CORONARY REVASCULARIZATION IN DIABETES MELLITUS AND MULTIVESSEL CAD :REVISITING THE EVIDENCE
Dr. Satyam Rajvanshi
Introduction Coronary artery disease (CAD) is a major
cause of morbidity and mortality among patients with diabetes mellitus
Compared to nondiabetic patients, patients with diabetes are more likely to have CAD, which is most often multivessel, and to have episodes of silent ischemia
Diabetic patients with CAD have a lower longterm survival rate than nondiabetic patients with CAD
Diabetics comprise 25 to 30 percent of those who undergo revascularization
The indications for revascularization, are generally similar in patients with and without diabetes
Short and longterm results of revascularization with PCI or CABG are often worse in diabetics
CURRENT RECOMMENDATIONS
Trial basis: PCI vs CABG
Trial basis: PCI vs CABG in DM
1st RCT of coronary revascularization in diabetic patients with complex CAD
510 patients multivessel or complex single-vessel CAD randomized to PCI plus stenting (and routine abciximab) or CABG
BMS used initially, later switched to Cypher (sirolimus drug-eluting) stents was made when these became available
Primary outcome - CE of all-cause mortality, MI, and stroke
Secondary outcome - repeat revascularization added to the primary outcome events
At 1 year NS for CE of death, MI, and stroke NS for all-cause mortality Significantly less frequent CE of death, MI,
stroke, or repeat revascularization in CABG (driven by less repeat revasc. but more strokes with CABG)
[Overall, Just like SYNTAX]
But PCI could not meet the prespecified Non-inferiority criteria to CABG!
SYNTAX: The Diabetic cohort 25% of 1800 study participants had diabetes “ALL-comers” design - consecutive
enrollment of all eligible patients with three-vessel or left main coronary artery disease – One of its kind!
Inclusion – Previously untreated CAD (≥50% target vessel stenosis) with stable/unstable angina or atypical chest pain
Exclusion – previous PCI or CABG, acute MI, or need for concomitant cardiac surgery
Primary outcome – CE of MACCE (death from any cause, stroke, MI, or repeat revascularization)
Follow-up upto 60 months
AT 5 yrs CABG vs PCI in DM NS in CE of all-cause death, MI, or stroke NS in individual components - all-cause death,
stroke, or MI MACCE (including repeat revascularization) less
with CABG driven by less Repeat revascularization Low SYNTAX score (≤ 22) subgroup
Rates of MACCE similar but repeat revascularization remained less frequent with CABG
Odds were stacked against PCI – at the beginning itself!
More complete revascularization in CABG Hard end points combined with soft end
points! Had Repeat Revascularization been a
separate (Secondary) outcome – it would have been a negative study!
DM with complex CAD randomized to drug-eluting stents or surgery
Inclusion – only those lesions whose revascularization known to increase survival (Symptom mitigating revascularization excluded)
Extremely slow recruitement, early termination to only 25% of intended participants!
Severely underpowered for its primary endpoint
NS in CE of All-cause death, Nonfatal MI
No firm conclusions about the comparative effectiveness of CABG and PCI made
Freedom from confusion..….?
……. Apparently not!
FREEDOM
Purpose of FREEDOM To determine the superior approach to
revascularization in patients with diabetes and multivessel CAD - contemporary PCI with DES or CABG techniques, both with currently recommended ancillary medical therapies
Methods 2 arm superiority RCT Unblinded, no placebo F/U upto 5 years Sites: 140 worldwide NHLBI funded
Patient Selection: Inclusion Criteria
Diabetes mellitus (Type 1 or Type 2), defined according to the American Diabetes Association as either: fasting plasma glucose elevation on more
than one occasion of ≥ 126 mg/dL classic symptoms of diabetes mellitus with
unequivocal elevation of plasma glucose (2 hour postprandial or random of greater than 200 mg/dL) or
Currently undergoing pharmacological or non-pharmacological treatment for diabetes
Angiographically confirmed multivessel CAD critical (greater than or equal to 70%) lesions in at least two major epicardial vessels in at least two separate coronary artery
territories (LAD, LCX, RCA)] Angiographic characteristics amenable to
both PCI/DES and CABG Indication for revascularization based upon
symptoms of angina and/or objective evidence of myocardial ischemia
Exclusion Criteria Severe congestive heart failure (class III or
IV according to New York Heart Association [NYHA] or pulmonary edema)
Prior CABG surgery; Prior valve surgery; Prior PCI with stent implantation within 6 months of study entry
Stroke within 6 months of study entry; if stroke occurred more than 6 months prior to study entry, must have significant residual neurologic involvement, as reflected in a Rankin Score of greater than 1
Instent restenosis of a target vessel Two or more chronic total occlusions in
major coronary territories Left main stenosis (at least 50%
diameter stenosis) Acute ST elevation MI (Qwave) within 72
hours of study entry requiring revascularization
Abnormal creatine kinase level (greater than twice the normal limit); or abnormal CKMB level at study entry
Intolerance to aspirin or both clopidogrel and ticlopidine
Planned simultaneous surgical procedure unrelated to coronary revascularization (e.g., valve surgery, aneurysmectomy, carotid endarterectomy, or carotid stent)
Prior history of significant bleeding (within 6 months of study entry) that may occur during CABG or PCI/DES related anticoagulation
Significant leukopenia, neutropenia, thrombocytopenia, anemia, or known bleeding diathesis
Pregnancy Severe degree of comorbidities (COPD, CKD, CLD,
Dementia)
Methods continued DES: majority sirolimus or paclitaxel
eluting. Newer generations could be used if approved for use. ASA and clopidogrel for at least 12 months
CABG: encouraged arterial revascularization when able
Medical therapy goals for both groups: LDL <70 BP <130/80 HbA1c <7%
Methods continued Outcomes
Primary Composite of death from any cause, nonfatal
MI, nonfatal stroke Secondary
Major adverse cardiovascular and cerebrovascular events 30 days and 12 months after procedure (includes components of primary end point + revascularization)
Annual all-cause and cardiovascular mortality
Characteristic Ineligible Eligible P value‡
Not enrolled Enrolledn 29657 1409 1900Mean age at screening, y
65.2 ± 10.8 64.4 ± 9.6 63.1 ± 9.1 <.0001
Male 64.7 ± 10.5 63.7 ± 9.4 62.6 ± 9.0 .005 Female 66.2 ± 11.2 66.4 ± 9.7 64.4 ± 9.2 .002Male 67.7% 72.8% 71.4% .38Did not meet angiographic inclusion criteria⁎
85.6% NA NA NA
Clinical exclusion present
57.7% NA NA NA
Prior cardiac surgery or planned cardiac surgery†
32% NA NA NA
Race/ethnicity <.0001 White, non-Hispanic 69.6% 51.3% Black or African American, non-Hispanic 4.7% 2.7% Asian, non-Hispanic 13.3% 9.7% Other, non-Hispanic 4.3% 1.8% Hispanic 8.2% 34.5%Planned management strategy PCI 51.8% 50% NA CABG 33.6% 50% Medical therapy alone 5.8% Unknown 8.8%
Table I. Baseline characteristics for N = 32966 patients screened for FREEDOM trial eligibility⁎Participants needed to have multivessel CAD defined as critical (≥70%) lesions in at least 2 major epicardial vessels. Angiographic characteristics needed to be amenable to both PCI/DES and CABG. Left main disease, in-stent restenosis, and >1 CTO were excluded.†Prior bypass surgery or valvular surgery or valve surgery planned.‡Test of significance for difference between enrolled patients and eligible but not enrolled patients
Overall (n = 1900)History of presenting illness (indication for coronary angiography)
Stable coronary heart disease (1317 participants)
69.3%
ACS (584 participants) 30.7% ST-elevation MI (>72 h before admission) 20.2%
Non–ST-elevation ACS (466 participants) 79.8%
No recurrent/provocable ischemia 33.3%
Provocable ischemia only 23.4% Spontaneous recurrent ischemia 41.3%
Refractory ischemia 1.9%
Table II. History of presenting illness
OverallMedical historyDiabetes mellitus Type 1 4.5%
Type 2 95.5%Complications associated with diabetes 18.0% Diabetic foot ulcer 9.3% Extremity amputation 3.8% Diabetic retinopathy/blindness 39.4% Diabetic nephropathy 32.7% Diabetic neuropathy 54.5%History of high BP 84.8%History of hyperlipidemia 83.7%Prior MI 25.6%Prior stroke 3.2%Peripheral arterial disease 11.2%History of valvular heart disease 1.3%History of arrhythmia 4.8% If yes: permanent pacemaker implanted 20.9% AICD 0.0%History of chronic renal insufficiency 6.8%History of dialysis 0.4%History of COPD or asthma 10.2%Ever smoked 54.5% If yes (n = 91): current smoker 28.8% Ex-smoker (quit >12 m ago) 65.8%History of gastrointestinal ulcer/bleed 4.7%Aspirin daily for last 7 d or longer 71.7%History of renal artery stenosis 0.5%
Surgical historyPrior PTCA (balloon angioplasty or atherectomy) within 12 m prior 0.6%Prior PCI w/stent within the last 12 m 0.6%
Variable Mean ± SD or %LDL (mg/dL) 92.7 ± 36.6LDL <100 62.4%LDL <70 29.1%HbA1c (%) 7.8 ± 1.7HbA1c (%) <7.0 36.0% 7.0-8.0 25.4% ≥8.0 38.7%SBP (mm Hg) 133.8 ± 19.8SBP (mm Hg) <120 18.9% 120-140 43.0% ≥140 38.2%DBP (mm Hg) 76.0 ± 11.1DBP (mm Hg) <80 53.2% 80-90 33.1% ≥ 90 13.7%Triglycerides (mg/dL) 177.9 ±132.1 (148.0) Triglycerides ≥150 48.0%HDL (mg/dL) 39.2 ± 11.2 HDL ≤40 (men), ≤50 (women)
75.4%
Waist (cm) 102.6 ± 14.2 Waist ≥102 (men), ≥88 (women)
59.4%
Current smoker (%) 15.7%Hemoglobin (g/dL) 13.6 ± 1.6Creatinine (mg/dL) 1.1 ± 0.5Presence of microalbuminuria (>30 mg/g)
40.3%
Table IV. Cardiovascular risk factor profile of the FREEDOM cohort
OverallMedicationAntiplatelet agent Aspirin 90.7% Clopidogrel 23.9% Ticlopidine 1.1% Cilostazol 0.1%Antianginal agent β-Blocker 75.3% Calcium-channel antagonist 31.9% Nitrate 39.4%Lipid-lowering agent Statin 82.3% Fibrate 4.8%Other cardiovascular medications ACE inhibitor 64.3% Angiotensin II antagonist 16.3% ACE inhibitor or ARB 78.2% Aldosterone antagonist 2.8% Loop diuretics 10.3% Thiazide diuretic 13.0%Diabetes medication Insulin 32.3% Sulfonylurea 43.7% Biguanides 55.8% α-Glucosidase inhibitor 1.3% Thiazolidinedione 8.2% Rosiglitazone 4.7% Pioglitazone 3.5% NSAID 5.3% PPI⁎ 14.4%
Variable Mean ± SD or%No. of diseased vessels 1 0.1%
2 16.6%3 83.3%
Location of disease LAD 98.9%LCX 92.6%RCA 91.7%
Proximal LAD involvement (target lesion = LAD located in proximal)
13.8%
No. of lesions per patient 5.7 ± 2.2 (1888)Extent of disease per patient (total length of lesions, mm)
77.6 ± 33.8 (1888)
Duke jeopardy score 9.3 ± 3.1 (1874)LVEF (%) 66.2 ± 11.3 (1291)LVEF >50% 90.9%
35%-50% 8.0%<35% 1.1%
Table VI. Baseline angiographic profile for 1888 participants with a centrally interpreted angiogram
SYNTAX SCORE Tool to score complexity of CAD based on
anatomy There were 395 participants (20.9%)
with a high SYNTAX score (>32), 839 (44.0%) with an intermediate score (22-32), and 662 (35.1%) with a low score (<22).
Results
Results
Results
Results
Results
Results
Primary composite outcome - subgroups
Results Primary outcome analysis for DES type
compared to CABG (898 pts) Sirolimus-eluting (469 pts) at 5 yrs: 6.7% more
events than CABG Paclitaxel-eluting (394 pts) at 5 yrs: 6.5% more
events than CABG No difference in 30 day major bleeding
event(P=0.13) ARF requiring dialysis at 30 days significantly
higher in CABG group (P=0.02): 8 pts compared to 1 patient
Limitations Unblinded
Investigators argue that this is less important given objective outcomes and similar medical therapy between groups
Generalizability: only 10% of screening population eligible, only half of those randomizedPI stated that of the eligible patients who
declined randomization, most requested PCI as reason for not wanting randomization
“
Variable Mean ± SD or%No. of diseased vessels 1 0.1%
2 16.6%3 83.3%
Location of disease LAD 98.9%LCX 92.6%RCA 91.7%
Proximal LAD involvement (target lesion = LAD located in proximal)
13.8%
No. of lesions per patient 5.7 ± 2.2 (1888)Extent of disease per patient (total length of lesions, mm)
77.6 ± 33.8 (1888)
Duke jeopardy score 9.3 ± 3.1 (1874)LVEF (%) 66.2 ± 11.3 (1291)LVEF >50% 90.9%
35%-50% 8.0%<35% 1.1%
Table VI. Baseline angiographic profile for 1888 participants with a centrally interpreted angiogram
Evidence: Limitations
Endpoint definitions Differ in different trials
SYNTAX used conventional MI definition FREEDOM – used 2 different definitions
Periprocedural MI – within 30 days of procedure – used conventional definition
18% of total MIsPost 30 days MI – included
asymptomatic elevation of Troponins as MI!
82% of total MIs in trial period - ?significance
Generalisability of results Most trials - only 10% or less of
screening population eligible – too many exclusion criteria
Generalisability of results FREEDOM excluded
LMCHFLow EF (Only 5% patients)Prior CABG and Valve surgeriesISRCTOs (Only 5% patients)Common comorbidities
Many excluded cohorts make CABG outcome less favourable
Generalisability of results Mean EUROSCORE in FREEDOM – 2.8
Mean in most registries of CABG in real world population is higher
3.7 ± 2.5 Circulation.2008; 118: S199-S2093.5 ± 2.5 Neth Heart J. 2010 Aug; 18(7-8): 355–359.5.0 ± 3.5 Interactive CardioVascular and Thoracic Surgery 3 (2004) 562–565
Euroscore > 5 indicates increased risk of mortalityLower risk and less representative population for
CABG!
Treatment not Uptodate FREEDOM
Only about half continued on DAPT > 1 yearNewer antiplatelets not used1st gen DES only
Aorta No-Touch CABG not usedMIDCAB not used
Treatment not Uptodate A Catch-22 situation
Shorter smaller more concurent trials….dismissed as they are small and
short duration!Longer Larger trials
…sidelined if the treatment is fast evolving – by the time results are produced – ‘intervention’ is old!
Is there a rescue?
SYNTAX and SYNTAX II The category based risk approach of the
anatomical based SYNTAX Score – i.e. ‘low’, ‘intermediate,’ or ‘high’ SYNTAX Scores – to guide decision making between CABG or PCI is potentially misleading
Post hoc analysis of the SYNTAX trial - low and high risk subjects existed in higher and lower SYNTAX Score tertiles, which appeared to have implications for the most appropriate revascularisation modality (CABG and PCI)
The SYNTAX Score II was designed to improve decision making between CABG and PCI, by allowing for a long term, individualized risk assessment of patients with complex coronary artery disease.
Combines the anatomical based SYNTAX Score with clinical variables
These variables include Unprotected LM-CAD female gender Chronic obstructive pulmonary disease Age left ventricular ejection fraction CrCl PVD
SYNTAX Score II was developed in SYNTAX Trial Validated in the multicentre DELTA Registry
(n=2891) DELTA Registry - multinational,
nonrandomised, allcomers registry, conducted in 14 centres in Europe, US and South Korea. The study population was heterogeneous, and included complex coronary artery disease – anatomical SYNTAX Score ≥33 existed in 30%, and 3VD in 26%
During development and validation of the SYNTAX Score II, it was shown that
…diabetes did not improve decision making between CABG and PCI - when age, kidney function and left ventricular ejection fraction are accounted for!
HYBRID procedures!