb All undergoing angiography: Upstream eptifibatide-tirofiban if delay to angiography > 4 hours Post-angiography abciximab, particularly if delay to angiography < 4 hours

Bivalirudin All undergoing PCI: iv bolus 0.75 mg/kg then 1.75 mg/kg/hour infusion during PCI

ICTUS Aspirin All patients: 300 mg (randomisation); 75 mg (indefinitely)

Clopidogrel All patients: 300 mg (randomisation); 75 mg (indefinitely)39

Statins All patients: 80 mg of atorvastatin (or equivalent) started after randomisation and continued indefinitely

Enoxaparin All patients: 1 mg/kg to a maximum of 70 mg bid sc (for at least 48 hours) Patients already on UFH switched to enoxaparin at randomisation

GPIIa/IIIb All undergoing angiography: abciximab 0.25 mg/kg bolus, followed by infusion of 0.125 μg/kg per minute for 12 hours, and started 10 to 60 minutes before the first balloon inflation Also available for patients who subsequently underwent PCI

RITA 3 Aspirin All patients: dose not specified

Nitrates All patients: dose not specified

Enoxaparin All patients: 1 mg/kg bid sc for 2-8 daysAll undergoing PCI: Continued for up to 8 days or hospital discharge Elective – last dose given 12 hours before Urgent or emergency within 6 hours of last dose – no additional anticoagulation given

GPIIb/IIIa40 All undergoing PCI: at discretion of operator

39 Following approval of clopidogrel in 2002. 40 And other antithrombotic agents.


January 2016

Trial Treatment Admission

VINO Aspirin All patients: 250 mg bolus iv followed by 200 mg/day for the duration of the study

UFH All patients: 5000 U followed by a continuous infusion to maintain an aPTT in the range of 50-75 seconds, or with a full therapeutic dose of LMWH

Ticlopidine All undergoing stenting: 250 mg bid for 1 month

Anti-ischaemic

At discretion of attending physician

Other drugs At discretion of attending physician

TACTICS-TIMI 18

Aspirin All patients: 325 mg daily (unless contraindicated)

UFH All patients: 5000 U as a bolus, followed by an infusion at a rate of 1000 U/hour for 48 hours

GPIIb/IIIa All patients: tirofiban loading dose of 0.4 μg/kg/min for 30 minutes followed by maintenance infusion of 0.1 μg/kg/min for 48 hours or until revascularisationAll undergoing PCI: tirofiban administered for at least 12 hours

Β-blockers All patients: recommended

Nitrates All patients: recommended

Statins All patients: recommended

FRISC II Aspirin All patients: 300-600 mg on admission followed by maintenance dose of 75-320 mg od

Β-blocker All patients: unless contraindicated

LMWH All patients: Dalteparin at 120 IU/kg every 12 hours sc (maximum 10,000 IU) Until procedure in invasive group For 5 days in non-invasive groupThereafter, women < 80 kg and men < 70 kg received 5000 IU dalteparin or placebo (as randomised) and other women or men received 7500 IU or placebo (as randomised), continued for 3 monthsAll undergoing angioplasty: dalteparin or placebo (as randomised) restarted after 2-6 hours (or 24 hours after infusion of GPIIb/IIIa or abciximab)

Nitrates All patients: as required

CCA All patients: as required

Statins All patients: according to treatment guidelines

ACEI All patients: according to treatment guidelines

Antidiabetic All patients: according to treatment guidelines

GPIIb/IIIa All undergoing PCI: abciximab use encouraged

Ticlopidine All undergoing stenting: recommended for 3-4 weeksNote: Studies that used GPIIb/IIIas routinely are shown in shading.Abbreviations: ACEI, angiotensin converting enzyme inhibitor; aPTT, activated partial thromboplastin time; bid, twice daily; CCA, calcium channel antagonist; GPIIb/IIIa, glycoprotein IIb/IIIa inhibitor; IU, International Units; iv, intravenous; LMWH, low molecular weight heparin; NSTE-ACS, non-ST-segment-elevation acute coronary syndrome; od, once daily; PCI, percutaneous coronary intervention; po, per oral; sc, subcutaneous; UFH, unfractionated heparin.


January 2016

Table 5.1-11 Medical therapy use during the included RCTs: diagnosis of NSTE-ACS – routine vs. selective invasive therapies

Medical therapy Routine%

Selective%

IES In-hospital/at discharge In-hospital/at discharge

Aspirin 95/92 99/97

Ticlopidine 4.6/2.7 1.9/1.9

Clopidogrel 90/73 92/86

GPIIb/IIIa (all) 17 6

GPIIb/IIIa (PCI) 2441 1740

UFH 25 24

Enoxaparin 64 59

Bivalirudin 3.8 1.3

Fondaparinux 8.5 8.5

TACTICS-TIMI 18 6 months

Aspirin 98

Heparin >99

Tirofiban (GPIIb/IIIa) >9942

β-blockers 82

Nitrates 94

Statins 52

FRISC II 3 months 3 months

Aspirin 96 94

β-blocker 74 84

Long-acting nitrates 17 38

CCA 18 23

ACEI 17 18

Statin 56 55Source: IES (Savonitto et al, 2012): Table 4, p 910; TACTICS-TIMI 18 (Cannon et al, 2001): text, p 1880; FRISC II (FRISC II Investigators, 1999): Table 7, p 712. Abbreviations: ACEI, angiotensin converting enzyme inhibitor; CCA, calcium channel antagonist; GPIIb/IIIa, glycoprotein IIb/IIIa receptor inhibitor; NSTE-ACS, non-ST-segment elevation acute coronary syndrome; PCI, percutaneous coronary intervention; RCT, randomised controlled trial; UFH, unfractionated heparin.

41 Percentage based on patients who received PCI42 PCI patients only


January 2016

Table 5.1-12 Angiography and revascularisation in the included RCTs: diagnosis of NSTE-ACS – routine vs. selective invasive therapies

RCT ID Pubn year Follow-up CAGRoutine

%

CAGSelective

%

Revasc.Routine

%

Revasc.Selective

%

PCIRoutine

%

PCISelective

%

CABGRoutine

%

CABGSelective

%

IES 2012 Hospitalisation 88 29 - - 51 23 6 <1

ICTUS 2005 2 days 97 11 56 4 53 4 2 <1

Hospitalisation 98 53 76 40 60 28 16 11

1 year 99 67 79 54 61 40 18 14

RITA-3 2002 Hospitalisation 96 16 44 10 33 7 12 4

1 year 97 48 57 28 36 16 22 12

VINO 2002 6 months 100 55 73 39 52 13 35 30

TACTICS-TIMI 18 2001 Hospitalisation 97 51 - - 41 24 20 13

6 month 98 61 - - 42 29 22 13

FRISC II 1999 10 days - - 71 9 - - - -

6 months 98 47 77 37 - - - -Source: IEA (Savonitto et al, 2012): Table 3, p 910; ICTUS (de Winter et al, 2005): Table 2, p 1099; RITA-2 (Fox et al, 2002): Table 2, p 746; VINO (Špaček et al, 2002): Table 3, p 233; TACTICS-TIMI 18 (Cannon et al, 2001): Table 2, p 1881; FRISC II (1999), Table 2, p 709 and text, p 711.Abbreviations: CABG, coronary artery bypass graft; CAG, coronary angiography/catheterisation; NSTE-ACS, non-ST-segment elevation acute coronary syndrome; PCI, Percutaneous coronary intervention; Pubn, publication; RCT, randomised controlled trial; revasc., revascularisation.


January 2016

5.1.3 Assessment of high risk based on diagnostic testing

Two recent systematic reviews that included meta-analyses of RCTs were identified that assessed the efficacy of PCI compared with medical therapy in patients considered to be at high risk of coronary events based on the results of diagnostic testing (Gada et al, 2015; Stergiopoulos et al, 2014). No systematic reviews were identified in this patient population that compared PCI with CABG. The diagnostic tests considered included non-invasive tests such as stress echocardiography or myocardial perfusion imaging, or invasive diagnostic testing such as FFR. The main characteristics of the two included studies are presented in Table 5.1-13.

It should be noted that a conference abstract by Kirtane et al (2013) met the inclusion criteria but has been excluded because it appears to be an earlier version of the meta-analysis by Gada et al (2015). While it includes one additional RCT compared with the meta-analysis by Gada et al (2015), the figure included with the abstract is poor quality and it is not possible to identify the additional study. An additional systematic review by Nascimento et al (2015) was also excluded because it was largely based on data from observational studies, and compared performance of PCI with deferred PCI.

The two included SR/MAs had slightly different inclusion criteria that resulted in inclusion of different RCTs, as shown in Table 5.1-14. Gada et al (2015) required that studies include patients who had been assessed as having ischaemia based on non-invasive stress testing or abnormal FFR findings, and excluded trials that relied exclusively on symptoms, electrocardiogram (ECG) or exercise treadmill testing (ETT) without imaging to qualify ischaemia. Thus, Gada et al (2015) included only three RCTs: COURAGE nuclear sub-study, FAME 2 and SWISSI II. The Gada et al (2015) systematic review was considered to be of poor methodological quality because it failed to report any details of the literature search used to identify relevant studies, and failed to undertake a quality assessment of the included studies.

Stergiopoulos et al (2014), on the other hand, included studies with ‘documented’ myocardial ischaemia or abnormal FFR in some or all patients. However, in studies where not all patients had documented ischaemia, the authors were contacted and provided data on the subset of patients with ischaemia at baseline. There is no indication that patients with ischaemia were identified via diagnostic testing and so the SR/MA by Stergiopoulos et al (2014) likely includes a broader patient population that the SR/MA by Gada et al (2015).

Table 5.1-15 includes a list of the RCTs included in the Gada and Stergiopoulos SR/MAs, as well as the specific patient inclusion criteria for these studies, and the types of PCI intervention undertaken in these trials. The three RCTs most relevant to this MBS Review are noted; each of these studies specifically required diagnostic testing as defined above.

As shown in Table 5.1-16, a range of medical therapies were included in the three RCTs included in the Gada et al (2015) review. The broadest range of medical therapies was included in the FAME 2 study; this is not surprising given the FAME 2 study is the most recent of the included RCTs.


January 2016

Table 5.1-13 Characteristics of included systematic reviews: high-risk based on diagnostic testing – PCI vs. medical therapy



SR/MA - RCT

Gada 2015Poor [unknown]

3 RCTs (1557) Stable coronary heart disease and objective evidence of myocardial ischaemia Ischaemia documented by

either non-invasive stress imaging or abnormal FFR

Excluded trials that relied exclusively on symptoms, ECG or ETT without imaging to qualify ischaemia

PCI + medical therapy Medical therapy All-cause mortality

Stergiopoulos 2014Good [fair]

5 RCTs (5286) Stable CAD with documented myocardial ischaemia or abnormal FFR in some or all patients Implantation of stents in

≥50% patients and statin use in ≥ 50% of patients

PCI + medical therapy Medical therapy DeathMIUnplanned revascularisationAngina

Note: Quality assessment forms for each SR/MA available in Appendix 8. Abbreviations: CAD, coronary artery disease; ECG, electrocardiography; ETT, exercise treadmill testing; FFR, fractional flow reserve; MI, myocardial infarction; PCI, percutaneous coronary intervention; RCT, randomised controlled trial; SR, systematic review; MA, meta-analysis.


January 2016

Table 5.1-14 Studies included in systematic reviews: high risk based on diagnostic testing – PCI vs. medical therapy

Study ID Publication year Gada 2015SR/MA – RCT

Stergiopoulos 2014SR/MA – RCT

RCT

COURAGE nuclear sub-study 2012

FAME 2 201243

BARI 2D 2009

COURAGE 2007

SWISSI II 2007

MASS II 2007

Hambrecht 2004 Abbreviations: MA, meta-analysis; PCI, percutaneous coronary intervention; RCT, randomised controlled trial; SR, systematic review.

Table 5.1-15 Definitions of ischaemia in the included RCTs: high risk based on diagnostic testing – PCI vs. medical therapy

Study ID Publication year

Criteria for diagnosis of ischaemia

RCT

COURAGE nuclear sub-study44

2012 Moderate to severe defined as ≥3 ischaemic segments on nuclear imaging

FAME 243 201242 Pressure wire showing FFR ≤0.80 during adenosine-induced hyperaemia in at least 1 major coronary artery

BARI 2D 2009 ≥1-mm horizontal ST depression or downsloping ST-segment depression or elevation for ≥60-80 milliseconds after the end of the QRS complex; myocardial perfusion defect; myocardial wall motion abnormality; decline in ejection fraction with stress; Doppler or pressure wire showing coronary flow reserve <2.0 or fractional flow reserve <0.75

COURAGE 2007 Any of >1-mm ST deviation on standard treadmill exercise ECG; ≥1 scintigraphic perfusion defect during exercise technetium, 99mTc sestamibi, or thallium imaging; ≥1 perfusion defect (reversible or partial reversible) with pharmacologic (dipyridamole, adenosine) stress during 99mTc sestamibi or thallium imaging; ≥1 wall motion abnormality during exercise radionuclide ventriculography or 2-dimensional echocardiography (exercise or dobutamine)

MASS II 2007 Clinical (angina) and/or ECG (magnitude of horizontal or downsloping ST-segment depression) and/or scintigraphic (severity and extent of the perfusion defects)

SWISSI II43 2007 Symptom-limited ETT with ST depression and confirming stress imaging

Hambrecht 2004 2004 Presence of angina ST-segment changes ≥1 mm horizontal or downsloping ST depression. Presence of any perfusion defect

Abbreviations: BMS, bare metal stent; ECG, electrocardiogram; ETT, exercise treadmill testing; FFR, fractional flow reserve; SPECT, single-photon emission computed tomography.

43 Updated publication in 2014. 44 The COURAGE nuclear sub-study, FAME 2 and SWISSI II trials are the most relevant to this MBS Review because they provide data on patients considered at high risk based on diagnostic testing.


January 2016

Table 5.1-16 Medical therapies used in the most relevant RCTs: high risk based on diagnostic testing – PCI vs. medical therapy

Study ID Time point

Aspirin

%

p value

P2Y12 inhibitors

%

p value

Anti-platelet

%

p value

Statin

%

p value

Β-blocker

%

p value

ACEI/ AIIRA

%

p value

CCB

%

p value

Nitrate

%

p value

RCT

COURAGE nuclear sub-study

Baseline - - 93 v 910.53

75 v 690.16

72 v 680.39

54 v 57NR

37 v 300.17

60 v 600.98

FAME 2 Baseline 87 v 900.25

49 v 450.20

- 83 v 820.73

76 v 780.43

69 v 700.72

23 v 230.94

-

1 mo 99 v 960.009

98 v 45<0.001

- 95 v 960.74

85 v 900.018

80 v 820.67

24 v 330.004

-

6 mo 99 v 950.001

96 v 49<0.001

- 96 v 950.41

81 v 840.25

81 v 830.60

26 v 320.037

-

12 mo 96 v 950.32

67 v 44<0.001

- 95 v 940.54

80 v 810.61

79 v 840.06

27 v 320.12

-

24 mo 93 v 930.90

20 v 250.10

- 92 v 920.99

77 v 800.32

81 v 820.60

30 v 320.71

-

SWISSI II 4-y fu - - - - 49 v 86<0.001

- 21 v 51<0.001

12 v 47<0.001

Final fu - - - - 39 v 84<0.001

- 17 v 320.09

4 v 45<0.001

Source: COURAGE nuclear sub-study (Shaw et al, 2012): Table 1, p 245; FAME 2 (De Bruyne et al (2014): Supplementary appendix Table S4, p20-21; SWISSI II (Erne et al, 2007): Table 3, p 1989. Notes: Statistically significant differences shown in bold. Abbreviations: ACEI, angiotensin converting enzyme inhibitor; AIIRA, angiotensin II receptor antagonist; CCB, calcium channel blocker; fu, follow-up; mo, months; MT, medical therapy; PCI, percutaneous coronary intervention; v, versus; y, year.

5.2 Effectiveness and safety of PCI

The following section outlines the findings of the clinical evidence for the three populations of interest to this MBS Review: (i) patients with chronic stable angina (Section 5.2.1), (ii) patients with a diagnosis of NSTE-ACS (Section 5.2.2) and (iii) patients considered to be at high risk of coronary events based on diagnostic testing (Section 5.2.3). Each section will initially include an assessment of Level I evidence (systematic reviews) followed by an assessment of the most relevant Level II evidence (RCTs) only where outcomes or subgroup analyses are lacking.

The review of the published CPGs showed that a number of recommendations are made on the expected risk of future events in patients who have particular clinical demographic and clinical characteristics. As such, while not specifically included as a subgroup in the Review Protocol, data on the benefits and risk of PCI in different risk subgroups have been included in this MBS Review.

An important point to note is that while the Review Protocol has defined the intervention as being PCI with stent use, not all patients included in the studies identified by included systematic reviews received stents following PCI. In addition, while one of the comparators is defined as medical therapy, not all studies used medical therapy that reflects current practice.


January 2016

As such, an effort has been made to ensure that the evidence given the most weight in this MBS Review is that in which the majority of patients undergoing PCI have received stents, and the medical therapies used reflect those used in current clinical practice.


The following section provides data on the assessment of patients with chronic stable angina, and includes comparisons between PCI and OMT, and PCI and CABG. First, the findings of Level I studies (SR/MAs) are shown. Where PICO outcomes and subgroups are not addressed by Level I evidence, the results of individual RCTs are then presented.

It is important to note that the majority of the included systematic reviews (and their included RCTs) were not limited only to patients with chronic stable angina. Many of the studies were conducted in patients with stable CAD, stable ischaemic disease or non-acute CAD, or in patients who were stable following an MI; patients with stable angina made up a subset of those patients.

PCI versus medical therapy

Level I evidence A summary of the results of the 11 included SR/MAs that compare PCI with medical therapy is presented in Table 5.2-1. Only four reviews will be discussed in detail: the HTA by Gorenoi et al (2011) and the SR/MAs by Bangalore et al (2013), Morrone et al (2013) and Pursnani et al (2012); these four reviews aimed to compare PCI with optimal medical therapy rather than any medical therapy.

Gorenoi et al (2011) systematically identified existing SR/MAs of PCI versus medical therapy in patients with stable angina. From these SR/MAs they identified all included RCTs and then applied their definition of OMT45 to select studies for meta-analysis. Based on their definition, they identified three RCTs for inclusion: COURAGE, OAT and BARI 2D. As shown in Table 5.2-1, the results of their analysis showed no difference between PCI and OMT for all-cause mortality, cardiac mortality, MI, the composite of death/MI, stroke, composite of death/MI and death/MI/stroke, severe heart failure or the composite of death/MI/stroke/severe heart failure. However, use of PCI compared with OMT resulted in less angina at 1 and 3 years (not 5 years) and fewer repeat revascularisations at 5 years. This SR/MA was rated as good quality and the included studies were also rated (by Gorenoi and colleagues) as good quality. There was no significant heterogeneity in any of the analyses except for the repeat revascularisation outcome (phet=0.04; I2=78%).

As noted in Section 5.1.1, Gorenoi et al (2011) included only the COURAGE, OAT and BARI-2D studies in their meta-analysis; however, three additional studies appear to meet their definition of OMT: DECOPI, INSPIRE and TOSCA-2. As noted in their review, TOSCA-2 was excluded because it was a sub-study of OAT. The primary outcome of the INSPIRE study is reduction in total and ischaemic left ventricular perfusion defect size (LV PDS), which is not included in the Gorenoi review or the current MBS Review, and this study has been excluded from further consideration. It is unclear why DECOPI has been excluded from their review. For this reason, where appropriate data are available, the Gorenoi meta-analysis has been replicated for the purpose of this MBS Review, with data from the DECOPI study added. As can be seen in Table 5.2-1 (and the relevant forest plots shown in Figure 5.2-1 to Figure 5.2-4), addition of data from the DECOPI study has no impact on the findings of the 45 Use of beta-adrenergic receptor blockers, aspirin and statins in about 80% of the included patients and use of ACE inhibitors in 50% of the included patients.


January 2016

Gorenoi review and did not result in significant heterogeneity in any of the analyses except for the repeat revascularisation outcome (phet=0.08; I2=60%).

Bangalore et al (2013) aimed to investigate whether PCI + OMT reduced spontaneous MI compared with OMT alone. In this SR, OMT was defined as a medical therapy consisting of at least an antiplatelet, antianginal and lipid-lowering agent. Analyses were stratified by stent use in the trials. As shown in Table 5.2-1, there was no significant difference between PCI + OMT and OMT alone for all-cause mortality and CV mortality in the all-study analysis. Interestingly, the point estimate for the no stent subgroup analyses were lower than for the stent subgroup analyses (incidence rate ratio [IRR] 0.71 vs. 0.95 for all-cause mortality and IRR 0.47 vs. 1.08 for CV mortality); CV mortality in the no stent trials was significantly reduced for PCI + OMT compared with OMT alone. There was also no significant difference in all MI between PCI + OMT and OMT alone, with no significant difference also seen in the stent and no stent subgroups (both IRR 1.02). However, procedural MI was significantly higher in the PCI + OMT group compared with the OMT alone group for the all-study analysis (IRRs 3.22), and the stent and no stent subgroups (IRRs 3.05 and 4.12, respectively). Spontaneous MI was significantly lower for PCI + OMT in the overall analysis (IRR 0.77; 95% CI 0.60, 0.99), but failed to reach statistical significance in the stent and no stent subgroups (IRR 0.86 and 0.72, respectively). This study was considered to be of good methodological quality. While quality assessment of the individual studies was assessed, the quality of the evidence base was not reported. However, the authors did note that a sensitivity analysis on study quality was not undertaken because all included studies fared similarly on the risk of bias assessment.

Morrone et al (2013) performed a meta-analysis of RCTs comparing PCI with OMT; it should be noted that OMT was not defined in the publication (available as a conference abstract). They performed an overall analysis of all patients with stable ischaemic disease (including 17 RCTs) and subgroup analyses of patients with stable CAD (8 RCTs) and patients following MI (9 RCTs) and found no benefit of PCI over OMT for any outcome, in the overall population, or both subgroups (Table 5.2-1). This study was rated as poor quality due to the lack of reported individual study details and quality assessment.

Pursnani et al (2012) compared PCI with OMT, defined as a medical regimen consisting of at least an antiplatelet, antianginal and lipid-lowering agent; 12 studies met this criteria and were included in the meta-analysis. The results of the analysis are presented in Table 5.2-1, and show that PCI provides no benefit, or harm, compared with OMT, with the exception being a significant reduction in angina at follow-up or up to 5 years. As noted by Pursnani et al (2012), angioplasty without stenting was performed in the majority of trials with only four included RCTs having stents used in >50% of participants: BARI 2D, COURAGE, MASS II and JSAP. A subgroup analysis of all-cause mortality including only these trials also showed no significant benefit of PCI over OMT. This study was rated as good quality and the included studies were rated (by Pursnani and colleagues) as fair quality.

The results of the seven additional included SR/MAs are also summarised in Table 5.2-1 and are generally consistent with the results reported above, finding that PCI provides no additional benefit over medical therapy for mortality and MI in patients with chronic stable angina (or a wider group that includes patients with chronic stable angina). The results suggest that PCI may provide benefit in reduction in angina and fewer repeat revascularisations; however, as noted by Wijeysundera et al (2010), the benefit in freedom from angina was largely attenuated in contemporary studies, which may be related to greater use of evidence-based medications in contemporary trials.


January 2016

The majority of the included SR/MAs were not limited to assessing PCI in patients with chronic stable angina; a number of SR/MAs included a broader patient population that included stable or non-acute coronary disease. The SR/MA by Stergiopoulos and Brown (2012), conducted in a patient population with stable CAD, examined the effect of PCI compared with medical therapy in subgroups of studies that included either patients post MI, or patients with angina or ischaemia (see Table 5.2-1). They found no difference between the subgroups of patients for all-cause mortality, unplanned revascularisation and freedom from angina, but did find a difference for non-fatal MI, which was numerically higher for PCI compared with medical therapy in patients post MI (p=0.05). Wijeysundera et al (2010) also assessed subgroups of studies that did nor did not include recent-MI patients and found that PCI provided significantly greater freedom from angina than medical therapy for both subgroups, although the point estimate was higher for the recent-MI group compared with the no recent-MI group (OR 1.92; 95% CI 1.11, 3.33 and OR 1.58; 95% CI 1.07, 2.33, respectively). These findings suggest that the results seen in the broader CAD population may be generalisable to a stable angina population.

Furthermore, in one of the RCTs included in the SR/MAs (BARI 2D), in which patients with CAD and diabetes were randomised to either revascularisation (PCI or CABG) or OMT, an assessment of the prognostic impact of angina was undertaken. Compared with patients without angina, patients with an angina equivalent,46 any angina, angina Canadian Cardiovascular Society (CCS) Class I or II, or CCS Class III or IV, had no significant difference in rate of all-cause mortality, death/MI/stoke, CV death, non-fatal MI or nonfatal stroke (Dagenais et al, 2013). The authors conclude that whatever the symptom status of the patient (i.e. whether or not they have angina and the severity of the angina), those with type 2 diabetes and stable CAD ‘may be similarly managed in terms of risk stratification and preventative therapies’.

DES vs BMSTrikalinos et al (2009) assessed the effect of PCI in patients with non-acute coronary disease using direct and indirect meta-analysis. As part of this assessment, they separately compared BMS and DES with medical therapy, as well as compared BMS with DES. As shown in Table 5.2-1, there was no significant difference between BMS and medical therapy for the direct or indirect analyses. There were no trials directly comparing DES and medical therapy so only indirect comparisons were available for the outcomes of interest (all-cause mortality, MI and CABG). These indirect comparisons showed no difference between DES and medical therapy for all-cause mortality and MI, and a significantly reduced risk of CABG for DES compared with medical therapy (RR 0.58; 95% CI 0.38, 0.88). It is important to note that the inclusion of trials in these analyses was not limited to those in which OMT was used, which may have biased the findings in favour of PCI. Finally, direct and indirect comparisons between DES and BMS were undertaken, showing no difference between the different types of stents for all-cause mortality and MI, and a significantly reduced risk of CABG for patients receiving DES compared with BMS for both the direct (RR 0.56; 95% CI 0.36, 0.88) and indirect (RR 0.56; 95% CI 0.39, 0.80) comparisons.

In summary, the results of the Level I comparison of PCI with OMT in patients with chronic stable angina suggest that the addition of PCI to OMT does not reduce the risk of death, but may have benefits in terms of reduction in angina, and harms associated with procedural MI.

46 Commonly defined as symptoms of myocardial ischaemia including shortness of breath, sweating, extreme fatigue, or pain at a site other than the chest, occurring in a patient at high cardiac risk.


January 2016

The use of DES or BMS does not result in differences in all-cause mortality or MI, while DES appears to reduce the risk of requiring CABG compared with the use of BMS.


January 2016

Table 5.2-1 Results of included systematic reviews: chronic stable angina – PCI versus medical therapy

Study ID Population Comparison Outcome Studies (patients)


Authors’ conclusions

HTA

Gorenoi 2011 Stable angina PCI vs. OMT All-cause mortalityAll-cause mortality + DECOPICardiac mortalityCardiac mortality + DECOPIMIMI + DECOPIDeath/MIStrokeDeath/MI/strokeSevere heart failureDeath/MI/severe heart failureAngina – 1 yAngina – 3 yAngina – 5 yRepeat revasc.Repeat revasc. + DECOPI

3 (6058)4 (6270)3 (6058)4 (6270)3 (6058)4 (6270)3 (6058)3 (6058)3 (3892)1 (2166)1 (2166)2 (3963)2 (2616)2 (1016)2 (5260)3 (4665)

RR 1.00 (0.85, 1.17); 0.99RR 0.99 (0.85, 1.16); 0.94RR 1.09 (0.87, 1.38); 0.45RR 1.08 (0.86, 1.36); 0.51RR 1.16 (0.99, 1.36); 0.06RR 1.16 (1.00, 1.36); 0.06RR 1.10 (0.98, 1.23); 0.10RR 1.09 (0.76, 1.56); 0.65RR 1.09 (0.94, 1.28); 0.26RR 0.98 (0.65, 1.48); 0.92RR 1.15 (0.93, 1.42); 0.19RR 0.80 (0.73, 0.89); <0.001RR 0.83 (0.72, 0.96); 0.01RR 0.94 (0.75, 1.18); 0.61RR 0.73 (0.57, 0.93); 0.01RR 0.75 (0.61, 0.91); 0.004

From a medical point of view the routine use of PCI in addition to the OMT in patients with stable angina pectoris can be recommended for the reduction of the proportion of patients with angina pectoris attacks after one year and after three years (recommendation degree weak). Otherwise, PCI is to be performed in patients with refractory or progressing angina pectoris despite OMT use; in this case PCI is expected to be applied in 27% to 30% of patients in five years.

SR/MA – Level I


January 2016




Bangalore 2013

Stable CAD PCI vs. OMT All-cause mortality (overall)All-cause mortality (stent trials)All-cause mortality (no stent trials)CV mortality (overall)CV mortality (stent trials)CV mortality (no stent trials)MI (overall)MI (stent trials)MI (no stent trials)Procedural MI (overall)Procedural MI (stent trials)Procedural MI (no stent trials)Spontaneous MI (overall)Spontaneous MI (stent trials)Spontaneous MI (no stent trials)

12 (7182)4 (4684)8 (2498)10 (6869)4 (4684)6 (2185)12 (7182)4 (4684)8 (2498)12 (7182)4 (4684)8 (2498)12 (7182)4 (4684)8 (2498)

IRR 0.88 (0.74, 1.04); 0.17 (int)IRR 0.95 (0.79, 1.14);IRR 0.71 (0.49, 1.03);IRR 0.74 (0.49, 1.11); 0.03 (int)IRR 1.08 (0.80, 1.45);IRR 0.47 (0.24, 0.93);IRR 0.94 (0.71, 1.25); 0.99 (int)IRR 1.02 (0.82, 1.27);IRR 1.02 (0.57, 1.83);IRR 3.22 (2.01, 5.16); 0.56 (int)IRR 3.05 (1.81, 5.13);IRR 4.12 (1.39, 12.2);IRR 0.77 (0.60, 0.99); 0.53 (int)IRR 0.86 (0.71, 1.05);IRR 0.72 (0.43, 1.22);

PCI compared with OMT reduced spontaneous MI at the risk of procedural MI without any difference in all MI. Consistent with prior studies showing that spontaneous MI but not procedural MI is related to subsequent mortality, in the present report the point estimate for reduced mortality with PCI compared with OMT paralleled the prevention of spontaneous MI with PCI. Further studies are needed to determine whether these associations are causal.

SR/MA – Level I


January 2016




Morrone 2013Abstract only

Stable IHD PCI vs. OMT All-cause mortality (overall)All-cause mortality (stable CAD)All-cause mortality (post MI)MI/death (overall)MI/death (stable CAD)MI/death (post MI)Repeat revasc. (overall)Repeat revasc. (stable CAD)Repeat revasc. (post MI)Angina (overall)Angina (stable CAD)Angina (post MI)

17 (NR)8 (NR)9 (NR)17 (NR)8 (NR)9 (NR)17 (NR)8 (NR)9 (NR)17 (NR)8 (NR)9 (NR)

RR 0.81 (0.64, 1.05)46; 0.48RR 0.98 (0.74, 1.31)46; 0.92RR 0.69 (0.47, 1.05)46; 0.36RR 0.99 (0.72, 1.33)47; 0.98RR 1.02 (0.83, 1.22)46; 0.89RR 1.03 (0.54, 2.01)46; 0.97RR 0.68 (0.48, 1.09)46; 0.50RR 0.58 (0.33, 1.00)46; 0.40RR 0.97 (0.37, 7.01)46; 0.98RR 0.84 (0.54, 1.18)46; 0.67RR 0.96 (0.53, 1.71)46; 0.94RR 0.53 (0.24, 1.19)46; 0.54

PCI does not yield any additional benefits above OMT in patients with stable ischaemic heart disease for the combined endpoint of MI/death or all-cause mortality alone.

Thomas 2013 Stable angina PCI vs. MT All-cause mortalityCV mortalityMIAngina relief

11 (6752)7 (4674)10 (5147)7 (2846)

RR 0.97 (0.84, 1.12); 0.66RR 0.91 (0.70, 1.17); 0.44RR 1.09 (0.92, 1.29); 0.33RR 1.10 (0.97, 1.26); 0.14

PCI was not associated with reductions in all-cause or CV mortality. Considering the cost implication and the lack of clear clinical benefit, these findings continue to support existing CPGs that MT be considered the most appropriate initial clinical management for patients with stable angina.

SR/MA – Level I

47 CI = credible interval; performed using a Bayesian meta-analysis. MBS Reviews – Percutaneous Coronary Intervention Review Report Page 145

January 2016




Pursnani 2012 Stable CAD PCI vs. OMT All-cause mortality (follow-up)All-cause mortality (≤ 1 y)All-cause mortality (1 to 5 y)All-cause mortality (≥ 5 y)All-cause mortality (≥ 50% stent use – follow-up)All-cause mortality (≥ 50% stent use – ≤ 1 y)All-cause mortality (≥ 50% stent use – 1 to 5 y)All-cause mortality (≥ 50% stent use – ≥ 5 y)Cardiac death (follow-up)Cardiac death (< 5 y)Cardiac death (≥ 5 y)Non-fatal MI (follow-up)Non-fatal MI (≤ 1 y)Non-fatal MI (1 to 5 y)Non-fatal MI (≥ 5 y)Repeat revasc. (follow-up)Repeat revasc. (≤ 1 y)Repeat revasc. (1 to 5 y)Repeat revasc. (≥ 5 y)Freedom from angina (follow-up)Freedom from angina (≤ 1 y)Freedom from angina (1 to 5 y)Freedom from angina (≥ 5 y)

12 (7177)8 (5436)5 (2131)9 (6245)4 (NR)NRNRNR9 (6523)4 (1986)8 (6144)12 (7177)5 (1165)4 (1113)9 (6245)13 (8195)6 (2770)5 (2131)8 (5945)9 (5539)6 (4899)3 (660)6 (4922)

RR 0.85 (0.71, 1.01); 0.07RR 1.34 (0.87, 2.08); 0.19RR 0.97 (0.56, 1.69); 0.92RR 0.82 (0.65, 1.02); 0.08RR 0.93 (0.78, 1.11); NRRR 1.48 (0.86, 2.55); NRRR 0.87 (0.30, 2.54); NRRR 0.93 (0.78, 1.12); NRRR 0.71 (0.47, 1.06); 0.09RR 1.53 (0.69, 3.38); 0.30RR 0.70 (0.46, 1.08); 0.10RR 0.93 (0.70, 1.24); 0.61RR 0.82 (0.37, 1.80); 0.62RR 1.11 (0.47, 2.59); 0.81RR 0.92 (0.67, 1.27); 0.63RR 0.93 (0.76, 1.14); 0.47RR 1.49 (0.71, 3.16); 0.29RR 0.98 (0.74, 1.30); 0.88RR 0.99 (0.75, 1.30); 0.92RR 1.20 (1.06, 1.37); 0.005RR 1.32 (1.13, 1.54); <0.001RR 1.57 (1.06, 2.32); 0.02RR 1.17 (1.00, 1.38); 0.05

PCI, as compared with OMT, did not reduce the risk of mortality, cardiovascular death, non-fatal MI, or revascularisation. PCI, however, provided greater angina relief compared with OMT alone. Larger studies with sufficient power are required to prove this conclusively.

SR/MA – Level I


January 2016




Stergiopoulos 2012

Stable CAD PCI vs. MT All-cause mortality48

Non-fatal MI (all patients)Non-fatal MI (post MI)Non-fatal MI (angina and ischaemia)Unplanned revasc.47

Persistent angina47

9 (NR)8 (NR)NRNR8 (NR)8 (NR)

OR 0.98 (0.83, 1.15); 0.82OR 1.12 (0.93, 1.34); 0.22OR 1.49 (1.00, 2.21); 0.05OR 1.04 (0.84, 1.28); 0.73OR 0.78 (0.57, 1.06); 0.11OR 0.79 (0.60, 1.05); 0.10

Initial stent implantation for stable CAD shows no evidence of benefit compared with initial MT for prevention of death, non-fatal MI, unplanned revascularisation or angina.

Wijeysundera 2010

Stable CAD PCI vs. MT Freedom from angina (follow-up)Freedom from angina (< 1 y)Freedom from angina (1 to 5 y)Freedom from angina ( > 5 y)Freedom from angina (≤ 1994)Freedom from angina (1995 to 1999)Freedom from angina (≥ 2000)Freedom from angina (recent MI)Freedom from angina (no recent MI)Freedom from angina (≥ 50% stent use)Freedom from angina (< 50% stent use)

14 (NR)8 (NR)10 (NR)5 (NR)3 (NR)6 (NR)5 (NR)6 (NR)8 (NR)NR (2644)NR (5174)

OR 1.69 (1.24, 2.30); 0.001OR 1.44 (1.18, 1.75); <0.001OR 1.70 (1.21, 2.38); 0.002OR 1.75 (0.96, 3.16); 0.07OR 3.38 (1.89, 6.04); <0.001OR 1.72 (1.11, 2.66); 0.01OR 1.13 (0.76, 1.68); 0.54OR 1.92 (1.11, 3.33); NROR 1.58 (1.07, 2.33); NROR 1.13 (0.76, 1.68); NROR 2.15 (1.48; 3.13); NR

PCI was associated with greater freedom from angina compared with MT, but this benefit was largely attenuated in contemporary studies. This observation may be related to greater use of evidence-based medications in contemporary trials.

Jeremias 2009 Non-acute CAD

Revasc. vs. MT

All-cause mortality (PCI or CABG)All-cause mortality (PCI)All-cause mortality (CABG)MI (PCI or CABG)

29 (13,121)21 (NR)8 (NR)26 (11,768)

OR 0.74 (0.63, 0.87); NROR 0.82 (0.68, 0.99); 0.33 (int)OR 0.62 (0.50, 0.77);OR 0.92 (0.81, 1.05); NR

Revascularisation by coronary artery bypass surgery49 or percutaneous intervention in conjunction with MT in patients with non-acute CAD is associated with significantly improved survival compared with MT alone.

SR/MA – Level I

48 No difference in point estimate between studies including post-MI patients and studies including patients with angina or ischaemia. 49 Result for CABG versus medical therapy not presented here. MBS Reviews – Percutaneous Coronary Intervention Review Report Page 147

January 2016




Trikalinos 2009--

Non-acute CAD--

PTCA vs. MT All-cause mortality (direct)All-cause mortality (direct and indirect)MI (direct)MI (direct and indirect)CABG (direct)CABG (direct and indirect)Repeat revasc. (direct)Repeat revasc. (direct and indirect)

7 (1991)51 (21,566)7 (1991)55 (23,622)5 (1646)43 (16,555)7 (1991)13 (8807)

RR 0.82 (0.59, 1.15); NRRR 0.91 (0.70, 1.18); NRRR 1.09 (0.59, 1.99): NRRR 1.23 (0.89, 1.70); NRRR 1.10 (0.81, 1.49): NRRR 1.06 (0.87, 1.29); NRRR 1.08 (0.74, 1.56); NRRR 0.92 (0.74, 1.14); NR

Sequential innovations in the catheter-based treatment of non-acute CAD showed no evidence of an impact on death or MI when compared with MT.--

BMS vs. MT All-cause mortality (direct)All-cause mortality (direct and indirect)MI (direct)MI (direct and indirect)CABG (direct)CABG (direct and indirect)Repeat revasc. (direct)Repeat revasc. (direct and indirect)

3 (4518)52 (23,557)4 (4619)55 (23,622)2 (2267)52 (18,024)3 (4518)13 (8809)

RR 0.96 (0.79, 1.18); NRRR 0.90 (0.70, 1.16); NRRR 1.18 (0.97, 1.43); NRRR 1.24 (0.88, 1.75); NRRR 0.97 (0.63, 1.50); NRRR 1.04 (0.83, 1.29); NRRR 0.78 (0.58, 1.05); NRRR 0.71 (0.58, 0.87); NR

DES vs. MT All-cause mortality (direct)All-cause mortality (direct and indirect)MI (direct)MI (direct and indirect)CABG (direct)CABG (direct and indirect)

0 (0)51 (23,557)0 (0)55 (23,622)0 (0)43 (18,201)

-RR 0.96 (0.60, 1.52); NR-RR 1.15 (0.73, 1.82); NR-RR 0.58 (0.38, 0.88); NR

SR/MA – Level I


January 2016




Trikalinos 2009

Non-acute CAD

DES vs. BMS All-cause mortality (direct)All-cause mortality (direct and indirect)MI (direct)MI (direct and indirect)CABG (direct)CABG (direct and indirect)

15 (7328)51 (23,557)14 (6303)55 (23,622)12 (4995)43 (18,201)

RR 1.09 (0.73, 1.63); NRRR 1.06 (0.71, 1.58); NRRR 1.03 (0.79, 1.35); NRRR 0.93 (0.68, 1.26); NRRR 0.56 (0.36, 0.88); NRRR 0.56 (0.39, 0.80); NR

-

Schömig 2008 Stable CAD PCI vs. MT All-cause mortality50

All-cause mortality (recent MI)49

All-cause mortality (no recent MI)49

All-cause mortality (no CABG)49

Cardiac death (REM)Cardiac death (FEM)Non-cardiac death49

Non-fatal MI49

Death/non-fatal MI (REM)Death/non-fatal MI (FEM)

17 (7513)4131313 (5619)13 (5619)13 (5619)17 (7513)NRNR

OR 0.80 (0.64, 0.99)OR 0.65 (0.37, 1.12)OR 0.83 (0.65, 1.04)OR 0.80 (0.64, 0.99)OR 0.74 (0.51, 1.06)OR 0.74 (0.57, 0.96)OR 0.96 (0.67, 1.36)OR 0.90 (0.66, 1.23)OR 0.80 (0.60, 1.05)OR 0.84 (0.74, 0.96)

A PCI-based invasive strategy may improve long-term survival compared with a MT-only strategy in patients with stable CAD.

SR/MA – Level I

Ioannidis Stable patients PCI vs. MT All-cause mortality (REM) 6 (NR) RR 0.95 (0.73, 1.23) PCI does not seem to confer any

50 Random effects model result shown only; no difference from fixed effects model result. MBS Reviews – Percutaneous Coronary Intervention Review Report Page 149

January 2016




2007 with previous MI

All-cause mortality (FEM)

MI (REM)

MI (FEM)

Death/MI (REM)

Death/MI (FEM)

CHF (REM)

CHF (FEM)

Change in LVEF (REM)

Change in LVEF (FEM)

All-cause mortality (small early trials)51

All-cause mortality (OAT/TOSCA-2)

MI (small early trials)50

MI (small early trials – REM)

MI (OAT/TOSCA-2)

Death/MI (small early trials)50

Death/MI (OAT/TOSCA-2)

CHF (small early trials)50

CHF (OAT/TOSCA-2)

6 (NR)

6 (NR)

6 (NR)

6 (NR)

6 (NR)

6 (NR)

6 (NR)

6 (NR)

6 (NR)

NR

1 (NR)

NR

NR

1 (NR)

NR

1 (NR)

NR

1 (NR)

RR 0.95 (0.73, 1.23)

RR 1.26 (0.89, 1.78)

RR 1.26 (0.89, 1.78)52

RR 0.99 (0.57, 1.70)

RR 1.14 (0.92, 1.41)

RR 0.67 (0.36, 1.22)

RR 0.76 (0.54, 1.08)

MD 1.7% (-0.2, 2.0)

MD 1.4% (0.1, 2.8)

RR 0.71 (0.35, 1.42)53

RR 0.98 (0.74, 1.30)

RR 0.95 (0.44, 2.05)

RR 0.86 (0.35, 2.13)

RR 1.34 (0.92, 1.97)

RR 0.86 (0.50, 1.47)

RR 1.20 (0.95, 1.51)

RR 0.37 (0.18, 0.77)

RR 0.98 (0.65, 1.48)

benefits when used for late revascularisation of occluded arteries after MI in stable patients.

51 Excluding OAT/TOSCA-2 study. MBS Reviews – Percutaneous Coronary Intervention Review Report Page 150

January 2016

Source: Gorenoi et al (2011): Figures 1 to 12, p 60-65; Bangalore et al (2013): Figures 2 to 6, p 772-776; Morrone et al (2013): Table, p 176; Thomas et al (2013): Figures 3 to 6, p 479-480; Pursnani et al (2012): Figures 2 to 6, p 484-488; Stergiopoulos et al (2012): Figure 2, p 317; Wijeysundera et al (2010): Figures 2 and 3, p 375-376 and text, p 375; Jeremias et al, 2009): Figures 1 to 4, p 156-159; Trikalinos et al (2009): Table 2; Schömig et al (2008): Figure 1, p 898, Figures 5 and 6, p 900-901; Ioannidis 2007: Table III, p 1067 and Table IV, p 1069.Note: Statistically significant results shown in bold.Abbreviations: BMS, bare metal stent; CABG, coronary artery bypass graft; CAD, coronary artery disease; CHF, congestive heart failure; CI, confidence interval; CPG, clinical practice guideline; CV, cardiovascular; DES, drug-eluting stent; FEM, fixed effects model; het, heterogeneity; HTA, health technology assessment; IHD, ischaemic heart disease; IRR, incident rate ratio; LVEF, left ventricular ejection fraction; m, months; MA, meta-analysis; MD, mean difference; MI, myocardial infarction; MT, medical therapy; NR, not reported; OMT, optimal medical therapy; OR, odds ratio; PCI, percutaneous coronary intervention; PTCA, percutaneous transluminal coronary angioplasty; revasc., revascularisation; REM, random effects model; RR, relative risk; SR, systematic review; y, years.

52 Publication graph shows RR 1.26 (0.89, 1.28) but this appears to be an error. 53 All analyses below FEM except otherwise stated.MBS Reviews – Percutaneous Coronary Intervention Review Report Page 151

January 2016

Figure 5.2-1 Forest plot of PCI versus OMT (including DECOPI): chronic stable angina – all-cause mortality

Study or SubgroupDECOPICOURAGEBARI 2DOAT

Total (95% CI)Total eventsHeterogeneity: Tau² = 0.00; Chi² = 1.20, df = 3 (P = 0.75); I² = 0%Test for overall effect: Z = 0.07 (P = 0.94)

Events8

8510287

282

Total109

1149798

1082

3138

Events9

959684

284

Total103

1138807

1084

3132

Weight2.9%

31.2%36.1%29.7%

100.0%

M-H, Random, 95% CI0.84 [0.34, 2.09]0.89 [0.67, 1.17]1.07 [0.83, 1.39]1.04 [0.78, 1.38]

0.99 [0.85, 1.16]

YearPCI OMT Risk Ratio Risk Ratio

M-H, Random, 95% CI

0.2 0.5 1 2 5Favours PCI Favours OMT

Source: Meta-analysis from Gorenoi et al (2011), updated with data from the DECOPI trial (Steg et al, 2004).Abbreviations: CI, confidence interval; OMT, optimal medical therapy; PCI, percutaneous coronary intervention.

Figure 5.2-2 Forest plot of PCI versus OMT (including DECOPI): chronic stable angina – cardiac mortality

Study or SubgroupDECOPIBARI 2DCOURAGEOAT


Events6

443958

147

Total109798

11491082

3138

Events7

334452

136

Total103807

11381084

3132

Weight4.7%

26.9%29.2%39.3%

100.0%

M-H, Random, 95% CI0.81 [0.28, 2.33]1.35 [0.87, 2.09]0.88 [0.57, 1.34]1.12 [0.78, 1.61]

1.08 [0.86, 1.36]

PCI OMT Risk Ratio Risk RatioM-H, Random, 95% CI

0.2 0.5 1 2 5Favours PCI Favours OMT


Figure 5.2-3 Forest plot of PCI versus OMT (including DECOPI): chronic stable angina – MI

Study or SubgroupDECOPIOATBARI 2DCOURAGE


Events4

5995

147

305

Total109

1082798

1149

3138

Events3

4488

126

261

Total103

1084807

1138

3132

Weight1.1%

16.9%32.9%49.1%

100.0%

M-H, Random, 95% CI1.26 [0.29, 5.49]1.34 [0.92, 1.97]1.09 [0.83, 1.43]1.16 [0.92, 1.44]

1.16 [1.00, 1.36]


0.1 0.2 0.5 1 2 5 10Favours [experimental] Favours [control]

Source: Meta-analysis from Gorenoi et al (2011), updated with data from the DECOPI trial (Steg et al, 2004).Abbreviations: CI, confidence interval; MI, myocardial infarction; OMT, optimal medical therapy; PCI, percutaneous coronary intervention.


January 2016

Figure 5.2-4 Forest plot of PCI versus OMT (including DECOPI): chronic stable angina – repeat revascularisation

Study or SubgroupDECOPIOATCOURAGE


Events30

170228

428

Total109

10821149

2340

Events33

205348

586

Total103

10841138

2325

Weight16.4%38.9%44.7%

100.0%

M-H, Random, 95% CI0.86 [0.57, 1.30]0.83 [0.69, 1.00]0.65 [0.56, 0.75]

0.75 [0.61, 0.91]


0.5 0.7 1 1.5 2Favours PCI Favours OMT


Level II evidenceFollowing the review of Level I (SR/MA) evidence it was deemed necessary to examine Level II (RCT) evidence for the following reasons:

High-risk, diabetes, multivessel, chronic kidney disease (CKD) or heart failure/known left ventricular dysfunction subgroup analyses were not undertaken in the identified SR/MAs.

Quality of life and adverse events were not assessed in the identified SR/MAs.

As such, four RCTs (BARI 2D, COURAGE, OAT and DECOPI), which included what Gorenoi and colleagues defined as OMT, and which had high rates of stent use, were individually assessed for relevant subgroup analyses and additional outcomes. In addition, a search was conducted to identify any more recent publications from these trials that may have included additional subgroup analyses or provided data on additional outcomes. Relevant subgroup analyses and additional outcomes for each of the RCTs and their associated publications are discussed below. The citation details for the RCTs are presented in Table 5.2-2.


January 2016

Table 5.2-2 Citation details for included RCTs: chronic stable angina – PCI vs. medical therapy

Ref ID CitationBARI-2D Primary publication:

BARI 2D Study Group (2009). "A randomized trial of therapies for type 2 diabetes and coronary artery disease." N Engl J Med 360(24): 2503-2515.

COURAGE Primary publication:Boden, W. E., R. A. O'Rourke, et al. (2007). "Optimal medical therapy with or without PCI for stable coronary disease." N Engl J Med 356(15): 1503-1516.Included secondary publications:Mancini, G. B., P. M. Hartigan, et al. (2013). "Prognostic importance of coronary anatomy and left ventricular ejection fraction despite optimal therapy: assessment of residual risk in the Clinical Outcomes Utilizing Revascularization and Aggressive DruG Evaluation Trial." Am Heart J 166(3): 481-487.Sedlis, S. P., C. T. Jurkovitz, et al. (2013). "Health status and quality of life in patients with stable coronary artery disease and chronic kidney disease treated with optimal medical therapy or percutaneous coronary intervention (post hoc findings from the COURAGE trial)." Am J Cardiol 112(11): 1703-1708.Maron, D. J., W. E. Boden, et al. (2011). "Impact of metabolic syndrome and diabetes on prognosis and outcomes with early percutaneous coronary intervention in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial." J Am Coll Cardiol 58(2): 131-137.Maron, D. J., J. A. Spertus, et al. (2009). "Impact of an initial strategy of medical therapy without percutaneous coronary intervention in high-risk patients from the Clinical Outcomes Utilizing Revascularization and Aggressive DruG Evaluation (COURAGE) trial." Am J Cardiol 104(8): 1055-1062.Sedlis, S. P., C. T. Jurkovitz, et al. (2009). "Optimal medical therapy with or without percutaneous coronary intervention for patients with stable coronary artery disease and chronic kidney disease." Am J Cardiol 104(12): 1647-1653.Weintraub, W. S., J. A. Spertus, et al. (2008). "Effect of PCI on quality of life in patients with stable coronary disease." N Engl J Med 359(7): 677-687.

OAT Primary publication:Hochman, J. S., G. A. Lamas, et al. (2006). "Coronary intervention for persistent occlusion after myocardial infarction." N Engl J Med 355(23): 2395-2407.Included secondary publication:Overgaard, C. B., V. Dzavik, et al. (2013). "Percutaneous revascularization and long term clinical outcomes of diabetic patients randomized in the Occluded Artery Trial (OAT)." Int J Cardiol 168(3): 2416-2422.Kruk, M., J. Kadziela, et al. (2008). "Predictors of outcome and the lack of effect of percutaneous coronary intervention across the risk strata in patients with persistent total occlusion after myocardial infarction: Results from the OAT (Occluded Artery Trial) study." JACC Cardiovasc Interv 1(5): 511-520.

DECOPI Primary publication:Steg, P. G., C. Thuaire, et al. (2004). "DECOPI (DEsobstruction COronaire en Post-Infarctus): a randomized multi-centre trial of occluded artery angioplasty after acute myocardial infarction." Eur Heart J 25(24): 2187-2194.

The main characteristics of the RCTs that included OMT are presented in Table 5.2-3. The studies were similar in terms of populations, follow-up duration and stent use. In three of the studies, the majority of patients who received stents received BMSs; the use of DESs ranged from 3% (in COURAGE) to 35% (in BARI 2D). The DECOPI trial noted that stent use was encouraged but the type of stents used was not stated. Given the timeframe of this trial (1998–2001) it is likely that BMSs were used in this trial. The included RCTs conclude that the addition of PCI to OMT does not reduce the risk of death or MI in the patient populations examined.


January 2016

Table 5.2-3 Characteristics and conclusions of the RCTs using OMT: chronic stable angina – PCI vs. medical therapyStudy ID Study

characteristicsPatient population Intervention Comparator Primary

outcomeAuthors conclusions

BARI-2D Randomised, parallel, open-label 5 y follow-up

Diabetes and stable CAD Diagnosis of CAD based on

angiography showing (i) ≥ 50% stenosis of a major epicardial coronary artery associated with a positive stress test or (ii) ≥ 70% stenosis of a major epicardial artery and classic angina

N=2368

Revascularisation within 4 w using PCI or CABG (as determined pre-randomisation by the responsible physician) Stent use 91% in

revascularisation patients who underwent PCI

DES 34.7%, BMS 56.0%, no stent 9.3%

Medical therapy

Death Overall, there was no significant difference in the rates of death and major cardiovascular events between patients undergoing prompt revascularisation and those undergoing medical therapy or between strategies of insulin sensitisation and insulin provision.

COURAGE Randomised, parallel, open-label Median 4.6 y

follow-up

Stable angina; stabilised unstable angina; myocardial ischaemia or stenosis > 80% CCS Class I angina – 29.8% CCS Class II angina – 36.4% CCS Class III angina – 21.1%N=2287

PCI + OMT Stent use 94% DES 3%

OMT Death/MI As an initial management strategy in patients with stable CAD, PCI did not reduce the risk of death, MI, or other major cardiovascular events when added to OMT.

OAT Randomised, parallel, open-label 4 y follow-up

Stable patients 2 to 28 d after MI with total occlusion of the infarct-related artery 23% had a history of anginaN=2166

PCI within 24 h + OMT Stent use 87% DES 8%

OMT Death/MI/ NYHA Class IV HF

PCI did not reduce the occurrence of death, reinfarction, or heart failure, and there was a trend towards excess reinfarction during 4 years of follow-up in stable patients with occlusion of the infarct-related artery 3 to 28 days after MI.


January 2016

Study ID Study characteristics

Patient population Intervention Comparator Primary outcome

Authors conclusions

DECOPI Randomised, parallel, open-label 3 y follow-up

Stable patients within 15 d of Q-wave MI, no ischaemia, and total occlusion of the infarct-related arteryN=212

PTCA ≤15 days Stent use 80%

Medical therapy

Death/MI/ tachy-arrhythmia

Systematic late PTCA of the infarct vessel was associated with a higher left ventricular ejection fraction at six months, no difference in clinical outcomes, and higher costs than medical therapy. These results must be interpreted with caution given the small size and low risk of the population.

Source: BARI 2D: BARI 2D Study Group (2009); COURAGE: Boden et al (2007); OAT: Hochman et al (2006). Abbreviations: BMS, bare metal stents; CABG, coronary artery bypass graft; CAD, coronary artery disease; CCS, Canadian Cardiovascular Society; d, days; DES, drug-eluting stents; h, hours; HF, heart failure; MI, myocardial infarction; NYHA, New York Heart Association; OMT, optimal medical therapy; PCI, percutaneous coronary intervention; PTCA, percutaneous transluminal coronary angioplasty; RCT, randomised controlled trial; w, weeks; y, years.


January 2016

Only the BARI 2D, COURAGE and OAT trials provide data on the additional subgroups and outcomes of interest.

High-risk subgroupIn the COURAGE study, patients considered at high risk were those with an onset of CCS Class III angina within 2 months or stabilised ACS within 2 weeks of enrolment. Of the 2287 patients included in the overall COURAGE trial, 12% met these criteria; the relative risk of death/MI in this group compared with patients not considered high risk was 1.56 (p<0.001; Maron et al, 2009). As shown in Table 5.2-4, there was no difference in the primary outcome, death/MI, the individual component outcomes, or ACS when PCI was added to OMT compared with OMT alone. Results were also examined across risk tertiles (low, medium and high) in the OAT study. Treatment by risk tertile subgroup interactions were shown to be not statistically significant for both the primary outcome and death.

Table 5.2-4 High-risk subgroup analyses in included RCTs: chronic stable angina – PCI vs. medical therapy


PCI + OMTn (%)

OMTn (%)


Subgroup p value

COURAGE Stable coronary disease

Death/MI* High-risk54 35 (27) 32 (24) HR 1.11 (0.69, 1.79); 0.68 -

Death High-risk 2 (9) 12 (9) HR 1.01 (0.45, 2.25); 0.98 -

MI High-risk 25 (19) 22 (17) HR 1.14 (0.64, 2.02); 0.66 -

ACS High-risk 22 (17) 27 (20) HR 0.78 (0.45, 1.37); 0.39 -

OAT Stable after MI

Death/MI/NYHA IV HF*

Low-risk tertile55

Medium-risk tertileHigh-risk tertile

NR (10.2)NR (13.1)NR (33.9)

NR (7.3)NR (13.8)NR (27.3)

NR; 0.57NR; 0.82NR 0.10

0.5156

Death Low-risk tertileMedium-risk tertileHigh-risk tertile

NR (3.8)NR (6.8)NR (23.5)

NR (6.8)NR (7.1)NR (21.7)

NR; 0.64NR; 0.26NR; 0.41

0.17

Source: COURAGE (Maron et al, 2009): Table 4, p 1058; OAT (Kruk et al, 2008): Table 3, p 18. Note: Primary outcome denoted by *. Statistically significant results shown in bold. Abbreviations: ACS, acute coronary syndrome; CI, confidence interval; HR, hazard ratio; MI, myocardial infarction; NR, not reported; NYHA IV HF, New York Heart Association Class IV Heart Failure; OMT, optimal medical therapy; PCI, percutaneous coronary intervention.

Diabetes subgroupA summary of the diabetes subgroup findings from the included RCTs is presented in Table 5.2-5. There was no significant difference in the primary outcome for patients with diabetes compared with patients without diabetes in patients in the COURAGE trial (HR 0.99; 95% CI 0.73, 1.32 versus HR 1.20; 95% CI 0.92, 1.56, respectively; p=0.33; Boden et al, 2007). The impact of metabolic syndrome and type 2 diabetes on the results of the comparison between PCI + OMT and OMT alone are also shown in Table 5.2-5. The results show that the lack of

54 High risk defined as onset of CCS Class III angina within 2 months or stabilised ACS within 2 weeks of enrolment; post hoc analysis conducted in a follow-up publication. 55 Increasing risk tertiles associated with older age, female sex, more comorbidities, diabetes, obesity, heart failure prior to study entry, higher heart rate, lower diastolic blood pressure, increasing glucose levels and decreasing glomerular filtration rate. 56 Risk tertile analyses conducted post hoc in a follow-up publication.


January 2016

benefit of PCI + OMT over OMT alone is consistent whether or not patients had metabolic syndrome or diabetes (Maron et al, 2011).

The OAT study (Hochman et al, 2006) also analysed its primary outcome (death, MI or heart failure) by diabetes status, and found that PCI + OMT did not provide any benefit over OMT alone in patients with or without diabetes (subgroup p = 0.41). A more recent analysis of data from the OAT trial, conducted by Overgaard et al (2013), based on 7 years of follow-up, showed that the effect of PCI + OMT compared with OMT alone on cardiovascular outcomes was not affected by whether or not patients had diabetes. The authors conclude that ‘despite the higher overall risk conferred by the presence of diabetes, PCI did not improve clinical outcomes in this subpopulation, and is not indicated in otherwise stable patients with a totally occluded infarct-related artery in the sub-acute phase after MI’.

Table 5.2-5 Diabetes subgroup analyses in included RCTs: chronic stable angina – PCI vs. medical therapy


PCI + OMTn (%)

OMTn (%)


Subgroup p value


Death/MI* DiabetesNo diabetes–MS/–DM+MS/–DM–MS/+DM+MS/+DM

NR (25)NR (17)60 (15)65 (18)10 (16)75 (25)

NR (24)NR (15)49 (13)52 (15)10 (17)86 (25)

HR 0.99 (0.73, 1.32); NRHR 1.20 (0.92, 1.56); NRNR; 0.37NR; 0.32NR; 0.90NR; 0.84

0.3357

OAT (Hochman) Stable after MI

Death/MI/HF* DiabetesNo diabetes

NR (29.3)NR (14.4)

NR (23.3)NR (13.5)

NRNR

0.4156

OAT (Overgaard) Stable after MI

Death/MI/HF* DiabetesNo diabetes

71 (35.3)159 (19.3)

76 (34.5)143 (19.5)

HR 1.19 (0.77, 1.82); 0.3058

HR 1.00 (0.74, 1.34); 0.98NR59

All-cause mortality DiabetesNo diabetes

45 (22.6)105 (12.8)

100 (13.5)53 (24.8)

HR 1.05 (0.62, 1.78); 0.81HR 0.92 (0.64, 1.32); 0.53

NR

CV mortality DiabetesNo diabetes

27 (14.2)50 (6.6)

25 (10.8)56 (7.2)

HR 1.34 (0.65, 2.75); 0.30HR 0.79 (0.48, 1.30); 0.22

NR

Non-fatal MI DiabetesNo diabetes

20 (10.1)55 (6.9)

20 (8.8)41 (6.2)

HR 1.31 (0.57, 3.01); 0.39HR 1.29 (0.76, 2.20); 0.22

NR

Heart failure60 DiabetesNo diabetes

23 (13.0)28 (3.6)

26 (12.2)27 (3.5)

HR 1.05 (0.50, 2.21); 0.87HR 0.95 (0.47, 1.91); 0.84

NR

57 Diabetes subgroup analysis prespecified.58 All analyses adjusted for age (per 10-years older), history of diabetes at study entry, lower estimated glomerular filtration rate (per 10 unit decrease), lower ejection fraction at baseline (per 10 percentage lower), history of cerebrovascular disease, history of PCI before study entry, shorter time from qualifying MI to randomisation (per one day decrease), history of peripheral vascular disease, and heart failure at baseline which was defined as 1 or more of the following: history of heart failure before randomisation, rales on examination, S3 gallop on examination, highest Killip Class >1 during index MI before randomisation, highest New York Heart Association (NYHA) Class >I before index MI, or NYHA Class II at randomisation. 59 Diabetes subgroup analysis prespecified in primary publication (Hochman et al, 2006). Additional diabetes subgroup analyses in follow-up publication (Overgaard et al, 2013). 60 NYHA Class III or IV


January 2016


PCI + OMTn (%)

OMTn (%)


Subgroup p value

OAT (Overgaard) Stable after MI

Stroke DiabetesNo diabetes

7 (3.7)22 (3.2)

7 (3.4)17 (2.1)

HR 1.19 (0.30, 4.80); 0.74HR 1.15 (0.50, 2.66); 0.66

NR

Revascularisation61 DiabetesNo diabetes

53 (28.7)159 (19.7)

62 (29.3)190 (24.6)

HR 1.03 (0.63, 1.67); 0.88HR 0.76 (0.58, 1.00); 0.01

NR

CABG DiabetesNo diabetes

18 (10.8)31 (3.9)

12 (5.4)36 (4.2)

HR 1.85 (0.70, 4.92); 0.10HR 0.82 (0.44, 1.55); 0.42

NR

Angina DiabetesNo diabetes

85 (50.1)354 (42.7)

113 (50.4)396 (50.6)

HR 0.91 (0.63, 1.32); 0.51HR 0.76 (0.63, 0.92); <0.001

NR

Source: COURAGE (Boden et al, 2007): Figure 3, p 1513; COURAGE (Maron et al, 2011): Table 4, p 135; OAT (Hochman et al, 2006): Figure 3, p 2405; OAT (Overgaard et al, 2013): Table 3, p 2419.Note: Primary outcome denoted by *. Statistically significant results shown in bold. Abbreviations: CABG, coronary artery bypass graft; CI, confidence interval; CV, cardiovascular; DM, type 2 diabetes; HF, heart failure; HR, hazard ratio; MI, myocardial infarction; MS, metabolic syndrome; NR, not reported; OMT, optimal medical therapy; PCI, percutaneous coronary intervention; RCT, randomised controlled trial.

Multivessel subgroupAs shown in Table 5.2-6, there was no significant difference in the primary efficacy outcome of the COURAGE trial (death or MI) for patients with multivessel disease compared with patients with single-vessel disease; in both cases PCI + OMT was shown to provide no benefit over OMT alone (HR 1.04; 95% CI 0.84, 1.30 versus HR 1.17; 95% CI 0.76, 1.80, respectively; p=0.65).

Table 5.2-6 Multivessel subgroup analyses in included RCTs: chronic stable angina – PCI vs. medical therapy


PCI + OMT OMT Risk estimate(95% CI); p value

Subgroup p value


Events (rate) Events (rate)

Death/MI* MultivesselSingle-vessel

NR (21)NR (15)

NR (21)NR (12)

HR 1.04 (0.84, 1.30); NRHR 1.17 (0.76, 1.80); NR

0.6562

Source: COURAGE (Boden et al, 2007): Figure 3, p 1513. Note: Primary outcome denoted by *. Statistically significant results shown in bold. Abbreviations: CI, confidence interval; HR, hazard ratio; MI, myocardial infarction; NR, not reported; OMT, optimal medical therapy; PCI, percutaneous coronary intervention; RCT, randomised controlled trial.

Chronic kidney disease subgroupSedlis et al (2009) examined the efficacy of PCI + OMT with OMT alone in patients with CKD who took part in the COURAGE trial. CKD was defined as a glomerular filtration rate <60 mL/min/1.73m2. There was no significant difference in the effect of PCI + OMT compared with OMT alone on any outcomes in subgroups of patients with or without CKD with two exceptions: repeat revascularisations and cardiac hospitalisations were significantly lower for PCI + OMT compared with OMT in patients with a GFR ≥ 60 (see Table 5.2-7). The authors concluded that ‘PCI did not reduce the risk of death or MI when added to OMT for patients with CKD, it also was not associated with worse outcomes in this high-risk group’.

61 PCI or CABG62 Multivessel subgroup analysis prespecified.


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Table 5.2-7 Chronic kidney disease subgroup analyses in included RCTs: stable chronic angina – PCI vs. medical therapy

Outcome Analysis/ subgroup PCI + OMTn (%)

OMTn (%)


Subgroup p value


Death/MI* GFR < 60GFR ≥ 60

NR (30)NR 18)

NR (33)NR (17)

HR 0.91 (0.60, 1.38); NRHR 1.09 (0.87, 1.36); NR

0.4563

Death GFR < 60GFR ≥ 60

NR (14)NR (7)

NR (17)NR (7)

HR 0.81 (0.44, 1.46); NRHR 0.88 (0.62, 1.24); NR

0.78

Cardiac mortality GFR < 60GFR ≥ 60

NR (9)NR (4)

NR (10)NR (3)

HR 0.70 (0.32, 1.53); NRHR 1.06 (0.63, 1.79); NR

0.39

MI GFR < 60GFR ≥ 60

NR (19)NR (13)

NR (21)NR (11)

HR 0.93 (0.54, 1.57); NRHR 1.18 (0.90, 1.56); NR

0.42

Stroke GFR < 60GFR ≥ 60

NR (3)NR (2)

NR (2)NR (1)

HR 1.11 (0.23, 5.54); NRHR 1.51 (0.71, 3.19); NR

0.75

Repeat revasc. GFR < 60GFR ≥ 60

NR (24)NR (22)

NR (33)NR (33)

HR 0.67 (0.44, 1.04); NRHR 0.61 (0.51, 0.74); NR

0.68

Repeat catheterisation GFR < 60GFR ≥ 60

NR (36)NR (22)

NR (32)NR (32)

HR 1.11 (0.74, 1.65); NRHR 1.06 (0.89, 1.25); NR

0.80

Cardiac hospitalisation GFR < 60GFR ≥ 60

NR (47)NR (36)

NR (46)NR (43)

HR 0.92 (0.65, 1.29); NRHR 0.81 (0.70, 0.95); NR

0.51

Source: COURAGE (Sedlis et al, 2009): Figure 4, p 1651. Note: Primary outcome denoted by *. Statistically significant results shown in bold. Abbreviations: CI, confidence interval; GFR, glomerular filtration rate; HR, hazard ratio; MI, myocardial infarction; NR, not reported; OMT, optimal medical therapy; PCI, percutaneous coronary intervention; RCT, randomised controlled trial.

Heart failure or known left ventricular dysfunction Subgroup analyses of the COURAGE trial were also undertaken based on coronary anatomy and left ventricular ejection fraction (LVEF; Mancini et al, 2013). As shown in Table 5.2-8, there was no significant interaction between treatment assignment and low LVEF and there were no statistically significant differences between results comparing PCI + OMT and OMT alone when separated into different coronary anatomy and LVEF subgroups.

63 CKD subgroup analysis performed post hoc in a follow-up publication.


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Table 5.2-8 Heart failure or known left ventricular dysfunction subgroup analyses in included RCTs: chronic stable angina – PCI vs. medical therapy

Outcome Analysis/ subgroup PCI + OM OMT Risk estimate(95% CI); p value

Subgroup p value


Events (%) Events (%) Adj. interaction64

Death/MI* TMT & low LVEF63

0-1VD, EF > 500-1VD, EF ≤ 502VD, EF > 502VD, EF ≤ 503VD, EF > 503VD, EF ≤ 50

-NR (11.5)NR (16.1)NR (13.3)NR (22.2)NR (23.6)NR (25.4)

-NR (10.4)NR (21.8)NR (18.3)NR (24.3)NR (24.3)NR (39.7)

HR 0.87 (NR); 0.55 -0.6265

All-cause mortality TMT & low LVEF63

0-1VD, EF > 5066

0-1VD, EF ≤ 502VD, EF > 502VD, EF ≤ 503VD, EF > 503VD, EF ≤ 50

-NR (4.1)NR (8.2)NR (7.7)NR (8.9)NR (10.2)NR (16.6)

-NR (5.5)NR (8.5)NR (6.5)NR (18.4)NR (9.7)NR (23.8)

HR 0.70 (NR); 0.29 -0.71

MI TMT & low LVEF63

0-1VD, EF > 500-1VD, EF ≤ 502VD, EF > 502VD, EF ≤ 503VD, EF > 503VD, EF ≤ 50

-NR (7.6)NR (8.2)NR (6.8)NR (16.3)NR (17.7)NR (14.0)

-NR (5.9)NR (14.0)NR (13.4)NR (8.4)NR (16.3)NR (22.1)

HR 1.16 (NR); 0.65 -0.09

Source: COURAGE (Mancini et al, 2013): Figure 1, p 484. Note: Primary outcome denoted by *. Statistically significant results shown in bold. Abbreviations: CI, confidence interval; EF, ejection fraction; HR, hazard ratio; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NR, not reported; OMT, optimal medical therapy; PCI, percutaneous coronary intervention; RCT, randomised controlled trial; TMT, treatment; VD, vessel disease.

Quality of lifeQuality of life was assessed in the overall COURAGE trial using the quality of life scale from the Seattle Angina Questionnaire (SAQ; see Table 5.2-9).67 Quality of life was significantly greater in the PCI + OMT group compared with the OMT alone group at 1, 3, 6 and 12 months; there was no significant difference between treatment arms at 2 years and 3 years (Weintraub et al, 2008). The authors concluded that based on the results of the SAQ (which included assessment of angina stability, angina frequency, physical limitation and treatment satisfaction, as well as quality of life, ‘both those treated with PCI and those treated with optimal medication alone had marked improvements in health status during follow-up. The 64 Adjusted for age, female sex, current smoker, diabetes, prior MI, prior CABG, heart failure, CCS Class, baseline low-density lipoprotein and baseline high-density lipoprotein. 65 Multivessel and ejection fraction subgroup analyses predefined in the primary publication (Boden et al, 2007). Subsequent subgroup analysis performed in follow-up publication. 66 Subgroups include number of diseased vessels (VD) and ejection fraction (EF).67 The SAQ contains five scales: (i) anginal stability: a measure of whether a patient’s symptoms are changing over time; (ii) anginal frequency: a measure of how often a patient is having symptoms now; (iii) physical limitation: a measure of how much a patient’s condition is hampering his ability to do what he wants to do; (iv) treatment satisfaction: a measure of well a patient understands her care and what she thinks of it; and (v) quality of life: a measure of the overall impact of a patient’s condition on a patient’s interpersonal relationships and state of mind.


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PCI group had small, but significant, incremental benefits that disappeared by 36 months’. In a subgroup analysis of patients with CKD conducted by Sedlis et al (2011), improvements in quality of life were seen over time in both the PCI + OMT and OMT alone groups. These improvements were not significantly different between groups at any time point for patients with CKD, but were significantly greater for PCI + OMT up to 12 months for patients without CKD. The authors concluded that CKD ‘neither precludes satisfactory treatment of angina with PCI plus OMT or OMT alone nor is it associated with an unsatisfactory quality of life’.

These results suggest that in the first year following intervention, use of PCI + OMT results in a significantly better quality of life than OMT alone. However, this difference reduces over longer time frames.

Table 5.2-9 Quality of life in included RCTs: chronic stable angina – PCI vs. medical therapy

Outcome PopulationSubgroup/time point

PCI + OMT OMT Risk estimate(95% CI); p value

COURAGE (Weintraub 2008)

Stable coronary disease

Mean ± SD Mean ± SD

SAQ – Quality of life Baseline1 month3 months6 months12 months24 months36 months

51 ± 2568 ± 2473 ± 2275 ± 2276 ± 2177 ± 2279 ± 20

51 ± 2562 ± 2468 ± 2370 ± 2373 ± 2276 ± 2277 ± 20

NR; 0.80NR; <0.001NR; <0.001NR; <0.001NR; 0.008NR; 0.10NR; 0.32

COURAGE (Sedlis 2011)

Stable coronary disease

Mean ± SD Mean ± SD

SAQ – Quality of life CKDBaseline1 month3 months6 months12 months24 months36 months

-47 ± 2367 ± 2372 ± 2272 ± 2574 ±2293 ± 1181 ± 19

-51 ± 2663 ± 2469 ± 2367 ± 2576 ± 2278 ± 2179 ± 19

-NR: 0.20NR; 0.17NR; 0.25NR; 0.14NR; 0.52NR; 0.53NR; 0.60

No CKDBaseline1 month3 months6 months12 months24 months36 months

-52 ± 2568 ± 2473 ± 2275 ± 2276 ± 2177 ± 2278 ± 20

-52 ± 2561 ± 2468 ± 2371 ± 2372 ± 2275 ± 2277 ± 21

-NR; 0.99NR; <0.001NR; <0.001NR; <0.001NR; 0.001NR; 0.20NR; 0.52

Source: COURAGE (Weintraub et al, 2008): Table 1, p 680; COURAGE (Sedlis et al, 2011): Table 2, p 1705. Note: Statistically significant results shown in bold. Abbreviations: CI, confidence interval; CKD, chronic kidney disease; NR, not reported; OMT, optimal medical therapy; PCI, percutaneous coronary intervention; RCT, randomised controlled trial; SAQ, Seattle Angina Questionnaire; SD, standard deviation.

Adverse eventsBARI 2D was the only study that reported results for adverse events by treatment in its primary publication; however; it should be noted that the adverse event results presented were related to the overall revascularisation arm, which includes patients randomised to either PCI


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or CABG, and not specifically related to PCI only. In addition, the adverse events reported were largely related to the underlying diabetes and the treatments given (i.e. hypoglycaemia and diabetic ketoacidosis or hyperosmolar nonketotic coma) or cardiovascular disease (e.g. transient ischaemic attack, congestive heart failure; shown below), rather than related to the revascularisation procedure. There was no significant difference between revascularisation (with PCI or CABG) and medical therapy for any of the adverse events examined (Table 5.2-10).

Adverse events in the OAT study were briefly reported in the publication by Overgaard et al (2013). As shown in Table 5.2-10, complications up to 48 hours post-randomisation were low, but generally higher in the PCI + OMT group compared with the OMT alone group. Specific major PCI-related complications were also reported in the primary publication by Hochman et al (2006), and shown to be rare: death 0.2%, centrally-adjudicated MI 0.6%. New York Heart Association (NYHA) Class IV heart failure 0.2%, cardiac tamponade 0.2% and stroke 0.1%.

Table 5.2-10 Adverse events in included RCTs: chronic stable angina – PCI vs. medical therapy


PCI + OMTn (%)

OMTn (%)


BARI 2D68 CAD + DM

TIA - 29 (2.5) 32 (2.7) NR; 075

Congestive heart failure

AnyHF historyNo HF history

230 (21.3)47 (64.4)180 (18.1)

236 (21.2)45 (66.2)186 (18.0)

NR; 0.96NR; 0.82NR; 1.00

OAT Stable after MI

All complications - NR NR NR; < 0.001

Vascular complications - NR (0.5) NR (0.1) NR; 0.22

Major haemorrhage - NR (0.7) NR (0.1) NR; 0.04

Non-fatal MI - NR (0.7) NR (0.2) NR; 0.11Source: BARI 2D (BARI 2D Study group 2009): Table 1, p 2509; OAT (Overgaard et al, 2013): text, p 2419. Note: Statistically significant results shown in bold. Abbreviations: CAD, coronary artery disease; CI, confidence interval; DM, type 2 diabetes; HF, heart failure; MI, myocardial infarction; MT, medical therapy; NR, not reported; OMT, optimal medical therapy; PCI, percutaneous coronary intervention; RCT, randomised controlled trial; TIA, transient ischaemic attack.

In summary, the finding that the addition of PCI did not improve death or MI in patients with chronic stable angina (or similar) appears to be consistent across various patient subgroups including those at high risk, and with diabetes, multivessel disease, CKD and left ventricular dysfunction. PCI improved quality of life over the shorter term (≤12 months) but not over the longer term. Major haemorrhage occurred more frequently following PCI than OMT, but the underlying risk was low.

PCI versus CABG

Level I/III evidenceA summary of the results of the included SR/MAs that compare PCI with CABG is presented in Table 5.2-11. The SR/MA of up to 20 RCTs by D’Ascenzo et al (2014) showed no significant benefit of PCI compared with CABG for death or MI in patients with stable angina. While PCI was shown to significantly reduce the risk of stroke compared with CABG,

68 Intervention is revascularisation (any method) and comparator is medical therapy.


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particularly in women, repeat revascularisation was significantly greater for PCI compared with CABG. This was particularly the case for women and those with diabetes. It is unclear if any of the analyses were subject to heterogeneity because the results of the tests for heterogeneity have not been reported.

It should be noted that in 14 out of the 20 included RCTs, 100% of patients in the PCI arm received stents, while in four studies, no patients received stents. In the remaining two studies, 54% and 68% of patients received stents. The authors of the D’Ascenzo SR/MA performed a meta-regression analysis that tested for interaction between baseline characteristics (including age, gender, diabetes, previous MI and ejection fraction) and revascularisation choice; as such it was not possible to replicate the analysis including only the studies in which 100% of patients in the PCI arm received stents.

Fanari et al (2014) aimed to compare PCI + DES with CABG in patients with multivessel CAD. As shown in Table 5.2-11, for PCI + DES compared with CABG, the risk of death was significantly higher at 5 years in patients with multivessel disease (RR 1.30; 95% CI 1.10, 1.54) and also in patients with multivessel disease plus diabetes (RR 1.36; 95% CI 1.11, 1.66). MI was similarly increased at 5 years in patients with multivessel disease ± diabetes (RR 2.21) and in patients with multivessel disease plus diabetes 2.01). Target vessel revascularisation at 1 year was also higher in patients receiving PCI + DES, while stroke was significantly reduced in patients with multivessel disease receiving PCI + DES compared with CABG at 1, 2 and 5 years (RR 0.35-0.60) and in patients with multivessel disease and diabetes receiving PCI + DES compared with CABG at 5 years (RR 0.59).

The SR/MA by Qi et al (2014) included RCTs and observational studies that compared PCI with CABG. Analysis of data from two RCTs that specifically examined PCI with DES (paclitaxel in Banning et al, 2010 and sirolimus or paclitaxel in FREEDOM) showed that all-cause mortality, MI and major adverse cardiac and cerebrovascular events (MACCE) were all significantly reduced in patients with diabetes mellitus and multivessel disease undergoing CABG compared with PCI + DES. It should be noted that approximately 30% of patients in the Banning et al (2010) RCT had stable angina, while it is unclear how many patients in FREEDOM had angina (although the methods note that all patients underwent routine assessment of angina). Analysis of eight observational studies showed no benefit of CABG compared with PCI + DES for mortality or MI; however, the analysis was performed on raw data from these studies and no adjustment for potential confounding was undertaken.

The final SR/MA by Takagi et al (2014) included observational studies only to assess the benefit of off-pump CABG over PCI + DES. Only one of six studies with results adjusted for potential confounders was specifically in patients with chronic stable angina; the remaining studies included patients with a mix of multivessel or triple-vessel disease and a variety of affected vessels including the left main trunk and the left anterior descending artery. All-cause mortality was not significantly reduced in patients undergoing off-pump CABG compared with PCI + DES in either the adjusted analysis or the unadjusted analysis.

Multivessel subgroupThe SR/MAs by D’Ascenzo and Fanari et al (2014) provide data on the subgroup of patients with multivessel disease. As shown in Table 5.2-11, results for the multivessel disease subgroup in the SR/MA by D’Ascenzo and colleagues were generally similar to the results in the overall population, with a significantly decreased risk of stroke seen for PCI compared with CABG, and a significantly increased risk of repeat revascularisation seen for PCI compared with CABG. However, in the SR/MA by Fanari and colleagues, which presented


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the results of studies utilising PCI + DES by different follow-up durations, mortality and MI were significantly higher in the patients with multivessel disease who received PCI + DES compared with CABG. Repeat revascularisation was significantly higher for PCI + DES and stroke was significantly lower for PCI + DES in both SR/MAs.

Diabetes subgroupThe SR/MA by Fanari et al (2014) provides data on the subgroup of patients with multivessel disease and diabetes. As shown in Table 5.2-11, the use of PCI + DES resulted in significantly higher rates of death and MI at 5 years compared with CABG. The increased risks were similar for the multivessel disease + diabetes subgroup compared with multivessel disease only group. Stroke was significantly higher in patients with multivessel disease and diabetes receiving CABG compared with PCI + DES.

In summary, the studies by D’Ascenzo et al (2014) and Fanari et al (2014) provide the evidence that is most relevant to this MBS Review: (i) both are based on RCT evidence; (ii) the D’Ascenzo SR/MA population of interest was stable angina and the majority of patients in the PCI arms of the included trials received stents; and (iii) the Fanari SR/MA population of interest was multivessel disease and the intervention assessed was PCI + DES. While D’Ascenzo et al (2014) showed no benefit of PCI over CABG in terms of death or MI, there was a benefit for stroke, and increased harm in terms of repeat revascularisation. Fanari et al (2014) showed increased risks of death and MI associated with PCI + DES over longer-term follow-up.


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Table 5.2-11 Results of included systematic reviews: chronic stable angina – PCI versus CABG

Study ID Population Comparison

Outcome (analysis/subgroup) Studies (patients)



SR/MA – Level I

D’Ascenzo 2014 Stable angina

PCI vs. CABG

Death (overall population)Death (multivessel disease)MI (overall population)MI (multivessel disease)Repeat revasc. (overall population)Repeat revasc. (multivessel disease)Stroke (30 days – overall population)Stroke (follow-up – overall population)Stroke (30 days – multivessel disease)Stroke (follow-up – multivessel disease)

NRNRNRNRNRNRNRNRNRNR

OR 0.99 (0.77, 1.27); NROR 1.11 (0.87, 1.43); NROR 1.03 (0.77, 1.37); NROR 1.00 (0.72, 1.39); NROR 4.71 (3.17, 7.01); NR69

OR 7.18 (4.32, 11.93); NROR 0.36 (0.20, 0.62); NR70

OR 0.57 (0.41, 0.80); NR69

OR 0.34 (0.19, 0.61); NR69

OR 0.49 (0.25, 0.97); NR69

PCI significantly reduces the risk of stroke compared to CABG, particularly in female patients; however, the risk of revascularisation is increased with PCI, especially in women and those with diabetes.

Fanari 2014 Multivessel CAD

PCI + DES vs. CABG

Death – 1 yDeath – 2 yDeath – 5 yDeath – 5 y (diabetes)MI – 1 yMI – 2 yMI – 5 yMI – 5 y (diabetes)Target vessel revasc. – 1 yStroke – 1 yStroke – 2 yStroke – 5 yStroke – 5 y (diabetes)

6 (5123)4 (4498)3 (4202)3 (2854)6 (5123)4 (4498)3 (4202)3 (2854)6 (5123)6 (5123)4 (4498)3 (4202)3 (2854)

RR 1.02 (0.77, 1.36); NRRR 1.31 (0.83, 2.08); NRRR 1.30 (1.10, 1.54); NRRR 1.36 (1.11, 1.66); NRRR 1.16 (0.72, 1.88); NRRR 1.21 (0.70, 2.11); NRRR 2.21 (1.75, 2.79); NRRR 2.01 (1.54, 2.62); NRRR 2.31 (1.80, 2.96); NRRR 0.35 (0.19, 0.62); NRRR 0.55 (0.35, 0.87); NRRR 0.60 (0.42, 0.86); NRRR 0.59 (0.39, 0.89); NR

In patients with multivessel CAD, PCI with DES is associated with no significant difference in death or MI at 1 or 2 years. However at 5 years, PCI is associated with higher incidence of death and MI.

69 Significant interactions seen between female gender (B = 3.4; p = 0.01) and diabetes mellitus (B = 1.8; p=0.002), and CABG benefit. 70 Significant interaction seen between female gender and PCI benefit (B = –0.12; p = 0.03)MBS Reviews – Percutaneous Coronary Intervention Review Report Page 166

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Outcome (analysis/subgroup) Studies (patients)



SR/MA – Level I/III

Qi 2014 Multivessel CAD and diabetes

CABG vs. PCI+BMS

All-cause mortality (RCT)All-cause mortality (OBS)All-cause mortality (all studies)MI (RCT)MI (OBS)MI (all studies)MACCE (RCT)MACCE (OBS)MACCE (all studies)

2 (2331)8 (2905)10 (5236)2 (2331)7 (2014)9 (4345)2 (2331)8 (2905)10 (5236)

OR 0.71 (0.54, 0.94); 0.0171

OR 1.11 (0.84, 1.45); 0.47OR 0.89 (0.73, 1.07); 0.22OR 0.50 (0.36, 0.70); <0.001OR 0.76 (0.47, 1.23); 0.26OR 0.57 (0.44, 0.75); <0.001OR 0.60 (0.47, 0.75); <0.001OR 0.60 (0.50, 0.72); <0.001OR 0.60 (0.52, 0.69); <0.001

CABG is better than PCI for diabetic patients with multivessel CAD. CABG can significantly reduce the rates of MI and MACCE and is comparable in mortality despite the worse baseline characteristics in patients who underwent CABG.

SR/MA – Level III

Takagi 2014 Any CAD OP CABG vs. PCI + DES

All-cause mortality (adjusted studies)All-cause mortality (unadjusted studies)

6 (3874)4 (2717)

HR 0.72 (0.45, 1.17); 0.1970

HR 1.00 (0.79, 1.25); 0.98OP CABG may not improve survival over DES despite greater number of treated vessels in OP CABG than in DES or greater number of distal anastomosis in OP CABG than that of implanted stents in DES.

Source: D’Ascenzo et al (2014): Text, p 52; Fanari et al (2014): Figures 1-4; Qi et al (2014): Figures 5-7, p 415-417; Takagi et al (2014): Figure 1, p 811. Note: Statistically significant results shown in bold. Abbreviations: BMS, bare metal stent; CABG, coronary artery bypass graft; CAD, coronary artery disease; CI, confidence interval; DES, drug-eluting stent; HR, hazard ratio; MA, meta-analysis; MACCE, major adverse cardiac and cerebrovascular events; MI, myocardial infarction; NR, not reported; OBS, observational study; OP, off-pump; OR, odds ratio; PCI, percutaneous coronary intervention; RCT, randomised controlled trial; RR, relative risk; SR, systematic review; y, year.

71 All analyses in this study represent a comparison between CABG vs. PCI (not PCI vs. CABG); therefore, point estimate < 1 favour CABG and point estimate > 1 favour PCI.MBS Reviews – Percutaneous Coronary Intervention Review Report Page 167

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High risk, chronic kidney disease and heart failure/left ventricular dysfunction subgroup analyses were not undertaken in the SR/MA of RCTs.

Although a diabetes subgroup was assessed in the Level I evidence, it is also included here because the Level I assessment was limited to diabetic patients with multivessel disease and only PCI + DES were considered.

Safety and quality of life was not assessed in the SR/MA of RCTs.

The RCTs considered eligible for assessment were those included in the review by D’Ascenzo et al (2014) in which 100% of patients randomised to PCI received stents. The citation details for the included RCTs are presented in Table 5.2-12. It should be noted that two of the RCTs included in the D’Ascenzo 2014 review (Seoul and Liepzig) could not be identified due to insufficient identifying information in the publication.

Table 5.2-12 Citation details for additional included RCTs: chronic stable angina – PCI vs. CABG

Ref ID CitationFREEDOM Primary publication:

Farkouh, M. E., M. Domanski, et al. (2012). "Strategies for multivessel revascularization in patients with diabetes." N Engl J Med 367(25): 2375-2384.Secondary publication:Abdallah, M. S., K. Wang, et al. (2013). "Quality of life after PCI vs CABG among patients with diabetes and multivessel coronary artery disease: a randomized clinical trial." JAMA 310(15): 1581-1590.

Budriot 2011 Primary publication:Boudriot, E., H. Thiele, et al. (2011). "Randomized comparison of percutaneous coronary intervention with sirolimus-eluting stents versus coronary artery bypass grafting in unprotected left main stem stenosis." J Am Coll Cardiol 57(5): 538-545.

PRECOMBAT Primary publication:Park, S. J., Y. H. Kim, et al. (2011). "Randomized trial of stents versus bypass surgery for left main coronary artery disease." N Engl J Med 364(18): 1718-1727.

CARDIa Primary publication:Kapur, A., R. J. Hall, et al. (2010). "Randomized comparison of percutaneous coronary intervention with coronary artery bypass grafting in diabetic patients. 1-year results of the CARDia (Coronary Artery Revascularization in Diabetes) trial." J Am Coll Cardiol 55(5): 432-440.

SYNTAX Primary publication:Serruys, P. W., M. C. Morice, et al. (2009). "Percutaneous coronary intervention versus coronary-artery bypass grafting for severe coronary artery disease." N Engl J Med 360(10): 961-972.Secondary publications:Head, S. J., P. M. Davierwala, et al. (2014). "Coronary artery bypass grafting vs. percutaneous coronary intervention for patients with three-vessel disease: final five-year follow-up of the SYNTAX trial." Eur Heart J 35(40): 2821-2830.Morice, M. C., P. W. Serruys, et al. (2014). "Five-year outcomes in patients with left main disease treated with either percutaneous coronary intervention or coronary artery bypass grafting in the synergy between percutaneous coronary intervention with taxus and cardiac surgery trial." Circulation 129(23): 2388-2394.Cohen, D. J., B. Van Hout, et al. (2011). "Quality of life after PCI with drug-eluting stents or coronary-artery bypass surgery." N Engl J Med 364(11): 1016-1026.

LE MANS Primary publication:Buszman, P. E., S. R. Kiesz, et al. (2008). "Acute and late outcomes of unprotected left main stenting in comparison with surgical revascularization." J Am Coll Cardiol 51(5): 538-545.


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Ref ID CitationSoS Primary publication:

SoS Investigators (2002). "Coronary artery bypass surgery versus percutaneous coronary intervention with stent implantation in patients with multivessel coronary artery disease (the Stent or Surgery trial): a randomised controlled trial." Lancet 360(9338): 965-970.Secondary publication:Booth, J., T. Clayton, et al. (2008). "Randomized, controlled trial of coronary artery bypass surgery versus percutaneous coronary intervention in patients with multivessel coronary artery disease: six-year follow-up from the Stent or Surgery Trial (SoS)." Circulation 118(4): 381-388.

ARTS 1 Primary publication:Serruys, P. W., F. Unger, et al. (2001). "Comparison of coronary-artery bypass surgery and stenting for the treatment of multivessel disease." N Engl J Med 344(15): 1117-1124.Secondary publication:Legrand, V. M., P. W. Serruys, et al. (2004). "Three-year outcome after coronary stenting versus bypass surgery for the treatment of multivessel disease." Circulation 109(9): 1114-1120.

ERACI II Primary publication:Rodriguez, A., V. Bernardi, et al. (2001). "Argentine Randomized Study: Coronary Angioplasty with Stenting versus Coronary Bypass Surgery in patients with Multiple-Vessel Disease (ERACI II): 30-day and one-year follow-up results. ERACI II Investigators." J Am Coll Cardiol 37(1): 51-58.Secondary publication:Rodriguez, A. E., J. Baldi, et al. (2005). "Five-year follow-up of the Argentine randomized trial of coronary angioplasty with stenting versus coronary bypass surgery in patients with multiple vessel disease (ERACI II)." J Am Coll Cardiol 46(4): 582-588.

SIMA Primary publication:Goy, J. J., U. Kaufmann, et al. (2000). "A prospective randomized trial comparing stenting to internal mammary artery grafting for proximal, isolated de novo left anterior coronary artery stenosis: the SIMA trial. Stenting vs. Internal Mammary Artery." Mayo Clin Proc 75(11): 1116-1123.Secondary publication:Goy, J. J., U. Kaufmann, et al. (2008). "10-year follow-up of a prospective randomized trial comparing bare-metal stenting with internal mammary artery grafting for proximal, isolated de novo left anterior coronary artery stenosis the SIMA (Stenting versus Internal Mammary Artery grafting) trial." J Am Coll Cardiol 52(10): 815-817.

The main characteristics and conclusions of the RCTs that compared PCI plus stent insertion with CABG that were included in the D’Ascenzo et al (2014) SR/MA are presented in Table 5.2-13. The studies were quite heterogeneous in terms of populations, with none appearing to be limited to patients with stable angina. DES were used exclusively in the more recent RCTs (FREEDOM, Boudriot 2011, PRECOMBAT and SYNTAX). Other trials either used a combination of both DES and BMS, either based on the timeframe in which patients were enrolled or in lesions of different sizes (CARDIa and LE MANS), while the remaining trials either used BMS, or did not state the stent type.

Most studies, in particular the more recent studies, conclude that PCI is either non-inferior or inferior to CABG in terms of outcomes such as death and MI, and inferior in terms of rates of revascularisation; CABG tends to be inferior to PCI in terms of stroke. The ERACI II study concluded that percutaneous transluminal coronary revascularisation with stent insertion was superior to CABG in terms of death and MI; however, the majority of patients included in this trial had unstable angina. In addition, the LE MANS study concluded that over longer-term follow-up (2 years) there was a trend towards improved survival following PCI. It should be noted that arterial graft use was ≥93% for all but two studies: ERACI II (89%) and LE MANS (72%). It is possible that these lower rates of graft use, compared with ~100% stent use in the PCI arms, biased these results in favour of PCI.


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Table 5.2-13 Characteristics and conclusions of the included RCTs: chronic stable angina – PCI vs. CABGStudy ID Study



FREEDOM Randomised, parallel, open-label Minimum 2 y

up to 5 y follow-up

Diabetes and angiographically confirmed multivessel CAD with stenosis of more than 70% in two or more major epicardial vessels involving at least two separate coronary artery territories and without left main coronary stenosisN=1900

PCI + DES Sirolimus-eluting

stents exclusively in 51% and paclitaxel-eluting stents exclusively in 43%

CABG 18.5% off-

pump 94%

arterial graft

Death/MI/ stroke

For patients with diabetes and advanced CAD, CABG was superior to PCI in that it significantly reduced rates of death and MI, with a higher rate of stroke.

Boudriot 2011

Randomised, parallel, open-label 12 m follow-up

Stenosis (≥50%) of the ULMCA with or without additional multivessel CADN=201

PCI + DES Sirolimus-eluting

stents used in all but two patients who received paclitaxel-eluting stents

CABG 46% off-

pump 99%

arterial graft

Freedom from MACCE (death/MI/ repeat revasc.)

PCI with sirolimus-eluting stents is inferior to CABG at 12-month follow-up with respect to freedom from major adverse cardiac events, which is mainly influenced by repeated revascularisation, whereas for hard end points, PCI results are favourable. A longer follow-up is warranted.

PRE-COMBAT

Randomised, parallel, open-label 2 y follow-up

Diagnosis of stable angina, unstable angina, silent ischaemia, or NSTEMI 49.5% of patients had stable

angina or no symptomsN=600

PCI + DES 100% sirolimus-

eluting stents

CABG 64% off-

pump 94%

arterial graft

MACCE PCI with sirolimus-eluting stents was shown to be non-inferior to CABG with respect to major adverse cardiac or cerebrovascular events. However, the non-inferiority margin was wide, and the results cannot be considered clinically directive.

CARDIa Randomised, parallel, open-label 1 y follow-up

Diabetes and either multivessel coronary disease or complex single-vessel disease (ostial or proximal left anterior descending artery disease) and were recommended to have coronary revascularisation on clinical groundsN=510

PCI + stenting Sirolimus-eluting

stents in 69% (15 patients also received BMS) and BMS exclusively in 31%

CABG 31% off-

pump 94%

arterial graft

Death/MI/ stroke

The one-year results did not show that PCI is non-inferior to CABG. However, the trial did show that multivessel PCI is feasible in patients with diabetes, but longer-term follow-up and data from other trials will be needed to provide a more precise comparison of the efficacy of these two revascularisation strategies.

SYNTAX Randomised, parallel, open-label 1 y follow-up

Three-vessel or left main CAD Stable angina 57%N=1800

PCI + stenting Paclitaxel-eluting

stents 100%

CABG 15% off-

pump 97%

arterial graft

MACCE CABG remains the standard of care for patients with three-vessel or left main CAD, since the use of CABG, as compared with PCI, resulted in lower rates of the combined end point of major adverse cardiac or cerebrovascular events at one year.


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Authors conclusions

LE MANS Randomised, parallel, open-label 1 y follow-up

>50% narrowing of ULMCA, with or without multivessel CAD suitable for equal revascularisation CCS Class ~IIIN=105

PCI + stenting BMS if LM

diameter ≥ 3.8 mm and DES if LM < 3.8

35% DES

CABG 2% off-

pump 72%

arterial graft

Change in LVEF

Patients with ULMCA disease treated with PCI had favourable early outcomes in comparison with the CABG group. At one year, LVEF had improved significantly only in the PCI group. After more than 2 years, MACCE-free survival was similar in both groups with a trend towards improved survival after PCI.

SoS Randomised, parallel, open-label Median 2 y

follow-up

Symptomatic patients with multivessel CAD were considered for inclusion and enrolled if the consensus view of the trial surgeon and interventionist was that revascularisation was clinically indicated and appropriate by either strategy CCS Class III 26% CCS Class IV 21%N=988

PCI + stenting Type not reported

CABG 100% on-

pump 93%

arterial graft

Repeat revasc.

The use of coronary stents has reduced the need for repeat revascularisation when compared with previous studies that used balloon angioplasty, though the rate remains significantly higher than in patients managed with CABG. The apparent reduction in mortality with CABG requires further investigation.

ARTS 1 Randomised, parallel, open-label

Median 2 y follow-up

Patients who had not previously undergone bypass surgery or angioplasty were eligible for coronary revascularisation if they had either stable angina pectoris (CCS I-IV) or unstable angina pectoris (Braunwald Class IB, IC, IIB, IIC, IIIB, or IIIC) or if they had silent ischaemia and at least two new lesions that were located in different vessels and territories (not including the left main coronary artery) and that were potentially amenable to stent implantation

Stable angina 59%N=1205

PCI + stenting Type not reported

CABG 100% on-

pump 93%

arterial graft

Freedom from MACCE

As measured one year after the procedure, coronary stenting for multivessel disease is less expensive than bypass surgery and offers the same degree of protection against death, stroke, and MI. However, stenting is associated with a greater need for repeated revascularisation.


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Authors conclusions

ERACI II Randomised, parallel, open-label Median 1.5 y

follow-up

Symptomatic patients with multivessel disease 91% unstable angina

PTCR + stenting 100% BMS

CABG 100% on-

pump 89%

arterial graft

MACCE In this selected high-risk group of patients with multivessel disease, PTCR with stent implantation showed better survival and freedom from MI than did conventional surgery. Repeat revascularisation procedures were higher in the PTCR group.

SIMA Randomised, parallel, open-label Mean 2.4 y

follow-up

Symptomatic or silent cardiac ischaemia ad isolated proximal LAD coronary artery stenosis with LVEF > 45% CCS I-II 52% CCS III-IV, unstable 48%

PTCA + stenting Type not reported

CABG 100% on-

pump 93%

arterial graft

Death/MI/repeat revasc.

Both stent implantation and CABG are safe and highly effective treatments to relieve symptoms in patients with isolated, proximal left anterior descending coronary artery stenosis. Both are associated with a low and comparable incidence of death and MI. However, similar to PTCA alone, a percutaneous approach using elective stent placement remains hampered by a higher need for repeated intervention because of restenosis.

Source: Adapted from D’Ascenzo et al (2014), Table 1, p 53 and FREEDOM: Farkouh et al (2012); Boudriot et al (2011); PRECOMBAT: Park et al (2011); CARDIa: Kapur et al (2010); SYNTAX: Serruys et al (2009); LE MANS: Buszman et al (2008); SoS: SoS Investigators (2002); ARTS 1: Serruys et al (2001); ERACI II: Rodriguez et al (2001); SIMA: Goy et al (2000). Abbreviations: BMS, bare metal stent; CABG, coronary artery bypass graft; CAD, coronary artery disease; CCS, Canadian Cardiovascular Society; DES, drug-eluting stent; LAD, left anterior descending; LM, left main; LVEF, left ventricular ejection fraction; MACCE, major adverse cardiac and cerebrovascular events; MI, myocardial infarction; NSTEMI, non-ST-segment elevation myocardial infarction; OP, off-pump; PCI, percutaneous coronary intervention; PTCA, percutaneous transluminal coronary angioplasty; PTCR, percutaneous transluminal coronary revascularisation; RCT, randomised controlled trial; revasc., revascularisation; ULMCA, upper left main coronary artery.


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All included RCTs provided data on at least one of the additional subgroups and outcomes of interest.

DES versus BMSAn analysis of the effect of using different types of stents (BMS or DES) with PCI, compared with CABG was presented in the CARDIa study. In this trial, PCI was initially conducted using BMS; however, DES were used once they became available. In order to minimise potential confounding in the comparison, patients receiving BMS were compared with patients who received CABG prior to the introduction of DES, while patients receiving DES were compared with patients who received CABG following the introduction of DES. As shown in Table 5.2-14, there was a higher (although not statistically significant) risk of death/MI/stroke in patients receiving BMS compared with patients receiving CABG (15.9% versus 5.7%), while there was no difference between patients receiving DES and CABG (11.6% versus 12.4%). There was also a higher rate of MACCE in patients receiving BMS compared with CABG (22.0% versus 7.1%), and no significant difference between patients receiving DES compared with CABG (18.0% vs. 12.9%). The authors acknowledge that the CARDIa trial was underpowered, however note that ‘there seemed to be a trend suggesting that DES may provide a better outcome than BMS’. It should be kept in mind that these comparisons are not randomised and may be subject to bias, particularly due to changes in the underlying medical therapies used over time.

Table 5.2-14 Stent type subgroup analyses in the included RCTs: chronic stable angina – PCI vs. CABG


PCI + stentn (%)

CABGn (%)


Subgroup p value

CARDIa (Kapur 2010)

Multivessel CAD and diabetes

Death/MI/stroke* BMSDES

13 (15.9)20 (11.6)

4 (5.7)22 (12.4)

HR 2.99 (0.97, 9.16); NRHR 0.93 (0.51, 1.71); NR

0.076

MACCE BMSDES

18 (22.0)31 (18.0)

5 (7.1)23 (12.9)

HR 3.42 (1.27, 9.22); NRHR 1.41 (0.82, 2.42); NR

0.131

Source: CARDIa (Kapur et al, 2010): Table 3, p 437. Note: Primary outcome denoted by *. Statistically significant results shown in bold. Abbreviations: BMS, bare metal stent; CABG, coronary artery bypass graft; CI, confidence interval; DES, drug-eluting stent; HR, hazard ratio; MACCE, major cardiac and cerebrovascular events; MI, myocardial infarction; PCI, percutaneous coronary intervention; RCT, randomised controlled trial.

Diabetes subgroupSix studies provided data on the subgroup of patients with diabetes; in two studies, only patients with diabetes were included (FREEDOM and CARDIa) while in the remaining studies, diabetes subgroup analyses were conducted (PRECOMBAT, SYNTAX, SoS, ERACI II). Therefore, only the FREEDOM and CARDIa trials are sufficiently powered to detect a difference for the primary outcomes.

In the FREEDOM trial, there was no difference in the primary outcome, death/MI/stroke, at 2 years (Table 5.2-15). At 5 years, however, the rate of death/MI/stroke was higher in the PCI group compared with the CABG group. This finding is driven by both a higher occurrence of deaths in the PCI arm (16.3% vs. 10.9%; p=0.049) and a higher occurrence of MI in the PCI arm (13.9% vs. 6.0%; p<0.001). Stroke was significantly higher in the CABG arm at 30 days (0.3% vs. 1.8%; p=0.002) and 5 years (2.4% vs. 5.2%; p=0.03). In the CARDIa trial, there was no significant difference in the primary outcome (death/MI/stroke) at 1 year, but the rate


January 2016

of late MI (i.e. not procedure-related) was higher in the PCI arm compared with the CABG arm (5.5% vs. 1.2%; p=0.02).

In the remaining trials that analysed outcomes by diabetes/no diabetes subgroups, there was no significant interaction between treatment and diabetes status for the primary outcomes. However, the greater risk associated with PCI for MACCE and repeat revascularisation in the SYNTAX and SoS trials, respectively, was of a larger magnitude for patients with diabetes compared with patients without diabetes (HR 2.30 vs 1.51 and HR 5.25 vs. 3.65, respectively).

Table 5.2-15 Diabetes subgroup analyses in the included RCTs: chronic stable angina – PCI vs. CABG


PCI + stentn (%)

CABGn (%)


Subgroup p value

FREEDOM Multivessel CAD and diabetes

Death/MI/stroke* 30 days1 year2 years5 years

NRNR121 (13.0)200 (26.6)

NRNR108 (11.9)146 (18.7)

--NR; NRNR; 0.00572

-

Death 30 days1 year2 years5 years

8 (0.8)32 (3.4)62 (6.7)114 (16.3)

15 (1.7)38 (4.2)57 (6.3)83 (10.9)

NR; 0.12NR; 0.35NR; NRNR; 0.04971

-

MI 30 days1 year2 years5 years

17 (1.8)54 (5.8)62 (6.7)98 (13.9)

15 (1.7)30 (3.4)42 (4.7)48 (6.0)

NR; 0.82NR; 0.02NR; NRNR; <0.00171

-

Stroke 30 days1 year2 years5 years

3 (0.3)8 (0.9)14 (1.5)20 (2.4)

16 (1.8)17 (1.9)24 (2.7)37 (5.2)

NR; 0.002NR; 0.06NR; NRNR; 0.0371

-

PRECOMBAT Left main CAD

MACCE* DiabetesNo diabetes

16 (16.3)20 (10.2)

10 (11.1)14 (6.8)

HR 1.43 (0.65, 3.16); 0.37HR 1.51 (0.76, 2.99); 0.24

0.9273

CARDIa Multivessel CAD and diabetes

Death/MI/stroke* 1 year 33 (13.0) 26 (10.5) HR 1.25 (0.75, 2.09); 0.39 -

Death 1 year 8 (3.2) 8 (3.2) HR 0.98 (0.37, 2.61); 0.97

MI – total 1 year 25 (9.8) 14 (5.7) HR 1.77 (0.92, 3.40); 0.09

MI – periprocedural 1 year 12 (4.7) 11 (4.4) HR 1.08 (0.47, 2.44); 0.82

MI – late 1 year 14 (5.5) 3 (1.2) HR 4.64 (1.33, 16.16); 0.02

Stroke 1 year 1 (0.4) 7 (2.8) HR 0.14 (0.02, 1.14); 0.07

SYNTAX Severe CAD – 3-vessel disease

MACCE* DiabetesNo diabetes

NR (45.5)NR (34.4)

NR (23.6)NR (24.5)

HR 2.30 (1.50, 3.55); <0.001HR 1.51 (1.15, 1.96); 0.002

0.09574

72 P value calculated on the basis of all available follow-up data (i.e. more than 5 years). 73 Diabetes subgroup analysis prespecified. 74 Diabetes subgroup analysis performed post hoc in a separate publication.


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PCI + stentn (%)

CABGn (%)


Subgroup p value

Death DiabetesNo diabetes

NR (20.2)NR (12.5)

NR (10.1)NR (8.9)

NR; 0.03NR; 0.10

NR

Stroke DiabetesNo diabetes

NR (3.8)NR (2.7)

NR (3.3)NR (3.4)

NR; 0.87NR; 0.53

NR

MI DiabetesNo diabetes

NR (9.2)NR (11.2)

NR (3.1)NR (3.3)

NR; 0.06NR; <0.001

NR

Repeat revasc. DiabetesNo diabetes

NR (33.2)NR (23.4)

NR (12.5)NR (12.6)

NR; <0.001NR; <0.001

NR

SoS Multivessel CAD

Repeat revasc.* DiabetesNo diabetes

17 (25.0)84 (20.0)

4 (5.4)26 (6.1)

HR 5.25 (1.77, 15.6); NRHR 3.65 (2.35, 5.67); NR

0.5575

Death DiabetesNo diabetes

3 (4.4)19 (4.5)

1 (1.4)7 (1.6)

HR 3.11 (0.32, 29.9); NRHR 2.88 (1.21, 6.85); NR

0.95

Death/MI DiabetesNo diabetes

7 (10.3)39 (9.3)

9 (12.2)40 (9.4)

HR 0.73 (0.27, 1.97); NRHR 1.00 (0.64, 1.55); NR

0.58

ERACI II Multivessel CAD

Death Diabetes76

No diabetesNR (10.0)NR (6.4)

NR (10.2)NR (11.8)

NRNR

NR

Source: FREEDOM (Farkouh et al, 2012): Table 2, p 2379 and Table 3, p 2381; PRECOMBAT (Park et al, 2011): Figure 3, p 1724; CARDIa (Kapur et al, 2010): Table 2, p 437; SYNTAX (Head et al, 2014): Text p 2825-2826 and Figure 3, p 2827; SoS (Booth et al, 2008): Table 3, p 385; ERACI II (Rodriguez et al, 2005): Text, p 584. Note: Primary outcome denoted by *. Statistically significant results shown in bold. Abbreviations: CABG, coronary artery bypass graft; CAD, coronary artery disease; HR, hazard ratio; MACCE, major adverse cardiac or cerebrovascular events; MI, myocardial infarction; NR, not reported; PCI, percutaneous coronary intervention; RCT, randomised controlled trial; revasc., revascularisation.

Chronic kidney disease subgroupA subgroup analysis based on presence or absence of renal insufficiency was conducted in the FREEDOM trial. As shown in Table 5.2-16, there was no significant interaction between treatment and renal insufficiency subgroup. The higher risk of the primary outcome (death/MI/stroke) was statistically significant in the no renal insufficiency subgroup and not the renal insufficiency subgroup; however, this is likely related to the number of patients available for each analysis – 1771 patients in the no renal insufficiency subgroup and 129 patients in the renal insufficiency subgroup.

Table 5.2-16 Chronic kidney disease subgroup analyses in the included RCTs: chronic stable angina – PCI vs. CABG


PCI + stentn (%)

CABGn (%)


Subgroup p value


Death/MI/stroke* Renal insufficiency77

No renal insufficiencyNR (44)NR (25)

NR (37)NR (17)

1.2 (0.6, 2.2);78 NR1.3 (1.1, 1.7);77 NR

0.6279

75 Diabetes subgroup analysis prespecified.76 Diabetes was investigated as an independent predictor in the primary publication (Rodriguez et al, 2001) and the subgroup analysis was included in a subsequent Rodriguez et al (2005) publication. 77 Not defined in publication. 78 Estimated from graph.79 Renal insufficiency subgroup analysis prespecified.


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Source: FREEDOM (Farkouh et al, 2012): Figure 2, p 2382. Note: Primary outcome denoted by *. Statistically significant results shown in bold. Abbreviations: CABG, coronary artery bypass graft; CAD, coronary artery disease; CI, confidence interval; MI. myocardial infarction; NR, not reported; PCI, percutaneous coronary intervention; RCT, randomised controlled trial.

Heart failure or known left ventricular dysfunction subgroupA subgroup analysis based on LVEF was conducted in the FREEDOM trial. As shown in Table 5.2-17, there was no significant interaction between treatment and LVEF subgroup. The higher risk of the primary outcome (death/MI/stroke) was not statistically significant in either subgroup. Once again, this may be due to the patient numbers available for each analysis; in particular, there were only 32 patients included in the LVEF <40% subgroup analysis.

Table 5.2-17 Heart failure or known left ventricular dysfunction subgroup analyses in the included RCTs: chronic stable angina – PCI vs. CABG


PCI + stentn (%)

CABGn (%)


Subgroup p value


Death/MI/stroke* LVEF <40%LVEF ≥40%

NR (62)NR (23)

NR (31)NR (18)

HR 2.3 (0.6, 4.2);80 NRHR 1.2 (0.9, 1.6);79 NR

0.3781

Source: FREEDOM (Farkouh et al, 2012): Figure 2, p 2382. Note: Primary outcome denoted by *. Statistically significant results shown in bold. Abbreviations: CABG, coronary artery bypass graft; CAD, coronary artery disease; CI, confidence interval; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NR, not reported; PCI, percutaneous coronary intervention; RCT, randomised controlled trial.

Quality of lifeQuality of life data was available from three studies: FREEDOM, SYNTAX and ARTS 1. The results of these studies are summarised in Table 5.2-18.

In the FREEDOM trial, quality of life (as measured by the SAQ) was significantly greater for PCI compared with CABG at 1 month, but significantly lower for PCI compared with CABG at 12, 24 and 60 months. The authors concluded that ‘for patients with diabetes and multivessel CAD, CABG surgery provided slightly better intermediate-term health status and quality of life than PCI using DES. The magnitude of benefit was small, without consistent differences beyond 2 years, in part due to the higher rate of repeat revascularisation with PCI’.

In the SYNTAX trial, improved quality of life was seen following PCI compared with CABG at 1 month for all scales measured. However, for the SAQ-Quality of Life subscale, a significantly greater benefit was seen following CABG at 12 months. For the other measures (SF-36 physical and mental summary and EQ-5D utilities) there was no significant difference between treatments at later time points. The authors concluded that ‘among patients with three-vessel or left main CAD who were suitable candidates for either PCI or CABG, both strategies resulted in significant relief from angina [data not shown] and improvements in overall health status over the first year of follow-up’.

In the ARTS 1 study, there was no significant difference in EQ-5D thermometer or summary scores between PCI and CABG at either 1 year or 3 years. In particular the authors noted that ‘the benefit observed after CABG in specific domains such as “mobility” and “anxiety or depression” at 1 year disappeared by 3 years’.

80 Estimated from graph. 81 LVEF subgroup analysis prespecified.


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Table 5.2-18 Quality of life in the included RCTs: chronic stable angina – PCI vs. CABG

Outcome PopulationTime point

PCI + stentMean ± SD

CABGMean ± SD

Mean difference(95% CI); p value


SAQ - QoL 1 month6 months12 months24 months36 months48 months60 months

NRNRNRNRNRNRNR

NRNRNRNRNRNRNR

MD 1.9 (0.2, 3.6); 0.0382

MD -0.4 (-1.8, 1.1); 0.62MD -1.9 (-3.4, -0.4,); 0.01MD -2.2 (-3.8, -0.7); 0.003MD -1.0 (-2.7, 0.7); 0.25MD -0.6 (-2.6, 1.4); 0.57MD -3.4 (-6.8, -0.1); 0.04

SYNTAX Severe CAD

SAQ – QoL 1 month6 months12 months

NRNRNR

NRNRNR

MD 5.0 (2.7, 7.3); <0.00181

MD -1.4 (-3.6, 0.8); NSMD -2.3 (-4.5, -0.1); 0.04

SF-36 – physical summary 1 month6 months12 months

NRNRNR

NRNRNR

MD 7.7 (6.8; 8.6); <0.001MD 0.4 (-0.5, 1.3); NSMD -0.8 (0.2, -1.7); NS

SF-36 – mental summary 1 month6 months12 months

NRNRNR

NRNRNR

MD 3.2 (2.1, 4.3); <0.001MD 0.6 (-0.5, 1.7); NSMD 0.5 (-0.6, 1.5); NS

EQ-5D utilities 1 month6 months12 months

NRNRNR

NRNRNR

MD 0.08 (0.07, 0.10); <0.001MD 0.01 (0.00, 0.03); NSMD 0.00 (-0.01, 0.02); NS

ARTS 1 Multivessel CAD

EQ-5D thermometer 1 year3 years

78 ± 1576 ± 16

80 ± 1578 ± 16

NR; 0.11NR; 0.16

EQ-5D summary 1 year3 years

86 ± 1685 ± 17

87 ± 1686 ± 17

NR; 0.24NR; 0.74

Source: FREEDOM (Abdallah et al, 2013): Table 2, p 1586; SYNTAX (Cohen et al, 2011): Table 3, p 1024; ARTS 1 (Legrand et al, 2004): Table 5, p 1119.Note: Statistically significant results shown in bold. Abbreviations: CABG, coronary artery bypass graft; CAD, coronary artery disease; CI, confidence interval; EQ-5D, EuroQol 5-dimension; MD, mean difference; MI. myocardial infarction; NR, not reported; NS, not significant; PCI, percutaneous coronary intervention; QoL, quality of life; RCT, randomised controlled trial; SAQ, Seattle Angina Questionnaire; SD, standard deviation; SF-36, 36-item Short Form Health Survey.

Adverse eventsEight studies provided data on the adverse events associated with PCI and CABG. Three studies reported on major bleeding and found higher rates in the CABG arms compared with the PCI arms (FREEDOM, CARDIa and LE MANS). This was statistically significant only in the CARDIa trial, which measured TIMI major bleeding up to 1 year and showed there was a significantly higher rate associated with CABG (6.1%) compared with PCI (1.2%; p=0.009). In the LE MANS trial, major bleeding occurred in 3 patients (5.7%) in the CABG group and no patients in the PCI group in the first 30 days, while in the first 30 days of the FREEDOM trial, there were 34 major bleeding events in the CABG arm (3.6%) compared with 23 (2.4%) in the PCI arm. Also in the first 30 days of the FREEDOM trial, acute renal failure occurred

82 Results presented as comparison between CABG and PCI in publication; converted to comparison between PCI and CABG for this MBS Review. Positive values indicate improved quality of life for PCI and negative values indicate improved quality of life for CABG.


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significantly more frequently in the CABG group (0.8%) compared with the PCI group (0.1%; p=0.02).

Periprocedural events occurred at a significantly higher rate in the CABG arm compared with the PCI arm up to 1 year in the Boudriot et al (2011) study (30% vs. 4%; p<0.001); this is largely driven by a higher rate of atrial fibrillation requiring treatment in the CABG arm (19% vs. 0%), as well as a higher rate of major infections in the CABG arm (5% vs. 0%).

In the SYNTAX trial, stent thrombosis (related to PCI) occurred at a significantly higher rate than graft occlusion (related to CABG) during days 2 to 30 of the trial (2.0% vs. 0.3%; p=0.001). However, between days 31 and 365, graft occlusion occurred more frequently than stent thrombosis (2.5% vs. 1.0%; p=0.02). Thus, overall over the course of the first year there is no significant difference in stent thrombosis versus graft occlusion between treatment arms (RR 0.96; 95% CI 0.57, 1.62). Furthermore, there is no significant difference between PCI and CABG in stent thrombosis and graft occlusion at 5 years (HR 1.15; 95% CI 0.57, 2.33).

Table 5.2-19 Adverse events in the included RCTs: chronic stable angina – PCI vs. CABG


PCI + stentn (%)

CABGMean ± SD



Major bleeding event 30 days 23 (2.4) 34 (3.6) NR; 0.13

Acute renal failure 30 days 1 (0.1) 8 (0.8) NR; 0.02

Boudriot 2011 Unprotected left main disease

Periprocedural eventAcute renal failureRenal insuff. requiring dialysisAtrial fibrillationAtrial fibrillation requiring tmtStrokeCritical illness neuropathyResternotomy for bleed + trans.Major infections

1 year 4 (4)1 (1)0 (0)3 (3)0 (0)0 (0)0 (0)0 (0)0(0)

30 (30)0 (0)1 (1)0 (0)19 (19)2 (2)1 (1)2 (2)5 (5)

NR; <0.001

CARDIa Multivessel CAD and diabetes

TIMI major bleeding 1 year 3 (1.2) 15 (6.1) HR 0.19 (0.06, 0.67); 0.009

SYNTAX (Serruys 2009) Severe CAD

Graft occlusion or stent thrombosis 1 year≤ 1 day2-30 days31-365 days

28 (3.3)2 (0.2)18 (2.0)9 (1.0)

27 (3.4)3 (0.3)3 (0.3)21 (2.5)

RR 0.96 (0.57, 1.62); 0.89RR 0.65 (0.11, 3.86); 0.68RR 5.83 (1.72, 19.7); 0.001RR 0.42 (0.19, 0.91); 0.02

SYNTAX (Morice 2014) Severe CAD KM event rate%

KM event rate%

Graft occlusion or stent thrombosis 5 years 5.1 4.4 HR 1.15 (0.57, 2.33); 0.70

LE MANS Unprotected left main disease

Major bleeding 1 year0-30 days1-12 months

0 (0)0 (0)0 (0)

3 (5.7)3 (5.7)0 (0)

NRNRNR


January 2016


PCI + stentn (%)

CABGMean ± SD


Renal insufficiency 1 year0-30 days1-12 months

0 (0)0 (0)0 (0)

1 (1.9)1 (1.9)0 (0)

NRNRNR

Other83 1 year0-30 days1-12 months

0 (0)0 (0)0 (0)

8 (15.1)7 (13.2)1 (1.9)

NRNRNR

Major adverse event84 1 year0-30 days1-12 months

20 (38.5)4 (7.7)16 (30.8)

24 (45.3)15 (28.3)9 (17.0)

NR0.006NR

ARTS 1 Multivessel CAD

Stent thrombosis 30 days 17 (2.8) NA -

SIMA Proximal, isolated de novo LACAS

Bleeding + reintervention Index hospitalisation

0 (0) 1 (1.7) NR

Bleeding + transfusion Index hospitalisation

2 (3.2) 5 (8.5) NR

Source: FREEDOM (Farkouh et al, 2012): Text, p 2381; Boudriot et al (2011): Text, p 541-542; CARDIa (Kapur et al, 2010): Text, p 436; SYNTAX (Serruys et al, 2009): Table 3, p 969; SYNTAX (Morice et al, 2014): Table 1, p 2391; LE MANS (Buszman et al, 2008): Table 2, p 541; ARTS 1 (Serruys et al, 2001): Text, p 1120; SIMA (Goy et al, 2000): Text, p 1118-1119. Note: Statistically significant results shown in bold. Abbreviations: CABG, coronary artery bypass graft; CAD, coronary artery disease; CI, confidence interval; insuff., insufficiency; LACAS, left anterior coronary artery stenosis; MD, mean difference; MI. myocardial infarction; NA, not applicable; NR, not reported; NS, not significant; PCI, percutaneous coronary intervention; QoL, quality of life; RCT, randomised controlled trial; RR, relative risk; SD, standard deviation; TIMI, Thrombolysis In Myocardial Infarction; tmt, treatment; trans., transfusion.

In summary, in patients with diabetes and multivessel CAD, there was no significant difference between PCI and CABG in terms of death over the shorter term (≤2 years) in one study, but there was a significantly increased risk of death and MI associated with PCI at 5 years. There was an increased risk of late MI associated with PCI in another study that included patients with diabetes and multivessel CAD. However, in studies comparing results in diabetes and no diabetes subgroups, no interaction between treatment and diabetes was seen. There was also no interaction between treatment and renal insufficiency and left ventricular dysfunction subgroups.

In the short term (≤1 month) quality of life was significantly greater in patients undergoing PCI compared with CABG. However, this difference did not persist into the longer term and in some cases, an improved quality of life was seen for CABG compared with PCI.

Major bleeding tended to be greater following CABG than PCI. Stent thrombosis occurred most commonly in the first month following PCI, while graft occlusion most commonly occurred after 1 month.

83 Includes infection, post-cardiotomy syndrome, sternal refixation. 84 MAE were defined as all-cause mortality, acute myocardial infarction (defined as an increase in creatine phosphokinase (CPK)-MB to higher than 3 times the upper limit of normal after PCI and 5 times after CABG), repeat revascularisation, acute heart failure (e.g., pulmonary oedema, cardiogenic shock), or low output syndrome requiring intravenous inotropic agents and/or intra-aortic balloon pump support, post-procedural complications leading to reintervention, stroke, arrhythmia (ventricular fibrillation, ventricular tachycardia, or atrial fibrillation), major bleeding requiring additional blood transfusion, and infections compromising post-procedural rehabilitation.


January 2016


The following section provides the evidence for the safety and effectiveness of PCI in patients with a diagnosis of NSTE-ACS, and includes comparisons between routine and selective invasive therapies, and PCI and CABG. First, the findings of Level I studies (SR/MAs) are shown. Where PICO outcomes and subgroups are not addressed by Level I evidence, the results of individual RCTs are then presented.

Selective PCI versus routine PCI

Level I evidence Eight SR/MAs and three IPD/MAs were identified by the literature search. As noted previously, all studies assessed an invasive strategy that involved angiography, followed by revascularisation if indicated. Revascularisation could be completed via either PCI (with or without stents) or CABG; no studies specifically compared routine PCI with selective PCI, although PCI was the method of choice in the majority of patients in the most recent and applicable included RCTs (see Table 5.1-12). In addition, in all of these SR/MAs and IPD/MAs, the intervention of interest was a routine/early invasive strategy and the comparator was a selective/conservative strategy. This differs from the criteria defined for this MBS Review, where the intervention of interest is a selective strategy and the comparator of interest is a routine strategy. The results presented below are from the perspective of the included published studies; i.e. a routine strategy is being compared with a selective strategy.

The Cochrane Review by Hoenig et al (2010) has been chosen as the primary review for this MBS Review for a number of reasons:

1. It limits inclusion of RCTs to those conducted during the ‘stent era’. While stent era is not defined in the review, included studies were published between 1999 and 2005 and stent use in the routine/early invasive strategy arms ranged from 47% to 88%.

2. It provides subgroup analyses of studies with and without GPIIb/IIIa use, as these treatments are considered to be important in contemporary clinical practice.

3. It provides the most comprehensive list of outcomes, assessing both efficacy and safety.

4. Where data are available, outcome results are presented at different time points: index (during initial hospitalisation), early (≤4 months), intermediate (6 – 12 months) and late (>12 months).

Three trials included in the other identified SR/MAs were excluded from the Hoenig et al (2010) review on the basis they were undertaken in the pre-stent era: MATE 1998, TIMI-3B 1995 and VANQWISH 1998. In addition, MATE 1998 was also excluded for including patients with STEMI, while VANQWISH 1998 was also excluded for including patients treated with thrombolysis.

The results of the Hoenig et al (2010) systematic review are summarised in Table 5.2-20. The subgroup analysis that included the ICTUS and TACTICS-TIMI 18 studies (routine GPIIb/IIIa use subgroup) is considered by the authors to be the closest to an ‘ideal’ strategy, as both studies included the routine use of both GPIIb/IIIa and stents. The results of this analysis suggest no significant benefit of a routine invasive strategy compared with a selective invasive strategy in terms of death, and benefits of a routine strategy for MI and rehospitalisation. In the overall analysis, a routine strategy was associated with a doubling of


January 2016

risk of procedure-related MI and 1.7 times the risk of bleeding, compared with a selective strategy.

Overall, Hoenig et al (2010) concluded that ‘compared to a conservative strategy for [NSTE-ACS], an invasive strategy is associated with reduced rates of refractory angina and rehospitalisation in the shorter term and MI in the longer term. However, the invasive strategy is associated with a doubled risk of procedure-related heart attack and increased risk of bleeding and procedural biomarker leaks. Available data suggest that an invasive strategy may be particularly useful in those at high risk for recurrent events’.

It should be noted that two additional studies have been published since the Hoenig Cochrane Review in 2010: the Italian Elderly Study (IES; Savonitto et al, 2012) and OASIS-5 (Swahn et al, 2012). Where applicable in Table 5.2-20, the Hoenig meta-analysis has been updated with data from the IES. The relevant forest plots are shown in Figure 5.2-5 to Figure 5.2-7. The addition of this study did not change the findings of the review.

The results of the OASIS-5 study were not included in Table 5.2-20 because they introduced substantial heterogeneity into the analysis (the OASIS-5 study was conducted exclusively in women and had a very high mortality rate in the PCI arm compared with other studies); however, the results of this study have been incorporated into the meta-analysis presented in Figure 5.2-8 to Figure 5.2-18.


January 2016

Table 5.2-20 Results of the included systematic reviews: diagnosis of NSTE-ACS – routine vs. selective invasive therapies (Hoenig 2010) Outcome Overall Risk estimate Routine

GPIIb/IIIa useRisk estimate No routine

GPIIb/IIIa useRisk estimate

Efficacy outcomes Studies (patients)

RR (95% CI); p value Studies (patients)

RR (95% CI); p value Studies (patients)

RR (95% CI); p value

Index death85

Early deathIntermediate deathIntermediate death + IESLate death

5 (7781)3 (4161)5 (7818)6 (8131)3 (5467)

RR 1.53 (0.98, 2.39); 0.06RR 1.11 (0.66, 1.88); 0.70RR 0.82 (0.57, 1.19); 0.29RR 0.84 (0.62, 1.13); 0.25RR 0.90 (0.76, 1.08); 0.25

2 (3383)1 (2220)2 (3420)3 (3733)1 (1200)

RR 1.67 (0.84, 3.31); 0.15RR 1.38 (0.76, 2.51); 0.29RR 0.95 (0.66, 1.39); 0.81RR 0.94 (0.68, 1.28); 0.67RR 1.11 (0.74, 1.67); 0.62

3 (4398)2 (1941)3 (4398)3 (4398)2 (4267)

RR 1.39 (0.65, 2.96); 0.40RR 0.67 (0.15, 3.02); 0.60RR 0.67 (0.33, 1.37); 0.27RR 0.67 (0.33, 1.37); 0.27RR 0.87 (0.72, 1.04); 0.13

Index MIEarly MIIntermediate MIIntermediate MI + IESLate MI

5 (7781)3 (4161)5 (7818)6 (8131)3 (5467)

RR 1.03 (0.52, 2.03); 0.93RR 0.64 (0.38, 1.06); 0.08RR 0.73 (0.62, 0.86); <0.001RR 0.73 (0.62, 0.86); 0.0001RR 0.78 (0.67, 0.92); <0.001

2 (3383)1 (2220)2 (3420)3 (3733)1 (1200)

RR 0.67 (0.44, 1.02); 0.07RR 0.53 (0.35, 0.79); 0.002RR 0.72 (0.54, 0.96); 0.03RR 0.71 (0.55, 0.93); 0.01RR 1.01 (0.66, 1.55); 0.96

3 (4398)2 (1941)3 (4398)3 (4398)2 (4267)

RR 1.43 (0.65, 3.12); 0.38RR 0.63 (0.18, 2.17); 0.47RR 0.72 (0.52, 0.98); 0.04RR 0.72 (0.52, 0.98); 0.04RR 0.75 (0.63, 0.90); 0.002

Index death/MIEarly death/MIIntermediate death/MIIntermediate death/MI + IESLate death/MI

4 (6618)2 (2351)4 (6618)5 (6931)3 (5467)

RR 1.14 (0.59, 2.21); 0.69RR 0.64 (0.45, 0.92); 0.015RR 0.76 (0.62, 0.94); 0.011RR 0.78 (0.66, 0.92); 0.003RR 0.89 (0.73, 1.08); 0.23

1 (2220)1 (2220)1 (2220)2 (2533)1 (1200)

RR 0.77 (0.51, 1.17); 0.22RR 0.67 (0.48, 0.94); 0.02RR 0.77 (0.58, 1.01); 0.06RR 0.79 (0.62, 1.00); 0.05RR 1.19 (0.87, 1.63); 0.28

3 (4398)1 (131)3 (4398)3 (4398)2 (4267)

RR 1.46 (0.75, 2.86); 0.27RR 0.30 (0.06, 1.39); 0.12RR 0.74 (0.52, 1.04); 0.08RR 0.74 (0.52, 1.04); 0.08RR 0.81 (0.72, 0.92); 0.001

Intermediate refractory angina 4 (7687) RR 0.67 (0.55, 0.83); <0.001 2 (3420) RR 0.82 (0.49, 1.38); 0.46 2 (4267) RR 0.57 (0.50, 0.64); <0.001

Intermediate rehospitalisation 4 (6008) RR 0.67 (0.61, 0.74); <0.001 2 (3240) RR 0.77 (0.63, 0.93); 0.007 2 (2588) RR 0.65 (0.59, 0.71); <0.001

Safety outcomes Studies (patients)

RR (95% CI); p value

Procedure-related MI 3 (5467) RR 2.00 (1.53, 2.61); <0.001 - - - -

Bleeding 3 (6487) RR 1.71 (1.27, 2.31); <0.001 - - - -

Stroke 2 (4677) RR 0.89 (0.34, 2.31); 0.81 - - - -

85 ‘Index’ end-points indicate follow up during the initial hospitalisation. ‘Early’ end-points indicate a follow up ≤4 months. ‘Intermediate’ end-points indicate a follow up ≥6 months, or ≤12 months. ‘Late’ end-points indicate a follow up ≥2 years.MBS Reviews – Percutaneous Coronary Intervention Review Report Page 182

January 2016

Source: Hoenig et al (2010): Analysis 1.1 to 2.3, p 35-51. Note: Statistically significant results shown in bold. Abbreviations: CI, confidence interval; GPIIb/IIIa, glycoprotein IIB/IIIa receptor antagonist; IES, Italian Elderly Study; MA, meta-analysis; MI, myocardial infarction; NSTE-ACS, non-ST-segment-elevation acute coronary syndrome; RR, relative risk; SR, systematic review.


January 2016

Figure 5.2-5 Forest plot of routine invasive therapy versus selective invasive therapy (including IES): NSTE-ACS – intermediate all-cause mortality

Study or Subgroup1.1.1 Routine GPIIb/IIIaICTUSIESTACTICS-TIMI 18Subtotal (95% CI)Total eventsHeterogeneity: Tau² = 0.00; Chi² = 0.05, df = 2 (P = 0.98); I² = 0%Test for overall effect: Z = 0.42 (P = 0.67)

1.1.2 No routine GPIIb/IIIaFRISC IIRITA 3VINOSubtotal (95% CI)Total eventsHeterogeneity: Tau² = 0.26; Chi² = 7.54, df = 2 (P = 0.02); I² = 73%Test for overall effect: Z = 1.10 (P = 0.27)

Total (95% CI)Total eventsHeterogeneity: Tau² = 0.05; Chi² = 8.17, df = 5 (P = 0.15); I² = 39%Test for overall effect: Z = 1.15 (P = 0.25)Test for subgroup differences: Chi² = 0.70, df = 1 (P = 0.40), I² = 0%

Events

151937

71

27412

70

141

Total

604154

11141872

122289564

2181

4053

Events

152239

76

48369

93

169

Total

596159

11061861

123591567

2217

4078

Weight

12.7%16.9%22.6%52.1%

21.4%22.8%3.6%

47.9%

100.0%

M-H, Random, 95% CI

0.99 [0.49, 2.00]0.89 [0.50, 1.58]0.94 [0.61, 1.47]0.94 [0.68, 1.28]

0.57 [0.36, 0.90]1.16 [0.75, 1.80]0.23 [0.05, 1.04]0.67 [0.33, 1.37]

0.84 [0.62, 1.13]

Routine strategy Selective strategy Risk Ratio Risk RatioM-H, Random, 95% CI

0.1 0.2 0.5 1 2 5 10Favours Invasive Favours selective

Source: Meta-analysis from Hoenig et al (2010), updated with data from the IES (Savonitto et al, 2012).Abbreviations: CI, confidence interval; MI, myocardial infarction; NSTE-ACS, non-ST-segment-elevation acute coronary syndrome.

Figure 5.2-6 Forest plot of routine invasive therapy versus selective invasive therapy (including IES): NSTE-ACS – intermediate MI




Events

221153

86

105342

141

227

Total

604154

11141872

122289564

2181

4053

Events

271776

120

1434410

197

317

Total

596159

11061861

123591567

2217

4078

Weight

8.9%5.1%

23.3%37.3%

47.3%14.1%1.2%

62.7%

100.0%

M-H, Random, 95% CI

0.80 [0.46, 1.40]0.67 [0.32, 1.38]0.69 [0.49, 0.97]0.71 [0.55, 0.93]

0.74 [0.58, 0.94]0.79 [0.51, 1.22]0.21 [0.05, 0.92]0.72 [0.52, 0.98]

0.73 [0.62, 0.86]


0.1 0.2 0.5 1 2 5 10Favours routine Favours selective



January 2016

Figure 5.2-7 Forest plot of routine invasive therapy versus selective invasive therapy (including IES): NSTE-ACS – intermediate death/MI

Study or Subgroup1.3.1 Routine GPIIb/IIIaIESTACTICS-TIMI 18Subtotal (95% CI)Total eventsHeterogeneity: Tau² = 0.00; Chi² = 0.15, df = 1 (P = 0.70); I² = 0%Test for overall effect: Z = 1.97 (P = 0.05)



Events

2881

109

127684

199

308

Total

15411141268

122289564

2181

3449

Events

34105

139

1747615

265

404

Total

15911061265

123591567

2217

3482

Weight

12.2%26.3%38.6%

37.0%22.0%2.5%

61.4%

100.0%

M-H, Random, 95% CI

0.85 [0.54, 1.33]0.77 [0.58, 1.01]0.79 [0.62, 1.00]

0.74 [0.60, 0.91]0.91 [0.67, 1.25]0.28 [0.10, 0.80]0.74 [0.52, 1.04]

0.78 [0.66, 0.92]




Figure 5.2-8 Forest plot of routine invasive therapy versus selective invasive therapy (including OASIS-5): NSTE-ACS – early mortality

Study or Subgroup1.4.1 Routine GPIIb/IIIaTACTICS-TIMI 18Subtotal (95% CI)Total eventsHeterogeneity: Not applicableTest for overall effect: Z = 1.05 (P = 0.29)

1.4.2 No routine GPIIb/IIIaOASIS-5RITA 3VINOSubtotal (95% CI)Total eventsHeterogeneity: Tau² = 1.07; Chi² = 5.41, df = 2 (P = 0.07); I² = 63%Test for overall effect: Z = 0.21 (P = 0.83)


Events

25

25

7261

34

59

Total

11141114

9289564

1051

2165

Events

18

18

1245

30

48

Total

11061106

9291567

1074

2180

Weight

40.3%40.3%

8.7%42.7%8.4%

59.7%

100.0%

M-H, Random, 95% CI

1.38 [0.76, 2.51]1.38 [0.76, 2.51]

7.00 [0.88, 55.77]1.11 [0.64, 1.91]0.21 [0.03, 1.74]1.17 [0.27, 5.11]

1.23 [0.64, 2.39]


0.02 0.1 1 10 50Favours routine Favours selective

Source: Meta-analysis from Hoenig et al (2010), updated with data from OASIS-5 (Swahn et al, 2012).Abbreviations: CI, confidence interval; NSTE-ACS, non-ST-segment-elevation acute coronary syndrome.


January 2016

Figure 5.2-9 Forest plot of routine invasive therapy versus selective invasive therapy (including IES and OASIS-5): NSTE-ACS – intermediate mortality


1.2.2 No routine GPIIb/IIIaFRISC IIOASIS-5RITA 3VINOSubtotal (95% CI)Total eventsHeterogeneity: Tau² = 0.41; Chi² = 12.29, df = 3 (P = 0.006); I² = 76%Test for overall effect: Z = 0.40 (P = 0.69)


Events

151937

71

278

412

78

149

Total

604154

11141872

122292

89564

2273

4145

Events

152239

76

481

369

94

170

Total

596159

11061861

123592

91567

2309

4170

Weight

13.8%17.0%20.8%51.6%

20.1%2.7%

20.9%4.7%

48.4%

100.0%

M-H, Random, 95% CI

0.99 [0.49, 2.00]0.89 [0.50, 1.58]0.94 [0.61, 1.47]0.94 [0.68, 1.28]

0.57 [0.36, 0.90]8.00 [1.02, 62.68]1.16 [0.75, 1.80]0.23 [0.05, 1.04]0.85 [0.38, 1.89]

0.88 [0.62, 1.25]


0.1 0.2 0.5 1 2 5 10Favours Invasive Favours selective

Source: Meta-analysis from Hoenig et al (2010), updated with data from IES (Savonitto et al, 2012) and OASIS-5 (Swahn et al, 2012).Abbreviations: CI, confidence interval; NSTE-ACS, non-ST-segment-elevation acute coronary syndrome.

Figure 5.2-10 Forest plot of routine invasive therapy versus selective invasive therapy (including OASIS-5): NSTE-ACS – late mortality

Study or Subgroup1.5.1 Routine GPIIb/IIIaICTUSSubtotal (95% CI)Total eventsHeterogeneity: Not applicableTest for overall effect: Z = 0.50 (P = 0.62)

1.5.2 No routine GPIIb/IIIaFRISC IIOASIS-5RITA 3Subtotal (95% CI)Total eventsHeterogeneity: Tau² = 0.04; Chi² = 5.01, df = 2 (P = 0.08); I² = 60%Test for overall effect: Z = 0.45 (P = 0.65)


Events

45

45

1178

102

227

272

Total

604604

122292

8952209

2813

Events

40

40

1242

132

258

298

Total

596596

123592

9152242

2838

Weight

22.9%22.9%

37.3%2.7%

37.1%77.1%

100.0%

M-H, Random, 95% CI

1.11 [0.74, 1.67]1.11 [0.74, 1.67]

0.95 [0.75, 1.21]4.00 [0.87, 18.33]0.79 [0.62, 1.01]0.93 [0.67, 1.29]

0.96 [0.74, 1.24]



Source: Meta-analysis from Hoenig et al (2010), updated with data from OASIS-5 (Swahn et al, 2012).Abbreviations: CI, confidence interval; NSTE-ACS, non-ST-segment-elevation acute coronary syndrome.


January 2016

Figure 5.2-11 Forest plot of routine invasive therapy versus selective invasive therapy (including OASIS-5): NSTE-ACS – early MI


1.6.2 No routine GPIIb/IIIaOASIS-5RITA 3VINOSubtotal (95% CI)Total eventsHeterogeneity: Tau² = 0.02; Chi² = 2.10, df = 2 (P = 0.35); I² = 5%Test for overall effect: Z = 0.54 (P = 0.59)

Total (95% CI)Total eventsHeterogeneity: Tau² = 0.08; Chi² = 4.79, df = 3 (P = 0.19); I² = 37%Test for overall effect: Z = 1.62 (P = 0.11)Test for subgroup differences: Chi² = 2.26, df = 1 (P = 0.13), I² = 55.8%

Events

34

34

4301

35

69

Total

11141114

9289564

1051

2165

Events

64

64

3345

42

106

Total

11061106

9291567

1074

2180

Weight

46.3%46.3%

8.7%40.5%4.5%

53.7%

100.0%

M-H, Random, 95% CI

0.53 [0.35, 0.79]0.53 [0.35, 0.79]

1.33 [0.31, 5.79]0.90 [0.56, 1.46]0.21 [0.03, 1.74]0.87 [0.52, 1.44]

0.68 [0.43, 1.08]



Source: Meta-analysis from Hoenig et al (2010), updated with data from OASIS-5 (Swahn et al, 2012).Abbreviations: CI, confidence interval; MI, myocardial infarction; NSTE-ACS, non-ST-segment-elevation acute coronary syndrome.

Figure 5.2-12 Forest plot of routine invasive therapy versus selective invasive therapy (including IES and OASIS-5): NSTE-ACS – intermediate MI




Events

221153

86

1057

342

148

234

Total

604154

11141872

122292

89564

2273

4145

Events

271776

120

1439

4410

206

326

Total

596159

11061861

123592

91567

2309

4170

Weight

8.6%5.0%

22.6%36.2%

45.9%2.9%

13.7%1.2%

63.8%

100.0%

M-H, Random, 95% CI

0.80 [0.46, 1.40]0.67 [0.32, 1.38]0.69 [0.49, 0.97]0.71 [0.55, 0.93]

0.74 [0.58, 0.94]0.78 [0.30, 2.00]0.79 [0.51, 1.22]0.21 [0.05, 0.92]0.74 [0.60, 0.90]

0.73 [0.62, 0.86]



Source: Meta-analysis from Hoenig et al (2010), updated with data from IES (Savonitto et al, 2012) and OASIS-5 (Swahn et al, 2012).Abbreviations: CI, confidence interval; MI, myocardial infarction; NSTE-ACS, non-ST-segment-elevation acute coronary syndrome.


January 2016

Figure 5.2-13 Forest plot of routine invasive therapy versus selective invasive therapy (including OASIS-5): NSTE-ACS – late MI




Events

40

40

1411146

198

238

Total

604604

122292

8952209

2813

Events

39

39

1951257

264

303

Total

596596

123592

9152242

2838

Weight

14.2%14.2%

63.3%4.4%

18.1%85.8%

100.0%

M-H, Random, 95% CI

1.01 [0.66, 1.55]1.01 [0.66, 1.55]

0.73 [0.60, 0.89]0.92 [0.43, 1.97]0.83 [0.57, 1.20]0.76 [0.64, 0.90]

0.79 [0.67, 0.93]




Figure 5.2-14 Forest plot of routine invasive therapy versus selective invasive therapy (including OASIS-5): NSTE-ACS – early mortality/MI


1.8.2 No routine GPIIb/IIIaOASIS-5VINOSubtotal (95% CI)Total eventsHeterogeneity: Tau² = 1.33; Chi² = 3.76, df = 1 (P = 0.05); I² = 73%Test for overall effect: Z = 0.20 (P = 0.84)


Events

52

52

82

10

62

Total

11141114

9264

156

1270

Events

77

77

47

11

88

Total

11061106

9267

159

1265

Weight

53.9%53.9%

26.9%19.2%46.1%

100.0%

M-H, Random, 95% CI

0.67 [0.48, 0.94]0.67 [0.48, 0.94]

2.00 [0.62, 6.41]0.30 [0.06, 1.39]0.83 [0.13, 5.33]

0.77 [0.34, 1.74]





January 2016

Figure 5.2-15 Forest plot of routine invasive therapy versus selective invasive therapy (including IES and OASIS-5): NSTE-ACS – intermediate mortality/MI

Study or Subgroup1.8.1 Routine GPIIb/IIIaIESTACTICS-TIMI 18Subtotal (95% CI)Total eventsHeterogeneity: Tau² = 0.00; Chi² = 0.15, df = 1 (P = 0.70); I² = 0%Test for overall effect: Z = 1.97 (P = 0.05)



Events

2881

109

12713684

212

321

Total

15411141268

122292

89564

2273

3541

Events

34105

139

174107615

275

414

Total

15911061265

123592

91567

2309

3574

Weight

12.5%25.1%37.6%

33.5%4.8%

21.4%2.7%

62.4%

100.0%

M-H, Random, 95% CI

0.85 [0.54, 1.33]0.77 [0.58, 1.01]0.79 [0.62, 1.00]

0.74 [0.60, 0.91]1.30 [0.60, 2.81]0.91 [0.67, 1.25]0.28 [0.10, 0.80]0.79 [0.57, 1.10]

0.79 [0.67, 0.95]



Source: Meta-analysis from Hoenig et al (2010), updated with data from IES (Savonitto et al, 2012) and OASIS-5 (Swahn et al, 2012).Abbreviations: CI, confidence interval; MI, myocardial infarction; NSTE-ACS, non-ST-segment-elevation acute coronary syndrome.

Figure 5.2-16 Forest plot of routine invasive therapy versus selective invasive therapy (including OASIS-5): NSTE-ACS – late mortality/MI




Events

76

76

21717

142

376

452

Total

604604

122292

8952209

2813

Events

63

63

27013

178

461

524

Total

596596

123592

9152242

2838

Weight

21.7%21.7%

37.9%7.3%

33.0%78.3%

100.0%

M-H, Random, 95% CI

1.19 [0.87, 1.63]1.19 [0.87, 1.63]

0.81 [0.69, 0.95]1.31 [0.67, 2.53]0.82 [0.67, 1.00]0.83 [0.73, 0.94]

0.92 [0.75, 1.11]





January 2016

Figure 5.2-17 Forest plot of routine invasive therapy versus selective invasive therapy (including OASIS-5): NSTE-ACS – bleeding

Study or SubgroupFRISC IIOASIS-5RITA 3TACTICS-TIMI 18


Events112

97361

255

Total1222

92895

1114

3323

Events812

3236

151

Total1235

92915

1106

3348

Weight38.6%4.0%

28.6%28.7%

100.0%

M-H, Random, 95% CI1.40 [1.06, 1.84]

4.50 [1.00, 20.26]2.33 [1.56, 3.50]1.68 [1.12, 2.52]

1.79 [1.31, 2.45]




Figure 5.2-18 Forest plot of routine invasive therapy versus selective invasive therapy (including OASIS-5): NSTE-ACS – stroke

Study or SubgroupFRISC IIOASIS-5TACTICS-TIMI 18


Events226

10

Total1222

921114

2428

Events346

13

Total1235

921106

2433

Weight21.5%24.6%53.9%

100.0%

M-H, Random, 95% CI0.67 [0.11, 4.03]0.50 [0.09, 2.66]0.99 [0.32, 3.07]

0.77 [0.34, 1.77]


0.01 0.1 1 10 100Favours [experimental] Favours [control]


The results and conclusions of the remaining SR/MAs and IPD/MAs are summarised in Table 5.2-21. Data for three of the subgroups of interest (high-risk patients, patients with diabetes and patients with CKD) were available in the included SR/MAs and IPD/MAs. Each will be described in turn.

High-risk subgroupWhile not a requested subgroup in the PICO for this Review, data on risk subgroups was extracted due to the large number of guidelines that recommend an early invasive strategy be used in patients considered to be at high risk of cardiac events. In addition, as noted above by Hoenig et al (2010), the use of a routine invasive strategy may be most useful in patients at high risk for recurrent events, due to the substantially increased risk of harms. Two of the included IPD/MAs assessed the impact of baseline risk on benefit of a routine invasive strategy compared with a selective invasive strategy. Fox et al (2010) showed that, when categorised into low, moderate and high-risk categories using a risk score based on age, diabetes, previous MI, ST-segment depression, hypertension and body mass index (BMI), a routine invasive strategy provided a greater reduction in death/MI compared with a selective invasive strategy for high-risk patients (RD –11.1%; 95% CI –18.4%, –3.8%), compared with moderate-risk (RD –3.8%; 95% CI –7.4%, –0.1%) and low-risk (RD –2.0%; 95% CI –4.1%, 0.1%) patients. Based on a subsequent analysis of the same dataset (IPD from the ICTUS, FRISC II and RITA-3 trials), Alfredsson et al (2014) showed that high-risk and medium-risk men gained a benefit from the use of a routine compared with a selective invasive strategy (HR 0.56; 95% CI 0.41, 0.75 and HR 0.74; 95% CI 0.58, 0.96, respectively), while low-risk men, and low-, medium- and high-risk women did not.


January 2016

While these results suggest that patients at high-risk will significantly benefit from undergoing a routine invasive strategy compared with a selective invasive strategy, there are some important points to note. The high-, medium/moderate- and low-risk subsets were a post hoc analysis from a selection of available trials only, and all patients included in the ICTUS trial were considered to be high-risk. The ICTUS trial was designed to bypass design problems in the FRISC and RITA trials: (i) ICTUS included only high-risk patients with abnormal biomarkers; (ii) ICTUS used the same biomarker level in both arms to define an MI; and (iii) ICTUS ensured that patients in both groups received OMT (whereas previous studies did not provide dual antiplatelet therapy for all selectively treated patients, nor was aggressive lipid-lowering therapy deployed). In addition, the methods used to categorise patients into risk groups were not based on validated methods. Australian and International CPGs recommend than an early invasive strategy should be used in patients considered to be at high-risk of cardiac events. However, these recommendations relate to the timing of routine intervention (i.e. early versus late), rather than whether or not an invasive strategy should be carried out, and are based on a completely separate body of evidence to the one assessed as part of this Review (see Section 5.1.2).

Diabetes subgroupO’Donoghue et al (2012) carried out a collaborative SR/MA in which nine trials that met inclusion criteria agreed to participate and supply data stratified by diabetes status. A greater benefit of a routine compared with a selective strategy was seen for MI in patients with diabetes (RR 0.71; 95% CI 0.55, 0.92) compared with patients without diabetes (RR 0.98; 95% CI 0.74, 1.29). Rehospitalisation with ACS was similarly reduced following a routine strategy compared with a selective strategy in both diabetic (RR 0.75; 95% CI 0.61, 0.92) and nondiabetic (RR 0.75; 95% CI 0.61, 0.93) patients.

Chronic kidney disease subgroupWhile not specifically requested as a subgroup for this population, one SR/MA assessed the effect of a routine versus a selective invasive strategy in patients with CKD. Charytan et al (2009) contacted the authors of five trials86 and received data on the subgroup of patients with CKD, defined as a GFR <60 mL/min per 1.73 m2. A benefit of a routine invasive strategy over a selective invasive strategy was seen for rehospitalisation at 1 year for all three analyses undertaken (overall, excluding the ICTUS study and excluding the TIMI 3B study). Benefits of a routine strategy over a selective strategy were seen for MI at 1 year and death/MI at 1 year in the analyses excluding the ICTUS study only.

In summary, the results of the identified SR/MAs and IPD/MAs suggest that a selective invasive strategy provides a similar benefit in terms of all-cause mortality to a routine invasive strategy, but with substantially reduced procedure-related risk. The results also suggest that a routine invasive strategy provides benefits over a selective strategy in terms of reduced MI and rehospitalisation. However, given the benefits of a routine invasive strategy are likely higher in those considered to be at high risk, it is recommended that a selective invasive strategy be used for patients considered to be at low to intermediate risk.

86 VINO, FRISC II, TIMI IIIb, TACTICS TIMI 18 and ICTUS.


January 2016

Table 5.2-21 Results of the included systematic reviews: diagnosis of NSTE-ACS – routine vs. selective invasive therapies (other reviews)


Risk estimate (95% CI); p value Authors’ conclusions

SR/MA – Level I

Angeli 2014 NSTE-ACS Early invasive strategy vs. selective invasive strategy

Death – overallMI – overallDeath/MI – overallRehospitalisation - overall

9 (9400)9 (9400)9 (9400)9 (9335)

OR 0.95 (0.83, 1.09); 0.49OR 0.75 (0.66, 0.87); <0.001OR 0.85 (0.76, 0.95); 0.004OR 0.71 (0.55, 0.90); 0.005

In patients with NSTE-ACS, a routine early invasive strategy reduces the risk of rehospitalisation and the composite endpoint of death and recurrent MI. Subgroup analyses found that reduced risk was greater in elderly (>65 years) compared with younger patients.


January 2016



O’Donoghue 2012

NSTE-ACS Invasive strategy vs. conservative strategy

Death – DM-Death – no DM-MI – DM-MI – no DM-Death/MI – DM-Death/MI – no DM-Rehospitalisation with ACS – DM-Rehospitalisation with ACS – no DM-Death/MI/rehosp. – DM-Death/MI/rehosp. – no DM-

NR (1789)-NR (8115)-NR (1789)-NR (8115)-NR (1789)-NR (8115)-NR (1768)-NR (7874)-NR (1768)-NR (7874)-

RR 1.01 (0.70, 1.45); 0.87 (int)ARR 0.4% (–4.1%, 3.2%); 0.77 (int)RR 1.00 (0.68, 1.48); NRARR 0.1% (–1.4%, 1.3%); NRRR 0.71 (0.55, 0.92); 0.09 (int)ARR 3.7% (1.1%, 6.3%); 0.02 (int)RR 0.98 (0.74, 1.29); NRARR 0.1% (–1.7, 1.9%); NRRR 0.89 (0.68, 1.16); 0.33 (int)ARR 2.2% (–3.4%, 7.9%); 0.27 (int)RR 1.04 (0.79, 1.37); NRARR 0.1% (–3.0%, 2.8%); NRRR 0.75 (0.61, 0.92); 0.68 (int)ARR 5.6% (2.2%, 9.1%); 0.20 (int)RR 0.75 (0.61, 0.93); NRARR 3.3% (0.4%, 6.2%); NRRR 0.87 (0.73, 1.03); 0.83 (int)ARR 5.1% (0.1%, 10.2%); 0.24 (int)RR 0.86 (0.70, 1.06); NRARR 3.2% (–0.9%, 7.4%); NR

An early invasive strategy yielded similar RR reductions in overall cardiovascular events in diabetic and nondiabetic patients. However, an invasive strategy appeared to reduce recurrent non-fatal MI to a greater extent in diabetic patients. These data support the updated guidelines that recommend an invasive strategy for patients with diabetes mellitus and NSTE-ACS.

SR/MA – Level I


January 2016



Swahn 2012 NSTE-ACS Early invasive strategy vs. selective invasive strategy

Death - maleDeath - femaleDeath/MI – maleDeath/MI – female

4 (5179)5 (7871)4 (5179)5 (7871)

OR 0.70 (0.51, 0.96); 0.012 (int)OR 0.93 (0.73, 1.18)OR 0.78 (0.66, 0.93); 0.01 (int)OR 0.89 (0.77, 1.03)

In a sub-study of a RCT, the rate of death, MI, or stroke in women was not different in patients treated with a routine invasive strategy compared with a selective invasive strategy, but there was a concerning trend towards higher mortality. When combined with data from previous trials in a meta-analysis, there does not appear to be a benefit of an early invasive strategy in women with ACS, which differs from the results in men. These data emphasise the lack of clear evidence in favour of an invasive strategy in women and suggest caution in extrapolating the results from men to women.

Charytan 2009

NSTE-ACS and CKD

Routine strategy vs. selective strategy

Stage 3-5 CKDDeath in-hospitalDeath at 1 year – overallDeath at 1 year – excl ICTUSDeath at 1 year – excl TIMI 3BMI in-hospitalMI at 1 year – overallMI at 1 year – excl ICTUSMI at 1 year – excl TIMI 3BDeath/MI in-hospitalDeath/MI at 1 year – overallDeath/MI at 1 year – excl ICTUSDeath/MI at 1 year – excl TIMI 3BRehospitalisation at 1 year – overallRehospitalisation at 1 year – excl ICTUSRehospitalisation at 1 year – excl TIMI 3B

NRNRNRNRNRNRNRNRNRNRNRNRNRNRNR

RR 0.77 (0.42, 1.44)RR 0.76 (0.49, 1.17); NRRR 0.67 (0.44, 1.02); NRRR 0.80 (0.43, 1.46); NRRR 1.06 (0.51, 2.20); NRRR 0.78 (0.52, 1.16); NRRR 0.67 (0.48, 0.94); NRRR 0.78 (0.44, 1.37); NRRR 1.00 (0.64, 1.56); NRRR 0.79 (0.53, 1.18); NRRR 0.66 (0.52, 0.85); NRRR 0.80 (0.45, 1.41); NRRR 0.76 (0.66, 0.87); NRRR 0.77 (0.67, 0.88); NRRR 0.73 (0.62, 0.86); NR

This collaborative study suggests that the benefits of an early invasive strategy are preserved in patients with CKD and that an early invasive approach reduces the risk for rehospitalisation and is associated with trends of reduction in the risk for death and non-fatal reinfarction in patients with CKD. Coronary angiography should be considered for patients who have CKD and are admitted with NSTE-ACS.


January 2016



SR/MA – Level I

O’Donoghue 2008

NSTEMI/UA Early invasive strategy vs. conservative strategy

Death – overallDeath – womenDeath – menMI – overallMI – womenMI – menDeath/MI – overallDeath/MI – overall (index hospitalisation)Death/MI – overall (discharge to 12 m)Death/MI – womenDeath/MI – women (index hospitalisation)Death/MI – women (discharge to 12 m)Death/MI – menDeath MI – men (index hospitalisation)Death/MI – men (discharge to 12 m)Rehospitalisation with ACS – overallRehospitalisation with ACS – womenRehospitalisation with ACS – menDeath/MI or rehosp. for ACS – overallDeath/MI or rehosp. for ACS – womenDeath/MI or rehosp. for ACS - men

NR (10,412)NR (3152)NR (7260)NR (10,412)NR (3152)NR (7260)NR (10,412)NR (10,411)NR (10,054)NR (3152)NR (3152)NR (3037)NR (7260)NR (7259)NR (7017)NR (10,150)NR (3075)NR (7075)NR (10,150)NR (3075)NR (7075)

OR 0.97 (0.71, 1.32); NROR 1.11 (0.72, 1.70); NROR 0.89 (0.58, 1.35); NROR 0.84 (0.63, 1.12); NROR 0.93 (0.59, 1.45); NROR 0.81 (0.59, 1.11); NROR 0.92 (0.69, 1.23); NROR 1.37 (0.93, 2.02); NROR 0.72 (0.52, 0.99); NROR 1.02 (0.67, 1.55); NROR 1.49 (0.72, 3.09); NROR 0.71 (0.48, 1.07); NROR 0.87 (0.61, 1.23); NROR 1.33 (0.93, 1.89); NROR 0.70 (0.50, 0.98); NROR 0.68 (0.55, 0.84); NROR 0.68 (0.54, 0.85); NROR 0.66 (0.54, 0.82); NROR 0.78 (0.61, 0.98); NROR 0.81 (0.65, 1.01); NROR 0.73 (0.55, 0.98); NR

In NSTE-ACS, an invasive strategy has a comparable benefit in men and high-risk women for reducing the composite end point of death, MI, or rehospitalisation with ACS. In contrast, the data provide evidence supporting the new guideline recommendation for a conservative strategy in low-risk women.


January 2016



SR/MA – Level I

Qayuum 2008 NSTE-ACS Routine invasive strategy vs. selective invasive strategy

Death – maximum follow-up (SA)Death – maximum follow-up (BA)87

MI – maximum follow-up (SA)MI – maximum follow-up (BA)Death/MI – maximum follow-up (SA)Death/MI – maximum follow-up (BA)Death – in-hospital (SA)Death – in-hospital (BA)MI – in-hospital (SA)MI – in-hospital (BA)Death/MI – in-hospital (SA)Death/MI – in-hospital (BA)Death – 1 year (SA)Death – 1 year (BA)MI – 1 year (SA)MI – 1 year (BA)Death/MI – 1 year (SA)Death/MI – 1 year (BA)

10 (10,648)-----10 (10,648)-----9 (10,447)88

-----

RR 0.95 (0.80, 1.14); NRRR 0.91 (0.72, 1.12); NRRR 0.86 (0.68, 1.08); NRRR 0.84 (0.64, 1.10); NRRR 0.90 (0.74, 1.08); NRRR 0.87 (0.67, 1.11); NRRR 1.37 (0.83, 2.28); NRRR 1.10 (0.74, 1.54); NRRR 1.21 (0.86, 1.68); NRRR 1.07 (0.73, 1.47); NRRR 1.26 (0.91, 1.74); NRRR 1.03 (0.65, 1.57); NRRR 0.90 (0.66, 1.22); NRRR 0.87 (0.62, 1.20); NRRR 0.88 (0.69, 1.12); NRRR 0.86 (0.63, 1.13); NRRR 0.88 (0.69, 1.11); NRRR 0.86 (0.63, 1.15); NR

Available trial evidence is heterogeneous and insufficient for comparing routine and selective invasive strategies. Therefore, in patients with NSTE-ACS a routine invasive strategy cannot be proven to reduce deaths or non-fatal MI.

Tarantini 2007

NSTE-ACS Routine invasive strategy vs. conservative strategy

DeathDeath/MIDeath (excl VANQWISH trial)Death/MI (excl VANQWISH trial)

8 (10,412)8 (10,412)7 (9492)7 (9492)

OR 0.92 (0.77, 1.09); 0.34OR 0.86 (0.76, 0.96); 0.009OR 0.81 (0.66, 0.95); 0.04OR 0.81 (0.71, 0.88); 0.001

Compared with a conservative strategy, the benefits of an invasive strategy for the management of NSTE-ACS in terms of death/MI reduction are related to the patient’s risk profile.

87 Hierarchical random effects model with a diffuse normal prior distribution {N(0,10)} for the summary relative risk and uniform priors {Unif(0,2)} to incorporate between study heterogeneity. 88 Figure 4, page 194 shows a total of 10,648 patients but data from only 9 trials (excludes MATE trial). Amended patient number of 10,447. MBS Reviews – Percutaneous Coronary Intervention Review Report Page 196

January 2016



IPD/MA

Alfredsson 2014

NSTE-ACS Routine invasive strategy vs. selective invasive strategy

CV death – women (5y)CV death – men (5y)MI – women (5y)MI – men (5y)CV death/MI – women (5y)CV death/MI – men (5y)CV death/MI – low risk/women (5y)CV death/MI – low risk/men (5y)CV death/MI – medium risk/women (5y)CV death/MI – medium risk/men (5y)CV death/MI – high risk/women (5y)CV death/MI – high risk/men (5y)

3 (1751)3 (3716)3 (1751)3 (3716)3 (1751)3 (3716)3 (NR)3 (NR)3 (NR)3 (NR)3 (NR)3 (NR)

HR89 0.97 (0.68, 1.39); 0.07 (int)HR 0.71 (0.56, 0.89)HR 1.13 (0.85, 1.50); 0.01 (int)HR 0.69 (0.57, 0.83)HR 1.05 (0.83, 1.34); 0.01 (int)HR 0.73 (0.63, 0.86)HR90 0.89 (0.56, 1.41); 0.97 (int)HR 0.88 (0.67, 1.14)HR 1.19 (0.82, 1.74); 0.04 (int)HR 0.74 (0.58, 0.96)HR 1.08 (0.71, 1.66); 0.02 (int)HR 0.56 (0.41, 0.75)

Benefit from a routine invasive strategy during long-term follow-up was confirmed in men. Conversely, in women, there was no evidence of benefit.

Damman 2012a

NSTE-ACS Routine invasive strategy vs. selective invasive strategy

CV death – overallCV death – <65 yearsCV death – 65–74 yearsCV death – ≥75 yearsMI – overallMI – <65 yearsMI – 65–74 yearsMI – ≥75 yearsCV death/MI – overallCV death/MI – <65 yearsCV death/MI – 65–74 yearsCV death/MI – ≥75 years

3 (5467)3 (2807)3 (1821)3 (839)3 (5467)3 (2807)3 (1821)3 (839)3 (5467)3 (2807)3 (1821)3 (839)

HR88 0.78 (0.64, 0.96); 0.02HR 0.84 (0.55, 1.27); 0.87 (int)HR 0.76 (0.55, 1.05)HR 0.77 (0.56, 1.07)HR 0.79 (0.68, 0.93); 0.004HR 1.10 (0.86, 1.41); <0.001 (int)HR 0.70 (0.54, 0.91)HR 0.52 (0.37, 0.73)0.81 (0.71, 0.92); 0.002HR 1.09 (0.87, 1.35); <0.001 (int)HR 0.71 (0.57, 0.88)HR 0.65 (0.50, 0.84)

The long-term benefit of the routine invasive strategy over the selective invasive strategy is attenuated in younger patients aged <65 years and in women by the increased risk of early events which seem to have no consequences for long-term CV mortality. No other clinical risk factors were able to identify patients with differential responses to a routine invasive strategy.

IPD/MA

89 Adjusted for FRISC II, ICTUS, RITA-2 (FIR) risk score. Risk score based on age, diabetes, previous MI, ST-segment depression on admission, hypertension and BMI. 90 Not adjusted for risk because stratified by risk. MBS Reviews – Percutaneous Coronary Intervention Review Report Page 197

January 2016



Fox 2010 NSTE-ACS Routine invasive strategy vs. selective invasive strategy

All-cause deathCV deathMIAll-cause death/MICV death/MICV death/MI – adjusted91

CV death/MI – low risk-CV death/MI – moderate risk-CV death/MI – high risk-

3 (5467)3 (5467)3 (5467)3 (5467)3 (5467)3 (5467)3 (2926)-3 (1932)-3 (709)-

HR 0.90 (0.77, 1.05); 0.19HR 0.83 (0.68, 1.01); 0.068HR 0.77 (0.65, 0.90); 0.001HR 0.85 (0.75, 0.96); 0.008HR 0.81 (0.71, 0.93); 0.002HR 0.76 (0.67, 0.87); NRHR 0.80 (0.63, 1.02); 0.10 (int)RD –2.0% (–4.1%, 0.1%); <0.0001 (int)HR 0.81 (0.66, 1.01); NRRD –3.8% (–7.4%, –0.1%); NRHR 0.68 (0.53, 0.86); NRRD –11.1% (–18.4%, –3.8%); NR

A routine invasive strategy reduces long-term rates of CV death or MI and the largest absolute effect is seen in higher-risk patients.

Source: Angeli et al (2014): Figures 2-5 and Tables 2-5, p690-694; O’Donoghue et al (2012): Table 2, p 109; Swahn et al (2012): Figure 3-4, p 57-58; Charyton et al (2009): Figure 2, p 1038; O’Donoghue et al (2008):Table 3, p 76; Qayuum et al (2008): Figure 2-3, p 192-194; Tarantini et al, 2007: Text, p 800; Alfredsson et al (2014): Table II, p 526, Table III, p 528; Damman et al (2012a): Table 3, p211; Fox et al (2010): Table 2, p 2439, Table 4 and Table 5, p 2443. Note: Statistically significant results shown in bold. Abbreviations: ACS, acute coronary syndrome; ARR, absolute risk reduction; BA, Bayesian analysis; CI, confidence interval; CKD, chronic kidney disease; CV, cardiovascular; DM, type 2 diabetes; HR, hazard ratio; int, subgroup interaction p value; MA, meta-analysis; MI, myocardial infarction; NR, not reported; NSTE-ACS, non-ST-segment elevation acute coronary syndrome; NSTEMI, non-ST-segment elevation myocardial infarction; OR, odds ratio; RD, risk difference; rehosp., rehospitalisation; RR, relative risk; SA, standard analysis; SR, systematic review; UA, unstable angina.

91 Adjusted for age (per 5 years >60 years), diabetes, previous MI, ST-segment depression, hypertension and BMI. MBS Reviews – Percutaneous Coronary Intervention Review Report Page 198

January 2016

Level II evidenceFollowing the review of Level I (SR/MA and IPD/MA) evidence it was deemed necessary to examine Level II (RCT) evidence for the following reasons:

All efficacy results presented in the identified SR/MAs and IPD/MAs were based on a comparison of routine or selective invasive strategies (which could include angiography only, PCI or CABG) rather than the specific intervention of interest for this Review, PCI, so no data was available looking at PCI alone.

A multivessel subgroup analysis was not undertaken in any of the SR/MAs or IPD/MAs. Quality of life was not assessed in any of the SR/MAs or IPD/MAs.

The assessment of Level II evidence for specific data on PCI, the subgroup of patients with multivessel disease, and quality of life was limited to the five studies included in the 2010 Cochrane Review by Hoenig and colleagues (ICTUS, RITA-3, VINO, TACTICS-TIMI 18 and FRISC II), as well as the more recently published IES, which was included in the SR/MA by Angeli et al (2014). The citation details for the included RCTs are presented in Table 5.2-22.

An additional RCT was identified that was recently published and not included in the systematic reviews described above. Dimitrov et al (2013) compared an early invasive strategy with a selective invasive strategy in patients with NSTE-ACS. The analyses were conducted in subgroups of patients with and without diabetes. A primary outcome was not defined but the composite outcome major coronary adverse events (MACE) was included. MACE included recurrence of angina, MI, rehospitalisation, selective coronary angiography (SCAG), coronary intervention, manifestations of HF, stroke and mortality. The authors concluded that ‘early invasive strategy in diabetic patients with non-ST-segment elevation acute coronary syndrome is associated with a reduced MACE rate compared with the selective invasive strategy used in these patients. Early invasive strategy applied in diabetic patients is also associated with a significantly longer time to MACE. In non-diabetics the advantages of early over selective invasive strategy are not so clearly differentiated’. It should be noted that the benefit seen for the early invasive strategy compared with a selective invasive strategy in patients with diabetes was largely driven by differences in recurrence of angina (4.5% vs. 60%), rehospitalisation (0% vs. 40%), SCAG (0% vs. 40%) and coronary intervention (0% vs. 33%); the study was too small to show differences in mortality (0% vs. 0%) and MI (0% vs. 7%).

Given the study is small (178 patients in total and only 55 patients in the diabetes subgroup), and conducted at only two centres in Bulgaria, it has not been considered further in this Review.

Table 5.2-22 Citation details for included RCTs: diagnosis of NSTE-ACS – routine vs. selective invasive therapies

Ref ID CitationIES Primary publication:

Savonitto, S., C. Cavallini, et al. (2012). "Early aggressive versus initially conservative treatment in elderly patients with non-ST-segment elevation acute coronary syndrome: a randomized controlled trial." JACC Cardiovasc Interv 5(9): 906-916.

ICTUS Primary publication:de Winter, R. J., F. Windhausen, et al. (2005). "Early invasive versus selectively invasive management for acute coronary syndromes." N Engl J Med 353(11): 1095-1104.


January 2016

Ref ID CitationRITA 3 Primary publication:

Fox, K. A., P. A. Poole-Wilson, et al. (2002). "Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial. Randomized Intervention Trial of unstable Angina." Lancet 360(9335): 743-751.Included secondary publications:Kim, J., R. A. Henderson, et al. (2005). "Health-related quality of life after interventional or conservative strategy in patients with unstable angina or non-ST-segment elevation myocardial infarction: one-year results of the third Randomized Intervention Trial of unstable Angina (RITA-3)." J Am Coll Cardiol 45(2): 221-228.

VINO Primary publication:Špaček, R., P. Widimsky, et al. (2002). "Value of first day angiography/angioplasty in evolving Non-ST segment elevation myocardial infarction: an open multicenter randomized trial. The VINO Study." Eur Heart J 23(3): 230-238.

TACTICS-TIMI 18 Primary publication:Cannon, C. P., W. S. Weintraub, et al. (2001). "Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban." N Engl J Med 344(25): 1879-1887.Included secondary publications:Brener, S. J., S. A. Murphy, et al. (2002). "Efficacy and safety of multivessel percutaneous revascularization and tirofiban therapy in patients with acute coronary syndromes." Am J Cardiol 90(6): 631-633.

FRISC II Primary publication:FRISC II Investigators (1999). "Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. FRagmin and Fast Revascularisation during InStability in Coronary artery disease Investigators." Lancet 354(9180): 708-715.Included secondary publications:Janzon, M., L. A. Levin, et al. (2004). "Invasive treatment in unstable coronary artery disease promotes health-related quality of life: results from the FRISC II trial." Am Heart J 148(1): 114-121.

A summary of the characteristics of the included RCTs is presented in Table 5.2-23. All studies included patients with NSTE-ACS, while some studies had additional requirements including increased age (IES) or elevated troponin levels and/or elevated CK-MB (IES, ICTUS, TACTICS-TIMI 18, VINO; FRISC II). Studies differed substantially in terms of duration of follow-up (6 months to 5 years) and percentage of patients undergoing PCI during the index hospitalisation in both the routine invasive and selective invasive arms (41% to 60% and 3% to 28%, respectively).

The conclusions of the included RCTs are mixed. The two most recent studies, IES and ICTUS, concluded that a routine invasive strategy could not be proven to be more effective than a selective invasive strategy, while the RITA 3 study notes that a routine invasive strategy significantly reduces angina without increasing the risk of death or MI. The remaining two studies conclude that a routine invasive strategy is more effective than a selective invasive strategy.


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Table 5.2-23 Characteristics of the included RCTs: diagnosis of NSTE-ACS – routine vs. selective invasive therapiesStudy ID Study



IES Randomised, parallel, open-label 1 y follow-up

NSTE-ACS and ≥75 years; cardiac ischaemic symptoms at rest within 48 h before randomisation; ischaemic ECG changes and/or elevated levels of either troponin or CK-MBN=313

Early aggressive strategy (CA, and when indicated revascularisation with PCI or CABG within 72 h)During index admission: 88% CA 6% CABG 51% PCI 47% stent 23% BMS 23% DES 2% BMS+DES

Initially conservative strategy (CA and revascularisation with PCI or CABG only for ischaemia)During index admission: 29% CA <1% CABG 23% PCI 21% stent 9% BMS 11% DES <1% BMS+DES

Death/MI/ disabling stroke/ repeat hospital stay for cardiac causes/severe bleeding

The present study does not allow a definite conclusion about the benefit of an early aggressive approach when applied systematically among elderly patients with NSTE-ACS. The finding of a significant interaction for the treatment effect according to troponin status at baseline should be confirmed in a larger size trial.

ICTUS Randomised, parallel, open-label 5 y follow-up

Symptoms of ischaemia that were increasing or occurred at rest, with the last episode occurring ≤24 hours prior to randomisation; elevated cardiac troponin T level (≥0.03 μg/L); either ischaemic changes as assessed by ECG (defined as ST-segment depression or transient ST-segment elevation exceeding 0.05 mV, or T-wave inversion of ≥0.2 mV in two contiguous leads) or a documented history of CAD as evidenced by previous MI, findings on previous coronary angiography, or a positive exercise testN=1200

Early invasive strategy (CA within 24-28 h and PCI when appropriate; CABG recommended in patients with extensive three-vessel disease or severe LM stem disease)During index admission: 98% catheterisation 16% CABG 60% PCI

Selective invasive strategy (CA and revascularisation only for refractory angina despite OMT, haemodynamic or rhythmic instability, or clinically significant ischaemia on exercise test)During index admission: 53% catheterisation 11% CABG 28% PCI

Death/MI/ rehospitalisation for anginal symptoms

We could not demonstrate that, given optimised medical therapy, an early invasive strategy was superior to a selectively invasive strategy in patients with acute coronary syndromes without ST-segment elevation and with an elevated cardiac troponin T level.


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Authors conclusions

RITA 3 Randomised, parallel, open-label 5 y follow-up

Suspected cardiac chest pain at rest and had documented evidence of: CAD with at least one of:

evidence of ischaemia on ECG (ST-segment depression, transient ST elevation, left bundle branch block [documented previously], or T-wave inversion)

pathological Q waves suggesting previous MI

arteriographically proven CAD on a previous arteriogram

N=1810

Interventional treatment (OMT and coronary arteriography within 72 h and revascularisation as considered appropriate by physician)During index admission: 97% CA 33% CABG 68% PCI 35% stent

Conservative treatment (OMT and CA and revascularisation when clinically indicated)During index admission: 16% CA 4% CABG 7% PCI 5% stent

Death/MI/ refractory angina at 4 mDeath/MI at 1 y

In patients presenting with unstable CAD, an interventional strategy is preferable to a conservative strategy, mainly because of the halving of refractory or severe angina, and with no increased risk of death or MI.

VINO Randomised, parallel, open-label 0.5 y follow-up

Ischaemic chest pain at rest, lasting more than 20 min, within the last 24 h before randomisation; ECG evidence of acute MI without ST-segment elevations (ST-segment depressions minimally 0·1 mm in at least two contiguous leads and/or negative T waves or documented old LBBB/RBBB; CK-MB higher than 1.5 x ULN and/or positive troponin I assayN=141

First day angiography/angioplastyAt 6 months: 100% CA 73% revasc. 35% CABG 52% PTCA

Conservative strategy (initial medical treatment with angiography/ revascularisation only where clinically indicated)At 6 months: 55% CA 39% revasc. 30% CABG 13% PCI

Death/MI First day coronary angiography followed by angioplasty whenever possible reduces mortality and reinfarction in evolving MI without persistent ST elevation, in comparison with an early conservative treatment strategy.


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Authors conclusions

TACTICS-TIMI 18

Randomised, parallel, open-label 0.5 y follow-up

An episode of angina (with an accelerating pattern or prolonged [>20 minutes] or recurrent episodes at rest or with minimal effort) within the preceding 24 hours, were candidates for coronary revascularisation, and had at least one of the following: a new finding of ST-segment

depression of at least 0.05 mV, transient (<20 minutes) ST-segment elevation of at least 0.1 mV, or T-wave inversion of at least 0.3 mV in at least two leads;

elevated levels of cardiac markers;

or coronary disease, as documented by a history of catheterisation, revascularisation, or MI.

N=2200

Early invasive (CA within 4-48 h and revascularisation as appropriate)During index hospitalisation 97% catheterisation 20% CABG 41% PCI 34% stent

Conservative strategy (medical treatment with angiography/revascularisation only if clinically appropriate)During index hospitalisation 51% catheterisation 13% CABG 24% PCI 20% stent

Death/ MI/ rehospitalisation for ACS

In patients with unstable angina and MI without ST-segment elevation who were treated with the glycoprotein IIb/IIIa inhibitor tirofiban, the use of an early invasive strategy significantly reduced the incidence of major cardiac events. These data support a policy involving broader use of the early inhibition of glycoprotein IIb/IIIa in combination with an early invasive strategy in such patients.


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Authors conclusions

FRISC II Randomised, parallel, open-label 0.5 y follow-up

Symptoms of ischaemia that were increasing or occurring at rest, or that warranted the suspicion of acute MI, with the last episode within 48 h before the start of dalteparin or standard heparin treatment; myocardial ischaemia had to be verified by ECG (ST depression ≥0.1 mV or T-wave inversion ≥0.1 mV) or by raised biochemical markers CK-MB >6 ug/L, troponin T >0.10 ug/L, qualitative troponin T test positive, or catalytic activity of CK, CK-B, or CK-MB higher than the local diagnostic limit for MI).N=2457

Invasive treatment (CA within a few days of enrolment aiming for revascularisation within 7 days of start of treatment)Within 6 months: 98% CA 35% CABG 43% PCI 26% stent

Non-invasive treatment (CA in patients with refractory or recurrent symptoms despite medical treatment)Within 6 months: 47% CA 19% CABG 18% PCI 12% stent

Death/MI The early invasive approach should be the preferred strategy in most patients with unstable CAD who have signs of ischaemia on electrocardiography or raised biochemical markers of myocardial damage.

Source: IES: Savonitto et al (2012); ICTUS: de Winter et al (2005); RITA 3: Fox et al (2002); VINO: Špaček et al (2002); TACTICS-TIMI 18: Cannon et al (2001); FRISC II: FRISC II Investigators (1999). Abbreviations: ACS, acute coronary syndrome; BMS, bare metal stent; CA, coronary angiography; CABG, coronary artery bypass graft; CAD, coronary artery disease; CK-MB, creatinine kinase-MB; d, days; DES, drug-eluting stent; ECG, electrocardiography; h, hour; LBBB/RBBB, left or right bundle branch block; LM, left main; MI, myocardial infarction; min, minute; NSTE-ACS, non-ST-segment elevation acute coronary syndrome; OMT, optimal medical therapy; PCI, percutaneous coronary intervention; RCT, randomised controlled trial; ULN, upper limit of normal; y, years.


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Only three of the most relevant RCTs provided data on the additional subgroups and outcomes of interest: RITA 3, TACTICS-TIMI 18 and FRISC II.

Efficacy of PCIThe TACTICS-TIMI 18 trial provides efficacy results by revascularisation status, and hence provides results for patients undergoing PCI only. The results, summarised in Table 5.2-24, show that patients who received PCI as part of an invasive strategy had lower death/MI and death/MI/rehospitalisation rates than patients who received PCI as part of a conservative strategy at both 30 days and 6 months. Patients who received CABG as part of an invasive strategy also had lower death/MI and death/MI/rehospitalisation rates than patients who received CABG as part of a conservative strategy. Caution should be used when interpreting these results, and in particular if trying to make comparisons between PCI and CABG, as they may be subject to selection bias. The decision to revascularise, and the method used, was based on the clinical characteristics of the patient. Thus, patients were not randomised to medical therapy only, PCI or CABG, so there may be substantial differences between the populations that underwent different procedures.

Table 5.2-24 Type of revascularisation subgroup analyses in the included RCTs: diagnosis of NSTE-ACS – routine vs. selective invasive therapies

TACTICS-TIMI 18NSTEMI/UA

Time point Invasive strategyn (%)

Conservative strategyn (%)

Medical therapy only

Death/MI/rehospitalisation for ACS* 30 days6 months

24 (5.6)46 (10.8)

24 (3.9)64 (10.3)

Death/MI 30 days6 months

14 (3.3)25 (5.9)

15 (2.4)32 (5.1)

PCI


44 (9.3)111 (23.5)

68 (21.1)113 (35.0)


26 (5.5)41 (8.7)

46 (14.2)51 (15.8)

CABG


17 (7.0)39 (16.0)

31 (17.4)50 (28.1)


14 (5.8)22 (9.1)

21 (11.8)27 (15.2)

Source: TACTICS-TIMI 18: Cannon et al (2001), Table 5, p 1885. Note: Primary outcome denoted by *. Abbreviations: ACS, acute coronary syndrome; CABG, coronary artery bypass graft; MI, myocardial infarction; NSTE-ACS, non-ST-segment elevation acute coronary syndrome; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; RCT, randomised controlled trial; UA, unstable angina.

Multivessel subgroupWhile not providing a comparison between a routine invasive strategy and a selective invasive strategy in patients with multivessel disease, Brener et al (2002) do provide efficacy data in patients from the TACTICS-TIMI 18 trial who were assigned to an early routine invasive strategy and who underwent PCI, stratified by those with single-vessel disease (SV), multivessel disease who underwent culprit vessel PCI (MV-C), and multivessel disease who underwent multivessel PCI (MV-M). The results of the analysis are shown in Table 5.2-25. There was no significant difference in outcome rates across vessel/PCI subgroups for any


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outcome, with the exception of revascularisation in non-culprit vessels. The authors note that the principal finding of their analysis of the TACTICS-TIMI 18 data was that ‘when appropriately selected, it appears that patients can safely undergo [multivessel] PCI when they present with ACS’.

Table 5.2-25 Multivessel subgroup analyses in the included RCTs: diagnosis of NSTE-ACS – routine vs. selective invasive therapies

TACTICS-TIMI 18NSTEMI/UA

PopulationTime point

SV % MV-C % MV-M % Subgroup p value


7.317.5

9.423.2

7.621.2

0.810.44

Death 30 days6 months

2.22.9

1.32.2

1.53.0

0.820.89

MI 30 days6 months

3.75.1

4.98.0

3.06.1

0.730.55

Revascularisation – culprit 6 months 13.9 13.8 10.6 0.78

Revascularisation – non-culprit 6 months 1.5 6.3 1.5 0.04Source: TACTICS-TIMI 18 (Brener et al, 2002): Figures 1-3, p 632-633. Note: Primary outcome denoted by *. Statistically significant results shown in bold. Abbreviations: ACS, acute coronary syndrome; MI, myocardial infarction; MV-C, multivessel disease - culprit vessel PCI; MV-M, multivessel disease – multivessel PCI; NSTEMI, non-ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; RCT, randomised controlled trial; SV, single vessel; UA, unstable angina.

Quality of lifeTwo of the selected RCTs provided data on quality of life. Kim et al (2005) provide an assessment of quality of life in patients participating in the RITA-3 trial using four different measures: the Short Form-36 (SF-36), SAQ, EuroQOL 5-Dimensional Classification (EQ-5D) and EuroQOL Visual Analogue Scale (EQ-VAS). As shown in Table 5.2-26, a significant incremental improvement in quality of life was seen for the invasive strategy over the conservative strategy at 4 months for a number of measures, and to a lesser degree at 1 year. The authors conclude that ‘an early [invasive strategy] provides greater gains in [health-related quality of life], as compared with [a conservative strategy], mainly due to improvements in angina grade’.

Quality of life was also assessed in the FRISC II trial (Janzon et al, 2004). Using the SF-36, patients in the invasive group had significantly better quality of life compared with patients in the non-invasive (selective) group in all domains at 3 months and 6 months, and in all domains except mental health at 12 months. Similar results were seen at 3 months for all domains and the global score using the Angina Pectoris Quality of Life Questionnaire (APQLQ), all domains and global score (except emotional distress) at 6 months, and only the physical activities domain at 12 months. The authors concluded that ‘patients receiving early invasive intervention after an unstable episode had substantial improvement in health-related quality of life until the 1-year follow-up, compared with patients receiving noninvasive treatment’ and noted that, at baseline, quality of life in their patient population was substantially lower than in a matched normative population.

In summary, quality of life was significantly improved in patients undergoing a routine invasive strategy compared with patients undergoing a selective invasive strategy up to 1 year follow-up.


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Table 5.2-26 Quality of life in the included RCTs: diagnosis of NSTE-ACS – routine vs. selective invasive therapies (RITA 3)

Outcome PopulationDomain

Invasive strategy4 months

Conservative strategy4 months

p value for trend4 months

Invasive strategy1 year

Conservative strategy1 year

p value for trend1 year

RITA-3 NSTEMI/UA % % % %

EQ-5D MobilityImprovedNo changeWorsened

-236512

-236413

-0.78

-236314

-246214

-0.41

Self-careImprovedNo changeWorsened

-9847

-8839

-0.37

-9847

-9

838

-0.39

Usual activitiesImprovedNo changeWorsened

-275914

-235918

-0.01

-295615

-265618

-0.04

Pain or discomfortImprovedNo changeWorsened

-176023

-175528

-0.07

-166024

-185527

-0.87

AnxietyImprovedNo changeWorsened

-226315

-215920

-0.03

-256015

-246016

-0.36

EQ-5D (VAS) Mean ± SEDiff. from baseline

0.748 ± 0.0090.077 ± 0.009

0.714 ± 0.0100.041 ± 0.009

- 0.752 ± 0.0090.079 ± 0.009

0.736 ± 0.0100.063 ± 0.009

-

Treatment difference 0.036 (0.011, 0.061) - 0.016 (–0.009, 0.042) -


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Invasive strategy4 months

Conservative strategy4 months

p value for trend4 months

Invasive strategy1 year

Conservative strategy1 year

p value for trend1 year

Mean ± SE Mean ± SE Diff., p value Mean ± SE Mean ± SE Diff. p value

SF-36 Physical functionPhysical role functionEmotional role functionSocial functionBodily painMental healthVitalityGeneral health

63.0 ± 1.051.7 ± 1.572.0 ± 1.473.4 ± 1.063.4 ± 1.072.4 ± 0.752.3 ± 0.859.5 ± 0.8

59.3 ± 1.044.9 ± 1.567.1 ± 1.469.7 ± 1.061.7 ± 1.070.6 ± 0.747.7 ± 0.854.4 ± 0.8

3.7, <0.0016.8, <0.001

4.9, 0.013.7, 0.011.7, 0.221.8, 0.07

4.6, <0.000015.1, <0.0001

62.5 ± 1.057.0 ± 1.574.9 ± 1.476.9 ± 1.065.2 ± 1.074.3 ± 0.752.9 ± 0.959.4 ± 0.8

61.0 ± 1.052.4 ± 1.572.4 ± 1.472.9 ± 1.064.1 ± 1.072.5 ± 0.750.3 ± 0.955.4 ± 0.8

1.5, 0.314.6, 0.032.5, 0.204.0, 0.011.1, 0.441.8, 0.072.6, 0.03

4.0, <0.001

Mean ± SE Mean ± SE Diff., p value Mean ± SE Mean ± SE Diff. p value

SAQ Exertional capacityAngina stabilityAnginal frequencyTreatment satisfactionDisease perception

75.4 ± 0.970.3 ± 1.080.2 ± 0.990.1 ± 0.572.1 ± 0.9

69.8 ± 0.963.9 ± 1.072.6 ± 0.986.3 ± 0.564.4 ± 0.8

5.6, <0.000016.4, <0.000017.6, <0.000013.8, <0.000017.7, <0.00001

76.9 ± 1.067.7 ± 1.082.4 ± 0.991.2 ± 0.575.9 ± 0.9

73.3 ± 1.063.7 ± 1.078.0 ± 0.988.6 ± 0.571.2 ± 0.9

3.6, <0.014.0, <0.01

4.4, <0.0012.6, <0.0014.7, <0.0001

Source: RITA 3 (Kim et al, 2005): Tables 2-5, p 224.Note: Statistically significant results shown in bold. Abbreviations: diff., difference; EQ-5D, European Quality of Life-5 Dimensions; NSTE-ACS, non-ST-segment elevation acute coronary syndrome; NSTEMI, non-ST-segment elevation myocardial infarction; RCT, randomised controlled trial; SAQ, Seattle Angina Questionnaire; SE, standard error; SF-36, Short Form-36; UA, unstable angina.


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Table 5.2-27 Quality of life in the included RCTs: diagnosis of NSTE-ACS – routine vs. selective invasive therapies (FRISC II)


Routine invasive strategy3 months

Selective invasive strategy3 months

p value

3 months

Routine invasive strategy6 months

Selective invasive strategy6 months

p value

6 months

Routine invasive strategy1 year

Selective invasive strategy1 year

p value

1 year

FRISC II Unstable CAD Mean ± SD Mean ± SD Diff., p value Mean ± SD Mean ± SD Diff., p value Mean ± SD Mean ± SD Diff., p value

SF-36 Physical functioningRole-physicalBodily painGeneral healthVitalitySocial functioningRole-emotionalMental healthPhysical component scoreMental component score

----------

----------

NR; <0.001NR; <0.001NR; <0.001NR; <0.001NR; <0.001NR; <0.001NR; <0.001NR; <0.001NR; <0.001NR; 0.002

----------

----------

NR; <0.001NR, <0.001NR, <0.001NR, <0.001NR, <0.001NR, <0.001NR, <0.01NR, <0.01NR; NRNR; NR

----------

----------

NR, <0.01NR, <0.01NR, <0.01NR, <0.001NR, <0.01NR, <0.05NR, <0.05NR, ≥0.052.8, 0.0011.1, 0.20

Mean ± SD Mean ± SD Diff., p value Mean ± SD Mean ± SD Diff., p value Mean ± SD Mean ± SD Diff., p value

APQLQ Physical activitiesSomatic symptomsEmotional distressLife satisfactionGlobal score

65.6 ± 21.277.3 ± 16.880.8 ± 18.172.4 ± 16.773.6 ± 16.8

58.8 ± 23.4371.2 ± 18.976.8 ± 19.267.1 ± 20.268.1 ± 17.5

6.83, <0.0016.17, <0.0014.07, 0.0085.33, 0.0015.44, <0.001

80.8 ± 16.181.4 ± 17.281.8 ± 17.680.4 ± 17.381.1 ± 16.7

76.3 ± 16.878.7 ± 16.979.5 ± 17.577.0 ± 17.077.9 ± 16.6

4.46, 0.0012.74, 0.0472.26, 0.1103.34, 0.0163.24, 0.016

81.6 ± 16.082.7 ± 16.682.8 ± 16.581.5 ± 16.982.2 ± 16.1

78.5 ± 17.380.3 ± 18.080.8 ± 18.478.9 ± 18.279.6 ± 17.7

3.04, 0.0232.48, 0.0762.04, 0.1462.70, 0.0562.58, 0.058

Source: FRISC II (Janzon et al, 2014): Figures 1-3 and Text, p 116-117, and Table III, p 118. Note: Statistically significant results shown in bold. Abbreviations: APQLQ, Angina Pectoris Quality of Life Questionnaire; CAD, coronary artery disease; Diff, difference; NR, not reported; NSTE-ACS, non-ST-segment elevation acute coronary syndrome; NSTEMI, non-ST-segment elevation myocardial infarction; RCT, randomised controlled trial; SD, standard deviation; SF-36, Short Form-36.


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PCI (selective or routine) versus CABG

Level I evidenceNo systematic reviews were identified that compared the use of PCI with CABG in patients with a diagnosis of NSTE-ACS; all identified systematic reviews compared different forms of invasive strategy (i.e. early or routine with selective or conservative). In the invasive strategies, patients could be revascularised using PCI ± stenting or CABG, depending on the decision of the physician.

Level II evidenceNo RCTs were identified that specifically compared the use of PCI with CABG in patients with a diagnosis of NSTE-ACS. As described previously, the TACTICS-TIMI 18 trial provides efficacy results by revascularisation status, and hence provides results for patients undergoing PCI only and CABG only (see Table 5.2-24). Patients who received PCI as part of an invasive strategy had lower death/MI and death/MI/rehospitalisation rates than patients who received PCI as part of a conservative strategy at both 30 days and 6 months. Patients who received CABG as part of an invasive strategy had lower death/MI and death/MI/rehospitalisation rates than patients who received CABG as part of a conservative strategy at 30 days only; there was little difference in outcome rates between treatment arms at 6 months. Caution should be used when interpreting these results, and in particular if trying to make comparisons between PCI and CABG, as they may be subject to selection bias; the decision to revascularise, and the method used, was based on the clinical characteristics of the patient. Thus, patients were not randomised to PCI or CABG and so there may be substantial differences between the populations that underwent different procedures.

5.2.3 Assessment of high risk based on diagnostic testing

PCI versus medical therapyThe following section describes the evidence around the efficacy and safety of PCI in patients considered to be at high risk of coronary events based on non-invasive imaging or invasive diagnostic testing. First, the findings of Level I studies (SR/MAs) will be described, followed by an assessment of Level II studies (RCTs) to cover off outcomes and subgroups in which Level I evidence is not available.

Level I evidenceThe results of the meta-analysis of RCTs conducted by Gada et al (2015) and Stergiopoulos et al (2014) are presented in Table 5.2-28. Of particular interest is the difference in findings between the two reviews: Gada and colleagues found that the addition of PCI to medical therapy resulted in a reduction in mortality compared with medical therapy alone, while Stergiopoulos and colleagues found no reduction in mortality, MI, repeat revascularisation or angina when PCI was added on to medical therapy.

The main difference between the two studies is the eligibility criteria for inclusion of RCTs. Gada et al (2015) excluded trials that did not use objective non-invasive or invasive imaging to qualify ischaemia, while the Stergiopoulos et al (2014) SR/MA included trials in which some patients had ischaemia diagnosed without imaging. Thus, the population included in the Stergiopoulos review is likely to be more heterogeneous than the population included in the Gada review, and possibly dilutes any benefit that might be occurring in the specific high-risk patient group. In particular, Stergiopoulos and colleagues have included data from the overall COURAGE study, while Gada and colleagues have included data only from the COURAGE


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sub-study, which provides data limited to patients diagnosed with mild ischaemia, or moderate to severe ischaemia, diagnosed by nuclear imaging. Mortality in this patient group was substantially, although not significantly, reduced for PCI plus medical therapy compared with medical therapy alone (HR 0.62; 95% CI 0.30, 1.28; p=0.20); mortality in the overall COURAGE study was reduced to a lesser degree for PCI plus medical therapy compared with medical therapy alone, although also not statistically significant (OR 0.84; 95% CI 0.61, 1.18; p=0.32).

The mortality benefit of PCI added to medical therapy in high-risk patients was not statistically significant in any of the three individual RCTs included in the Gada et al (2015) SR/MA (COURAGE nuclear sub-study, FAME 2 or SWISSI II), which is not surprising given none of the studies were powered to detect a difference between treatments for all-cause mortality. A significant mortality benefit was seen when all three RCTs were included in the meta-analysis, and when the SWISSI II trial was included with the COURAGE sub-study or FAME 2 trials. When the SWISSI II RCT (in which no patients received stents) was excluded from the study statistical significance was lost (although the point estimate was still low; i.e. HR 0.59).

The authors note that the benefit of revascularisation (using either PCI or CABG) in addition to medical therapy is currently being assessed by the International Study of Comparative Health Effectiveness with Medical and Invasive Approaches (ISCHEMIA) trial.92 The ISCHEMIA trial is being conducted in approximately 8000 patients who have at least moderate ischaemia on stress imaging; Australian sites are included. The study is currently recruiting and is due for completion in May 2019. It should be noted that the primary outcome in this trial is a composite of cardiovascular death or non-fatal MI, so this study may also be underpowered to detect a difference between treatments in all-cause mortality.

In summary, all-cause mortality was not significantly reduced following PCI with stenting plus medical therapy compared with medical therapy alone in patients with myocardial ischaemia based on diagnostic testing.

92 NCT01471522 on clinicaltrial.gov website.


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Table 5.2-28 Results of included systematic reviews: high risk based on diagnostic testing – PCI vs. medical therapy


Outcome Studies (patients)



SR/MA – Level I

Gada 2015 Stable CAD and objective evidence of ischaemia using imaging (non-invasive or invasive)

PCI vs. MT All-cause mortality – allAll-cause mortality – excl COURAGE nuclear sub-studyAll-cause mortality – excl FAME-2All-cause mortality – excl SWISSI II

3 (1557)2 (1089)2 (669)2 (1356)

HR 0.52 (0.30, 0.92); 0.02HR 0.41 (0.17, 0.99); 0.04HR 0.54 (0.30, 0.96); 0.04HR 0.59 (0.29, 1.17); 0.13

PCI was shown to have a mortality benefit over MT in patients with SIHD and objective assessment of ischaemia using noninvasive imaging or its invasive equivalent. In conclusion, this study provides insight into the management of a higher-risk SIHD population that is the focus of the ongoing International Study of Comparative Health Effectiveness with Medical and Invasive Approaches trial.

Stergiopoulos 2014

Stable CAD and documented myocardial ischaemia

PCI vs. MT DeathNon-fatal MIUnplanned revascularisationAngina

5 (4064)5 (4064)5 (4064)5 (4064)

OR 0.90 (0.71, 1.16); 0.42OR 1.24 (0.99, 1.56); 0.06OR 0.64 (0.35, 1.17); 0.14OR 0.91 (0.57, 1.44); 0.67

In patients with stable CAD and objectively documented [with or without imaging] myocardial ischaemia, PCI with MT was not associated with a reduction in death, non-fatal MI, unplanned revascularisation, or angina compared with MT alone.

Source: Gada et al (2015): Figure 2, p 1196, and Table 3, p 1197; Stergiopoulos et al (2014): Table 4, p 236. Notes: Statistically significant results shown in bold. Abbreviations: CAD, coronary artery disease; CI, confidence interval; HR, hazard ratio; MI, myocardial infarction; MT, medical therapy; NR, not reported; OR, odds ratio; PCI, percutaneous coronary intervention; SIHD, stable ischaemic heart disease.


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To understand in greater detail the results of the studies included in the Gada 2015 SR/MA.

Diabetes and multivessel subgroup analyses were not undertaken in either of the SR/MAs.

Quality of life and adverse events were not assessed in either of the SR/MAs.

Assessment of RCTs was limited to those that were included in the Gada et al (2015) SR/MA that included stent use (FAME 2, COURAGE nuclear sub-study); the SWISSI II study was excluded from consideration in this Review because no patients received stents as part of their PCI, and the specific purpose of the Review was to examine the effectiveness of PCI with stent insertion (see Section 2.3). The citation details for the included RCTs are presented in Table 5.2-29.

In addition to the COURAGE sub-study identified above (Shaw et al, 2012), there is an additional publication available for the COURAGE nuclear sub-study (Shaw et al, 2008). This earlier publication includes paired data for 22.6% of the population included in the Shaw et al (2012) publication. Shaw et al (2008) was excluded from consideration because the primary outcome (≥5% reduction in ischaemic myocardium) was not one of the outcomes defined for examination in this Review. In addition, the assessment of event-free survival presented in this publication was based on a comparison between patients who had an ischaemic response and those who did not have an ischaemic response, not a comparison between treatments.

Table 5.2-29 Citation details for included RCTs: high risk based on diagnostic testing – PCI vs. medical therapy

Ref ID CitationFAME 2 Primary publications:

De Bruyne, B., W. F. Fearon, et al. (2014). "Fractional flow reserve-guided PCI for stable coronary artery disease." N Engl J Med 371(13): 1208-1217.De Bruyne, B., N. H. Pijls, et al. (2012)."Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease." N Engl J Med 367(11): 991-1001.Comments:Shah, R. (2015). "Fractional flow reserve-guided PCI." N Engl J Med 372(1): 94-95.Goodney, P. P., S. Woloshin, et al. (2012). "Fractional flow reserve-guided PCI in stable coronary disease." N Engl J Med 367(24): 2355; author reply 2356.


Primary publication:Shaw, L. J., W. S. Weintraub, et al. (2012). "Baseline stress myocardial perfusion imaging results and outcomes in patients with stable ischemic heart disease randomized to optimal medical therapy with or without percutaneous coronary intervention." Am Heart J 164(2): 243-250.

A summary of the main characteristics of the included RCTs is presented in Table 5.2-30. The two studies classified patients at increased risk based on different types of testing: COURAGE used stress myocardial perfusion SPECT while FAME 2 used FFR testing. In addition, the PCI techniques used in the PCI arms of the two trials also differed, with most patients receiving BMS in the COURAGE nuclear sub-study, and second-generation DES received by most patients in the FAME 2 study.


January 2016

It should be noted that the COURAGE nuclear sub-study includes a subset of the patients included in the COURAGE study. Of the 2287 patients randomised, 1381 patients who underwent baseline stress myocardial perfusion SPECT were divided into two groups based on the presence of mild ischaemia (<3 ischaemic segments; N=913) or moderate to severe ischaemia (≥3 ischaemic segments; N=468); the group with moderate to severe ischaemia are of interest to this section of the MBS Review. Including only a subgroup of patients from the original trial has the potential to cause imbalance between the treatments arms as the assignment of patients to treatment groups is no longer randomised; however, as shown in Table 1 of the Shaw et al (2012) publication, the baseline characteristics of patients with moderate to severe ischaemia appeared reasonably similar across the PCI + OMT and OMT treatment groups, with no significant difference seen for any of the demographic, clinical or treatment characteristics assessed.

Due to differences in the primary outcomes examined, the COURAGE nuclear sub-study and FAME 2 came to different conclusions. In the COURAGE nuclear sub-study, there was no difference between PCI + OMT and OMT alone in the primary outcome, the composite of death and MI, and the authors concluded that effectiveness was not altered by severity of ischaemia. In the FAME study, there was a significant difference in favour of PCI + OMT for the primary outcome (death/MI/urgent revascularisation). In their 2014 publication, De Bruyne and colleagues conclude that FFR-guided PCI + OMT, compared with OMT alone, improved the primary outcome. This will be discussed in greater detail below.


January 2016

Table 5.2-30 Characteristics of the selected RCTs: high risk based on diagnostic testing – PCI vs. medical therapyStudy ID Study characteristics Patient population Intervention Comparator Primary

outcomeAuthors conclusion


Randomised, parallel, open-label Median 4.6 y

follow-up

Stable IHD; at least one major epicardial coronary artery with ≥70% stenosis; investigator-determined rest (i.e. new ST-T changes) or stress (i.e. ≥1 mm ST depression or an imaging defect) SPECT testing CCS Class 0 – 12% CCS Class 1 – 34% CCS Class II – 34% CCS Class III – 20%N= 1381 (468 with moderate to severe ischaemia)

PCI + OMT Stent use 94% DES 3%

OMT Death/MI The extent of site-defined ischaemia did not predict adverse events and did not alter treatment effectiveness. Currently, evidence supports equipoise as to whether the extent and severity of ischaemia impact on therapeutic effectiveness.

FAME 2 Randomised, parallel, open-label 2 y follow-up

Stable coronary disease and pressure wire showing FFR ≤0.80 during adenosine-induced hyperaemia in at least one major coronary arteryN=888

PCI + OMT Stent use 97% Second-

generation DES 95%

OMT Death/MI/ urgent revasc.

In patients with stable CAD and functionally significant stenoses, FFR-guided PCI plus the best available medical therapy, as compared with the best available medical therapy alone, decreased the need for urgent revascularisation.

Source: COURAGE nuclear sub-study: Shaw et al (2012); FAME2: De Bruyne et al (2012).Abbreviations: CCS, Canadian Cardiovascular Society; DES, drug-eluting stent; FFR, fractional flow reserve; IHD, ischaemic heart disease; MI, myocardial infarction; OMT, optimal medical therapy; PCI, percutaneous coronary intervention; RCT, randomised controlled trial; revasc., revascularisation; SPECT, single-photon emission computed tomography; y, years.


January 2016

The main results of the included RCTs are presented in Table 5.2-31. The results from both studies will be described in turn. It should be noted that the FAME 2 study may be most relevant to the current MBS Review given that nearly all patients randomised to the PCI arm received stents, and the majority of stents used were second-generation DES. In addition, FFR was used to identify patients considered to be at high risk of coronary events.

The results of the COURAGE nuclear sub-study, which provided results separately for patients with no to mild ischaemia, or moderate to severe ischaemia, are presented in Table 5.2-31. In this study, patients with moderate to severe ischaemia, and no to mild ischaemia, received no significant benefit in mortality following PCI added to medical therapy compared with medical therapy alone, although the point estimates were numerically lower for PCI (HR 0.62 and 0.70, respectively). Similarly, there was no significant difference in MI between PCI plus medical therapy compared with medical therapy alone in either the moderate to severe, or no to mild, ischaemia subgroups, although in this case the point estimates were numerically higher (HR 1.37 and 1.21, respectively). The authors conclude that ‘the extent of site-defined ischaemia did not predict adverse events and did not alter treatment effectiveness’. The authors note that the small sample size lacked sufficient power to detect treatment differences and that a lack of standardised image interpretation may have impacted on the results.

The discussion of the FAME 2 study is largely limited to the results presented in the publication by De Bruyne et al (2014), as this represents the most complete follow-up (Table 5.2-31). Recruitment for this study was stopped early due to the statistically significant between-group difference for the primary endpoint (a composite of death/MI/urgent revascularisation) that favoured those randomised to PCI over medical therapy, resulting from the lower rate of urgent revascularisation in the PCI group compared with the medical therapy group (1.6% vs. 11.1%, respectively) at 2 years. After 2 years of follow-up, the rate of the primary endpoint was significantly lower in the PCI group compared with the medical therapy group (HR 0.39; 95% CI 0.26, 0.57; p <0.001). This was driven by the very large number of urgent revascularisations undertaken in the medical therapy arm compared with the PCI arm from 8 days to 2 years’ follow-up (15.6% of medical therapy patients vs. 3.6% of PCI patients). The authors concluded that ‘in patients with stable coronary artery disease, FFR-guided PCI, as compared with medical therapy alone, improved the outcome’. However, this ‘outcome’ includes urgent revascularisations; there was no significant difference in death or MI overall between PCI or medical therapy, although there was a significant increase in risk of the composite outcome of death/MI related to PCI in the first 7 days (HR 9.01; 95% CI 1.13, 72.0; p = 0.012) and a significant increase in the risk of death/MI related to medical therapy after 7 days (HR 0.56; 0.32, 0.97; p = 0.037).

There have been a number of criticisms regarding the interpretation of the results from this study. Following publication of the initial FAME 2 results by De Bruyne and colleagues (2012), Goodney et al (2012) questioned whether the conclusion that PCI resulted in fewer urgent revascularisations was valid; they argue that elective revascularisation was higher in the PCI arm (100%) than the medical therapy arm (8.6%), and did not provide any benefit in terms of reductions in MI or death. De Bruyne and colleagues argued that their landmark analysis suggested that after 7 days follow-up, FFR-guided PCI resulted in lower rates of MI and death (HR 0.52; 95% CI 0.21, 1.32 and HR 0.33; 95% CI 0.03, 3.17, respectively). It should be noted that individually, these results failed to reach statistical significance, although there was a statistically significant increased risk of MI associated with PCI in the first 7 days (HR 7.99; 95% CI 0.99, 64.57; p=0.04).


January 2016

Following publication of the 2-year follow-up in De Bruyne et al (2014), Shah (2015) suggested that the higher rate of MI after 7 days may have specifically been periprocedural infarctions related to the greater number of revascularisations undertaken in the medical therapy arm during that period. The authors responded with data suggesting that it was spontaneous (not periprocedural) MI that was higher in the medical therapy arm. Shah also noted that the high rate of urgent revascularisations in the medical therapy arm may have been related to the open-label nature of the trial; patients in the medical therapy arm knew they had untreated stenosis and Shah has speculated that they may be more likely to report symptoms, which along with bias from physicians, may have led to higher rates of hospitalisation, cardiac catheterisation, and subsequently revascularisation. De Bruyne and colleagues acknowledge this is possible but note that patients included in a registry and treated with medical therapy only as part of this study (patients in whom all stenoses had a FFR ≥0.80) had a low number of events despite their knowledge of having functionally significant CAD. In addition, they note that outcomes were adjudicated by assessors who were unaware of treatment assignment.

The use of urgent revascularisation as part of a composite primary outcome in a trial comparing PCI with medical therapy is problematic. Because all patients in the PCI arm of the trial undergo revascularisation initially, any additional revascularisations that occur during the trial are repeat revascularisations. However, because patients in the medical therapy arm of the trial only undergo revascularisation when considered clinically necessary, the revascularisation procedures they undergo are initial revascularisations. Thus, the outcomes being compared are not the same – the rate of repeat revascularisation is being compared largely with the rate of initial revascularisation – and therefore the validity of the comparison is questionable.

As noted in an editorial by Kazi and Hlatky (2012), ‘composite outcomes are problematic in general, but composites that include repeat revascularization are particularly problematic. Having a repeat revascularization procedure is hardly as bad as having a myocardial infarction, let alone dying, but each has the same weight in the composite major adverse cardiac events outcome. In addition, repeat revascularization events vastly outnumber the deaths and myocardial infarctions in any trial so that they become the primary driver of the composite end point’.

Table 5.2-31 Results of the included RCTs: high risk based on diagnostic testing – PCI vs. medical therapy

Outcome Population (test)Subgroup/time point

PCI + MTn (%)

MTn (%)


Subgroup p value


Stable IHD (SPECT)

Death/MI* Mod. to sev. ischaemiaNo to mild ischaemia

48 (NR)82 (NR)

47 (NR)80 (NR)

HR 1.08 (0.71, 1.65); 0.72HR 0.99 (0.72, 1.38); 0.97

NR

Death Mod. to sev. ischaemiaNo to mild ischaemia

16 (NR)33 (NR)

22 (NR)43 (NR)

HR 0.62 (0.30, 1.28); 0.20HR 0.70 (1.13, 9.43); 0.14

NR

MI Mod. to sev. ischaemiaNo to mild ischaemia

37 (NR)57(NR)

29 (NR)45 (NR)

HR 1.37 (0.82, 2.26); 0.23HR 1.21 (0.80, 1.83); 0.36

NR


January 2016

Outcome Population (test)Subgroup/time point

PCI + MTn (%)

MTn (%)


Subgroup p value

FAME 2 Stable CAD (FFR)

Death/MI/urgent revasc.*

Any≤ 7 days> 7 days

36 (8.1)10 (2.2)26 (6.0)

86 (19.5)4 (0.9)82 (18.8)

HR 0.39 (0.26, 0.57); <0.001HR 2.49 (0.78, 8.00); 0.11HR 0.29 (0.18, 0.45); <0.001

-<0.001


Death Any≤ 7 days> 7 days

6 (1.3)0 (0)6 (1.3)

8 (1.8)0 (0)8 (1.8)

HR 0.74 (0.26, 2.14); 0.58NEHR 0.74 (0.26, 2.14); 0.58

NE

CV death Any 3 (0.7) 3 (0.7) HR 0.99 (0.20, 4.90); 0.99 -

MI AnyPeriprocedural93

Spontaneous92

≤ 7 days> 7 days

26 (5.8)8 (1.8)18 (4.0)9 (2.0)17 (3.9)

30 (6.8)5 (1.1)25 (5.7)1 (0.2)29 (6.6)

HR 0.85 (0.50, 1.45); 0.56HR 1.59 (0.52, 4.86); NRHR 0.70 (0.38, 1.29); NRHR 9.01 (1.13, 72.0); 0.012HR 0.58 (0.32, 1.05); 0.07

-NR-0.002

Death/MI Any≤ 7 days> 7 days

29 (6.5)9 (2.0)20 (4.6)

36 (8.2)1 (0.2)35 (8.0)

HR 0.79 (0.49, 1.29); 0.35HR 9.01 (1.13, 72.0); 0.012HR 0.56 (0.32, 0.97); 0.037

-0.002

Stroke Any 7 (1.6) 4 (0.9) HR 1.74 (0.51, 5.94); 0.37 -

Urgent revasc. Any≤ 7 days> 7 days

18 (4.0)2 (0.4)16 (3.6)

72 (16.3)4 (0.9)68 (15.6)

HR 0.23 (0.14, 0.38); <0.001HR 0.49 (0.09, 2.70); 0.41HR 0.21 (0.12, 0.37); <0.001

-0.34

Source: COURAGE nuclear sub-study (Shaw et al, 2012): Table IV, p 248; FAME 2 (De Bruyne et al, 2014): Table 1, p 1211 and Supplementary appendix Table S3, p 19. Note: Primary outcome denoted by *. Statistically significant results shown in bold. Abbreviations: CAD, coronary artery disease; CI, confidence interval; FFR, fractional flow reserve; HR, hazard ratio; IHD, ischaemic heart disease; MI, myocardial infarction; mod, moderate; MT, medical therapy; NE, not estimable; NR, not reported; PCI, percutaneous coronary intervention; sev, severe; SPECT, single-photon emission computed tomography.

Diabetes subgroupOnly the FAME 2 trial provided results for subgroups based on diabetes status. As shown in Table 5.2-32, for the primary outcome (death/MI/urgent revascularisation) there was a statistically significant benefit of PCI plus medical therapy over medical therapy alone in groups of patients with or without diabetes. There was no significant interaction between treatment group and diabetes status.

Table 5.2-32 Diabetes subgroup analyses in the included RCTs: high risk based on diagnostic testing – PCI vs. medical therapy

Outcome Population (test)Subgroup

PCI + MTn (%)

MTn (%)

Risk estimate(95% CI)

Subgroup p value


Death/MI/revasc.* DiabetesNo diabetes

14 (11.2)22 (6.8)

27 (23.1)59 (18.2)

HR 0.46 (0.24, 0.88)HR 0.35 (0.21, 0.57)

0.5094

93 Results from author reply to letter by Shah (2015) NEJM 372: 94-95. 94 Subgroup analyses were presented in a supplementary appendix; it is unclear whether these were pre-planned or post hoc.


January 2016

Source: FAME 2 (De Bruyne et al, 2014): Supplementary appendix Figure S3, p 11.Note: Primary outcome denoted by *. Statistically significant results shown in bold. Abbreviations: CAD, coronary artery disease; CI, confidence interval; FFR, fractional flow reserve; HR, hazard ratio; MI, myocardial infarction; MT, medical therapy; PCI, percutaneous coronary intervention; RCT, randomised controlled trial; revasc., revascularisation.

Multivessel subgroupOnly the FAME 2 trial provided results based on vessel status subgroups. As shown in Table 5.2-33, there was a significant benefit of PCI plus medical therapy over medical therapy alone for the primary outcome (death/MI/revascularisation) in patients with both multivessel or single-vessel disease. There was no significant interaction between treatment group and multivessel disease status.

Table 5.2-33 Multivessel disease subgroups in the included RCTs: high risk based on diagnostic testing – PCI vs. medical therapy

Outcome Population (test)Subgroup

PCI + MTn (%)

MTn (%)


Subgroup p value


Death/MI/revasc.* Multivessel diseaseSingle-vessel disease

8 (7.0)28 (8.4)

24 (24.7)62 (18.0)

HR 0.26 (0.12, 0.58)HR 0.44 (0.28, 0.69)

0.2693

Source: FAME 2 (De Bruyne et al, 2014): Supplementary appendix Figure S3, p 11.Note: Primary outcome denoted by *. Statistically significant results shown in bold. Abbreviations: CAD, coronary artery disease; CI, confidence interval; FFR, fractional flow reserve; HR, hazard ratio; MI, myocardial infarction; m/s, moderate to severe disease; MT, medical therapy; PCI, percutaneous coronary intervention; RCT, randomised controlled trial; revasc., revascularisation.

Quality of lifeNo studies provided data on quality of life for this high-risk patient group. As noted previously, the ISCHAEMIA trial is currently underway. This trial will assess disease-specific quality of life via the Seattle Angina Questionnaire (SAQ).

Adverse eventsThe FAME 2 trial provided data on serious adverse events (SAEs), as shown in Table 5.2-34. There was no significant difference in the number of any cardiovascular or non-cardiovascular SAEs between patients receiving PCI plus medical therapy compared with medical therapy alone. When clinical events were included (which included revascularisation), the rate of clinical event or any SAE, and clinical event or cardiovascular SAE were statistically significantly higher in the medical therapy only group compared with the PCI plus medical therapy group.

Table 5.2-34 Adverse events in the included RCTs: high risk based on diagnostic testing – PCI vs. medical therapy

Outcome Population (test)Time point

PCI + MTn (%)

MTn (%)



Clinical event or SAE 2 years 151 (33.8) 232 (52.6) HR 0.55 (0.44, 0.67); <0.001

Clinical event or CV SAE 2 years 110 (24.6) 204 (46.3) HR 0.45 (0.36, 0.57); <0.001

Clinical event or non-CV SAE 2 years NR (17.2) NR (17.2) HR 1.00 (0.73, 1.38); 0.98

Any SAE 2 years 120 (26.8) 112 (25.4) NR; 0.62

CV SAE 2 years 76 (17.0) 61 (13.8) NR; 0.19

Non-CV SAE 2 years 72 (16.1) 71 (16.1) NR; 1.00


January 2016

Source: FAME 2 (De Bruyne et al, 2014): Text, p 1214 and Supplementary appendix Table S5, p 22.Note: Statistically significant results shown in bold. Abbreviations: CAD, coronary artery disease; CI, confidence interval; CV, cardiovascular; FFR, fractional flow reserve; HR, hazard ratio; MT, medical therapy; NR, not reported; PCI, percutaneous coronary intervention; RCT, randomised controlled trial; SAE, serious adverse event.

In summary, there was no interaction between treatment and either diabetes or multivessel subgroups. The rate of SAEs was similar between PCI and CABG.

PCI versus CABG

Level I evidenceNo systematic reviews were identified that compared the use of PCI with CABG in patients considered to be at high risk of coronary events based on diagnostic testing.

Level II evidenceNo RCTs were identified that compared the use of PCI with CABG in patients considered to be at high risk of coronary events based on diagnostic testing.

The FAME 3 study aims to compare FFR-guided PCI (stenting with DES in those with FFR ≤0.80 or deferral in those with FFR >0.80) with CABG in patients with multivessel CAD. This study is currently recruiting and final data collection for the primary outcomes (MACCE) is due in August 2017.


January 2016

6 REVIEW OF THE ECONOMIC EVIDENCE FOR PCI

6.1 Evidence base

Nine published economic analyses were identified that are relevant to the PICO criteria for this Review. Four studies examined the cost-effectiveness of PCI added onto OMT in patients with stable angina or stable CAD (Wijeysundera et al, 2013; Gada et al, 2012; Zhang et al, 2011; Weintraub et al, 2008), while two studies examined the cost-effectiveness of CABG compared with PCI in specific subgroups of patients with stable CAD (Cohen et al, 2014; Magnuson et al, 2013). A routine invasive strategy (which includes angiography and CABG, as well as PCI) was examined in patients with NSTE-ACS in two studies (Dijksman et al, 2009; Henriksson et al, 2008). The cost-effectiveness of PCI in a high-risk population identified by FFR was examined in a study by Fearon et al (2013).

Seven of these analyses based their clinical data on one of the RCTs selected for inclusion in this Review in Section 5.2; these included SYNTAX, FREEDOM, COURAGE, ICTUS, RITA 3 and FAME 2. The remaining two economic analyses based their clinical outcomes on observational data.

The main characteristics of the nine identified economic analyses are summarised in Table 6.1-1. The authors’ conclusions have been included in the table but should be considered in light of the results and shortcomings of the analyses, which are discussed in more detail below. All analyses were conducted from a healthcare perspective with time horizons varying from one year to lifetime. Importantly, none of the published studies were conducted from an Australian healthcare perspective. Furthermore, the published studies are not reflective of the situation in regional and rural areas of Australia, where routine urgent transfer of patients places additional burden on ambulance services as well as tertiary PCI units.


January 2016

Table 6.1-1 Characteristics of included economic analysesStudy ID Country/

perspectivePopulation Comparison Economic analysis Source of health

outcomesSource of utility weights

Authors’ conclusion

Chronic stable angina PCI vs OMT

Trial-based analyses

Zhang 2011 US and Canada

Health care perspective

Stable angina

PCI+OMT vs OMT

(OMT as defined by the COURAGE trial)

ICER expressed as cost per patient with a clinically significant improvement.

Time horizon

3 years

COURAGE trial NA The incremental cost of PCI to provide meaningful clinical benefit above that achieved by OMT alone was lower for patients with severe angina than for those with mild or no angina. However, it is uncertain that at any level of angina severity that PCI as an initial strategy would achieve a socially acceptable cost threshold.

Weintraub 2008

US and Canada

Healthcare system perspective

Stable CAD (optimally treated)

PCI (BMS)+OMT vs OMT

(OMT as defined by the COURAGE trial)

ICER expressed as cost per life-year gained and cost per QALY.

Costs after the first year and life expectancy were discounted at 3% per year.

Time horizon

In-trial and lifetime

COURAGE trial Assessed in-trial using the SAQ and standard gamble.

The COURAGE trial did not find the addition of PCI to optimal medical therapy to be a cost-effective initial management strategy for symptomatic, chronic coronary artery disease.


January 2016

Study ID Country/ perspective

Population Comparison Economic analysis Source of health outcomes

Source of utility weights


Modelled-analyses

Wijeysundera 2013

Canada

Ontario Ministry of Health and Long Term Care (payer perspective)

Stable CAD PCI (DES or BMS)+OMT vs OMT

(as defined by the COURAGE trial)

Markov cohort simulation model.

ICER expressed as cost per QALY.

All outcomes were discounted at 5% per year.

Time horizon

Lifetime

Ontario CCN PCI registry

Published literature.

In patients with stable CAD, an initial BMS strategy is cost-effective.

Gada 2012 US

Provider perspective

Chronic stable angina

CTO-PCI vs OMT

(OMT was not defined by the study)

Markov model with Monte Carlo simulations.


All future costs and outcomes were discounted at 5% per year.

Time horizon

5 years

Observational studies

Published literature (observational studies) and study group clinical experience.

On the basis of the supporting evidence, this decision-analytic model suggests that CTO-PCI is cost-effective in a patient population with severe symptoms.

Chronic stable angina PCI vs CABG


January 2016






Cohen 2014 US

Health care system perspective

Patients with 3-vessel or left main CAD

PCI (DES) vs CABG

Patient-level microsimulation model. ICER expressed as cost per life-years

gained and cost per QALY. Costs, life-years, and QALYs were

discounted at 3% per year.Time horizon

Lifetime

SYNTAX trial Assessed in-trial using EQ-5D.

For most patients with three-vessel or left main coronary artery disease, CABG is a clinically and economically attractive revascularisation strategy compared with DES-PCI. However, among patients with less complex disease, DES-PCI may be preferred on both clinical and economic grounds.

Magnuson 2013

US

Health care system perspective

Diabetes mellitus and multivessel CAD

PCI (with DES) vs CABG

Markov disease-simulation model. ICER expressed as cost per life-years

gained and cost per QALY. All projected life-years, QALYs, and costs

were discounted 3% annually based on time from randomisation.

Time horizon

Lifetime

FREEDOM trial Assessed in-trial using EQ-5D.

Despite higher initial costs, CABG is a highly cost-effective revascularisation strategy compared with DES-PCI for patients with diabetes mellitus and multivessel coronary artery disease.

Diagnosis of NSTE-ACS Routine vs selective


January 2016






Dijksman 2009 Netherlands

Provider perspective

NSTE-ACS with elevated cardiac troponin T

Routine invasive vs selective invasive strategy

ICER expressed as cost per prevented cardiac event.

Time horizon

1 year

ICTUS trial NA The overall results of the ICTUS study showed that an early invasive strategy was not superior to a selectively invasive strategy for patients with NSTE-ACS and an elevated cardiac troponin T. This economic analysis of the ICTUS study showed that an early invasive strategy was slightly more expensive during the first year without gain in prevented cardiac events. In fact, we demonstrated a very moderate probability of the early invasive strategy being cost-efficient, even at a high level of willingness to pay.

Diagnosis of NSTE-ACS Routine vs selective



January 2016





Henriksson 2008

UK

Health-service perspective

NSTE-ACS (UA)

Early invasive strategy vs conservative invasive strategy

Decision-analytic model comprising two stages: (i) a short-term decision tree representing the index hospitalisation period; and (ii) a long-term Markov structure characterising the post-index period.


Costs and QALYs were discounted by 3.5% per year.

Time horizon

Lifetime

RITA 3 trial Assessed in-trial using the EQ-5D, based on preferences of the UK general population.

An early interventional strategy in patients presenting with NSTE-ACS is likely to be considered cost-effective for patients at high and intermediate risk, but this is less likely to be the case for patients at low risk.

High risk based on diagnostic testing PCI vs OMT


Fearon 2013 US and Europe

Societal perspective, using direct costs

Stable CAD and abnormal FFR (≤0.80)

PCI (with 2nd generation DES)+OMT vs OMT

(OMT as defined by the FAME trial)


No discount costs were applied because of the limited follow-up period.

Time horizon

1 year

FAME 2 trial Assessed in-trial using the EQ-5D with US weights at baseline, 1 month, and 12 months.

PCI of coronary lesions with reduced FFR improves outcomes and appears economically attractive compared with best medical therapy among patients with stable angina.

Abbreviations: BMS, bare metal stent; CABG, coronary artery bypass graft; CAD, coronary artery disease; CCN, Cardiac Care Network; CTO, chronic total occlusion; DES, drug-eluting stent; EQ-5D, EuroQoL-5 dimensions; FFR, fractional flow reserve; ICER, incremental cost-effectiveness ratio; NA, not applicable; NSTE-ACS, non-ST-segment elevation acute coronary syndrome; OMT, optimal medical therapy; PCI, percutaneous coronary intervention; QALY, quality-adjusted life-year; SAQ, Seattle Angina Questionnaire; UA, unstable angina; UK, United Kingdom; US, United States.


January 2016

6.2 Chronic stable angina

As noted in Section 5.1, in order to contain the scope of the review, the literature search string was confined to search terms describing the three specific populations of interest, including chronic stable angina. The search string did not include terms to identify the broader population with stable CAD. As such, while economic analyses assessing PCI in populations with stable CAD were identified via the RCTs included in Section 5, additional searches were not conducted to identify all recent economic analyses in a CAD population. Thus, the studies described below do not represent the entirety of economic evidence for the stable CAD population.

6.2.1 PCI versus OMT

Four studies were identified that assessed the cost-effectiveness of PCI compared with OMT. Two of these studies (Zhang et al, 2011; Weintraub et al, 2008) were trial-based analyses based on data from the COURAGE RCT, which was conducted in patients with stable CAD. The remaining two analyses were modelled and have a higher risk of bias: Gada et al (2012) was based on a systematic review of observational studies in patients with chronic stable angina; Wijeysundera et al (2013) was based on propensity-matched observational data from patients with stable CAD.


Zhang 2011Zhang et al (2011) evaluated the cost-effectiveness of PCI as a function of patients’ angina severity at baseline on the Seattle Angina Questionnaire (SAQ), based on the COURAGE trial. The COURAGE trial included 2,287 patients who were randomised to OMT with or without PCI in one of 50 US and Canadian centres between 1999 and 2004. Over a median follow-up of 4.6 years, there was no difference between the two groups for the primary endpoint of death/MI.

Patients were divided into tertiles based on their SAQ scores for three domains of angina-related health status—physical limitation, angina frequency, and quality of life—with higher tertiles representing better health status, and event rates correlated with the severity of angina for all three domains. The ICER for PCI was calculated for one additional patient to have clinically significant improvement in the three domains. Clinically significant intra-individual change in the physical limitation, angina frequency, and quality-of-life domains were defined as increases in scores of ≥8, ≥20, and ≥16, respectively. Clinically significant change was defined as the smallest difference in a score in a domain of interest that patients perceive as beneficial and that would warrant a change in the patient’s management.

Adding PCI to OMT produced clinically significant improvements in physical limitation, angina frequency and quality of life for more patients in the lowest (most severe angina) and middle tertiles for each domain at six months, while among patients with the least severe angina (highest tertile), PCI did not show an advantage over optimal medical therapy alone for any domain (as shown in Table 6.2-1).

Regardless of baseline angina severity, costs to improve any of the three angina-related domains were higher for the PCI group over the course of the trial, due primarily to an initial procedural cost of about US$10,000. From six months to three years, the cost difference between the treatment groups remained stable within each tertile, ranging from US$9,770 to US$13,100.


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The cost per patient significantly improved using PCI over OMT and was lower among those in the lowest tertile (most severe angina) compared with the highest tertile (least severe angina) for all health domains; however, all ICERs were high, ranging from US$79,000 to >US$3 million (as presented in Table 6.2-1).

Table 6.2-1 Results of the included economic analyses: chronic stable angina – PCI vs. medical therapy (Zhang 2011)

OutcomeTertile (angina severity)

Incremental costPCI vs. OMT

US$

Incremental benefit

% patients significantly

improved

ICERUS$/patient significantly

improved

PCI dominateda

%

PCI dominanta

%

WTP <US$50,000/

patientsignificantly improveda

%

Physical limitation

Lowest $9,392 11.82 $79,448 0.2 0 19.96

Middle $8,691 8.73 $99,614 2.5 0 8.8

Highest $10,419 1.98 $526,560 27.3 0 0

Angina frequency

Lowest $13,070 4.05 $322,966 12.7 0 0

Middle $8,468 8.15 $103,878 1.8 0 6.9

Highest $8,272 0 NA NA NA NA

QoL

Lowest $11,577 10.16 $113,962 0.1 0 2.0

Middle $10,036 9.69 $103,634 1.1 0 3.96

Highest $7,321 0.2 $3,704,391 48.9 0 0.5Source: Zhang et al (2011), Table 3, p176Abbreviations: ICER, incremental cost-effectiveness ratio; NA, not available; OMT, optimal medical therapy; PCI, percutaneous coronary intervention; QoL, quality of life; US$, US dollar; WTP, willingness to pay.Note: Patients were grouped into tertiles based on the distribution of baseline scores such that higher tertiles represented better health status. Clinically significant improvement from baseline within individual patients was defined as score increases of >8 for physical limitation, >20 for angina frequency, and >16 for quality-of-life domains.a To estimate the variability in cost and relief from angina, a bootstrap method was used (with 5000 replicates). The percentage dominated represents the percentage of replicates that showed PCI added to OMT to be more expensive and less effective than OMT alone; the percentage dominant represents the percentage of replicates that showed PCI added to OMT to be less expensive and more effective than OMT along. The WTP <US$50,000 represents the percentage of replicates considered to be cost-effective if the cost-effectiveness threshold was set at US$50,000 per patient significantly improved.

The authors note that potential limitations of their study are missing data in the COURAGE study (although they state that analyses to account for missing data did not identify meaningful bias), crossovers from the OMT only arm to the PCI arm, and the fact that few DES were used in the trial. The authors concluded that ‘it is uncertain that at any level of angina severity that PCI as an initial strategy would achieve a socially acceptable cost threshold’.

Weintraub 2008Weintraub et al (2008) conducted an assessment of the relative costs and cost-effectiveness of PCI and OMT based on data from the COURAGE trial. The trial included 2,287 patients who were treated in one of 50 US and Canadian centres between 1999 and 2004. At randomisation to PCI (n=1,149) and OMT (n=1,138), 88% of the study population had angina and 69% had multivessel coronary artery disease. From a clinical perspective, the COURAGE trial found no difference in the primary end point of death or MI (based on follow-up data at median 4.6 years), although PCI improved quality of life in the short term.


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For the cost-utility analysis, Weintraub et al (2008) included direct medical costs for hospitalisations, pharmaceuticals, outpatient care, and follow-up tests (in 2004 US dollars). Costs after the first year and life expectancy were discounted at 3% annually. The average initial cost was US$12,162 in the PCI group and US$752 in the OMT group, while subsequent in-trial costs averaged US$22,681 in the PCI group and US$23,966 for OMT.

Quality of life was assessed in the COURAGE trial using the quality of life scale from the SAQ and utility weights were derived using standard gamble assessments. The Framingham study database was used to project survival based on age, sex, and cardiovascular events.

The incremental life-year and quality-adjusted life-year (QALY)95 gains with PCI were used to calculate the ICERs presented in Table 6.2-2, which were all in excess of US$150,000. Based on the entire distribution of cost and effectiveness differences, OMT frequently dominated PCI (i.e. was shown to be less costly and more effective than PCI), whereas PCI did not dominate OMT during the in-trial period. Additionally, using a willingness-to-pay (WTP) threshold of US$50,000 per LYG or QALY, PCI was not shown to be cost-effective.

A sensitivity analysis was conducted based on the assumption that DES are now commonly used in clinical practice and are associated with different costs and outcomes compared with BMS (used in the COURAGE trial). The analysis assumed that PCI using DES would cost an additional US$600 plus the cost of clopidogrel therapy for one year after PCI. In addition, the cost of repeat revascularisation performed within 12 months after the first PCI were excluded from the sensitivity analysis. It is unclear whether these assumptions are appropriate; for example, the use of clopidogrel may extend well beyond one year and the additional cost of DES in Australia is in excess of US$60096. Nonetheless, the resulting in-trial ICERs for PCI compared with OMT were US$176,430 and US$197,465 per life-year and QALY gained, respectively, while lifetime ICERs were US$263,660 and US$164,590.

Table 6.2-2 Results of the included economic analyses: chronic stable angina – PCI vs. medical therapy (Weintraub 2008)

Time horizonOutcome

Incremental cost

PCI vs. OMTUS$

Incremental outcome

PCI vs. OMT

ICERUS$/outcome

PCI dominateda

(%)

PCI dominanta

(%)

WTP <US$50,000/

outcomea

(%)

In-trial - - - - - -LYG $10,125 0.0338 $299,518/LYG 26.5 0 0

QALY $10,125 0.0491 $206,229/QALY 19.0 0 0

Lifetime - - - - - -

LYG $9,451 0.036 $262,116/LYG 34.2 0 3.29

QALY $9,451 0.056 $168,019/QALY 27.7 0 10.12Source: Weintraub et al (2008), Table 6, p16.Note: 3% discount applied.Abbreviations: ICER, incremental cost-effectiveness ratio; LYG, life-years gained; OMT, optimal medical therapy; PCI, percutaneous coronary intervention; QALY, quality-adjusted life-year; US$, US dollar; WTP, willingness to pay.a To estimate the variability in cost and outcomes (LYG and QALY), a bootstrap method using 5000 replicates was used. The percentage dominated represents the percentage of replicates that showed PCI added to OMT to be more expensive and less effective than OMT alone; the percentage dominant represents the percentage of replicates that showed PCI added to OMT to be less expensive and more effective than OMT alone. The WTP <US$50,000 represents the percentage of replicates considered to be cost-effective if the cost-effectiveness threshold was set at US$50,000 per LYG or QALY.

95 Quality-adjusted life-year is a measure of disease burden that captures both the quantity and quality of life. For example, 1 QALY could represent 1 year of life with perfect health (i.e. where the health utility = 1) or 2 years of life where the health utility = 0.5. 96 According to the August 2015 Prostheses List, the cost of DES is nearly 180% higher than the cost of BMS ($3,450 vs. $1,248).


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A number of limitations of the analysis are noted by the authors. These include: (i) that diagnosis-related group-based costing may not adequately account for resource utilisation; (ii) resource use, life expectancy and cost beyond the trial period is modelled; (iii) utility was measured in only a minority of patients in the trial; and (iv) results may not be generalisable across different healthcare systems.

Weintraub et al (2008) concluded that, based on clinical data from the COURAGE trial, the addition of PCI to OMT is not a cost-effective initial management strategy for symptomatic, chronic CAD.

Modelled-analyses

Wijeysundera 2013Wijeysundera et al (2013) evaluated the incremental cost-effectiveness of PCI using either BMS or DES compared with medical therapy alone for patients with stable CAD, using a Markov cohort simulation model developed using data from the Ontario Cardiac Care Network PCI Registry. Effectiveness and utility data were obtained from the published literature, with costs from the Ontario Case Costing Initiative. The analysis was based on a base-case with 64% of patients having severe CCS III–IV symptoms, 24% of medical therapy patients undergoing PCI for inadequately controlled symptoms, and a subsequent procedure for restenosis in 15.8% of patients who underwent initial PCI with a BMS and 12.1% of patients who underwent initial PCI with a DES.

The results of the base-case analysis are presented in Table 6.2-3. BMS was cost-effective compared with medical therapy for the overall cohort and all subgroups examined (based on diabetes/lesion characteristics), while DES was dominated by BMS (which was deemed less costly and more effective) for a number of scenarios. In sensitivity analyses, when analysed with varying time horizons (up to 15 years), medical therapy remained the least expensive strategy but had the lowest QALYs, while the two stenting options were both deemed cost-effective (being more costly than OMT, but with higher QALYs). The model was critically sensitive to the relative mortality estimates for both medical therapy and DES in comparison to BMS, and not sensitive to the frequency of revascularisation. At a WTP threshold of <CA$50,000/QALY, BMS was the preferred strategy in 40% of simulations; at the same threshold, stenting (with either BMS or DES) was the preferred strategy in 70% of simulations.

Table 6.2-3 Results of the included economic analyses: chronic stable angina – PCI vs. medical therapy (Wijeysundera 2013)

Strategy Incremental costPCI vs. OMT

CA$

Incremental QALYPCI vs. OMT

ICERCA$/QALY

Overall cohortMedical therapy $22,952 10.10 -

BMS $25,081 10.26 $13,271

DES $25,536 10.20 Dominateda

Nondiabetic short lesion (<20mm) and large artery (≥3mm)Medical therapy $22,482 10.11 -

BMS $23,541 10.29 $5,814


Nondiabetic long lesion (≥20 mm) and small artery (<3 mm)Medical therapy $23,014 10.10 -


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Strategy Incremental costPCI vs. OMT

CA$


ICERCA$/QALY

BMS $25,367 10.27 $14,414


Diabetic short lesion (<20 mm) and large artery (≥ 3 mm)Medical therapy $25,266 10.07 -

BMS $28,029 10.21 $19,414


Diabetic short lesion (<20 mm) and small artery (< 3 mm)Medical therapy $24,604 10.08 -

BMS $26,827 10.19 $19,311

DES $27,240 10.22 $14,345

Diabetic long lesion (≥20 mm) and large artery (≥3 mm)Medical therapy $22,536 10.11 -

BMS $23,566 10.23 $8,949

DES $23,596 10.29 $463

Diabetic long lesion (≥20 mm) and small artery (<3 mm)Medical therapy $23,128 10.10 -

BMS $25,135 10.21 $18,286

DES $26,727 10.24 $61,985Source: Wijeysundera et al (2013), Table 6, p901.Abbreviations: BMS, bare metal stent; CA$, Canadian dollars; DES, drug-eluting stent; ICER, incremental cost-effectiveness ratio; OMT, optimal medical therapy; PCI, percutaneous coronary intervention; QALY, quality-adjusted life-year.a DES is dominated by BMS; that is, BMS is less costly and more effective (in terms of QALYs) than DES.

The authors note that there is the possibility of residual confounding in their analysis, as important prognostic factors (such as left ventricular function) could not be adjusted for. They also note that the estimates regarding DES are based on first-generation stents, and so may not be applicable to current clinical practice. Finally, their probabilistic sensitivity analysis did not consider correlations between parameters.

The authors concluded that in patients with stable CAD, ‘an initial strategy of PCI with a BMS is cost-effective’. However, this conclusion should be viewed with caution as it is based on a modelled analysis in which outcomes data is derived from observational data and the published literature. This finding was consistent across the spectrum of clinically relevant subgroups, as defined by diabetic status and lesion characteristics. DES was cost-effective only in the highest risk group, those with diabetes with long lesions and small arteries.

Gada 2012Gada et al (2012) evaluated the cost-effectiveness of chronic total occlusion (CTO)-PCI versus OMT in patients with chronic stable angina. There are currently no RCTs comparing CTO-PCI with OMT and the modelled analysis was therefore based on a review of observational studies.

Gada et al (2012) calculated the relative cost benefits of CTO intervention over a five-year period in patients with CCS Class III-IV angina using a Markov model that examined a hypothetical cohort of 10,000 patients.


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The reference case was defined as mean age 60 years, rate of successful CTO-PCI of 67.9%, and mean transition probabilities, utilities, and costs as defined by the literature and clinical experience. In the reference case with a five-year model duration, CTO-PCI incurred higher costs than OMT (US$31,512 vs US$27,805), but also accumulated more QALYs (2.38 vs 1.99). Overall, CTO-PCI appeared to be cost-effective, with an ICER of US$9,505/QALY, as shown in Table 6.2-4.

With the addition of further variables, including the costs of a repeat CTO-PCI that increased the overall procedure success rate to 80%, the ICER rose to US$14,047/QALY. CTO-PCI was more cost-effective with a longer model duration and achieved the threshold of US$50,000/QALY with a model duration of two years or greater. The most influential drivers of model outcome were the utility of OMT, utility post-successful CTO-PCI, and utility post-unsuccessful CTO-PCI. Procedural success held limited influence over model outcome at particular utility threshold values.

Table 6.2-4 Results of the included economic analyses: chronic stable angina – PCI vs. medical therapy (Gada 2012)

Analysis Incremental costPCI vs. OMT

US$


ICERUS$/QALY

WTP <US$50,000/QALYa

(%)

Base-case – 5 years $3707 0.39 $9,505 60%Source: Gada et al (2012): Text, p 1792-1793. Note: 3% discount applied.Abbreviations: ICER, incremental cost-effectiveness ratio; LYG, life-year gained; OMT, optimal medical therapy; PCI, percutaneous coronary intervention; QALY, quality-adjusted life-year; US$, US dollars; WTP, willingness to pay.a To estimate the variability in cost and outcomes (QALY), a bootstrap method with 10,000 simulations was used. The WTP <US$50,000 represents the percentage of simulations considered to be cost-effective if the cost-effectiveness threshold was set at US$50,000 per QALY.

The authors note that the base-case of their analysis did not take into account that current practice may include second attempts at revascularisation, and that these may be more costly. They attempted to capture this in a sensitivity analysis in which the success rate was increased from 67% to 80%, and the cost increased by 150%. This resulted in an ICER of US$14,047/QALY. They also note issues around the applicability of the study population (which was based on 16 observational studies) to the clinical setting, the lack of detail about the reasons for patients undergoing PCI, and the use of BMS in the studies.

The authors concluded that ‘CTO-PCI is cost-effective in a patient population with severe symptoms. Quality-of-life metrics should be employed in future appropriateness criteria developed for CTO-PCI’.

6.2.2 PCI versus CABG

Two studies were identified that assessed the cost-effectiveness of CABG versus PCI in subgroups of patients with stable CAD (Cohen et al, 2014; Magnuson et al, 2013). Both analyses were based on RCTs: the SYNTAX trial (used by Cohen et al, 2014) enrolled patients with left main or three-vessel CAD, while the FREEDOM trial (used by Magnuson et al, 2013) enrolled patients with diabetes and multivessel CAD.


Cohen 2014Cohen et al (2014) evaluated the cost-effectiveness of DES-PCI versus CABG based on data from the SYNTAX trial. The SYNTAX trial demonstrated that in patients with three-vessel or


January 2016

left main CAD, CABG was associated with a lower rate of the composite outcome comprising cardiovascular death, MI, stroke or repeat revascularisation compared with DES-PCI. Costs were assessed from a US health care system perspective, and health state utilities were evaluated with the EQ-5D. A patient-level microsimulation model based on the five-year in-trial data was used to extrapolate costs, life expectancy, and QALY expectancy over a lifetime horizon.

The results of the cost-effectiveness analysis are summarised in Table 6.2-5 and show that CABG is cost-effective compared with PCI in the base-case analysis, as well as sensitivity analyses based on removing discounting and including the prognostic effect of MI (which is higher for PCI compared with CABG) and stroke (which is higher for CABG compared with PCI). The base-case analysis was based on the assumption that the effect of CABG would taper between 5 and 10 years; additional analyses were conducted in which (i) the effect of CABG was fixed between 5 and 10 years, and (ii) there was no effect of CABG between 5 and 10 years. Both additional analyses (and their associated sensitivity analyses) showed CABG to be cost-effective compared with PCI, with the highest ICER being US$27,485/QALY. In addition, cost/QALYs across various subgroups also showed CABG to be cost-effective compared with PCI, except for two cases where PCI was shown to be dominant. These were (i) in patients with left main disease, and (ii) in patients with a SYNTAX score ≤22.

Table 6.2-5 Results of the included economic analyses: chronic stable angina – PCI vs. CABG (Cohen 2014)

Analysis Incremental costCABG vs. PCIUS$ (95% CI)

Incremental outcome

CABG vs. PCI

ICERUS$/outcome

CABG dominanta

%

CABG dominateda

%

WTP <US$50,000/

outcomea

%Tapered CABG effect between 5 and 10 yBase-case lifetime (QALY)

$5,081($1802, $8241)

0.307(-0.105, 0.678)

$16,537/QALY 0.1 5.8 84.7

Base-case lifetime (LYG)

$5,081($1802, $8241)

0.412(-0.060, 0.831)

$12,329/LYG 0.1 3.7 91.9

Undiscounted (QALY) $4,984($852, $8802)

0.492(-0.093, 1.027)

$10,139/QALY 0.5 4.0 92.0

Prognostic effect MI/stroke (QALY)

$5,331($2264, $8368)

0.338(-0.077, 0.705)

$15,758/QALY 0.0 4.5 87.7

Fixed CABG effect between 5 and 10 yLifetime (QALY) $4,180

($672, $7483)0.391

(-0.140, 0.853)

$10,695/QALY 0.9 5.3 89.1

Lifetime (LYG) $4,180($672, $7483)

0.512(-0.093, 1.026)

$8,171/LYG 0.9 3.5 93.3

Undiscounted (QALY) $3,941($-614, $7922)

0.623(-0.114, 1.295)

$6,327/QALY 3.0 3.0 91.7


$4,448($1066, $7642)

0.423(-0.097, 0.874)

$10,523/QALY 0.5 4.2 91.3

No effect of CABG beyond 5 yLifetime (QALY) $6,082

($3046, $9064)0.221

(-0.091, 0.511)

$27,485/QALY 0.0 6.7 74.8

Lifetime (LYG) $6,082($3046, $9064)

0.310(-0.047, 0.633)

$19,639/LYG 0.0 3.4 87.4


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Incremental outcome

CABG vs. PCI

ICERUS$/outcome

CABG dominanta

%

CABG dominateda

%

WTP <US$50,000/

outcomea

%Undiscounted (QALY) $6,094

($2372, $9793)0.362

(-0.067, 0.780)

$16,848/QALY 0.1 4.9 87.6


$6,311($3535, $9163)

0.251(-0.052, 0.539)

$25,149/QALY 0.0 4.6 79.6

Source: Cohen et al (2014), Table 6, p1152.Note: 3% discount applied.Abbreviations: CABG, coronary artery bypass graft; ICER, incremental cost-effectiveness ratio; LYG, life-year gained; MI, myocardial infarction; PCI, percutaneous coronary intervention; QALY, quality-adjusted life-year; US$, US dollars; WTP, willingness to pay.a To estimate the variability in cost and outcomes (LYG and QALY), a bootstrap method with 1000 replicates was used. The percentage dominated represents the percentage of replicates that showed CABG to be more expensive and less effective than PCI; the percentage dominant represents the percentage of replicates that showed CABG to be less expensive and more effective than PCI. The WTP <US$50,000 represents the percentage of replicates considered to be cost-effective if the cost-effectiveness threshold was set at US$50,000 per LYG or QALY.

Limitations of the study noted by the author include: (i) the fact that the analysis is from a US healthcare perspective while the SYNTAX trial was conducted in 18 countries; (ii) the lifetime extrapolation required a number of assumptions about the impact of CABG on long-term survival, healthcare costs and quality of life; and (iii) that all patients in the SYNTAX trial received the first-generation DES paclitaxel; second-generation DES result in lower rates of MI, revascularisation and stent thrombosis.

The authors concluded that, ‘for most patients with three-vessel or left main CAD, CABG is a clinically and economically attractive revascularisation strategy compared with DES-PCI. However, among patients with less complex disease, DES-PCI may be preferred on both clinical and economic grounds’.

Magnuson 2013Magnuson et al (2013) evaluated the cost-effectiveness of PCI with DES versus CABG in patients with diabetes mellitus and multivessel CAD. The analysis was done alongside the FREEDOM trial. Health state utilities were assessed using the EQ-5D. A patient-level microsimulation model, based on US life-tables and in-trial results, was used to estimate lifetime cost-effectiveness.

The results of the analysis are presented in Table 6.2-6. CABG was shown to be cost-effective compared with PCI in patients with diabetes and multivessel disease in the base-case lifetime analysis in which the CABG effect was tapered between 5 and 10 years, and sensitivity analyses based on the per-protocol population and over a 10 year time frame. When the CABG effect was fixed between 5 and 10 years, the ICER was similar to the base-case analysis, while the ICER increased to US$18,167/QALY when it was assumed there was no CABG effect on long-term costs. Assuming no effect of CABG after five years increased the lifetime ICER to US$27,022 and the 10 year ICER to US$79,779.

In addition, cost/QALYs across various subgroups also showed CABG to be cost-effective compared with PCI (the highest ICER was US$21,582/QALY in patients with a SYNTAX score <23), and dominant in two subgroups: those aged 60-69 years and those with a glycosylated haemoglobin <7% .


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Table 6.2-6 Results of the included economic analyses: chronic stable angina – PCI vs. CABG (Magnuson 2013)


Incremental outcome

CABG vs. PCI

ICERUS$/outcome

CABG dominanta

%

CABG dominateda

%

WTP < US$50,000/ outcomea

%Base-case lifetime (QALY)

$5392($399, $10,320)

0.663(0.177, 1.132)

$8,132/QALY 1.5 0.4 99.02

Base-case lifetime (LYG)

$5392($399, $10,320)

0.794 $6,791/LYG 1.5 0.2 99.7

Per-protocol population (QALY)

$5,976($1207, $10,925)

0.708(0.202, 1.221)

$8440/QALY 0.7 0.2 99.3

10 y time frame (QALY)

$1416($-2061, %5017)

0.230(-0.008, 0.457)

$6,156/QALY 22.8 1.7 95.8

Source: Magnuson et al (2013), Table 7, p 827.Note: Assumes the effect of CABG tapers between 5 and 10 years; 3% discount applied.Abbreviations: CABG, coronary artery bypass graft; ICER, incremental cost-effectiveness ratio; LYG, life-year gained; PCI, percutaneous coronary intervention; QALY, quality-adjusted life-year; US$, US dollar; WTP, willingness to pay.a To estimate the variability in cost and outcomes (LYG and QALY), a bootstrap method was used (number of replicates not stated). The percentage dominated represents the percentage of replicates that showed CABG to be more expensive and less effective than PCI; the percentage dominant represents the percentage of replicates that showed CABG to be less expensive and more effective than PCI. The WTP <US$50,000 represents the percentage of replicates considered to be cost-effective in favour of CABG over PCI if the cost-effectiveness threshold was set at US$50,000 per LYG or QALY.

Like the study by Cohen et al (2014), Magnusson et al (2013) note that while the analysis is performed from the perspective of the US healthcare system, data from the trial that provides the basis for the analysis (FREEDOM) was performed in 18 countries. In addition, the authors note that five-year trial data needed to be extrapolated to a lifetime horizon, which required a number of assumptions, and the trial was based on first-generation DES, which may limit applicability to current clinical practice.

Based on these results, the authors concluded that ‘despite higher initial costs, CABG is a highly cost-effective revascularisation strategy compared with DES-PCI for patients with diabetes mellitus and multivessel CAD’.

6.3 Diagnosis of NSTE-ACS

Two studies were identified that assessed the cost-effectiveness of a routine invasive strategy versus a selective invasive strategy, using trial-based analyses. The study by Dijksman et al (2009) was a cost-effectiveness analysis based on data from the ICTUS trial while the study by Henrikson et al (2008) was a cost-utility analysis based on data from the RITA 3 trial.

6.3.1 Trial-based analyses

Dijksman 2009Dijksman et al (2009) evaluated the cost-effectiveness of an early invasive strategy compared with a selectively invasive strategy in high-risk patients with NSTE-ACS and an elevated cardiac troponin T. The analysis was based on the ICTUS trial that failed to show superiority of an early invasive strategy over a selectively invasive strategy for patients with NSTE-ACS. The study showed no reduction in the composite endpoint (death/MI/rehospitalisation for angina) with an early invasive strategy. Volume and costs data for one year after randomisation were averaged per patient.


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Total costs per patient were €1,379 more expensive in the early invasive group (€13,364) than in the selectively invasive group (€11,985) (as presented in Table 6.3-1). Costs of revascularisation were the main determinant of the cost difference between the two groups (€1,925). The ICER for early invasive treatment versus selectively invasive treatment was €89,477 per prevented cardiac event.

Table 6.3-1 Results of the included economic analyses: diagnosis of NSTE-ACS – routine vs. selective invasive strategy (Dijksman 2009)

Analysis Incremental cost

Early vs. selective

€ (95% CI)

Incremental outcome

Early vs. selective%

ICERCost per

prevented cardiac event

€

Dominateda

%WTP

<€50,000/prevented cardiac eventa

%

Base-case €1,379(€416, €2,356)

1.5 €89,477 75 6

Sensitivity analysesWorst-case scenario (decreased unit costs by 50% and increased hospitalisation costs by 50%)

NR 1.5 NR NR 18

FRISC II trial unit costs NR 1.5 NR NR 4.4

USA cost level NR 1.5 NR NR 4

Reduce CABG ICU days from 3 to 1

NR 1.5 €82,470 NR NR

Source: Dijksman et al (2009), Table 1, p 205, Table 3, p 207 and text p 209.Abbreviations: €, Euros; CABG, coronary artery bypass graft; ICER, incremental cost-effectiveness ratio; ICU, intensive care unit; NR, not reported; PCI, percutaneous coronary intervention; WTP, willingness to pay.a To estimate the variability in cost and outcome (prevented cardiac event), a bootstrap method was used (25,000 replicates). The percentage dominated represents the percentage of replicates that showed an early invasive strategy to be more expensive and less effective than a selective invasive. The WTP <€50,000 represents the percentage of replicates considered to be cost-effective in favour of an early invasive strategy over a selective invasive strategy if the cost-effectiveness threshold was set at €50,000/prevented cardiac event.

The authors note that there may be limited applicability to other health systems given the perspective of the analysis is the Netherlands healthcare system, and that outpatient visits were not captured in the analysis.

The authors concluded that, ‘an early invasive strategy was slightly more expensive during the first year without gain in prevented cardiac events’ and that the study ‘demonstrated a very moderate probability of the early invasive strategy being cost-efficient’, with only 6% of simulations being considered cost-effective at a WTP of €50,000/prevented cardiac event.

Henriksson (2008)The aim of the study by Henriksson et al (2008) was to assess the cost-effectiveness of an early interventional strategy compared with a selective interventional strategy in patients with NSTE-ACS. The analysis was based on data from the RITA 3 study, which was a RCT conducted in 1,810 patients from 45 hospitals in Scotland and England that found a significant reduction in the composite endpoint of death/MI/refractory angina for interventional versus conservative treatment, but no difference in deaths or MI individually.

Henriksson et al (2008) undertook a modelled cost-utility analysis with utilities collected during the trial using the EQ-5D. Costs and QALYs were assigned to the outcomes of the index hospitalisation (no event, MI or death) and for each year that the patient spent in each state in the long-term Markov structure. The analysis took a UK health-service perspective


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and costs were expressed in UK Sterling (GBP) at 2003/2004 prices. Costs and QALYs were discounted by 3.5% per annum.

Since baseline risk is a potentially important predictor of both cardiovascular events and the effectiveness of early intervention, the model investigated cost-effectiveness in patients with different risk profiles at randomisation. In the RITA 3 trial, a multivariate predictive model for death/MI within 5 years was used to calculate a risk score.

The results of the analysis are summarised in Table 6.3-2. The ICER ranged from £53,760/QALY in a low-risk group to approximately £12,000/QALY in the highest risk groups. Based on a threshold of £20,000/QALY, an early interventional strategy is cost-effective for a greater proportion of high-risk patients (>90%) compared with low-risk patients (approximately 1-30%).

Two additional scenarios were investigated in the analysis: (i) using data from a meta-analysis of trials in the same population (Mehta et al, 2005, plus data from ICTUS, FRISC II and RITA 3), and (ii) varying the treatment effect according to baseline RITA 3 risk. The results of the expanded data analysis were similar to those of the base-case analysis, with an ICER of £58,490/QALY in the lowest risk patients (risk group 1) and ICERs of approximately £14,000/QALY in the highest risk groups (risk groups 4a and 4b). When treatment effect was permitted to vary according to risk, an early interventional strategy was dominated by a conservative strategy in the lowest risk group, and ICERs were approximately £11,000/QALY in the highest risk groups.

Table 6.3-2 Results of the included economic analyses: diagnosis of NSTE-ACS – routine vs. selective invasive strategy (Henriksson 2008)

Risk group #

Risk group characteristics Incremental cost

Early vs. conservative

£

Incremental QALY

Early vs. conservative

ICER£/QALY

WTP < £20,000/QALYa

%

WTP <£30,000/QALYa

%

Risk group 1 45 y, no diabetes, no previous MI, non-smoker, HR 72 bpm, no ST depression, angina grade 3 or 4, female, no LBBB

£4,885 0.091 £53,760 0.9 12.3

Risk group 2 52 y, no diabetes, no previous MI, smoker, HR 82 bpm, no ST depression, no angina grade 3 or 4, male, no LBBB

£4,898 0.213 £22,949 32.8 74.9

Risk group 3 52 y, no diabetes, previous MI, non-smoker, HR 82 bpm, ST depression, angina grade 3 or 4, male, no LBBB

£6,045 0.283 £21,325 40.5 80.5

Risk group 4a

61 y, no diabetes, previous MI, smoker, HR 87 bpm, ST depression, no angina grade 3 or 4, male, no LBBB

£6,538 0.547 £11,957 94.5 98.4

Risk group 4b

66 y, diabetes, previous MI, non-smoker, HR 97 bpm, ST depression, no angina grade 3 or 4, male, no LBBB

£6,530 0.512 £12,750 92.4 98.4

Source: Henriksson et al (2008): Table 4, p 721. Abbreviations: £, Pounds Sterling; bpm, beats per minute; HR, heart rate; ICER, incremental cost-effectiveness ratio; LBBB, left bundle branch block; MI, myocardial infarction; QALY, quality-adjusted life-year; WTP, willingness to pay; y, years. a To estimate the variability in cost and outcome (QALY), probabilistic sensitivity analysis was used (number of simulations not reported). The WTP <£20,000 or £30,000 represents the percentage of simulations considered to be cost-effective in favour of an early invasive strategy over a selective invasive strategy if the cost-effectiveness threshold was set at £20,000 or £30,000/QALY.

A potential limitation of this analysis is that cost data was only collected for up to one year in the RITA 3 study; however, the authors claim that their assumptions for long-term extrapolation were conservative.


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Based on these findings, the authors concluded that, ‘an early interventional strategy in patients presenting with NSTE-ACS is likely to be considered cost-effective for patients at high and intermediate risk, but this is less likely to be the case for patients at low risk’.

6.4 High risk based on diagnostic testing

One study was identified that assessed the cost-effectiveness of PCI + OMT with OMT alone in patients considered to be at high risk based on diagnostic testing.

6.4.1 Trial-based analyses

Fearon (2013)Fearon et al (2013) evaluated the cost-effectiveness of PCI in patients with stable CAD using a trial-based economic analysis. The analysis was based on data from the FAME 2 trial that enrolled more than 1,200 patients with stable CAD and angiographically significant stenoses. Patients found to have at least one flow-limiting lesion (FFR ≤0.8) were randomised to either PCI + OMT or OMT alone. The study was halted early after interim data showed that FFR-guided patients had substantially fewer events related to the primary composite endpoint of all-cause death, MI, or urgent revascularisation. However, there was no significant difference between PCI + OMT compared with OMT alone for either death or MI when assessed individually.

The study calculated 12-month costs based on resource use during the index procedure, hospitalisation and follow-up. Extrapolations were necessary to compute 12-month costs because the median follow-up was only seven months. Patient utility was assessed using the EQ-5D. As only 11% of patients provided 12-month EQ-5D scores, baseline and one-month scores were used assuming a linear decline over three years in the one-month utility improvements. There are concerns regarding how the QALYs were calculated in the analysis given (i) they were extrapolated from measurement at one month, and (ii) there was a substantial difference in utility at baseline between PCI + OMT and OMT (–0.027 compared with 0.025 at one month; see Table 6.4-1).

The ICER of PCI + OMT over OMT alone was $36,000/QALY. Sensitivity analyses resulted in largely similar ICERs, with the exception of the analysis including patients with CCS Class 0/1 angina, which resulted in an ICER of $102,000/QALY.


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Table 6.4-1 Results of the included economic analyses: high-risk based on diagnostic testing – PCI + OMT vs. OMT (Fearon 2013)

Analysis Incremental cost

PCI vs. OMTUS$


ICERUS$/QALY

WTP <US$50,000/

QALYa

%

1 year $2,883 ~0.0897 $36,000 80

Sensitivity analysesIncrease stent cost by $400 - - $44,000 -

Decrease stent cost by $400 - - $29,000 -

Cost of pressure wire in OMT group $0 - - $44,000 -

PCI utility benefit dissipated over 2 years - - $54,000 -

PCI utility benefit dissipated over 4 years - - $27,000 -

Cost of non-urgent PCI in OMT group $0 - - $55,000 -

Limit follow-up to 12 months and assume PCI utility of 0.053 in OMT group

- - $60,000 -

CCS Class 0/1 angina - - $102,000 -

CCS Class 2-4 angina - - $26,000 -

Medicare costs for index PCI and no change in baseline OMT group costs

- - $63,000 -

Exclude baseline cost of catheterisation procedure and hospital stay in OMT group

- - $63,000 -

Source: Fearon et al (2013), Table 2, Table 3 and text, p 1337, Figure 2, p 1338.Abbreviations: CCS, Canadian Cardiovascular Society; ICER, incremental cost-effectiveness ratio; OMT, optimal medical therapy; PCI, percutaneous coronary intervention; QALY, quality-adjusted life-year; US$, US dollar; WTP, willingness to pay.a To estimate the variability in cost and outcome (QALY), a bootstrap method was used (with 10,000 replications). The WTP <US$50,000 represents the percentage of replications considered to be cost-effective in favour of PCI + OMT over OMT alone if the cost-effectiveness threshold was set at US$50,000 per QALY.

Limitations of the Fearon et al (2013) analysis include the limited time horizon due to the early stoppage of the trial, which resulted in a number of assumptions being made about the follow-up costs and continuation of benefit of PCI, and the fact that early study termination may have led to an overestimation of the benefit of PCI. In addition, as noted above, there are substantial concerns regarding the calculation of the QALY benefit based on the utility scores collected in the trial.

Based on the findings the authors concluded that in patients with stable angina with FFR ≤0.80, PCI ‘improves outcomes and appears economically attractive compared with best medical therapy’. However, given the only outcome improved in the FAME 2 study was urgent revascularisations, and that there are concerns regarding the calculation of QALYs in the cost-effectiveness analysis, it is questionable whether this conclusion is appropriate.

97 The individual treatment arm QALYs and difference in QALYs are not reported. The QALY value of 0.08 was calculated using the reported cost difference ($2,883) and the reported ICER ($36,000/QALY). QALYs were calculated assuming a linear decline in utility from 1 month to 3 years. The difference in utility at 1 month between PCI + OMT and OMT alone was 0.025, while the difference at baseline was –0.028.


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7 FINDINGS AND CONCLUSIONS

7.1 Current usage of PCI in Australia

The MBS includes seven items (MBS items 38300 to 38318) that describe PCI procedures and were the focus of the secondary data analysis in Section 3.1. MBS item 38306 (angioplasty with the insertion of stent/s, one occluded site) is the most commonly used of those items, accounting for $7,867,506 in benefits paid in the 2013-14 financial year and 23,746 services, which represents 92% of all PCI services. Due to the predominance of this item, many characteristics of overall PCI usage including age, gender, and geographical trends are similar to the individual usage of that item; however, no important differences were observed in any patient, geographic or temporal trends between MBS item 38306 and the other six PCI-related MBS items.

In addition to the analysis of MBS data, hospital separations data for both public and private patients were analysed in Section 3.2 using 11 ACHI procedures codes (38300-00 to 38318-01). Importantly, the four additional ACHI procedures codes (compared with the seven MBS items) provided further information about the number of coronary arteries involved or the number of stents that were inserted during a particular procedure.

Both the number of MBS services undertaken and the number of hospital separations involving PCI have increased gradually over the five-year period from July 2009 to June 2014, with percentage growth over the time of 8.5% and 6.4%, respectively. While MBS expenditure has increased more rapidly (18.3%) this growth is likely to be largely attributable to several increases in MBS fees over that time. Out-of-pocket costs have remained relatively consistent over the same five-year period.

PCI is nearly always undertaken in patients aged 50 years or older, with the number of MBS services as well as hospital separations increasing with age and commonly peaking in one of two age groups: 65 to 69 years; or 70 to 74 years. The predominance of PCI usage in an older population is unsurprising given that the prevalence of CHD and incidence of acute coronary events both increase with age according to the National Health Survey (AIHW, 2011; see 1.1.4). The same Australian survey indicated that CHD and acute coronary events are more common in males, which is consistent with the MBS data that showed that around three-quarters of patients who underwent MBS-funded PCI procedures in 2013-14 were males.

According to MBS data from 2013-14, approximately 96% of PCI procedures were undertaken in-hospital and nearly all services (90%) were requested by cardiology specialists.

Finally, as well as the aforementioned patient characteristics, the NHMD allows for the examination of underlying conditions (i.e. principal diagnoses) that commonly lead to PCI. Based on 2013-14 data, 43% of hospital separations in which PCI was undertaken were linked to acute MI. Patients with a principal diagnosis of atherosclerotic heart disease or angina made up the majority of the remaining hospital separations, accounting for approximately 30% and 20%, respectively.

7.2 Appropriateness of the MBS items for service

The descriptors for three of the seven MBS items 38300, 38303 and 38306 (angioplasty ± stenting) do not provide details of the target population for PCI, or restrict the use of PCI to


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any particular population(s). The only guidance on patient selection that is provided in the item descriptors (and the associated Explanatory Notes) relates to the atherectomy items (38309, 38312, 38315 and 38318), which are suitable for revascularisation of complex and heavily calcified coronary artery stenoses in patients for whom CABG surgery is contraindicated.

This Review focused on specific populations where the value of PCI with stent insertion is uncertain or controversial; i.e. those with chronic stable angina, a diagnosis of NSTE-ACS or assessed as being at high risk based on diagnostic testing. Australian and international clinical guidance regarding revascularisation is summarised below for each of the populations of interest.

The role of PCI in the management of patients with STEMI is well established, and as such, this population was not specifically addressed in the MBS Review. However, a brief overview of clinical guidance relating to PCI use in STEMI patients is included here as it is a legitimate indication for PCI services on the MBS.

Based on the findings from the CPGs, and the unrestricted indications for angioplasty ± stenting items on the MBS, it is possible that PCI may be used in a broader patient population than is supported by recommendations arising from the clinical evidence base. However, there is no evidence available to confirm whether this is the case.

7.2.1 Stable angina

The NICE 2011 guidance for the management of patients with stable angina highlights the importance of optimising medical therapy before considering revascularisation (PCI or CABG). For those patients who remain symptomatic after OMT, the guidelines suggest that a review of the diagnosis, together with a review of anatomical and/or functional tests, is needed before offering revascularisation with CABG or PCI. Therefore, revascularisation is recommended for symptomatic relief in patients with stable angina and in whom medical therapy fails.

According to the ESC/EACTS 2014 guidance, with respect to the selection of stable CAD patients who require revascularisation, emphasis is placed on the documentation of ischaemia. If non-invasive proof of ischaemia is not available in stable patients, identification of haemodynamically relevant coronary lesions with FFR measurement is recommended. For prognostic reasons, revascularisation is recommended for left main stenoses. The guideline also recommends revascularisation for any other stenosis causing ischaemia of 10%98 or more of the left ventricle. In addition, revascularisation is also recommended for all stenoses that cause ischaemia and symptoms that cannot be relieved by medical therapy.

If the decision to revascularise is made, the following recommendations (which are relevant to this Review) are made between the choice of PCI or CABG:

In patients with three-vessel coronary artery disease, the use of PCI is discouraged in the case of complex anatomies.

98 The 10% value is based on consensus only.


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Specific recommendations are also made for specific patient subgroups:

In patients with diabetes, revascularisation is recommended where multivessel CAD or evidence of ischaemia is present. CABG is recommended over PCI in patients with an acceptable surgical risk. New-generation DES are recommended over BMS.

In patients with CKD, CABG should be considered over PCI in patients with multivessel CAD and symptoms/ischaemia whose surgical risk profile is acceptable and life expectancy is beyond one year. PCI should be considered over CABG in patients with multivessel CAD and symptoms/ischaemia whose surgical risk profile is high or life expectancy is less than one year.

Specific recommendations regarding stable angina are made in the ESC 2013 guideline. PCI is recommended in patients with CCS Class I-IV angina despite medical therapy who have single or multivessel disease, and those with CCS Class I angina despite medical therapy with objective evidence of ischaemia. CABG is also recommended in these populations as well as other populations including left main stem disease, objective large ischaemia, two- or three-vessel disease including severe disease of the proximal LAD, and those with multivessel disease (with or without diabetes). Similar recommendations were made in the US and UK guidelines.

These recommendations for the use of PCI are not consistent with the findings of the evidence review in Section 5 of this report, which is based on Level I evidence.

7.2.2 NSTE-ACS

The NHFA/CSANZ guidelines (2006) recommend that patients presenting with symptoms consistent with ACS are evaluated and stratified into high, intermediate or low-risk categories, which then guides the management strategy. For patients designated as low-risk, outpatient follow-up is recommended following discharge from hospital on upgraded medical therapy. It is recommended that intermediate-risk patients with NSTE-ACS should undergo an accelerated diagnostic evaluation and further assessment to allow reclassification as low or high risk. Patients designated high risk are recommended to undergo both aggressive medical management and invasive therapy, except patients with severe comorbidities. High-risk features include:

Repetitive or prolonged (>10 minutes) ongoing chest pain or discomfort Elevated level of at least one cardiac biomarker (troponin or creatine kinase-MB

isoenzyme) Persistent or dynamic electrocardiographic changes of ST-segment depression ≥0.5 mm

or new T-wave inversion ≥2 mm Transient ST-segment elevation (≥0.5 mm) in more than two contiguous leads Haemodynamic compromise – systolic blood pressure <90 mmHg, cool peripheries, diaphoresis, Killip Class >I, and/or new-onset mitral

regurgitation Sustained ventricular tachycardia Syncope Left ventricular systolic dysfunction (left ventricular ejection fraction <0.40) Prior PCI within 6 months or prior coronary artery bypass surgery Presence of known diabetes (with typical symptoms of ACS) Chronic kidney disease (estimated glomerular filtration rate <60 mL/minute) (with

typical symptoms of ACS).


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The type of revascularisation is not specified by the Australian guidelines, and the only recommendation around timing is that coronary angiography should occur within 48 hours, which is referred to as early invasive therapy.

International CPGs for NSTE-ACS incorporate risk criteria similar to those in the Australian guideline, as well as specific risk assessment tools (such as the GRACE or TIMI risk score), into their clinical management pathways to inform decisions about which patients are appropriate for invasive intervention (AHA/ACC, 2014; ESC/EACTS, 2014). The choice between an immediate, early or delayed invasive strategy is multifactorial. In the case of patients at very high ischaemic risk (e.g. refractory angina, signs or symptoms of heart failure, life-threatening ventricular arrhythmias, haemodynamic instability), an immediate invasive approach (within two hours) is recommended (AHA/ACC, 2014; ESC/EACTS, 2014). In patients at high risk, with at least one primary high-risk criterion, an early invasive strategy within 24 hours could be considered. In lower-risk subsets, with at least one secondary high-risk criterion, the invasive evaluation can be delayed but should be performed during the same hospital stay, preferably within 72 hours of admission. An early invasive strategy is not recommended in patients with extensive comorbidities (e.g. hepatic, renal, pulmonary failure, cancer), in whom the risks of revascularisation and comorbid conditions are likely to outweigh the benefits of revascularisation.

The international guidelines do not make firm recommendations about the preferred approach for revascularisation, stating the choice depends on many factors including the patient’s condition, the presence of risk features, comorbidities, and the extent and severity of the lesions as identified by coronary angiography.

7.2.3 High risk based on diagnostic testing

NHFA/CSANZ (2006) made no recommendation on the use of FFR in the risk stratification of patients who are being considered for revascularisation. However, recent international guidelines place emphasis on the documentation of ischaemia by non-invasive or invasive diagnostic tests prior to revascularisation. In cases where ischaemia is not documented using non-invasive diagnostic testing, FFR measurement may be useful for the identification of haemodynamically relevant coronary lesions. There is consensus in the international guidelines that patients with FFR >0.8 should not be stented as these lesions are considered to be haemodynamically insignificant. None of the guidelines made recommendations on the use of FFR for determining the type of revascularisation that is undertaken (i.e. the preference for PCI or CABG).

As noted in Section 5 of this report, patients with FFR ≤0.8 were assessed in the FAME 2 study in which patients were randomised to either PCI or OMT. The results of this study do not support routine use of PCI over OMT on the basis of FFR ≤0.8. There was no difference in death, MI or death/MI in the two groups. Urgent revascularisation was required in 12.3% of patients in the OMT group in this study; however, the relevance of this endpoint to patients is unclear given that planned revascularisation was required in 100% of patients in the PCI group.

None of the MBS item descriptors incorporate FFR measurements as a factor in determining appropriateness for PCI. However, the descriptor for MBS item 38241, which relates to FFR measurement, specifies that it is to be used to determine whether revascularisation should be performed, where previous stress testing has either not been performed or the results are inconclusive.


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7.3 Evidence for the effectiveness and safety of PCI

The evidence base for the assessment of the effectiveness and safety of PCI was largely based on the findings of systematic reviews of RCTs (Level I evidence). Individual RCT results were used only to supplement this evidence where data on specific subgroups or outcomes of interest were lacking.

The 2014 ESC/EACTS guidelines note the limitations of the available evidence base, including: (i) that the majority of RCTs included mainly male patients who were relatively young, had preserved left ventricular function, and had not previously undergone revascularisation; (ii) that patients were highly selected, as randomisation was usually performed following delineation of coronary anatomy by angiography without routine assessment of ischaemia; and (iii) that there was a high rate of cross-over, where RCTs compared treatment strategies that allowed subsequent revascularisation when patients deteriorated on medical therapy.

Overall, there was no Level I or Level II evidence identified in this Review to support the use of PCI in the three populations of interest in terms of reducing risk of death. Reductions in other endpoints such as subsequent MI, refractory angina and urgent revascularisation were found for particular populations and/or subgroups, as were associated harms. It should be noted that there is evidence (not assessed in this Review but considered in published CPGs) that suggests that an early invasive strategy (which may include PCI) is of benefit in high-risk patients with NSTE-ACS.

(1)A. What is the evidence for the safety and effectiveness of PCI with stent insertion combined with medical therapy compared with medical therapy alone in patients with chronic stable angina?

The findings for this comparison were largely based on the conclusions of one HTA conducted on behalf of the German Federal Ministry of Health (Gorenoi et al, 2010). This review limited inclusion of studies to those that used what it defined as optimal medical therapy: individual RCTs were eligible for inclusion if beta-adrenergic receptor blockers, aspirin and statins were used in at least 80% of the included patients, and ACEI were used in at least 50% of the included patients. An additional RCT that met these criteria (DECOPI) was incorporated into the Gorenoi meta-analysis for the purpose of this MBS Review.

On the basis of four RCTs totalling 6270 patients (COURAGE, OAT, BARI-2D, DECOPI), there was no significant difference in all-cause mortality (RR 0.99; 95% CI 0.85, 1.16; p=0.94), cardiac mortality (RR 1.08; 95% CI 0.86, 1.36; p=0.51) or MI (RR 1.16; 95% CI 1.00, 1.36; p=0.06) between patients receiving PCI + OMT compared with patients receiving OMT alone.99 Although not an outcome pre-specified in the PICO criteria for this Review, the Gorenoi review found that the proportion of patients with angina attacks was lower after PCI at one and three years, but not at five years.

Based on the results of RCTs that used OMT, these findings were consistent across different patient subgroups including those at high risk, and those with diabetes, multivessel disease, CKD and left ventricular dysfunction.

99 Repeat revascularisation was also significantly reduced for PCI + OMT compared with OMT alone (RR 0.75; 95% CI 0.61, 0.91; p=0.004) but given the inappropriateness of this outcome for a comparison between PCI and medical therapy (see Section 5.2.3 for discussion), it is not being considered here.


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PCI improved quality of life over the shorter term (≤12 months) but not over the longer term.

Major haemorrhage occurred more frequently following PCI + OMT than OMT alone, but the underlying risk was low (0.7% vs. 0.1%; p=0.04).

(1)B. What is the evidence for the safety and effectiveness of PCI with stent insertion combined with medical therapy compared with medical therapy alone in patients who are assessed at higher risk of coronary events following diagnostic testing?

The findings for this comparison were largely based on the conclusions of one recent SR/MA (Gada et al, 2015). This review limited inclusion in their analysis to trials in which objective evidence of ischaemia (using non-invasive imaging or its invasive equivalent) was required. One of the three RCTs included in the Gada review was excluded from consideration from this MBS Review because no patients included in the PCI arm received stents; all patients in SWISSI II received balloon angioplasty only.

When all three studies (COURAGE nuclear sub-study, FAME 2, SWISSI II) were included in the Gada et al (2015) meta-analysis, all-cause mortality was significantly reduced in patients receiving PCI compared with patients receiving medical therapy (HR 0.52; 95% CI 0.30, 0.92; p=0.02). When the SWISSI II study was excluded from the analysis (because no patients received stents), the reduction in all-cause mortality was lost (HR 0.59; 95% CI 0.29, 1.17; p=0.13). There was no heterogeneity in this analysis (p=0.61; I2=0%).

Of the two studies that used stents (COURAGE nuclear sub-study and FAME 2), neither showed an overall benefit in favour of PCI for death or MI. However, when separate time point analyses were conducted in the FAME 2 study, a significantly increased risk of MI was seen for PCI in the first 7 days (HR 9.01; 95% CI 1.13, 72.0; p=0.012). For >7 days, a trend towards a decreased risk of MI was seen for PCI compared with medical therapy (HR 0.58; 95% CI 0.32, 1.05; p=0.07).100 Some benefits were seen for PCI in terms of reduced urgent revascularisation, and quality of life in the short-term.

There was no interaction seen between treatment type and multivessel or diabetes subgroups for the primary outcome death/MI/urgent revascularisation in the FAME 2 study.

Also in the FAME 2 study, the rate of SAEs was similar between the PCI and medical therapy groups.

(2)A. What is the evidence for the safety and effectiveness of PCI with stent insertion combined with medical therapy compared with CABG combined with medical therapy in patients with chronic stable angina?

The findings for this comparison were largely based on the conclusions of two SR/MAs of RCTs (D’Ascenzo et al, 2014; Fanari et al, 2014). It should be noted that in the D’Ascenzo SR/MA, 14 out of the 20 RCTs included in the review, 100% of patients in the PCI arm received stents, while in four studies, no patients received stents. In the remaining two studies, 54% and 68% of patients received stents. In the Fanari SR/MA, all studies included patients who received PCI + DES.

100 There was a significant benefit seen for PCI compared with medical therapy for the primary outcome in the FAME 2 study, death/MI/urgent revascularisation. As discussed in Section 5.2.3, urgent revascularisation is not considered an appropriate outcome for the PCI versus medical therapy comparison.


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In the D’Ascenzo SR/MA, there was no significant difference between PCI and CABG for death or MI in the overall population (OR 0.99; 95% CI 0.77, 1.27 and OR 1.03; 95% CI 0.77, 1.37, respectively) or the subpopulation with multivessel disease (OR 1.11; 95% CI 0.87, 1.43 and OR 1.00; 95% CI 0.72, 1.39, respectively). However, Fanari et al (2014) showed increased risks of death and MI associated with PCI + DES over longer-term follow-up in patients with multivessel disease (OR 1.30 and 2.21, respectively). Repeat revascularisation was significantly higher in patients receiving PCI compared with patients receiving CABG, both in the overall population (OR 4.71; 95% CI 3.17, 7.01) and the multivessel subpopulation (OR 7.18; 95% CI 4.32, 11.93). Stroke was significantly increased in patients undergoing CABG compared with PCI in both the overall population and the multivessel subpopulation, and at two time points: 30 days and follow-up. The ORs for these comparisons ranged from 0.36 to 0.57. Target vessel revascularisation was also higher for PCI + DES compared with CABG in the Fanari SR/MA (RR 2.31; 95% CI 1.80, 2.96), and stroke was significantly lower for PCI + DES at 1, 2 and 5 years (OR 0.35, 0.55 and 0.66, respectively).

Based on the results of the individual RCTs included in the D’Ascenzo review, there was no significant interaction between PCI and CABG and subgroups including renal insufficiency and left ventricular dysfunction. In the Fanari et al (2014) review, the risk of death and MI was significantly greater for patients with multivessel disease and diabetes who received PCI + DES compared with CABG (RR 1.36; 95% CI 1.11, 1.66 and RR 2.01; 95% CI 1.54, 2.62, respectively); this review included data from the SYNTAX, FREEDOM and CARDIa trials. However, in other RCTs comparing results in diabetes and no diabetes subgroups, no interaction between treatment and diabetes was seen.

In the short term (≤1 month) quality of life was significantly greater in patients undergoing PCI compared with CABG. However, this difference did not persist into the longer term and in some cases, an improved quality of life was seen for CABG compared with PCI.

Major bleeding tended to be greater following CABG than PCI; for example, in the CARDIa trial, TIMI major bleeding occurred in 1.2% of patients following PCI and 6.1% of patients following CABG (HR 0.19; 95% CI 0.06, 0.67; p=0.009). In the SYNTAX study, stent thrombosis occurred most commonly in the first month following PCI (2.0%), while graft occlusion most commonly occurred after 1 month (2.5%).

(2)B. What is the evidence for the safety and effectiveness of PCI with stent insertion combined with medical therapy compared with CABG combined with medical therapy in patients with a diagnosis of NSTE-ACS?

No Level I or Level II studies were identified that specifically compared the use of PCI with CABG in patients with NSTE-ACS. The TACTICS-TIMI 18 trial, which compared a routine invasive strategy (catheterisation in all patients with revascularisation with PCI ± stenting or CABG as appropriate) with a conservative strategy (medical therapy with revascularisation when clinically indicated) provides efficacy results by revascularisation status, and hence provides results for patients undergoing PCI only and CABG only.

Caution should be used if trying to make comparisons between PCI and CABG in this study, as they may be subject to selection bias; the decision to revascularise, and the method used, was based on the clinical characteristics of the patient. Thus, patients were not randomised to PCI or CABG so there may be substantial differences between the populations that underwent these procedures.


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(2)C. What is the evidence for the safety and effectiveness of PCI with stent insertion combined with medical therapy compared with CABG combined with medical therapy in patients who are assessed at higher risk of coronary events following diagnostic testing?

No Level I or Level II studies were identified that specifically compared the use of PCI with CABG in patients assessed at higher risk of coronary events following diagnostic testing.

(3)What is the evidence for the safety and effectiveness of a selective PCI strategy compared with a routine PCI strategy in patients with a diagnosis of NSTE-ACS?

The findings for this comparison were largely based on a Cochrane Review conducted by Hoenig and colleagues (2010), for a number of reasons: (i) it limits inclusion of RCTs to those conducted during the ‘stent era’; (ii) it provides subgroup analyses of studies with and without GPIIb/IIIa use, as these treatments are considered to be important in contemporary clinical practice; (iii) it provides the most comprehensive list of outcomes, assessing both efficacy and safety; and (iv) where data are available, outcome results are presented at different time points: index (during initial hospitalisation), early (≤4 months), intermediate (6 – 12 months) and late (>12 months). The Hoenig review included data from up to five RCTs (ICTUS, RITA-3, VINO, TACTICS-TIMI 18 and FRISC II). One additional RCT (IES) was identified that was published after the Hoenig review. For the purpose of this MBS Review, this RCT was incorporated (where applicable) into the Hoenig review meta-analysis.

It should be noted that the Hoenig review, and the other 10 SRs identified, all compared a routine/early invasive strategy with a selective invasive/conservative strategy. All strategies included revascularisation with either PCI or CABG depending on the clinicians’ choice; no systematic review or included RCT specifically looked at routine versus selective PCI.

There was no significant difference in mortality between the routine and selective invasive strategies at any of the time points examined. A routine invasive strategy resulted in significantly fewer MIs at intermediate and late time points (RR 0.73; 0.62, 0.86; p<0.001 and RR 0.78; 95% CI 0.67, 0.92; p<0.001, respectively). However, both procedure-related MI (RR 2.00; 95% CI 1.53, 2.61; p<0.001) and bleeding (RR 1.71; 95% CI 1.27, 2.31; p<0.001) occurred significantly more frequently in the routine invasive strategy group compared with the selective invasive strategy group. Thus, while there was some benefit of a routine strategy in this population, there were also risks associated with the increased number of procedures.

Two reviews assessed outcomes by risk subgroups. Based on analysis of IPD from three RCTs (ICTUS, RITA 3 and FRISC II), Fox et al (2010) showed that, when categorised into low, moderate and high-risk categories101, a routine invasive strategy provided a greater reduction in CV death/MI compared with a selective invasive strategy for high-risk patients (RD –11.1%; 95% CI –18.4%, –3.8%), compared with moderate-risk (RD –3.8%; 95% CI –7.4%, –0.1%) and low-risk (RD –2.0%; 95% CI –4.1%, 0.1%) patients. Based on a subsequent analysis of the same dataset, Alfredsson et al (2014) showed that high-risk and medium-risk men gained a benefit in CV death/MI from the use of a routine compared with a selective invasive strategy (HR 0.56; 95% CI 0.41, 0.75 and HR 0.74; 95% CI 0.58, 0.96, respectively), while low-risk men, and low, medium and high-risk women did not. Data on harms were not assessed in these studies.

101 Using a risk score based on age, diabetes, previous MI, ST-segment depression, hypertension and BMI.


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While these results suggest that patients at high risk will significantly benefit from undergoing a routine invasive strategy compared with a selective invasive strategy, there are some important points to note. The high-, medium/moderate- and low-risk subsets were a post hoc analysis from a selection f available trials only, and all patients included in the ICTUS trial were considered to be high risk. The ICTUS trial was designed to bypass design problems in the FRISC and RITA trials: (i) ICTUS included only high-risk patients with abnormal biomarkers; (ii) ICTUS used the same biomarker level in both arms to define an MI; and (iii) ICTUS ensured that patients in both groups received OMT (whereas previous studies did not provide dual antiplatelet therapy for all selectively treated patients, nor was aggressive lipid-lowering therapy deployed). In addition, the methods used to categorise patients into risk groups were not based on validated methods. Australian and International CPGs recommend than an early invasive strategy should be used in patients considered to be at high risk of cardiac events. However, these recommendations relate to the timing of routine intervention (i.e. early versus late), rather than whether or not an invasive strategy should be carried out, and are based on a separate body of evdience to the one assessed as part of this Review (see Section 5.1.2).

With regards to patients with diabetes, O’Donoghue et al (2012) compared an invasive strategy with a conservative strategy in patients with and without diabetes, and found that MI was significantly reduced in patients with diabetes who receive an invasive strategy compared with a conservative strategy (RR 0.71; 95% CI 0.55, 0.92).

Based on the results of two of the RCTs that were included in the Hoenig et al (2010) SR/MA (RITA-3 and FRISC II), quality of life was significantly improved in patients undergoing a routine invasive strategy compared with patients undergoing a selective invasive strategy up to 1 year follow-up.

(4)A. Supplementary question: What is the evidence for the safety and effectiveness of DES compared with BMS in patients with chronic stable angina?

One Level I study was identified that specifically compared the use of BMS with DES as part of a PCI strategy in patients with non-acute CAD. Trikalinos et al (2009) assessed the effect of PCI using direct and indirect meta-analysis. As part of this assessment they separately compared BMS and DES with medical therapy, as well as comparing DES with BMS. There was no significant difference between BMS and medical therapy for the direct or indirect analyses. There were no trials directly comparing DES and medical therapy so only indirect comparisons were available for all-cause mortality, MI and CABG. These indirect comparisons showed no difference between DES and medical therapy for all-cause mortality and MI, and a significantly reduced risk of CABG for DES compared with medical therapy (RR 0.58; 95% CI 0.38, 0.88). It is important to note that the inclusion of trials in these analyses was not limited to those in which OMT was used, which may have biased the findings in favour of PCI. Finally, direct and indirect comparisons between DES and BMS were undertaken, showing no difference between the different types of stents for all-cause mortality and MI, and a significantly reduced risk of CABG for patients receiving DES compared with BMS for both the direct (RR 0.56; 95% CI 0.36, 0.88) and indirect (RR 0.56; 95% CI 0.39, 0.80) comparisons.

In summary, the use of DES or BMS does not result in differences in all-cause mortality or MI, while DES appears to reduce the risk of requiring CABG compared with the use of BMS.


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One RCT that compared PCI + stent insertion with CABG, indirectly compared the effect of different types of stents. In the CARDIa trial (Kapur et al, 2010), PCI was initially conducted using BMS; however, DES were used once they became available. In order to minimise potential confounding in the comparison, patients who received BMS were compared with patients who received CABG prior to the introduction of DES, while patients who received DES were compared with patients who received CABG following the introduction of DES. There was a higher (although not statistically significant) risk of death/MI/stroke in patients who received BMS compared with patients who received CABG (HR 2.99; 95% CI 0.97, 9.16), while there was no difference in risk of death/MI/stroke between patients who received DES compared with CABG (HR 0.93; 95% CI 0.51, 1.71). There was also a significantly higher rate of MACCE in patients who received BMS compared with CABG (HR 3.42; 95% CI 1.27, 9.22), and no significant difference between patients who received DES compared with CABG (HR 1.41; 95% CI 0.82, 2.42). It should be kept in mind that these comparisons are not randomised and may be subject to bias, particularly due to changes in underlying medical therapies over time.

(4)B. Supplementary question: What is the evidence for the safety and effectiveness of DES compared with BMS in patients with a diagnosis of NSTE-ACS?

No Level I or Level II studies were identified that specifically compared the use of BMS with DES as part of a PCI strategy in patients with a diagnosis of NSTE-ACS.

(4)C. Supplementary question: What is the evidence for the safety and effectiveness of DES compared with BMS in patients who are assessed at higher risk of coronary events following diagnostic testing?

No Level I or Level II studies were identified that specifically compared the use of BMS with DES as part of a PCI strategy in patients assessed at higher risk of coronary events following diagnostic testing.

7.4 Evidence for the cost-effectiveness of PCI

The findings of the published economic analyses of PCI in each of the populations of interest should be interpreted while keeping in mind that there was no strong published clinical evidence to support the use of PCI in these populations.

(1)A. What is the evidence for the cost- effectiveness of PCI with stent insertion combined with medical therapy, compared with medical therapy alone, in patients with chronic stable angina?

Two studies assessed the cost-effectiveness of PCI added onto OMT compared with OMT alone using data from the COURAGE RCT. Both studies showed that adding PCI to OMT was not cost-effective. Weintraub et al (2008) showed ICERs >US$150,000/QALY and >US$250,000/LYG for both the trial-based and lifetime analyses. Zhang et al (2011) reported their results as ‘cost per patient significantly improved’ and showed ICERs for the lowest risk patients of approximately US$500,000 (based on physical limitation) and nearly US$4 million (based on quality of life). Even in the highest risk group of patients, the ICER ranged from US$79,448 to US$322,966 per patient significantly improved. It should be noted that in the COURAGE trial, the majority of patients received BMS, which does not reflect current clinical practice where patients often receive second-generation DES. In a sensitivity analysis


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where the increased cost and additional clinical benefits of DES were taken into account, the ICERs remained >US$150,000 per QALY and per LYG.

In a study using observational data from Canada, Wijeysundera et al (2013) concluded that PCI was a cost-effective treatment option in patients with stable CAD, with the cost/QALY ranging from CA$5,814 to CA$19,414 for BMS in various subgroups based on diabetes and lesion characteristics; DES was dominated by BMS in most of these analyses. The authors suggest a number of reasons for the discrepancy with previous studies, including: (i) their use of a lifetime time horizon when other studies have used shorter time horizons; (ii) the greater proportion of patients with severe angina (CCS III-IV) in their study compared with other studies (64% vs. 21% in the COURAGE trial); and (iii) the broader population included in their dataset compared with the COURAGE trial (in which only 6.4% of screened patients with coronary disease were included).

The findings of these studies, that PCI is not cost-effective in patients with stable CAD, are consistent with the findings of the clinical review that PCI is not more clinically effective than OMT alone.

(1)B. What is the evidence for the cost-effectiveness of PCI with stent insertion combined with medical therapy, compared with medical therapy alone, in patients who are assessed at higher risk of coronary events following diagnostic testing?

The economic analysis by Fearon et al (2013), which was based on data from the FAME 2 RCT, concluded that in patients with an FFR ≤0.80, PCI added to OMT was cost-effective, with an overall ICER of US$36,000/QALY. In patients with CCS Class 0/1 angina the ICER was US$102,000 and in patients with CCS Class 2-4 angina the ICER was US$26,000.

The robustness and usefulness of the results of this study are limited by the one-year time horizon, and the fact utilities were collected at one month, and extrapolated over the 12 month period. In addition, there was a substantial difference in utilities at baseline, being 0.817 in the PCI group and 0.845 in the OMT group. Thus, the uncertainty around the findings of this study, coupled with the lack of clear clinical benefit displayed in the FAME 2 trial, do not support the cost-effectiveness of PCI in this patient population.

(2)A. What is the evidence for the cost-effectiveness of PCI with stent insertion combined with medical therapy, compared with CABG combined with medical therapy, in patients with chronic stable angina?

Two studies were identified that assessed the cost-effectiveness of CABG over PCI in specific subgroups of patients with stable CAD. Cohen et al (2014) used data from the SYNTAX trial and concluded that CABG was cost-effective in patients with left main or three-vessel disease, with lifetime ICERs of US$16,537/QALY and US$12,329/LYG. ICERs remained relatively consistent under different assumptions of duration of CABG effectiveness, when undiscounted and including the prognostic effect of MI and stroke. In subgroup analyses, PCI was shown to be dominant in only two cases: (i) in patients with left main disease, and (ii) in patients with a SYNTAX score ≤22.

Magnuson et al (2013) used data from the FREEDOM trial, and concluded that CABG was cost-effective in patients with diabetes and multivessel disease. The base-case ICERs were US$8,132/QALY and US$6,791/LYG, while sensitivity and subgroup analyses were consistent.


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These findings, in conjunction with the clinical benefits of CABG over PCI in these specific patient populations, support the finding that CABG is cost-effective compared with PCI in these patient groups.

(2)B. What is the evidence for the cost-effectiveness of PCI with stent insertion combined with medical therapy, compared with CABG combined with medical therapy, in patients with a diagnosis of NSTE-ACS?

No economic analyses were identified that specifically compared the cost-effectiveness of PCI with CABG in patients with a diagnosis of NSTE-ACS.

(2)C. What is the evidence for the cost-effectiveness of PCI with stent insertion combined with medical therapy, compared with CABG combined with medical therapy, in patients who are assessed at higher risk of coronary events following diagnostic testing?

No economic analyses were identified that specifically compared the cost-effectiveness of PCI with CABG in patients assessed at higher risk of coronary events following diagnostic testing.

(3) What is the evidence for the cost-effectiveness of a selective PCI strategy compared with a routine PCI strategy in patients with a diagnosis of NSTE-ACS?

Two studies were identified that assessed the cost-effectiveness of a routine invasive strategy compared with a selective invasive strategy in patients with NSTE-ACS. Dijksman et al (2009) used data from the ICTUS trial and concluded that a routine invasive strategy was unlikely to be cost-effective in this patient population. The ICER ratio for this analysis was €82,470/prevented cardiac event.

Using data from the RITA 3 trial, Henriksson et al (2008) assessed the cost-effectiveness of an early invasive strategy in patients divided into risk subgroups based on baseline characteristics. In the highest risk subgroups (which included men with or without diabetes, previous MI, high heart rate and ST depression) the cost/QALY was approximately £12,000 while in the lowest risk subgroup (which included younger women with no diabetes, no previous MI, lower heart rate and no ST depression) the cost/QALY was £53,760. Intermediate-risk groups had costs/QALY of approximately £22,000.

These findings are in line with the clinical evidence that suggests that a routine invasive strategy does not provide clinical benefit over a selective invasive strategy in low- to intermediate-risk patients, while there may be some benefits in higher-risk patients. However, as noted previously, these trials did not use a validated method to identify patients considered to be at high risk of cardiac events.

7.5 Conclusions

(i) The identified Level I or Level II evidence does not support the use of PCI in terms of reducing rates of death or MI in patients with chronic stable angina that is well controlled with OMT. No Level I or II evidence was identified that assessed the effect of PCI in patients with chronic stable angina who are refractory to OMT.

(ii) The identified Level I or Level II evidence does not support the routine use of an invasive strategy in terms of reducing rates of death or MI in low- to intermediate-


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risk patients with a diagnosis of NSTE-ACS. However, there is some low quality evidence102 that suggests that death and MI may be reduced following a routine invasive strategy in high-risk patients with a diagnosis of NSTE-ACS. Australian and International CPGs note the existence of a body of evidence that supports the use of an early invasive strategy in intermediate- and high-risk patients with NSTE-ACS; however, this body of evidence was not assessed as part of this Review.

(iii) The identified Level I or Level II evidence does not support the use of PCI in terms of reducing rates of death and MI in patients with stable CAD on OMT who are assessed at higher risk of coronary events following diagnostic testing such as FFR.

(iv) Like many descriptors for MBS items, the item numbers that relate to angioplasty with or without stenting (items 38300, 38303 and 38306) do not provide details of the target population for PCI, or restrict the use of PCI to any particular population(s).

(v) It is unclear whether PCI services are being used in a broader patient population in Australia than is currently supported by the clinical evidence base.

102 This evidence is considered to be low quality because it is based on a post hoc analysis of data from selected trials, and validated methods were not used to stratify patients into risk categories.


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Stergiopoulos K & Brown DL (2012). Initial coronary stent implantation with medical therapy vs medical therapy alone for stable coronary artery disease: Meta-analysis of randomized controlled trials. Archives of Internal Medicine, 172(4):312-319.

Stergiopoulos K, Boden WE, Hartigan P, Mobius-Winkler S, Hambrecht R, Hueb W, et al. (2014). Percutaneous coronary intervention outcomes in patients with stable obstructive coronary artery disease and myocardial ischemia: A collaborativemeta-analysis of contemporary randomized clinical trials. JAMA Internal Medicine, 174(2):232-240.

Stettler C, Allemann S, Wandel S, Kastrati A, Morice MC, Schomig A, et al. (2008). Drug eluting and bare metal stents in people with and without diabetes: collaborative network meta-analysis. Bmj, 337:a1331.

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APPENDIX 2 - REVIEW WORKING GROUP MEMBERS

As part of the MBS Review process, the Department of Health established a Review Working Group (RWG). The RWG is a time-limited working group of nominated representatives to provide advice to the Department on the scope of the review, clinical practice and policy issues. The members of the PCI RWG are listed in Table A-2.1.

Table A-.2.1 Members of the RWG for the MBS Review of PCI

Name RepresentingDr '''''''''' ''''''''''''' Internal Medicine Society of Australia and New Zealand

Dr ''''''''''''''' '''''' Cardiac Society of Australia and New Zealand

Dr '''''''''''''' '''''''''''''''''' Evidence Based Health Care Expert and Clinical Cardiologist

Dr '''''''' '''''''''''' Australian Medical Association

Associate Professor '''''''' ''''''''''''' Consultant General Physician

Professor '''''''''''''' ''''''''''''''''''' Australian and New Zealand Society of Cardiac and Thoracic Surgeons

Professor ''''''''''''''''' ''''''''''''''''' Interventional Cardiologist

Professor '''''''''''''''''''' '''''''''''''''''''''' '''''''''''''''''''''''' ''''''''''''''''''''''''''''''''' '''''''''''''' '''''' ''''''''''''''''' '''''''''''''''''' ''''''''''''''''''' ''''''''''''''''''''''' '''''''''''''''''''''

Dr ''''''''''''''''''''' '''''''''''''''''' ''''''''''''''''''' '''''''''''''''''''''' '''''''''''''''''''''''''''''''''' ''''''''''''''''' ''''' '''''''''''''''''

Chair and Secretariat Department of Health


January 2016

APPENDIX 3 - MBS INFORMATION

The MBS item numbers for PCI in-scope of this Review include all items in Group T8 (Surgical operations); Subgroup 6 (Cardio-thoracic); Subheading 3 (Endovascular interventional procedures) on the MBS. The seven relevant MBS items are listed in Table A-3.1.

Table A-3.1 MBS items relating to PCI

MBS item no.

MBS item descriptor MBS item details

38300TRANSLUMINAL BALLOON ANGIOPLASTY of 1 coronary artery, percutaneous or by open exposure, excluding associated radiological services or preparation, and excluding aftercareMultiple Services Rule(Anaes.) (Assist.)

Fee: $515.35 Benefit: 75% = $386.55 85% = $439.15

Item start date:01 Nov 2005

Description start date:

01 Nov 2005

Schedule fee start date:

01 Nov 2012

38303TRANSLUMINAL BALLOON ANGIOPLASTY of more than 1 coronary artery, percutaneous or by open exposure, excluding associated radiological services or preparation and excluding aftercareMultiple Services Rule(Anaes.) (Assist.)

Fee: $660.80 Benefit: 75% = $495.60 85% = $584.60



01 Nov 2005


01 Nov 2012

38306 TRANSLUMINAL INSERTION OF STENT OR STENTS into 1 occlusional site, including associated balloon dilatation for coronary artery, percutaneous or by open exposure, excluding associated radiological services and preparation, and excluding aftercareMultiple Services Rule(Anaes.) (Assist.)

Fee: $762.35 Benefit: 75% = $571.80 85% = $686.15(See para T8.63 of explanatory notes to this Category)



01 Nov 2006


01 Nov 2012

38309 PERCUTANEOUS TRANSLUMINAL ROTATIONAL ATHERECTOMY of 1 coronary artery, including balloon angioplasty with no stent insertion, where:- no lesion of the coronary artery has been stented; and- each lesion of the coronary artery is complex and heavily calcified; and- balloon angioplasty with or without stenting is not suitable;excluding associated radiological services or preparation, and excluding aftercareMultiple Services Rule(Anaes.) (Assist.)

Fee: $885.45 Benefit: 75% = $664.10 85% = $809.25(See para T8.42 of explanatory notes to this Category)



01 Nov 2005


01 Nov 2012

38312 PERCUTANEOUS TRANSLUMINAL ROTATIONAL ATHERECTOMY of 1 coronary artery, including balloon angioplasty with insertion of 1 or more stents, where:- no lesion of the coronary artery has been stented; and- each lesion of the coronary artery is complex and heavily calcified; and- balloon angioplasty with or without stenting is not suitable;excluding associated radiological services or preparation, and excluding aftercareMultiple Services Rule(Anaes.) (Assist.)



01 Nov 2005


01 Nov 2012


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MBS item no.


Fee: $1,132.35 Benefit: 75% = $849.30 85% = $1,056.15(See para T8.42 of explanatory notes to this Category)

38315 PERCUTANEOUS TRANSLUMINAL ROTATIONAL ATHERECTOMY of more than 1 coronary artery, including balloon angioplasty with no stent insertion, where:- no lesion of the coronary arteries has been stented; and- each lesion of the coronary arteries is complex and heavily calcified; and- balloon angioplasty with or without stenting is not suitable;excluding associated radiological services or preparation, and excluding aftercareMultiple Services Rule(Anaes.) (Assist.)

Fee: $1,215.85 Benefit: 75% = $911.90 85% = $1,139.65(See para T8.42 of explanatory notes to this Category)



01 Nov 2005


01 Nov 2012

38318 PERCUTANEOUS TRANSLUMINAL ROTATIONAL ATHERECTOMY of more than 1 coronary artery, including balloon angioplasty, with insertion of 1 or more stents, where:- no lesion of the coronary arteries has been stented; and- each lesion of the coronary arteries is complex and heavily calcified; and- balloon angioplasty with or without stenting is not suitable,excluding associated radiological services or preparation, and excluding aftercareMultiple Services Rule(Anaes.) (Assist.)

Fee: $1,586.35 Benefit: 75% = $1,189.80 85% = $1,510.15(See para T8.42 of explanatory notes to this Category)



01 Nov 2005


01 Nov 2012

Source: MBS Online, accessed 23 July 2015.Note: item start date refers to the date when the item was allocated a 5-digit number (previously 4-digits). Hence some of these services may have been available prior to the item start date provided on MBS Australia online.

Table A-3.2 shows the explanatory notes relating to MBS items 38300 to 38318.

Table A-3.2 Explanatory notes relating to PCI

Explanatory notes

T8.2Multiple Operation RuleThe fees for two or more operations, listed in Group T8 (other than Subgroup 12 of that Group), performed on a patient on the one occasion (except as provided in paragraph T8.2.3) are calculated by the following rule:100% for the item with the greatest Schedule feeplus 50% for the item with the next greatest Schedule feeplus 25% for each other item.

Note:

(a) Fees so calculated which result in a sum which is not a multiple of 5 cents are to be taken to the next higher multiple of 5 cents.(b) Where two or more operations performed on the one occasion have Schedule fees which are equal, one of these amounts shall be treated as being greater than the other or others of those amounts.(c) The Schedule fee for benefits purposes is the aggregate of the fees calculated in accordance with the above formula.(d) For these purposes the term "operation" only refers to all items in Group T8 (other than Subgroup 12 of that Group).This rule does not apply to an operation which is one of two or more operations performed under the one anaesthetic on the same patient if the medical practitioner who performed the operation did not also perform or assist at the other operation or any of the other operations, or administer the anaesthetic. In such cases the fees specified in the Schedule apply.Where two medical practitioners operate independently and either performs more than one operation, the method of assessment outlined above would apply in respect of the services performed by each medical practitioner.If the operation comprises a combination of procedures which are commonly performed together and for which a specific combined item is provided in the Schedule, it is regarded as the one item and service in applying the multiple operation rule.


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Explanatory notes

There are a number of items in the Schedule where the description indicates that the item applies only when rendered in association with another procedure. The Schedule fees for such items have therefore been determined on the basis that they would always be subject to the "multiple operation rule".Where the need arises for the patient to be returned to the operating theatre on the same day as the original procedure for further surgery due to post-operative complications, which would not be considered as normal aftercare - see paragraph T8.2, such procedures would generally not be subject to the "multiple operation rule". Accounts should be endorsed to the effect that they are separate procedures so that a separate benefit may be paid.

Extended Medicare Safety Net Cap

The Extended Medicare Safety Net (EMSN) benefit cap for items subject to the multiple operations rule, where all items in that claim are subject to a cap are calculated from the abated (reduced) schedule fee.For example, if an item has a Schedule fee of $100 and an EMSN benefit cap equal to 80 per cent of the schedule fee, the calculated EMSN benefit cap would be $80. However, if the schedule fee for the item is reduced by 50 per cent in accordance with the multiple operations rule provisions, and all items in that claim carry a cap, the calculated EMSN benefit cap for the item is $40 (50% of $100*80%).

T8.42Percutaneous Transluminal Coronary Angioplasty – (Items 38309, 38312, 38315 and 38318)A coronary artery lesion is considered to be complex when the lesion is a chronic total occlusion, located at an ostial site, angulated, tortuous or greater than 1cm in length. Percutaneous transluminal coronary rotational atherectomy is suitable for revascularisation of complex and heavily calcified coronary artery stenoses in patients for whom coronary artery bypass graft surgery is contraindicated.Each of the items 38309, 38312, 38315 and 38318 describes an episode of service. As such, only one item in this range can be claimed in a single episode.

T8.63Transluminal Insertion of Stent or Stents - (Item 38306)Item 38306 should only be billed once per occlusional site. It is not appropriate to bill item 38306 multiple times for the insertion of more than one stent at the same occlusional site in the same artery. However, it would be appropriate to claim this item multiple times for insertion of stents into the same artery at different occlusional sites or into another artery or occlusional site. It is expected that the practitioner will note the details of the artery or site into which the stents were placed, in order for the Department of Human Services to process the claims.Source: MBS Online, accessed 23 July 2015.

Table A-3.3 Other relevant MBS items

MBS item no.


38241 USE OF A CORONARY PRESSURE WIRE during selective coronary angiography to measure fractional flow reserve (FFR) and coronary flow reserve (CFR) in one or more intermediate coronary artery or graft lesions (stenosis of 30-70%), to determine whether revascularisation should be performed where previous stress testing has either not been performed or the results are inconclusiveMultiple Services Rule(Anaes.)

Fee: $469.70 Benefit: 75% = $352.30 85% = $399.25



01 Nov 2006


01 Nov 2012Source: MBS Online, accessed 27 July 2015.

Table A-3.4 MBS items of interest in Group T8: Surgical operations

Group T8 Surgical operations

Subgroup 6Subheading 1

Cardio-thoracicCardiology procedures

38215 SELECTIVE CORONARY ANGIOGRAPHY, placement of catheters and injection of opaque material into the native coronary arteries, not being a service associated with a service to which item 38218, 38220, 38222, 38225, 38228, 38231, 38234, 38237, 38240 or 38246 applies

38218 SELECTIVE CORONARY ANGIOGRAPHY, placement of catheters and injection of opaque material with right or left heart catheterisation or both, or aortography, not being a service associated with a service to which item 38215, 38220, 38222, 38225, 38228, 38231, 38234, 38237, 38240 or 38246 applies


January 2016

Group T8 Surgical operations

Subgroup 6Subheading 1

Cardio-thoracicCardiology procedures

38220 SELECTIVE CORONARY GRAFT ANGIOGRAPHY placement of catheter(s) and injection of opaque material into free coronary graft(s) attached to the aorta (irrespective of the number of grafts), not being a service associated with a service to which item 38215, 38218, 38222, 38225, 38228, 38231, 38234, 38237, 38240 or 38246 applies (Anaes.)

38222 SELECTIVE CORONARY GRAFT ANGIOGRAPHY, placement of catheter(s) and injection of opaque material into direct internal mammary artery graft(s) to one or more coronary arteries (irrespective of the number of grafts), not being a service associated with a service to which item 38215, 38218, 38220, 38225, 38228, 38231, 38234, 38237, 38240 or 38246 applies (Anaes.)

38225 SELECTIVE CORONARY ANGIOGRAPHY, placement of catheters and injection of opaque material into the native coronary arteries and placement of catheter(s) and injection of opaque material into free coronary graft(s) attached to the aorta (irrespective of the number of grafts), not being a service associated with a service to which item 38215, 38218, 38220, 38222, 38228, 38231, 38234, 38237, 38240 or 38246 applies (Anaes.)

38228 SELECTIVE CORONARY ANGIOGRAPHY, placement of catheters and injection of opaque material into the native coronary arteries and placement of catheter(s) and injection of opaque material into direct internal mammary artery graft(s) to one or more coronary arteries (irrespective of the number of grafts), not being a service associated with a service to which item 38215, 38218, 38220, 38222, 38225, 38231, 38234, 38237, 38240 or 38246 applies (Anaes.)

38231 SELECTIVE CORONARY ANGIOGRAPHY, placement of catheters and injection of opaque material into the native coronary arteries and placement of catheter(s) and injection of opaque material into the free coronary graft(s) attached to the aorta (irrespective of the number of grafts), and placement of catheter(s) and injection of opaque material into direct internal mammary artery graft(s) to one or more coronary arteries (irrespective of the number of grafts), not being a service associated with a service to which item 38215, 38218, 38220, 38222, 38225, 38228, 38234, 38237, 38240 or 38246 applies (Anaes.)

38234 SELECTIVE CORONARY ANGIOGRAPHY, placement of catheters and injection of opaque material with right or left heart catheterisation or both, or aortography and placement of catheter(s) and injection of opaque material into free coronary graft(s) attached to the aorta (irrespective of the number of grafts), not being a service associated with a service to which item 38215, 38218, 38220, 38222, 38225, 38228, 38231, 38237, 38240 or 38246 applies (Anaes.)

38237 SELECTIVE CORONARY ANGIOGRAPHY, placement of catheters and injection of opaque material with right or left heart catheterisation or both, or aortography and placement of catheter(s) and injection of opaque material into direct internal mammary artery graft(s) to one or more coronary arteries (irrespective of the number of grafts), not being a service associated with a service to which item 38215, 38218, 38220, 38222, 38225, 38228, 38231, 38234, 38240 or 38246 applies (Anaes.)

38240 SELECTIVE CORONARY ANGIOGRAPHY, placement of catheters and injection of opaque material with right or left heart catheterisation or both, or aortography and placement of catheter(s) and injection of opaque material into free coronary graft(s) attached to the aorta (irrespective of the number of grafts) and placement of catheter(s) and injection of opaque material into direct internal mammary artery graft(s) to one or more coronary arteries (irrespective of the number of grafts), not being a service associated with a service to which item 38215, 38218, 38220, 38222, 38225, 38228, 38231, 38234, 38237 or 38246 applies (Anaes.)

38243 PLACEMENT OF CATHETER(S) and injection of opaque material into any coronary vessel(s) or graft(s) prior to any coronary interventional procedure, not being a service associated with a service to which item 38246 applies (Anaes.)

38246 SELECTIVE CORONARY ANGIOGRAPHY, placement of catheters and injection of opaque material with right or left heart catheterisation or both, or aortography followed by placement of catheters prior to any coronary interventional procedure, not being a service associated with a service to which item 38215, 38218, 38220, 38222, 38225, 38228, 38231, 38234, 38237, 38240 or 38243 applies (Anaes.)

Table A-3.5 MBS items of interest in Group I3: Diagnostic radiology

Group I3 Diagnostic radiology

Subgroup 13 Angiography59903 ANGIOCARDIOGRAPHY including the service described in item 59970, 59974 or 61109, not being

a service to which item 59912 or 59925 applies (R) (K)59912 SELECTIVE CORONARY ARTERIOGRAPHY (R) (K), including the services described in item


January 2016

Group I3 Diagnostic radiology

Subgroup 13 Angiography59970, 59974 or 61109, not being a service to which item 59903 or 59925 applies (Anaes.)

59925 SELECTIVE CORONARY ARTERIOGRAPHY AND ANGIOCARDIOGRAPHY, including the services described in items 59903, 59912, 59970, 59974 or 61109 (R) (K)

59970 ANGIOGRAPHY AND/OR DIGITAL SUBTRACTION ANGIOGRAPHY with fluoroscopy and image acquisition using a mobile image intensifier, 1 or more regions including any preliminary plain films, preparation and contrast injection (R) (K) (Anaes.)

59971 ANGIOCARDIOGRAPHY including the service described in item 59970, 59974 or 61109, not being a service to which item 59972 or 59973 applies (R) (NK)

59972 SELECTIVE CORONARY ARTERIOGRAPHY (R) (NK), including the service described in item 59970, 59974 or 61109, not being a service to which item 59971 or 59973 applies (Anaes.)

59973 SELECTIVE CORONARY ARTERIOGRAPHY AND ANGIOCARDIOGRAPHY, including the services described in items 59970, 59971, 59972, 59974 or 61109 (R) (NK)

61109 FLUOROSCOPY in an ANGIOGRAPHY SUITE with image intensification, in conjunction with a surgical procedure, using interventional techniques, not being a service associated with a service to which another item in this Table applies (R)

61110 FLUOROSCOPY in an ANGIOGRAPHY SUITE with image intensification, in conjunction with a surgical procedure, using interventional techniques, not being a service associated with a service to which another item in this Table applies (R) (NK)

Table A-3.6 MBS items of interest in Group I1: Ultrasound

Group I1 Ultrasound

Subgroup 1 General55054 ULTRASONIC CROSS-SECTIONAL ECHOGRAPHY, in conjunction with a surgical procedure

using interventional techniques, not being a service associated with a service to which any other item in this Group applies (R)

Subgroup 2 Cardiac55113 M-MODE and 2 DIMENSIONAL REAL TIME ECHOCARDIOGRAPHIC EXAMINATION of the

heart from at least 2 acoustic windows, with measurement of blood flow velocities across the cardiac valves using pulsed wave and continuous wave Doppler techniques, and real time colour flow mapping from at least 2 acoustic windows, with recordings on video tape or digital medium, not being a service associated with a service to which an item in Subgroups 1 (with the exception of item 55054) or 3, or another item in this Subgroup (with the exception of items 55118 and 55130), applies, for the investigation of symptoms or signs of cardiac failure, or suspected or known ventricular hypertrophy or dysfunction, or chest pain (R)

55114 M-MODE and 2 DIMENSIONAL REAL TIME ECHOCARDIOGRAPHIC EXAMINATION of the heart from at least 2 acoustic windows, with measurement of blood flow velocities across the cardiac valves using pulsed wave and continuous wave Doppler techniques, and real time colour flow mapping from at least 2 acoustic windows, with recordings on video tape or digital medium, not being a service associated with a service to which an item in Subgroups 1 (with the exception of item 55054) or 3, or another item in this Subgroup (with the exception of items 55118 and 55130), applies, for the investigation of suspected or known acquired valvular, aortic, pericardial, thrombotic, or embolic disease, or heart tumour (R)

55115 M-MODE and 2 DIMENSIONAL REAL TIME ECHOCARDIOGRAPHIC EXAMINATION of the heart from at least 2 acoustic windows, with measurement of blood flow velocities across the cardiac valves using pulsed wave and continuous wave Doppler techniques, and real time colour flow mapping from at least 2 acoustic windows, with recordings on video tape or digital medium, not being a service associated with a service to which an item in Subgroups 1 (with the exception of item 55054) or 3, or another item in this Subgroup (with the exception of items 55118 and 55130), applies, for the investigation of symptoms or signs of congenital heart disease (R)

55116 EXERCISE STRESS ECHOCARDIOGRAPHY performed in conjunction with item 11712, with two-dimensional recordings before exercise (baseline) from at least three acoustic windows and matching recordings from the same windows at, or immediately after, peak exercise, not being a service associated with a service to which an item in Subgroups 1 (with the exception of item 55054) or 3, or another item in this Subgroup applies (with the exception of items 55118 and 55130). Recordings must be made on digital media with equipment permitting display of baseline and matching peak images on the same screen (R)

55117 PHARMACOLOGICAL STRESS ECHOCARDIOGRAPHY performed in conjunction with item 11712, with two-dimensional recordings before drug infusion (baseline) from at least three acoustic


January 2016

Group I1 Ultrasoundwindows and matching recordings from the same windows at least twice during drug infusion, including a recording at the peak drug dose not being a service associated with a service to which an item in Subgroups 1 (with the exception of item 55054) or 3, or another item in this Subgroup, applies (with the exception of items 55118 and 55130). Recordings must be made on digital media with equipment permitting display of baseline and matching peak images on the same screen (R)

Subgroup 2 Cardiac55118 HEART, 2 DIMENSIONAL REAL TIME TRANSOESOPHAGEAL EXAMINATION of, from at

least two levels, and in more than one plane at each level:(a) with:

(i) real time colour flow mapping and, if indicated, pulsed wave Doppler examination; and (ii) recordings on video tape or digital medium; and(b) not being an intra-operative service or a service associated with a service to which an item in Subgroups 1 (with the exception of item 55054) or 3, applies (R)

55130 INTRA-OPERATIVE 2 DIMENSIONAL REAL TIME TRANSOESOPHAGEAL ECHOCARDIOGRAPHY incorporating Doppler techniques with colour flow mapping and recording onto video tape or digital medium, performed during cardiac surgery incorporating sequential assessment of cardiac function before and after the surgical procedure - not associated with item 55135 (R)

55135 INTRA-OPERATIVE 2 DIMENSIONAL REAL TIME TRANSOESOPHAGEAL ECHOCARDIOGRAPHY incorporating Doppler techniques with colour flow mapping and recording onto video tape or digital medium, performed during cardiac valve surgery (repair or replacement) incorporating sequential assessment of cardiac function and valve competence before and after the surgical procedure - not associated with item 55130 (R)


January 2016

APPENDIX 4 - LITERATURE SEARCH

The literature search strategies focused on the safety and effectiveness of PCI with stent insertion, and the cost implications associated with PCI with stent insertion.

The initial literature search strategy focused on three key areas: (i) current clinical practice for PCI with stent insertion; (ii) the effectiveness and safety of PCI with stent insertion; and (iii) the cost implications associated with PCI with stent insertion. The searches of EMBASE/Medline and the Cochrane Library are presented below as follows: guideline search (Table A-4.1), clinical evidence search (Table A-4.2) and economic evidence search (Table A-4.3).

Table A-4.1 Search strategy for guideline evidence

Search terms CitationsEMBASE/MedlinePopulation('stable angina pectoris'/exp OR 'chronic stable angina':ab,ti OR ('stable angina':ab,ti AND chronic:ab,ti) OR 'non st segment elevation acute coronary syndrome'/exp OR ('acute coronary syndrome'/exp OR 'acute coronary syndrome':ab,ti OR 'acute coronary syndromes':ab,ti OR 'myocardial infarction':ab,ti OR 'heart attack':ab,ti AND ('non-st elevation':ab,ti OR 'non-st segment':ab,ti OR 'non-st-segment':ab,ti)) OR 'cardiac imaging'/exp OR 'stress echocardiography'/exp OR 'stress echocardiography':ab,ti OR 'myocardial perfusion imaging'/exp OR 'myocardial perfusion imaging':ab,ti OR 'fractional flow reserve'/exp OR 'fractional flow reserve':ab,ti)Intervention('percutaneous coronary intervention'/exp OR 'transluminal coronary angioplasty'/exp OR 'atherectomy'/exp OR 'percutaneous coronary intervention':ab,ti OR pci:ab,ti OR angioplasty:ab,ti OR 'coronary stent'/exp OR 'bare metal stent'/exp OR 'drug-eluting stent':ab,ti OR stent:ab,ti OR 'bare metal':ab,ti OR 'drug eluting':ab,ti OR 'invasive strategy':ab,ti OR 'invasive therapy':ab,ti)Study type('practice guideline'/exp OR 'practice guideline':ab,ti OR 'treatment guideline':ab,ti OR 'treatment guidelines':ab,ti OR 'management guideline':ab,ti OR 'management guidelines':ab,ti OR 'clinical guideline':ab,ti OR 'clinical guidelines':ab,ti OR 'evidence based guideline':ab,ti OR 'evidence based guidelines':ab,ti OR 'consensus guideline':ab,ti OR 'consensus guidelines':ab,ti)Limits[english]/lim AND [2007-2015]/py

465


January 2016

Table A-4.2 Search strategy for clinical evidence

Search terms Citations

Level I evidenceEMBASE/MedlinePopulation('stable angina pectoris'/exp OR 'chronic stable angina':ab,ti OR ('stable angina':ab,ti AND chronic:ab,ti) OR 'non st segment elevation acute coronary syndrome'/exp OR ('acute coronary syndrome'/exp OR 'acute coronary syndrome':ab,ti OR 'acute coronary syndromes':ab,ti OR 'myocardial infarction':ab,ti OR 'heart attack':ab,ti AND ('non-st elevation':ab,ti OR 'non-st segment':ab,ti OR 'non-st-segment':ab,ti)) OR 'cardiac imaging'/exp OR 'stress echocardiography'/exp OR 'stress echocardiography':ab,ti OR 'myocardial perfusion imaging'/exp OR 'myocardial perfusion imaging':ab,ti OR 'fractional flow reserve'/exp OR 'fractional flow reserve':ab,ti)Intervention('percutaneous coronary intervention'/exp OR 'transluminal coronary angioplasty'/exp OR 'atherectomy'/exp OR 'percutaneous coronary intervention':ab,ti OR pci:ab,ti OR angioplasty:ab,ti OR 'coronary stent'/exp OR 'bare metal stent'/exp OR 'drug-eluting stent':ab,ti OR stent:ab,ti OR 'bare metal':ab,ti OR 'drug eluting':ab,ti OR 'invasive strategy':ab,ti OR 'invasive therapy':ab,ti)Study type('meta analysis'/exp OR 'meta analysis':ab,ti OR 'systematic review'/exp OR 'systematic review':ab,ti OR 'pooled analysis':ab,ti OR ('review'/exp OR 'review':ab,ti AND (systemat*:ab,ti OR pool*:ab,ti)))Limits[english]/lim AND [2007-2015]/py

212

Cochrane Library (CDSR, Other Reviews, HTA)Population(stable AND angina) OR (('non-ST elevation' OR 'non-ST segment') AND 'acute coronary syndrome') OR (cardiac AND imaging) OR 'stress echocardiography' OR 'myocardial perfusion imaging' OR 'fractional flow reserve' in Title, Abstract, KeywordsIntervention''percutaneous coronary intervention' OR angioplasty OR atherectomy OR pci OR 'coronary stent' OR 'bare metal stent' OR 'drug-eluting stent' OR 'invasive strategy' OR 'invasive treatment' in Title, Abstract, KeywordsLimitsPublication Year from 2007 to 2015

22


January 2016


Level II evidenceEMBASE/MedlinePopulation('stable angina pectoris'/exp OR 'chronic stable angina':ab,ti OR ('stable angina':ab,ti AND chronic:ab,ti) OR 'non st segment elevation acute coronary syndrome'/exp OR ('acute coronary syndrome'/exp OR 'acute coronary syndrome':ab,ti OR 'acute coronary syndromes':ab,ti OR 'myocardial infarction':ab,ti OR 'heart attack':ab,ti AND ('non-st elevation':ab,ti OR 'non-st segment':ab,ti OR 'non-st-segment':ab,ti)) OR 'cardiac imaging'/exp OR 'stress echocardiography'/exp OR 'stress echocardiography':ab,ti OR 'myocardial perfusion imaging'/exp OR 'myocardial perfusion imaging':ab,ti OR 'fractional flow reserve'/exp OR 'fractional flow reserve':ab,ti)Intervention('percutaneous coronary intervention'/exp OR 'transluminal coronary angioplasty'/exp OR 'atherectomy'/exp OR 'percutaneous coronary intervention':ab,ti OR pci:ab,ti OR angioplasty:ab,ti OR 'coronary stent'/exp OR 'bare metal stent'/exp OR 'drug-eluting stent':ab,ti OR stent:ab,ti OR 'bare metal':ab,ti OR 'drug eluting':ab,ti OR 'invasive strategy':ab,ti OR 'invasive therapy':ab,ti)Study type('comparative study'/exp OR 'comparative study':ab,ti OR 'clinical trial'/exp OR 'clinical trial':ab,ti OR 'randomized controlled trial'/exp OR 'randomization'/exp OR 'single blind procedure'/exp OR 'double blind procedure'/exp OR 'triple blind procedure'/exp OR 'crossover procedure'/exp OR 'placebo'/exp OR placebo*:ab,ti OR random*:ab,ti OR rct:ab,ti OR 'single blind':ab,ti OR 'single blinded':ab,ti OR 'double blind':ab,ti OR 'double blinded':ab,ti OR 'treble blind':ab,ti OR 'treble blinded':ab,ti OR 'triple blind':ab,ti OR 'triple blinded':ab,ti)Limits[english]/lim AND [2007-2015]/py

1995

Cochrane Library (CCTR)Population(stable AND angina) OR (('non-ST elevation' OR 'non-ST segment') AND 'acute coronary syndrome') OR (cardiac AND imaging) OR 'stress echocardiography' OR 'myocardial perfusion imaging' OR 'fractional flow reserve' in Title, Abstract, KeywordsIntervention''percutaneous coronary intervention' OR angioplasty OR atherectomy OR pci OR 'coronary stent' OR 'bare metal stent' OR 'drug-eluting stent' OR 'invasive strategy' OR 'invasive treatment' in Title, Abstract, KeywordsLimitsPublication Year from 2007 to 2015

876


January 2016

Table A-4.3 Search strategy for economic evidence


Level I evidenceEMBASE/MedlinePopulation('stable angina pectoris'/exp OR 'chronic stable angina':ab,ti OR ('stable angina':ab,ti AND chronic:ab,ti) OR 'non st segment elevation acute coronary syndrome'/exp OR ('acute coronary syndrome'/exp OR 'acute coronary syndrome':ab,ti OR 'acute coronary syndromes':ab,ti OR 'myocardial infarction':ab,ti OR 'heart attack':ab,ti AND ('non-st elevation':ab,ti OR 'non-st segment':ab,ti OR 'non-st-segment':ab,ti)) OR 'cardiac imaging'/exp OR 'stress echocardiography'/exp OR 'stress echocardiography':ab,ti OR 'myocardial perfusion imaging'/exp OR 'myocardial perfusion imaging':ab,ti OR 'fractional flow reserve'/exp OR 'fractional flow reserve':ab,ti)Intervention('percutaneous coronary intervention'/exp OR 'transluminal coronary angioplasty'/exp OR 'atherectomy'/exp OR 'percutaneous coronary intervention':ab,ti OR pci:ab,ti OR angioplasty:ab,ti OR 'coronary stent'/exp OR 'bare metal stent'/exp OR 'drug-eluting stent':ab,ti OR stent:ab,ti OR 'bare metal':ab,ti OR 'drug eluting':ab,ti OR 'invasive strategy':ab,ti OR 'invasive therapy':ab,ti)Study type('cost effectiveness analysis'/exp OR 'cost effectiveness':ab,ti OR 'economic evaluation'/exp OR 'economic evaluation':ab,ti OR 'health economics'/exp OR 'health economic':ab,ti OR 'cost minimization analysis'/exp OR 'cost minimization':ab,ti OR 'cost minimisation':ab,ti OR 'cost utility analysis'/exp OR 'cost utility':ab,ti OR 'quality adjusted life year'/exp OR 'quality adjusted life year':ab,ti OR 'qaly'/exp OR 'qaly':ab,ti OR 'life year saved':ab,ti)Limits[english]/lim AND [2007-2015]/py

362

Cochrane Library (Economic Evaluations)Population(stable AND angina) OR (('non-ST elevation' OR 'non-ST segment') AND 'acute coronary syndrome') OR (cardiac AND imaging) OR 'stress echocardiography' OR 'myocardial perfusion imaging' OR 'fractional flow reserve' in Title, Abstract, KeywordsIntervention'percutaneous coronary intervention' OR angioplasty OR atherectomy OR pci OR 'coronary stent' OR 'bare metal stent' OR 'drug-eluting stent' OR 'invasive strategy' OR 'invasive treatment' in Title, Abstract, KeywordsLimitsPublication Year from 2007 to 2015

9


January 2016

APPENDIX 5 - NHMRC TOOLS FOR ASSESSING THE EVIDENCE

The levels of evidence hierarchy developed by the NHMRC (Table A-5.1) were used to select studies according to study design. The evidence base was appraised in accordance with the five-component body of evidence matrix recommended by the NHMRC (2009), which considers the evidence base (in terms of quantity, level and quality), the consistency of results, the potential clinical impact, and the generalisability and applicability of the evidence.

The quality of included clinical studies was assessed using a study-specific quality assessment checklist adapted from the NHMRC. The quality assessment checklists for each included study are presented in Appendix 8.

Table A-5.1 Designations of levels of evidence for interventional studies

Level InterventionIa A systematic review of Level II studies

II A randomised controlled trial

III-1 A pseudo-randomised controlled trial (i.e. alternate allocation or some other method)

III-2 A comparative study with concurrent controls: Non-randomised, experimental trialb

Cohort study

Case-control study

Interrupted time series with a control group

III-3 A comparative study without concurrent controls: Historical control study

Two or more single arm studyc

Interrupted time series without a parallel control group

IV Case series with either post-test or pre-test/post-test outcomesSource: National Health and Medical Research Council. NHMRC Levels of evidence and grades for recommendations for developers of guidelines. Canberra: National Health and Medical Research Council, 2009.a A systematic review will only be assigned a level of evidence as high as the studies it contains, excepting where those studies are of Level II evidence. Systematic reviews of Level II evidence provide more data than the individual studies and any meta-analyses will increase the precision of the overall results, reducing the likelihood that the results are affected by chance. Systematic reviews of lower level evidence present results of likely poor internal validity and thus are rated on the likelihood that the results have been affected by bias, rather than whether the systematic review itself is of good quality. Systematic review quality should be assessed separately. A systematic review should consist of at least two studies. In systematic reviews that include different study designs, the overall level of evidence should relate to each individual outcome/result, as different studies (and study designs) might contribute to each different outcome.b This also includes controlled before-and-after (pre-test/post-test) studies, as well as adjusted indirect comparisons (i.e. utilise A vs B and B vs C, to determine A vs C with statistical adjustment for B).c Comparing single arm studies i.e. case series from two studies. This would also include unadjusted indirect comparisons (i.e. utilise A vs B and B vs C, to determine A vs C but where there is no statistical adjustment for B).


January 2016

APPENDIX 6 - ADDITIONAL ANALYSES OF SECONDARY DATA

A-6.1 - Use of a coronary pressure wire

While the majority of the secondary data analysis in Section 2.5.2 focused on MBS items 38300 to 38318, one additional MBS item was identified as being relevant to this Review. Data describing the use of MBS item 38241 (use of a coronary pressure wire during selective coronary angiography to measure fractional flow reserve and coronary flow reserve) has been summarised below, based on services processed between July 2009 and June 2014, inclusive.

Data presented in Table A-6.1 and Table A-6.2 show that a substantial increase occurred in the use of MBS item 38241 over a five-year period up to 2013-14, as well as the corresponding benefits paid. Figure A-6.1 shows that this growth took place throughout Australia, with annual increases in services per capita being observed in nearly all states and territories over that time. Growth was highest in New South Wales and Queensland and lowest in South Australia and the Australian Capital Territory.

Table A-6.1 Number of services for MBS item 38241, 2009-10 to 2013-14

Description MBS item 2009-10 2010-11 2011-12 2012-13 2013-14 Five-year growth

Use of a coronary pressure wire

38241 481 805 1,486 2,394 3,060 536%

Source: Department of Human Services, Medicare Australia Statistics. Accessed 29 July 2015

Table A-6.2 Benefits paid for MBS item 38241, 2009-10 to 2013-14

Description MBS item 2009-10 2010-11 2011-12 2012-13 2013-14 Five-year growth

Use of a coronary pressure wire

38241 $84,167 $146,553 $258,197 $424,481 $559,375 565%


Figure A-6.1 Number of services per capita (100,000 population) for MBS item 38241, 2009-10 to 2013-14



January 2016

Co-claiming data from 2013-14 indicate that many services for MBS item 38241 do not occur on the same occasion as another PCI-related service. Table A-6.3 shows that only 817 of the 3,060 services (27%) for MBS item 38241 in that financial year were claimed in the same patient and on the same day as one of the main PCI items (MBS items 38300 to 38318).

Table A-6.3 Frequency of co-claiming between PCI items and MBS item 38241

MBS item38300

(N=1,188)n (%)

38303(N=168)n (%)

38306(N=15,971)

n (%)

38309(N=30)n (%)

38312(N=244)n (%)

38315(N=9)n (%)

38318(N=41)n (%)

38241 55 (4.6) 4 (2.4) 743 (4.7) 1 (3.3) 10 (4.1) 1 (11.1) 3 (7.3)Source: Department of Health, Medical Benefits Division, Medicare Financing & Listings Branch, MBS Analytics Section. Data received 10 July 2015.Note: N in the header row refers to the number of occurrences of each PCI number (same patient, same day).Abbreviations: MBS, Medicare Benefits Schedule; PCI, percutaneous coronary intervention.

A-6.2 - Co-claiming of MBS item 38306

Table A-6. shows the patterns of co-claiming between MBS item 38306 (angioplasty with the insertion of stent/s) and the relevant diagnostic radiology and ultrasound items, outlined in Section 3.1.6. Co-claiming data for the 14 most common combinations of services undertaken in 2013-14 was shown in Table 3.1-9. Those co-claiming combinations each accounted for at least 1% of total occasions (same patient, same day) and collectively made up 74% of occasions on which MBS item 38306 was undertaken. Of the 11,887 occasions shown in Table 3.1-9, 91% included two additional items (most often item 38246 for selective coronary angiography and item 59925 for selective coronary arteriography/angiocardiography); 5% included three additional items and 2% included four additional items.

Table A-6.4 shows 24 ‘less common’ co-claiming combinations, all of which included at least five services for MBS item 38306 in the same patient on the same day. The purpose of this analysis was to assess whether the extent of co-claiming changed with an increase in multiple billing of MBS item 38306. The data presented below indicate that in 2013-14 there were 54 occasions on which extensive multiple billing (≥5 services) of MBS item 38306 occurred. On the majority of those occasions (70%), two additional diagnostic radiology services were undertaken. The use of three or four diagnostic radiology items was more common on occasions where extensive multiple billing of item 38306 occurred.

Table A-6.4 Co-claiming data for MBS item 38306 on occasions with extensive multiple billing, 2013-14


N (%)38306 [5] 38246, 59925 14 (0.09)

38306 [5] 38243, 59912 8 (0.05)

38306 [5] 38246, 59912 5 (0.03)

38306 [5] 38218, 38243, 59912, 59925 3 (0.02)

38306 [5] 38215, 38243, 359912 [2] 2 (0.01)

38306 [5] 38218, 59925 2 (0.01)

38306 [5] 38240, 59925 2 (0.01)

38306 [5] 38215, 38243, 59912 1 (0.01)

38306 [5] 38218, 59912 1 (0.01)

38306 [5] 38237, 38246, 59912, 59925 1 (0.01)

38306 [5] 38240, 38243, 59973 1 (0.01)

38306 [5] 38241, 38243, 59912 1 (0.01)


January 2016


N (%)38306 [5] 38241, 38246 1 (0.01)

38306 [5] 38241, 38246, 59925 1 (0.01)

38306 [5] 38243, 59912 [2] 1 (0.01)

38306 [5] 38243, 59925 1 (0.01)

38306 [5] 38246 1 (0.01)

38306 [5] 38246, 38300, 38312, 59925 1 (0.01)

38306 [5] 38246, 38300, 59912 1 (0.01)

38306 [6] 38243, 59912 1 (0.01)

38306 [6] 38246, 59925 1 (0.01)

38306 [7] 38246 1 (0.01)

38306 [8] 38246, 59925 2 (0.01)

38306 [10] 38218, 38246, 59912, 59925 1 (0.01)Source: Department of Health, Medical Benefits Division, Medicare Financing & Listings Branch, MBS Analytics Section. Data received 13 July 2015.Note 1: N in the header row refers to the number of occasions in which the items were co-claimed (same patient, same day).Note 2: Numbers shown in square brackets indicate multiple billing of the preceding MBS item (i.e. item 38306 was billed five or more times in the same patient on the same day).


January 2016

APPENDIX 7 - CLINICAL PRACTICE GUIDELINE LEVELS OF EVIDENCE AND RECOMMENDATION GRADES

A-7.1 NHFA/CSANZTable A-7.1 2006 NHFA/CSANZ guideline: Levels of evidence and grades of recommendationsLevel of evidence

Study design Grade of recommendation

Description

I Evidence obtained from a systematic review of all relevant randomised controlled trials.

A Rich body of high-quality RCT data

II Evidence obtained from at least one properly designed randomised controlled trial.

B Limited body of RCT data or high-quality non-RCT data

III-1 Evidence obtained from well designed pseudo-randomised controlled trials (alternate allocation or some other method).

B

III-2 Evidence obtained from comparative studies with concurrent controls and allocation not randomised (cohort studies), case-control studies, or interrupted time series without a control group.

B

III-3 Evidence obtained from comparative studies with historical control, two or more single-arm studies, or interrupted time series with a parallel control group.

C Limited evidence

IV Evidence obtained from case series, either post-test or pre-test and post-test.

C

D No evidence available – panel consensus judgement

A-7.2 ESC/EACTSTable A-7.2 2014 ESC/EACTS guideline: Levels of evidenceLevel of evidence DescriptionA Data derived from multiple randomised clinical trials or meta-analysis

B Data derived from a single randomised clinical trial or large non-randomised studies.

C Consensus of opinion of the experts and/or small studies, retrospective studies, registries.

Table A-7.3 2014 ESC/EACTS guideline: Classes of recommendationsClasses of recommendations

Definition Suggested wording to use

I Evidence and/or general agreement that a given treatment or procedure is beneficial, useful, effective.

Is recommended/is indicated

II Conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the given treatment or procedure.

-

IIa Weight of evidence/opinion is in favour of usefulness/efficacy. Should be considered

IIb Usefulness/efficacy is less well established by evidence/opinion. May be considered

III Evidence or general agreement that the given treatment or procedure is not useful/effective, and in some cases may be harmful.

Is not recommended


January 2016

A-7.3 ACCF/AHAFigure A-7.4 2012 ACCF/AHA guideline: Levels of evidence and classification of recommendations

Source: 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the diagnosis and management of patients with stable ischemic heart disease. Circulation 2012;126:e354–e471.A recommendation with Level of evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do not lend themselves to clinical trials.Although randomised trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful or effective.* Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as sex, age, history of diabetes, history of prior myocardial infarction, history of heart failure, and prior aspirin use. †For comparative effectiveness recommendations (Class I and IIa; Level of evidence A and B only), studies that support the use of comparator verbs should involve direct comparisons of the treatments or strategies being evaluated.


January 2016

APPENDIX 8 - STUDY QUALITY ASSESSMENT

A-8.1 Systematic reviews

A-8.1.1 Chronic stable angina

Study type: Systematic review Error categories

Citation: Gorenoi, V., M. P. Schönermark, et al. (2011). Percutaneous coronary intervention with optimal medical therapy vs. optimal medical therapy alone for patients with stable angina pectoris. Accessed from the University of York website.

Y N NR NA Quality criteria

A. Was an adequate search strategy used? Was a systematic search strategy reported? I Were the databases searched reported? III Was more than one database searched? III Were search terms reported? IV Did the literature search include hand searching? IV

B. Were the inclusion criteria appropriate and applied in an unbiased way? Were inclusion/exclusion criteria reported? II Was the inclusion criteria applied in an unbiased way? III Was only Level II evidence included? I-IV

C. Was a quality assessment of included studies undertaken? Was the quality of the studies reported? III Was a clear, pre-determined strategy used to assess study quality? IV

D. Were the characteristics and results of the individual studies appropriately summarised?

Were the characteristics of the individual studies reported? III Were baseline demographic and clinical characteristics reported for patients in the

individual studies?IV

Were the results of the individual studies reported? III

E. Were the methods for pooling the data appropriate? If appropriate, was a meta-analysis conducted? III-IV

F. Were the sources of heterogeneity explored? Was a test for heterogeneity applied? III-IV

If there was heterogeneity, was this discussed or the reasons explored? III-IV

Comments: Published in German. Google Translate used to determine methodological characteristics of the study.

Quality rating: Systematic review: Good

[Good/Fair/Poor] Included studies: GoodNote: Quality criteria adapted from NHMRC (2000) How to use the evidence: assessment and application of scientific evidence. NHMRC, Canberra.Assess criterion using Y (yes), N (no), NR (not reported) or NA (not applicable).Error categories as follows: (I) leads to exclusion of the study; (II) automatically leads to a poor rating; (III) leads to a one grade reduction in quality rating (eg, good to fair, or fair to poor); and (IV) errors that are may or may not be sufficient to lead to a decrease in rating.Where applicable, provide clarification for any of the criteria, particularly where it may result in downgrading of the study quality. For quality assessment of systematic reviews, this should include a statement regarding the methodological quality of the studies included in the systematic review.Quality ratings are good, fair or poor.


January 2016

Study type: Systematic review Error cateagories

Citation: D'Ascenzo, F., U. Barbero, et al. (2014) Percutaneous coronary intervention versus coronary artery bypass graft for stable angina: meta-regression of randomized trials. Contemporary Clinical Trials 38: 51-58.


A. Was an adequate search strategy used? Was a systematic search strategy reported? I Were the databases searched reported? III Was more than one database searched? III Were search terms reported? IV

Did the literature search include hand searching? IV




Were the characteristics of the individual studies reported? III Were baseline demographic and clinical characteristics reported for patients in

the individual studies?IV





Comments: Heterogeneity explored but not reported and no indication if reasons explored.

Quality rating: Systematic review: Fair

[Good/Fair/Poor] Included studies: FairNote: Quality criteria adapted from NHMRC (2000) How to use the evidence: assessment and application of scientific evidence. NHMRC, Canberra.Assess criterion using Y (yes), N (no), NR (not reported) or NA (not applicable).Error categories as follows: (I) leads to exclusion of the study; (II) automatically leads to a poor rating; (III) leads to a one grade reduction in quality rating (eg, good to fair, or fair to poor); and (IV) errors that are may or may not be sufficient to lead to a decrease in rating.Where applicable, provide clarification for any of the criteria, particularly where it may result in downgrading of the study quality. For quality assessment of systematic reviews, this should include a statement regarding the methodological quality of the studies included in the systematic review.Quality ratings are good, fair or poor.


January 2016


Citation: Fanari, Z., S. A. Weiss, et al. (2014). "Short, Intermediate and long term outcomes of CABG vs. PCI with DES in Patients With Multivessel Coronary Artery Disease. Meta-Analysis of Six Randomized Controlled Trials." Eur J Cardiovasc Med 3(1): 382-389.




C. Was a quality assessment of included studies undertaken? Was the quality of the studies reported? III

Was a clear, pre-determined strategy used to assess study quality? IV








Comments: No quality assessment undertaken; patient characteristics provided from time point cohorts (i.e. 1 year cohort, 2 year cohort and 5 year cohort); heterogeneity assessed and present in 3/13 analyses; reasons not assessed.


[Good/Fair/Poor] Included studies: Not reportedNote: Quality criteria adapted from NHMRC (2000) How to use the evidence: assessment and application of scientific evidence. NHMRC, Canberra.Assess criterion using Y (yes), N (no), NR (not reported) or NA (not applicable).Error categories as follows: (I) leads to exclusion of the study; (II) automatically leads to a poor rating; (III) leads to a one grade reduction in quality rating (eg, good to fair, or fair to poor); and (IV) errors that are may or may not be sufficient to lead to a decrease in rating.Where applicable, provide clarification for any of the criteria, particularly where it may result in downgrading of the study quality. For quality assessment of systematic reviews, this should include a statement regarding the methodological quality of the studies included in the systematic review.Quality ratings are good, fair or poor.


January 2016


Citation: Bangalore, S., S. Pursnani, et al. (2013). "Percutaneous coronary intervention versus optimal medical therapy for prevention of spontaneous myocardial infarction in subjects with stable ischemic heart disease." Circulation 127(7): 769-781.










F. Were the sources of heterogeneity explored? Was a test for heterogeneity applied? III-IV If there was heterogeneity, was this discussed or the reasons explored? III-IV

Comments: Re quality assessment, authors note that ‘all included studies fared similarlyon the risk of bias assessment, and we therefore did notpursue a sensitivity analysis based on quality of trials’;




January 2016


Citation: Morrone, D., A. Horne, et al. (2013). "Bayesian meta-analysis of percutaneous coronary intervention compared to optimal medical therapy in stable ischemic heart disease patients." European Heart Journal 34: 176.


A. Was an adequate search strategy used? Was a systematic search strategy reported? I Were the databases searched reported? III

Was more than one database searched? III Were search terms reported? IV


B. Were the inclusion criteria appropriate and applied in an unbiased way? Were inclusion/exclusion criteria reported? II Was the inclusion criteria applied in an unbiased way? III

Was only Level II evidence included? I-IV









Comments: Abstract only so minimal reporting of methodology; only Medline searched; no search terms provided; no definition of optimal medical therapy provided; no individual study characteristics or results reported; heterogeneity not assessed.

Quality rating: Systematic review: Poor

[Good/Fair/Poor] Included studies: UnknownNote: Quality criteria adapted from NHMRC (2000) How to use the evidence: assessment and application of scientific evidence. NHMRC, Canberra.Assess criterion using Y (yes), N (no), NR (not reported) or NA (not applicable).Error categories as follows: (I) leads to exclusion of the study; (II) automatically leads to a poor rating; (III) leads to a one grade reduction in quality rating (eg, good to fair, or fair to poor); and (IV) errors that are may or may not be sufficient to lead to a decrease in rating.Where applicable, provide clarification for any of the criteria, particularly where it may result in downgrading of the study quality. For quality assessment of systematic reviews, this should include a statement regarding the methodological quality of the studies included in the systematic review.Quality ratings are good, fair or poor.


January 2016


Citation: Thomas, S., R. Gokhale, et al. (2013). "A Meta-analysis of Randomized Controlled Trials Comparing Percutaneous Coronary Intervention With Medical Therapy in Stable Angina Pectoris." Canadian Journal of Cardiology 29(4): 472-482.











Comments: Heterogeneity explored and reported for all outcomes; angina relief was heterogeneous – noted but not explored. Not an outcome requested for this Review (although has been included) so has not affected quality assessment.


[Good/Fair/Poor] Included studies: Body of evidence rated high for all outcomes except angina relief (low).

Note: Quality criteria adapted from NHMRC (2000) How to use the evidence: assessment and application of scientific evidence. NHMRC, Canberra.Assess criterion using Y (yes), N (no), NR (not reported) or NA (not applicable).Error categories as follows: (I) leads to exclusion of the study; (II) automatically leads to a poor rating; (III) leads to a one grade reduction in quality rating (eg, good to fair, or fair to poor); and (IV) errors that are may or may not be sufficient to lead to a decrease in rating.Where applicable, provide clarification for any of the criteria, particularly where it may result in downgrading of the study quality. For quality assessment of systematic reviews, this should include a statement regarding the methodological quality of the studies included in the systematic review.Quality ratings are good, fair or poor.


January 2016


Citation: Pursnani, S., F. Korley, et al. (2012) Percutaneous coronary intervention versus optimal medical therapy in stable coronary artery disease: a systematic review and meta-analysis of randomized clinical trials (Provisional abstract). Circulation: Cardiovascular Interventions 5(4): 476-490.












Comments: Heterogeneity measured and REM used for analysis. Not discussed in any greater detail.




January 2016


Citation: Stergiopoulos, K. and D. L. Brown (2012). "Initial coronary stent implantation with medical therapy vs medical therapy alone for stable coronary artery disease: Meta-analysis of randomized controlled trials." Archives of Internal Medicine 172(4): 312-319.



Was more than one database searched? III Were search terms reported? IV Did the literature search include hand searching? IV









Comments: Only Medline database searched.




January 2016


Citation: Wijeysundera, H. C., B. K. Nallamothu, et al. (2010). "Meta-analysis: effects of percutaneous coronary intervention versus medical therapy on angina relief." Ann Intern Med 152(6): 370-379.











Comments:




January 2016


Citation: Jeremias, A., S. Kaul, et al. (2009). "The impact of revascularization on mortality in patients with nonacute coronary artery disease." Am J Med 122(2): 152-161.













Comments: No quality assessment of included studies carried out.


[Good/Fair/Poor] Included studies: Nor reportedNote: Quality criteria adapted from NHMRC (2000) How to use the evidence: assessment and application of scientific evidence. NHMRC, Canberra.Assess criterion using Y (yes), N (no), NR (not reported) or NA (not applicable).Error categories as follows: (I) leads to exclusion of the study; (II) automatically leads to a poor rating; (III) leads to a one grade reduction in quality rating (eg, good to fair, or fair to poor); and (IV) errors that are may or may not be sufficient to lead to a decrease in rating.Where applicable, provide clarification for any of the criteria, particularly where it may result in downgrading of the study quality. For quality assessment of systematic reviews, this should include a statement regarding the methodological quality of the studies included in the systematic review.Quality ratings are good, fair or poor.


January 2016


Citation: Trikalinos, T. A., A. A. Alsheikh-Ali, et al. (2009). "Percutaneous coronary interventions for non-acute coronary artery disease: a quantitative 20-year synopsis and a network meta-analysis." Lancet 373(9667): 911-918.













Comments: Only Medline searched; no study quality assessment; network meta-analysis performed using direct and indirect comparisons; no information provided on individual study characteristics or results.




January 2016


Citation: Schomig, A., J. Mehilli, et al. (2008). "A meta-analysis of 17 randomized trials of a percutaneous coronary intervention-based strategy in patients with stable coronary artery disease." J Am Coll Cardiol 52(11): 894-904.


A. Was an adequate search strategy used? Was a systematic search strategy reported? I Were the databases searched reported? III Was more than one database searched? III

Were search terms reported? IV Did the literature search include hand searching? IV










Comments: No quality assessment reported; re heterogeneity, presented both REM and FEM results and performed subgroup analyses.




January 2016


Citation: Ioannidis, J. P. and D. G. Katritsis (2007). "Percutaneous coronary intervention for late reperfusion after myocardial infarction in stable patients." Am Heart J 154(6): 1065-1071.












Comments: No quality assessment of included studies.




January 2016


Citation: Takagi, H., T. Watanabe, et al. (2014). "A review with meta-analysis of observational studies for survival following off-pump coronary artery bypass versus drug-eluting stent implantation." Interactive Cardiovascular and Thoracic Surgery 18(6): 807-813.



B. Were the inclusion criteria appropriate and applied in an unbiased way? Were inclusion/exclusion criteria reported? II Was the inclusion criteria applied in an unbiased way? III

Was only Level II evidence included? I-IV









Comments: No quality assessment undertaken; meta-analysis of observational study data but analysed separately adjusted and unadjusted results; heterogeneity explored via exclusion of studies and meta-regression.




January 2016

A-8.1.2 Diagnosis of NSTE-ACS


Citation: Hoenig, M. R., C. N. Aroney, et al. (2010). "Early invasive versus conservative strategies for unstable angina and non-ST elevation myocardial infarction in the stent era." Cochrane Database of Systematic Reviews (Online): CD004815.











Comments: Heterogeneity reported and possible reasons for it discussed but no further assessment undertaken.


[Good/Fair/Poor] Included studies: Fair overall (two GPIIbIIIa trials good quality)Note: Quality criteria adapted from NHMRC (2000) How to use the evidence: assessment and application of scientific evidence. NHMRC, Canberra.Assess criterion using Y (yes), N (no), NR (not reported) or NA (not applicable).Error categories as follows: (I) leads to exclusion of the study; (II) automatically leads to a poor rating; (III) leads to a one grade reduction in quality rating (eg, good to fair, or fair to poor); and (IV) errors that are may or may not be sufficient to lead to a decrease in rating.Where applicable, provide clarification for any of the criteria, particularly where it may result in downgrading of the study quality. For quality assessment of systematic reviews, this should include a statement regarding the methodological quality of the studies included in the systematic review.Quality ratings are good, fair or poor.


January 2016


Citation: Angeli, F., P. Verdecchia, et al. (2014). "Early invasive versus selectively invasive strategy in patients with non-ST-segment elevation acute coronary syndrome: Impact of age." Catheterization and Cardiovascular Interventions 83(5): 686-701.












Comments: No quality assessment undertaken.




January 2016


Citation: O'Donoghue, M. L., A. Vaidya, et al. (2012). "An invasive or conservative strategy in patients with diabetes mellitus and non-ST-segment elevation acute coronary syndromes: A collaborative meta-analysis of randomized trials." Journal of the American College of Cardiology 60(2): 106-111.














Comments: Only Medline database searched but trials included similar to those in other reviews; no quality assessment undertaken; no baseline characteristics by trial but were reported for diabetes/no diabetes groups.




January 2016


Citation: Swahn, E., J. Alfredsson, et al. (2012). "Early invasive compared with a selective invasive strategy in women with non-ST-elevation acute coronary syndromes: A substudy of the OASIS 5 trial and a meta-analysis of previous randomized trials." European Heart Journal 33(1): 51-60.













Comments: Only one database searched but contacted authors for other studies and did handsearching; no quality assessment undertaken.




January 2016


Citation: Charytan, D. M., L. Wallentin, et al. (2009). "Early angiography in patients with chronic kidney disease: A collaborative systematic review." Clinical Journal of the American Society of Nephrology 4(6): 1032-1043.











Comments:




January 2016


Citation: O'Donoghue, M., W. E. Boden, et al. (2008). "Early invasive vs conservative treatment strategies in women and men with unstable angina and non-ST-segment elevation myocardial infarction: A meta-analysis." JAMA - Journal of the American Medical Association 300(1): 71-80.













Comments: No quality assessment undertaken; baseline characteristics reported but not by study, only by treatment group and gender.




January 2016


Citation: Qayyum, R., M. R. Khalid, et al. (2008). "Systematic review: Comparing routine and selective invasive strategies for the acute coronary syndrome." Annals of Internal Medicine 148(3): 186-196.











Comments:




January 2016


Citation: Tarantini, G., R. Razzolini, et al. (2007). "Patient risk profile and benefit from an invasive approach in the initial management of non-ST-segment elevation acute coronary syndrome." Journal of Cardiovascular Medicine 8(10): 799-802.














Comments: Only PubMed/Medline searched, no search terms reported; no quality assessment undertaken; little information reported for the individual trials.




January 2016

A-8.1.3 Considered at high risk based on diagnostic testing


Citation: Gada, H., A. J. Kirtane, et al. (2015). "Meta-analysis of trials on mortality after percutaneous coronary intervention compared with medical therapy in patients with stable coronary heart disease and objective evidence of myocardial ischemia." American Journal of Cardiology 115(9): 1194-1199.


A. Was an adequate search strategy used? Was a systematic search strategy reported? I

Were the databases searched reported? III Was more than one database searched? III

Were search terms reported? IV Did the literature search include hand searching? IV










Comments: No details provided on conduct of literature search; no quality assessment undertaken.




January 2016


Citation: Stergiopoulos, K., W. E. Boden, et al. (2014). "Percutaneous coronary intervention outcomes in patients with stable obstructive coronary artery disease and myocardial ischemia: A collaborative meta-analysis of contemporary randomized clinical trials." JAMA Internal Medicine 174(2): 232-240.











Comments: Literature search well documented; inclusion criteria clearly reported; study quality undertaken using Jadad scale; individual trial characteristics and results reported; heterogeneity present only in unplanned revascularisation and angina outcomes.




January 2016

APPENDIX 9 - EARLY VS DELAYED INVASIVE STRATEGIES IN PATIENTS WITH NSTE-ACS

Table A-9.1 Selected results of excluded SR/MAs: NSTE-ACS – early vs delayed invasive strategies

Study ID Outcome Studies (patients)

Risk estimate (95% CI); p value

Author’s conclusion/comment

Milasinovic 2015

MortalityMIRecurrent ischaemia

10 (6089)9 (6035)7 (5762)

OR 0.83 (0.64, 1.08); 0.16OR 1.02 (0.63, 1.64); 0.94OR 0.56 (0.40, 0.79); 0.001

Early invasive strategy appears to reduce the occurrence of recurrent ischemia, but confers no mortality benefit. The true effect on the occurrence of new MI is obscured by the high between-study heterogeneity that stems mainly from non-uniform timing of early intervention and new MI definitions across the trials.

Jiang 2014 Mortality103

< 48 hr vs > 48 hr< 24 hr vs > 24 hr< 12 hr vs > 12 hr< 2 hr vs > 2 hr

MI104

< 48 hr vs > 48 hr< 24 hr vs > 24 hr< 12 hr vs > 12 hr< 2 hr vs > 2 hr< 3 hr vs > 3 hr

Stroke102

< 48 hr vs > 48 hr< 24 hr vs > 24 hr< 12 hr vs > 12 hr

Major bleeding103

< 48 hr vs > 48 hr< 24 hr vs > 24 hr< 12 hr vs > 12 hr< 2 hr vs > 2 hr105

NRNRNRNR

5 (5022)7 (5328)5 (1987)2 (542)3 (952)

NRNRNR

5 (5076)6 (5240)4 (1845)3 (917)

OR 0.86 (0.70, 1.06); 0.15OR 0.86 (0.70, 1.06); 0.16OR 0.96 (0.62, 1.48); 0.86OR 1.07 (0.47, 2.44); 0.86

OR 0.83 (0.52, 1.32); 0.43OR 0.97 (0.62, 1.51); 0.88OR 1.03 (0.52, 2.06); 0.93OR 2.01 (1.29, 3.14); 0.002OR 1.34 (0.58, 3.08); 0.49

OR 0.86 (0.55, 1.34); 0.51OR 0.83 (0.48, 1.46); 0.53OR 0.54 (0.14, 1.99); 0.35

OR 0.81 (0.58, 1.13); 0.22OR 0.81 (0.58, 1.13); 0.22OR 0.67 (0.36, 1.26); 0.21OR 0.61 (0.28, 1.30); 0.20

Angiography within 12 hours reduces the risk of major bleeding. There is no need to push for angiography within 2 hours.*It should be noted that angiography within 12 hours only reduces bleeding when the results from 1 month and 6-12 month timeframes are combined (OR 0.65; (95% CI 0.44, 0.96). It is not appropriate to pool the results from the time point analyses because data from the same groups of patients are being pooled; thus, patient data is being double-counted. Reduction in bleeding at < 12 hr vs > 12 hr does not reach statistical significance at 1 month follow-up or 6-12 months follow-up.

Nairooz 2014106

MortalityMIMajor bleeding

NRNRNR

OR 0.77 (0.17, 3.45); 0.73OR 1.57 (0.58, 4.20); 0.37OR 0.48 (0.16, 1.43); 0.19

Immediate stenting is associated with significantly more procedural complications [not shown here], but may result in less bleeding and improved survival. Strategies to reduce intraprocedural complications further as we move towards earlier intervention are needed.

103 It is unclear what follow-up time is included here. 104 Meta-analysis included data up to 1 month follow-up and 6-12 month follow-up from the same studies. Due to the issue of double counting, only results for 6-12 follow-up data are presented here. 105 Follow-up not specified. 106 Conference abstract assessing stenting specifically and not just an invasive strategy. Included 5 observational studies and 2 RCTs; 5 studies were in NSTEMI patients and 2 trials were in STEMI patients.


January 2016

Study ID Outcome Studies (patients)

Risk estimate (95% CI); p value

Author’s conclusion/comment

Navarese 2013107

Mortality – RCTMortality – OBSMI – RCTMI – OBSMajor bleeding – RCTMajor bleeding - OBS

7 (5370)4 (77,499)7 (5370)3 (70,253)7 (5370)3 (21,147)

OR 0.83 (0.64, 1.09); 0.18OR 0.80 (0.63, 1.02); 0.07OR 1.15 (0.65, 2.01); 0.63OR 0.86 (0.69, 1.08); 0.19OR 0.76 (0.56, 1.04); 0.09OR 1.12 (0.69, 1.82); 0.64

At present, there is insufficient evidence either in favour of or against an early invasive approach in the NSTE-ACS population. A more definitive RCT is warranted to guide clinical practice.

Rajpurohit 2013108

MortalityMIDeath/MI within 30 daysRepeat revasc.Bleeding

6 (11,904)6 (11,904)7 (13,762)5 (13,132)5 (8873)

OR 0.57 (0.23, 1.38); 0.21OR 0.93 (0.64, 1.34); 0.69OR 0.83 (0.62, 1.10); 0.20OR 1.33 (1.14, 1.56); 0.0004OR 0.76 (0.63, 0.91); 0.003

In NSTE-ACS patients early PCI does not reduce the odds of the composite endpoint of death or non-fatal MI at 30 day. This strategy is associated with lower odds of bleeding and higher odds of repeat revascularisation at 30 days than a strategy of delayed PCI.

Damman 2012b

CV deathMICV death/MIFIR low-riskFIR intermediate-riskFIR high-risk

3 (2116)3 (2116)3 (2116)3 (NR)3 (NR)3 (NR)

HR 1.05 (0.75, 1.47); 0.78109

HR 0.98 (0.75, 1.28); 0.88HR 0.93 (0.75, 1.16); 0.54HR 0.97 (0.63, 1.48); 0.89 (int)HR 0.70 (0.49, 0.99)HR 1.14 (0.76, 1.71)

The timing of angiography was not related to long-term cardiovascular mortality or MI.

Katritisis 2011

DeathMIMajor bleedingRecurrent ischaemiaRepeat interventionStrokeDeath/MI/stroke

4 (NR)4 (NR)4 (NR)4 (NR)4 (NR)3 (NR)3 (NR)

RR 0.85 (0.64, 1.11); 0.24RR 0.94 (0.61, 1.45); 0.79RR 0.78 (0.57, 1.07); 0.13RR 0.59 (0.38, 0.92); 0.02RR 0.96 (0.67, 1.38); 0.84RR 0.84 (0.47, 1.49); 0.55RR 0.91 (0.82, 1.01); 0.09

Early catheterisation and intended coronary intervention within the first day of admittance is superior to a strategy of preceding anticoagulation and subsequent intervention in patients with NSTE-ACS. It reduces residual ischaemia and the duration of hospital stay and may also reduce complications, such as bleeding, and major events (death, MI, or stroke).

Source: Milasinovic et al (2015): Figure 2, p 51; Jiang et al (2014): Table 3 and Figure 3; Nairooz et al (2014): Table; Navarese et al (2013): Figures 1-3, p 265-267; Rajpurohit et al (2013): Figures 1-5, p 227-229; Damman et al (2012b): Table 4, p 196; Katritisis et al (2011): Table 4, p 37. Note: Statistically significant results shown in bold. Abbreviations: CI, confidence interval; hr, hours; int, p value for interaction; MI, myocardial infarction; NA, not applicable; OBS, observational study; OR, odds ratio; RCT, randomised controlled trial; revasc., revascularisation; RR, relative risk.

107 A conference abstract by Navarese 2013 describing this study has been excluded from this table. 108 Specifically relating to early or delayed PCI and not just an invasive strategy.109 All analyses adjusted for FRISC II/ICTUS/RITA 3 (FIR) risk score and inverse probability of treatment weight.


Documents

PCI Review Report · Web viewCPG Clinical practice guideline CSANZ Cardiology Society of Australia and New Zealand CTA Computed tomography angiography CTCA Computed tomography coronary