View
213
Download
0
Category
Tags:
Preview:
Citation preview
The Science and Medicine of Acute Coronary Syndrome
The Emergence of Consistent and Unified Management Strategies for STEMI and NSTEMI
The Science and Medicine of Acute Coronary Syndrome
The Emergence of Consistent and Unified Management Strategies for STEMI and NSTEMI
Program ModeratorSunil V. Rao, MD, FACC
Host, Duke University Medical Center Cardiac Catheterization ConferenceAssistant Professor of MedicineDuke University Medical Center
Director, Cardiac Catheterization LaboratoriesDurham VA Medical Center
Durham, North Carolina
Program ModeratorSunil V. Rao, MD, FACC
Host, Duke University Medical Center Cardiac Catheterization ConferenceAssistant Professor of MedicineDuke University Medical Center
Director, Cardiac Catheterization LaboratoriesDurham VA Medical Center
Durham, North Carolina
A Year 2008 UpdateA Year 2008 Update
CME-accredited symposium jointly sponsored by the University of CME-accredited symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLCMassachusetts Medical School and CMEducation Resources, LLC
Commercial Support: Sponsored by an independent educational grant Commercial Support: Sponsored by an independent educational grant from The Medicines Companyfrom The Medicines Company
Mission statement: Improve patient care through evidence-based Mission statement: Improve patient care through evidence-based education, expert analysis, and case study-based managementeducation, expert analysis, and case study-based management
Processes: Strives for fair balance, clinical relevance, on-label Processes: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and indications for agents discussed, and emerging evidence and information from recent studiesinformation from recent studies
COI: Full faculty disclosures provided in syllabus and at the beginning COI: Full faculty disclosures provided in syllabus and at the beginning of the programof the program
CME-accredited symposium jointly sponsored by the University of CME-accredited symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLCMassachusetts Medical School and CMEducation Resources, LLC
Commercial Support: Sponsored by an independent educational grant Commercial Support: Sponsored by an independent educational grant from The Medicines Companyfrom The Medicines Company
Mission statement: Improve patient care through evidence-based Mission statement: Improve patient care through evidence-based education, expert analysis, and case study-based managementeducation, expert analysis, and case study-based management
Processes: Strives for fair balance, clinical relevance, on-label Processes: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and indications for agents discussed, and emerging evidence and information from recent studiesinformation from recent studies
COI: Full faculty disclosures provided in syllabus and at the beginning COI: Full faculty disclosures provided in syllabus and at the beginning of the programof the program
Welcome and Program OverviewWelcome and Program Overview Welcome and Program OverviewWelcome and Program Overview
Program Educational ObjectivesProgram Educational Objectives
As a result of this educational activity, physicians will:
► Learn to identify signs, symptoms, and prognostic features of acute coronary syndrome and related ischemic conditions, and their implications for invasive vascular management.
► Learn how recently issued AHA/ACC Guidelines for Non ST-Elevation Myocardial Infarction are best applied to appropriately risk-stratified patients with UA and NSTEMI.
► Learn to assess and implement optimal pharmacologic interventions, especially antithrombotic therapy in the upstream setting, for patients presenting with manifestations of UA, NSTEMI, STEMI, and related conditions.
► Learn to understand the implications of recent clinical data, trials, and recommendations on switching antithrombotic therapy in patients who present with acute ischemic coronary syndromes, with an emphasis on determining when switching from one agent to another is appropriate, safe, and feasible, and when switching among antithrombotic agents may be problematic.
As a result of this educational activity, physicians will:
► Learn to identify signs, symptoms, and prognostic features of acute coronary syndrome and related ischemic conditions, and their implications for invasive vascular management.
► Learn how recently issued AHA/ACC Guidelines for Non ST-Elevation Myocardial Infarction are best applied to appropriately risk-stratified patients with UA and NSTEMI.
► Learn to assess and implement optimal pharmacologic interventions, especially antithrombotic therapy in the upstream setting, for patients presenting with manifestations of UA, NSTEMI, STEMI, and related conditions.
► Learn to understand the implications of recent clinical data, trials, and recommendations on switching antithrombotic therapy in patients who present with acute ischemic coronary syndromes, with an emphasis on determining when switching from one agent to another is appropriate, safe, and feasible, and when switching among antithrombotic agents may be problematic.
Program FacultyProgram FacultyProgram FacultyProgram Faculty
Program ModeratorProgram ModeratorSunil V. Rao, MD, FACCSunil V. Rao, MD, FACCHost, Duke University Medical Center Cardiac Host, Duke University Medical Center Cardiac Catheterization ConferenceCatheterization ConferenceAssistant Professor of Medicine | Duke Assistant Professor of Medicine | Duke University Medical Center | Director, Cardiac University Medical Center | Director, Cardiac Catheterization Laboratories | Durham VA Catheterization Laboratories | Durham VA Medical Center | Durham, NCMedical Center | Durham, NC
Distinguished Faculty PresentersDistinguished Faculty PresentersDeepak L. Bhatt, MD, FACC, FSCAI, Deepak L. Bhatt, MD, FACC, FSCAI, FESC, FAHAFESC, FAHA Associate Director, Cardiovascular Associate Director, Cardiovascular Coordinating Center | Staff, Cardiac, Coordinating Center | Staff, Cardiac, Peripheral, and Carotid Intervention | Peripheral, and Carotid Intervention | Associate Professor of Medicine | Department Associate Professor of Medicine | Department of Cardiovascular Medicine | Cleveland Clinicof Cardiovascular Medicine | Cleveland Clinic
Program ModeratorProgram ModeratorSunil V. Rao, MD, FACCSunil V. Rao, MD, FACCHost, Duke University Medical Center Cardiac Host, Duke University Medical Center Cardiac Catheterization ConferenceCatheterization ConferenceAssistant Professor of Medicine | Duke Assistant Professor of Medicine | Duke University Medical Center | Director, Cardiac University Medical Center | Director, Cardiac Catheterization Laboratories | Durham VA Catheterization Laboratories | Durham VA Medical Center | Durham, NCMedical Center | Durham, NC
Distinguished Faculty PresentersDistinguished Faculty PresentersDeepak L. Bhatt, MD, FACC, FSCAI, Deepak L. Bhatt, MD, FACC, FSCAI, FESC, FAHAFESC, FAHA Associate Director, Cardiovascular Associate Director, Cardiovascular Coordinating Center | Staff, Cardiac, Coordinating Center | Staff, Cardiac, Peripheral, and Carotid Intervention | Peripheral, and Carotid Intervention | Associate Professor of Medicine | Department Associate Professor of Medicine | Department of Cardiovascular Medicine | Cleveland Clinicof Cardiovascular Medicine | Cleveland Clinic
Harold L. Dauerman, MDHarold L. Dauerman, MDDirector, Cardiovascular Catheterization Director, Cardiovascular Catheterization Laboratories | Professor of Medicine | Laboratories | Professor of Medicine | University of Vermont/Fletcher Allen Health University of Vermont/Fletcher Allen Health Care | Burlington, VTCare | Burlington, VT
Gregg W. Stone, MD Gregg W. Stone, MD Professor of Medicine | Director of Professor of Medicine | Director of Cardiovascular Research and Education | Cardiovascular Research and Education | Center for Interventional Vascular Therapy | Center for Interventional Vascular Therapy | Columbia University Medical Center | Columbia University Medical Center | Chairman, The Cardiovascular Research Chairman, The Cardiovascular Research Foundation | New York, NYFoundation | New York, NY
Ron Waksman, MD, FACCRon Waksman, MD, FACCAssociate Director, Division of Cardiology | Associate Director, Division of Cardiology | Washington Hospital Center | Director of Washington Hospital Center | Director of Experimental Angioplasty and Vascular Experimental Angioplasty and Vascular Brachytherapy | Cardiovascular Research Brachytherapy | Cardiovascular Research Institute | Washington Hospital Center | Institute | Washington Hospital Center | Clinical Professor of Medicine | Clinical Professor of Medicine | Georgetown University | Washington, DCGeorgetown University | Washington, DC
Harold L. Dauerman, MDHarold L. Dauerman, MDDirector, Cardiovascular Catheterization Director, Cardiovascular Catheterization Laboratories | Professor of Medicine | Laboratories | Professor of Medicine | University of Vermont/Fletcher Allen Health University of Vermont/Fletcher Allen Health Care | Burlington, VTCare | Burlington, VT
Gregg W. Stone, MD Gregg W. Stone, MD Professor of Medicine | Director of Professor of Medicine | Director of Cardiovascular Research and Education | Cardiovascular Research and Education | Center for Interventional Vascular Therapy | Center for Interventional Vascular Therapy | Columbia University Medical Center | Columbia University Medical Center | Chairman, The Cardiovascular Research Chairman, The Cardiovascular Research Foundation | New York, NYFoundation | New York, NY
Ron Waksman, MD, FACCRon Waksman, MD, FACCAssociate Director, Division of Cardiology | Associate Director, Division of Cardiology | Washington Hospital Center | Director of Washington Hospital Center | Director of Experimental Angioplasty and Vascular Experimental Angioplasty and Vascular Brachytherapy | Cardiovascular Research Brachytherapy | Cardiovascular Research Institute | Washington Hospital Center | Institute | Washington Hospital Center | Clinical Professor of Medicine | Clinical Professor of Medicine | Georgetown University | Washington, DCGeorgetown University | Washington, DC
Faculty DisclosuresFaculty DisclosuresFaculty DisclosuresFaculty Disclosures
Sunil V. Rao, MD, FACCSunil V. Rao, MD, FACCGrant/Research Support:Grant/Research Support: Cordis CordisConsultant:Consultant: Sanofi-Aventis, The Medicines Company Sanofi-Aventis, The Medicines CompanySpeaker’s BureauSpeaker’s Bureau: Sanofi-Aventis, The Medicines Company, Cordis: Sanofi-Aventis, The Medicines Company, Cordis
Deepak L. Bhatt, MD, FACC, FSCAI, FESC, FAHA Deepak L. Bhatt, MD, FACC, FSCAI, FESC, FAHA Grant/Research Support:Grant/Research Support: The Medicines Co., BMS, Sanofi-Aventis, Eisai, Ethicon The Medicines Co., BMS, Sanofi-Aventis, Eisai, EthiconConsultant:Consultant: Astra Zeneca, BMS, Cardax, Centocor, Daiichi-Sankyo, Eisai, Eli Lilly, GSK, Astra Zeneca, BMS, Cardax, Centocor, Daiichi-Sankyo, Eisai, Eli Lilly, GSK, Millennium, Otsuka, Paringenix, PDL, Sanofi-Aventis, Schering Plough, The Medicines Co., Millennium, Otsuka, Paringenix, PDL, Sanofi-Aventis, Schering Plough, The Medicines Co., tns Healthcaretns HealthcareSpeaker’s Bureau:Speaker’s Bureau: BMS, Sanofi-Aventis, The Medicines Co BMS, Sanofi-Aventis, The Medicines Co
Harold L. Dauerman, MDHarold L. Dauerman, MDConsultant:Consultant: The Medicines Company, Abbott Vascular The Medicines Company, Abbott VascularResearch Grants:Research Grants: Abbott Vascular and Boston Scientific Abbott Vascular and Boston ScientificFellowship SupportFellowship Support: Boston Scientific, Cordis/JNJ and Medtronic: Boston Scientific, Cordis/JNJ and Medtronic
Gregg W. Stone, MD Gregg W. Stone, MD Grant/Research Support:Grant/Research Support: The Medicines Co. and Boston Scientific The Medicines Co. and Boston Scientific
Ron Waksman, MD, FACCRon Waksman, MD, FACCConsultant and speaker or research grant supportConsultant and speaker or research grant support: Medtronic, Boston Scientific, Biotronik, : Medtronic, Boston Scientific, Biotronik, GSK, Sanofi, BMSGSK, Sanofi, BMS
Sunil V. Rao, MD, FACCSunil V. Rao, MD, FACCGrant/Research Support:Grant/Research Support: Cordis CordisConsultant:Consultant: Sanofi-Aventis, The Medicines Company Sanofi-Aventis, The Medicines CompanySpeaker’s BureauSpeaker’s Bureau: Sanofi-Aventis, The Medicines Company, Cordis: Sanofi-Aventis, The Medicines Company, Cordis
Deepak L. Bhatt, MD, FACC, FSCAI, FESC, FAHA Deepak L. Bhatt, MD, FACC, FSCAI, FESC, FAHA Grant/Research Support:Grant/Research Support: The Medicines Co., BMS, Sanofi-Aventis, Eisai, Ethicon The Medicines Co., BMS, Sanofi-Aventis, Eisai, EthiconConsultant:Consultant: Astra Zeneca, BMS, Cardax, Centocor, Daiichi-Sankyo, Eisai, Eli Lilly, GSK, Astra Zeneca, BMS, Cardax, Centocor, Daiichi-Sankyo, Eisai, Eli Lilly, GSK, Millennium, Otsuka, Paringenix, PDL, Sanofi-Aventis, Schering Plough, The Medicines Co., Millennium, Otsuka, Paringenix, PDL, Sanofi-Aventis, Schering Plough, The Medicines Co., tns Healthcaretns HealthcareSpeaker’s Bureau:Speaker’s Bureau: BMS, Sanofi-Aventis, The Medicines Co BMS, Sanofi-Aventis, The Medicines Co
Harold L. Dauerman, MDHarold L. Dauerman, MDConsultant:Consultant: The Medicines Company, Abbott Vascular The Medicines Company, Abbott VascularResearch Grants:Research Grants: Abbott Vascular and Boston Scientific Abbott Vascular and Boston ScientificFellowship SupportFellowship Support: Boston Scientific, Cordis/JNJ and Medtronic: Boston Scientific, Cordis/JNJ and Medtronic
Gregg W. Stone, MD Gregg W. Stone, MD Grant/Research Support:Grant/Research Support: The Medicines Co. and Boston Scientific The Medicines Co. and Boston Scientific
Ron Waksman, MD, FACCRon Waksman, MD, FACCConsultant and speaker or research grant supportConsultant and speaker or research grant support: Medtronic, Boston Scientific, Biotronik, : Medtronic, Boston Scientific, Biotronik, GSK, Sanofi, BMSGSK, Sanofi, BMS
Challenges and Uncertainties inChallenges and Uncertainties in Managing Acute Coronary Syndrome (ACS) Managing Acute Coronary Syndrome (ACS)
Connecting Evidence Across All the Streams: Connecting Evidence Across All the Streams: How and Why Bleeding MattersHow and Why Bleeding Matters
Challenges and Uncertainties inChallenges and Uncertainties in Managing Acute Coronary Syndrome (ACS) Managing Acute Coronary Syndrome (ACS)
Connecting Evidence Across All the Streams: Connecting Evidence Across All the Streams: How and Why Bleeding MattersHow and Why Bleeding Matters
The Science and Medicine of Acute Coronary SyndromeThe Science and Medicine of Acute Coronary Syndrome
Program ModeratorProgram ModeratorSunil V. Rao, MD, FACCSunil V. Rao, MD, FACC
Host, Duke University Medical Center Cardiac Catheterization ConferenceHost, Duke University Medical Center Cardiac Catheterization ConferenceAssistant Professor of MedicineAssistant Professor of MedicineDuke University Medical CenterDuke University Medical Center
Director, Cardiac Catheterization LaboratoriesDirector, Cardiac Catheterization LaboratoriesDurham VA Medical CenterDurham VA Medical Center
Durham, North CarolinaDurham, North Carolina
Program ModeratorProgram ModeratorSunil V. Rao, MD, FACCSunil V. Rao, MD, FACC
Host, Duke University Medical Center Cardiac Catheterization ConferenceHost, Duke University Medical Center Cardiac Catheterization ConferenceAssistant Professor of MedicineAssistant Professor of MedicineDuke University Medical CenterDuke University Medical Center
Director, Cardiac Catheterization LaboratoriesDirector, Cardiac Catheterization LaboratoriesDurham VA Medical CenterDurham VA Medical Center
Durham, North CarolinaDurham, North Carolina
► Is there a consistent approach to care of STEMI and NSTEMI Is there a consistent approach to care of STEMI and NSTEMI patients that can be use across the ACS risk spectrum? Across patients that can be use across the ACS risk spectrum? Across institutional needs in patients undergoing PCI?institutional needs in patients undergoing PCI?
► How should recent ACC/AHA 2007 NSTEMI Guidelines impact How should recent ACC/AHA 2007 NSTEMI Guidelines impact our choices for upstream antithrombotic therapy?our choices for upstream antithrombotic therapy?
► What is the relationship between bleeding avoidance and What is the relationship between bleeding avoidance and mortality in ACS patents? Should bleeding avoidance be mortality in ACS patents? Should bleeding avoidance be primary driver for selection of antithrombotic therapy? In all primary driver for selection of antithrombotic therapy? In all patients? In some?patients? In some?
► How should recent STEMI trials impact our approachHow should recent STEMI trials impact our approachto upstream care for STEMI? For NSTEMI?to upstream care for STEMI? For NSTEMI?
Questions We Will Illuminate and Debate
Questions We Will Illuminate and Debate
► What do know about changing anticoagulantWhat do know about changing anticoagulanttherapy “midstream?” Problematic? Safe? Agent-therapy “midstream?” Problematic? Safe? Agent-specific?specific?
► What is the ideal “alignment” between oral antiplatelet What is the ideal “alignment” between oral antiplatelet therapy and anticoagulation in STEMI and NSTEMI?therapy and anticoagulation in STEMI and NSTEMI?
► What does a “consistent and unified” approach toWhat does a “consistent and unified” approach toupstream care look like in an institutional setting? A upstream care look like in an institutional setting? A university-based case study.university-based case study.
► Doing the right thing: What do the trials tell us?Doing the right thing: What do the trials tell us?
++++
Ischemic Discomfort Ischemic Discomfort at Restat Rest
Ischemic Discomfort Ischemic Discomfort at Restat Rest
No ST-segment No ST-segment ElevationElevation
No ST-segment No ST-segment ElevationElevation
Non-Q-wave MINon-Q-wave MIUnstable Angina
Unstable Angina
Q-wave MIQ-wave MI
ST-segment ST-segment ElevationElevation
ST-segment ST-segment ElevationElevation
++ ++
( : positive cardiac biomarker)
EmergencyEmergencyDepartmentDepartmentEmergencyEmergencyDepartmentDepartment
In-hospitalIn-hospital6-24hrs6-24hrsIn-hospitalIn-hospital6-24hrs6-24hrs
PresentationPresentationPresentationPresentation
Acute Coronary SyndromesAcute Coronary SyndromesClinical Spectrum and PresentationClinical Spectrum and Presentation
NSTEMINSTEMI
Adapted from AHA/ACC NSTEMI GuidelinesAdapted from AHA/ACC NSTEMI Guidelines
SYNERGY
LMWHLMWH
ESSENCEESSENCE
19941994 19951995 19961996 19971997 19981998 19991999 20002000 20022002 20032003 20042004 20052005 2006200620012001
CURECURE
ClopidogrelClopidogrel
Bleeding riskBleeding risk
Ischemic riskIschemic risk
GP IIb/IIIa GP IIb/IIIa blockersblockers
PRISM-PLUSPRISM-PLUS
PURSUITPURSUIT
ACUITYTACTICS TIMI-18TACTICS TIMI-18
Early invasiveEarly invasive
PCIPCI ~ 5% stents~ 5% stents ~85% stents~85% stents Drug-eluting stentsDrug-eluting stents
ISAR-REACT 2
Milestones in ACS Management
OASIS-5
[ Fondaparinux ][ Fondaparinux ]
Anti-Thrombin RxAnti-Thrombin Rx
Anti-Platelet RxAnti-Platelet Rx
Treatment StrategyTreatment Strategy
HeparinHeparin
AspirinAspirin
ConservativeConservative
ICTUS
BivalirudinBivalirudin
REPLACE 2REPLACE 2
Adapted from and with the courtesy of Steven Manoukian, MD.Adapted from and with the courtesy of Steven Manoukian, MD.Adapted from and with the courtesy of Steven Manoukian, MD.Adapted from and with the courtesy of Steven Manoukian, MD.
Algorithm for Patients With UA/NSTEMI Managed by Algorithm for Patients With UA/NSTEMI Managed by an Initial Invasive Strategy: ACC/AHA 2007 Guidelinesan Initial Invasive Strategy: ACC/AHA 2007 Guidelines
Diagnosis of UA/NSTEMI is Likely or DefiniteDiagnosis of UA/NSTEMI is Likely or DefiniteDiagnosis of UA/NSTEMI is Likely or DefiniteDiagnosis of UA/NSTEMI is Likely or Definite
ASA (Class I, LOE:A)* ASA (Class I, LOE:A)* Clopidogrel if ASA intolerant (Class I, LOE: A)Clopidogrel if ASA intolerant (Class I, LOE: A)
ASA (Class I, LOE:A)* ASA (Class I, LOE:A)* Clopidogrel if ASA intolerant (Class I, LOE: A)Clopidogrel if ASA intolerant (Class I, LOE: A)
Select Management StrategySelect Management Strategy††Select Management StrategySelect Management Strategy††
Invasive StrategyInvasive StrategyInitiate anticoagulant therapy (Class I, LOE: A): Initiate anticoagulant therapy (Class I, LOE: A):
Acceptable options*: enoxaparin or UFH (Class I, Acceptable options*: enoxaparin or UFH (Class I, LOE: A), bivalirudin or fondaparinux are preferable LOE: A), bivalirudin or fondaparinux are preferable
(Class I, LOE: B)(Class I, LOE: B)
Invasive StrategyInvasive StrategyInitiate anticoagulant therapy (Class I, LOE: A): Initiate anticoagulant therapy (Class I, LOE: A):
Acceptable options*: enoxaparin or UFH (Class I, Acceptable options*: enoxaparin or UFH (Class I, LOE: A), bivalirudin or fondaparinux are preferable LOE: A), bivalirudin or fondaparinux are preferable
(Class I, LOE: B)(Class I, LOE: B)
InitialInitialConservative Conservative
StrategyStrategy
InitialInitialConservative Conservative
StrategyStrategy
AAAA
B1B1B1B1
ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.
Algorithm for Patients With UA/NSTEMI Algorithm for Patients With UA/NSTEMI Managed by an Initial Invasive StrategyManaged by an Initial Invasive Strategy
Prior to AngiographyPrior to AngiographyInitiate at least one (Class I, LOE: A) orInitiate at least one (Class I, LOE: A) orBoth (Class IIa, LOE: B) of the following:Both (Class IIa, LOE: B) of the following:
Clopidogrel* Clopidogrel* ‡‡ IV GP IIb/IIIa inhibitor* IV GP IIb/IIIa inhibitor* ‡‡
Factors favoring administration of both clopidogrel Factors favoring administration of both clopidogrel and GP IIb/IIIa inhibitor include:and GP IIb/IIIa inhibitor include:
Delay to angiographyDelay to angiographyHigh risk featuresHigh risk features
Early recurrent ischemic discomfortEarly recurrent ischemic discomfort
Prior to AngiographyPrior to AngiographyInitiate at least one (Class I, LOE: A) orInitiate at least one (Class I, LOE: A) orBoth (Class IIa, LOE: B) of the following:Both (Class IIa, LOE: B) of the following:
Clopidogrel* Clopidogrel* ‡‡ IV GP IIb/IIIa inhibitor* IV GP IIb/IIIa inhibitor* ‡‡
Factors favoring administration of both clopidogrel Factors favoring administration of both clopidogrel and GP IIb/IIIa inhibitor include:and GP IIb/IIIa inhibitor include:
Delay to angiographyDelay to angiographyHigh risk featuresHigh risk features
Early recurrent ischemic discomfortEarly recurrent ischemic discomfort
Diagnostic AngiographyDiagnostic AngiographyDiagnostic AngiographyDiagnostic Angiography
B2B2B2B2
ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.
Considerations in the Modern Era of ACS/PCI Considerations in the Modern Era of ACS/PCI
► 55-year-old male with 3 55-year-old male with 3 hours of chest painhours of chest pain● Hx of HTN, Hx of HTN, lipids lipids● Marked ST-segment Marked ST-segment
depression leads II, III, depression leads II, III, aVLaVL
● Elevated serum Elevated serum troponin T, CKMB 4 X troponin T, CKMB 4 X ULNULN
● Normal renal functionNormal renal function
► 55-year-old male with 3 55-year-old male with 3 hours of chest painhours of chest pain● Hx of HTN, Hx of HTN, lipids lipids● Marked ST-segment Marked ST-segment
depression leads II, III, depression leads II, III, aVLaVL
● Elevated serum Elevated serum troponin T, CKMB 4 X troponin T, CKMB 4 X ULNULN
● Normal renal functionNormal renal function
► 86-year-old female with 3 86-year-old female with 3 hours of chest painhours of chest pain● Hx of DM, HTN, Hx of DM, HTN,
lipidslipids● ECG non-specific (no ECG non-specific (no
prior study for prior study for comparison)comparison)
● Elevated troponin, Elevated troponin, normal CKMBnormal CKMB
● Est. GFR 45 ml/minEst. GFR 45 ml/min
► 86-year-old female with 3 86-year-old female with 3 hours of chest painhours of chest pain● Hx of DM, HTN, Hx of DM, HTN,
lipidslipids● ECG non-specific (no ECG non-specific (no
prior study for prior study for comparison)comparison)
● Elevated troponin, Elevated troponin, normal CKMBnormal CKMB
● Est. GFR 45 ml/minEst. GFR 45 ml/min
8.6
5.1
0
1
2
3
4
5
6
7
8
9
10
Ischemia vs. Bleeding: NSTE ACS vs. STEMIIschemia vs. Bleeding: NSTE ACS vs. STEMI
1.41.6
0
0.5
1
1.5
2
2.5
3
3.53.1
2.1
0
0.5
1
1.5
2
2.5
3
3.5
5.7
3.0
0
1
2
3
4
5
6
7
8
9
10
30
-Da
y M
ort
alit
y (%
)3
0-D
ay
Mo
rta
lity
(%)
30
-Da
y M
ort
alit
y (%
)3
0-D
ay
Mo
rta
lity
(%)
47%47%47%47%
41%41%41%41%
Stone GW Stone GW NEJMNEJM 2007 2007Stone GW. Stone GW. TCTTCT 2007 2007
Stone GW Stone GW NEJMNEJM 2007 2007Stone GW. Stone GW. TCTTCT 2007 2007
HORIZONS AMIHORIZONS AMIHORIZONS AMIHORIZONS AMIACUITYACUITYACUITYACUITY
Ma
jor
Ble
ed
ing
(%
)M
ajo
r B
lee
din
g (
%)
Ma
jor
Ble
ed
ing
(%
)M
ajo
r B
lee
din
g (
%)
Heparin +IIb/IIIa Bivalirudin
Heparin +IIb/IIIa Bivalirudin
Heparin +IIb/IIIa Bivalirudin
Heparin +IIb/IIIa Bivalirudin
P=NSP=NS
P=0.047P=0.047
0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 4500 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450
Days After RandomizationDays After Randomization
Prim
ary
Effi
cacy
End
Poi
nt (
%)
Prim
ary
Effi
cacy
End
Poi
nt (
%)
8
7
6
5
4
3
2
1
0
8
7
6
5
4
3
2
1
0
ClopidogrelClopidogrel
PrasugrelPrasugrel P=0.003P=0.003
6.96.9
5.65.6
Wiviott SD, et al. Wiviott SD, et al. NEJMNEJM 2007 Nov 15;357(20):2001-15 2007 Nov 15;357(20):2001-15 Wiviott SD, et al. Wiviott SD, et al. NEJMNEJM 2007 Nov 15;357(20):2001-15 2007 Nov 15;357(20):2001-15
Is the Bleeding Issue Still Relevant in 2008?Is the Bleeding Issue Still Relevant in 2008?
3 30 60 90 120 150 180 210 240 270 300 330 360 390 420 4503 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450
Key
Saf
ety
End
Poi
ntK
ey S
afet
y E
nd P
oint
PrasugrelPrasugrel
ClopidogrelClopidogrel
2.42.4
1.81.8
Days After RandomizationDays After Randomization
↑ 35 EventsHazard ratio, 1.32;95% CI, 1/03-1.68;P=0.03
↑ 35 EventsHazard ratio, 1.32;95% CI, 1/03-1.68;P=0.03
4
3
2
1
0
4
3
2
1
0
Wiviott SD, et al. Wiviott SD, et al. NEJMNEJM 2007 Nov 15;357(20):2001-15 2007 Nov 15;357(20):2001-15 Wiviott SD, et al. Wiviott SD, et al. NEJMNEJM 2007 Nov 15;357(20):2001-15 2007 Nov 15;357(20):2001-15
Even in 2008, the balance between efficacy Even in 2008, the balance between efficacy and safety is paramountand safety is paramount
Even in 2008, the balance between efficacy Even in 2008, the balance between efficacy and safety is paramountand safety is paramount
Is the Bleeding Issue Still Relevant in 2008?Is the Bleeding Issue Still Relevant in 2008?
*p<0.0001*p<0.0001
ISAR-REACT 3: ResultsISAR-REACT 3: Results
Kastrati A, et al. ACC 2008
EndpointEndpoint Bivalirudin (%)Bivalirudin (%) UFH (%)UFH (%) pp
PrimaryPrimary 8.38.3 8.78.7 0.570.57
SecondarySecondary 5.95.9 5.05.0 0.230.23
Major bleeding*Major bleeding* 3.13.1 4.64.6 0.0080.008
Minor bleeding*Minor bleeding* 6.86.8 9.99.9 0.00010.0001
TransfusionTransfusion 1.31.3 1.81.8 0.150.15
TIMI majorTIMI major 0.50.5 1.01.0 0.040.04
TIMI minorTIMI minor 1.31.3 2.22.2 0.010.01
* as per ISAR-REACT 3 definition * as per ISAR-REACT 3 definition * as per ISAR-REACT 3 definition * as per ISAR-REACT 3 definition
ACS-related Bleeding—Relevant Questions
► Who bleeds? Can we risk stratify?Who bleeds? Can we risk stratify?
► Should bleeding risk affect upstream Should bleeding risk affect upstream antithrombotic care? If so, how?antithrombotic care? If so, how?
► Is bleeding bad or a necessary evil?Is bleeding bad or a necessary evil?
► Can blood transfusion “correct” risks associated Can blood transfusion “correct” risks associated with bleeding?with bleeding?
► Does bleeding affect resource use?Does bleeding affect resource use?
Independent predictors of major bleeding in marker- positive acute coronary syndromes
Independent predictors of major bleeding in marker- positive acute coronary syndromes
Moscucci, GRACE Registry, Eur Heart J. 2003 Oct;24(20):1815-23.
Predictors of Major Bleeding in ACSPredictors of Major Bleeding in ACS
► Older AgeOlder Age
► Female GenderFemale Gender
► Renal FailureRenal Failure
► History of BleedingHistory of Bleeding
► Right Heart CatheterizationRight Heart Catheterization
► GPIIb-IIIa AntagonistsGPIIb-IIIa Antagonists
► Older AgeOlder Age
► Female GenderFemale Gender
► Renal FailureRenal Failure
► History of BleedingHistory of Bleeding
► Right Heart CatheterizationRight Heart Catheterization
► GPIIb-IIIa AntagonistsGPIIb-IIIa Antagonists
0 1 2 3
P-valueP-valueRR (95% CI)RR (95% CI)Risk ratio ± 95% CIRisk ratio ± 95% CI
Predictors of Major BleedingPredictors of Major Bleeding
Age Age >>75 (vs. 55-75)75 (vs. 55-75)
AnemiaAnemia
CrCl <60mL/minCrCl <60mL/min
DiabetesDiabetes
Female genderFemale gender
High-risk (ST / biomarkers)High-risk (ST / biomarkers)
HypertensionHypertension
No prior PCINo prior PCI
Prior antithrombotic therapyPrior antithrombotic therapy
Heparin(s) + GPI (vs. Bivalirudin)Heparin(s) + GPI (vs. Bivalirudin)
1.56 (1.19-2.04)1.56 (1.19-2.04) 0.00090.0009
1.89 (1.48-2.41)1.89 (1.48-2.41) <0.0001<0.0001
1.68 (1.29-2.18)1.68 (1.29-2.18) <0.0001<0.0001
1.30 (1.03-1.63)1.30 (1.03-1.63) 0.02480.0248
2.08 (1.68-2.57)2.08 (1.68-2.57) <0.0001<0.0001
1.42 (1.06-1.90)1.42 (1.06-1.90) 0.01780.0178
1.33 (1.03-1.70)1.33 (1.03-1.70) 0.02870.0287
1.47 (1.15-1.88)1.47 (1.15-1.88) 0.00190.0019
1.23 (0.98-1.55)1.23 (0.98-1.55) 0.07680.0768
2.08 (1.56-2.76)2.08 (1.56-2.76) <0.0001<0.0001
Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.
Results: The ACUITY Trial — PCI PopulationResults: The ACUITY Trial — PCI PopulationResults: The ACUITY Trial — PCI PopulationResults: The ACUITY Trial — PCI Population
0 1 2 3 4 5
P-valueP-valueRR (95% CI)RR (95% CI)
Age Age >>75 (vs. 55-75)75 (vs. 55-75)
AnemiaAnemia
CrCl <60mL/minCrCl <60mL/min
DiabetesDiabetes
Female genderFemale gender
High-risk (ST / biomarkers)High-risk (ST / biomarkers)
HypertensionHypertension
Heparin(s) + GPI (vs. BivalirudinHeparin(s) + GPI (vs. Bivalirudin))
1.420 (1.055-1.910)1.420 (1.055-1.910) 0.00600.0060
3.764 (2.919-4.855)3.764 (2.919-4.855) <0.0001<0.0001
2.097 (1.568-2.803)2.097 (1.568-2.803) <0.0001<0.0001
1.560 (1.209-2.014)1.560 (1.209-2.014) 0.00600.0060
2.233 (1.739-2.867)2.233 (1.739-2.867) <0.0001<0.0001
1.754 (1.297-2.372)1.754 (1.297-2.372) 0.00030.0003
1.457 (1.051-2.020)1.457 (1.051-2.020) 0.02410.0241
1.728 (1.256-2.379)1.728 (1.256-2.379) 0.00070.0007
Predictors of TransfusionPredictors of Transfusion
Risk ratio ± 95% CIRisk ratio ± 95% CI
Results: The ACUITY TrialResults: The ACUITY TrialResults: The ACUITY TrialResults: The ACUITY Trial
Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.
► Older age, chronic kidney disease, female gender Older age, chronic kidney disease, female gender are consistently associated with bleeding and blood are consistently associated with bleeding and blood transfusiontransfusion
► Analysis of large randomized trials have also Analysis of large randomized trials have also identified novel risk factors for bleeding such as identified novel risk factors for bleeding such as diabetes and anemiadiabetes and anemia
Bleeding Predictors — Conclusions
log rank p-value for all four categories <0.0001log-rank p-value for no bleeding vs. mild bleeding = 0.02log-rank p-value for mild vs. moderate bleeding <0.0001log-rank p-value for moderate vs. severe <0.001
Bleeding and Outcomes in ACSBleeding and Outcomes in ACS
Rao SV, et al. Am J Cardiol. 2005 Nov 1;96(9):1200-6. Epub 2005 Sep 12.
Kaplan Meier Curves for 30-Day Death, Stratified by Bleed SeverityKaplan Meier Curves for 30-Day Death, Stratified by Bleed Severity
N=26,452 ACS patients from GUSTO IIb, PARAGON A, PARAGON B, & PURSUIT N=26,452 ACS patients from GUSTO IIb, PARAGON A, PARAGON B, & PURSUIT
Kaplan Meier Curves for 30-Day Death, Stratified by Bleed SeverityKaplan Meier Curves for 30-Day Death, Stratified by Bleed Severity
N=26,452 ACS patients from GUSTO IIb, PARAGON A, PARAGON B, & PURSUIT N=26,452 ACS patients from GUSTO IIb, PARAGON A, PARAGON B, & PURSUIT
NoneMildModerateSevere
NoneMildModerateSevere
0 5 10 15 20 25 30 0 5 10 15 20 25 30
1.00
0.95
0.90
0.85
0.80
0.75
0.70
1.00
0.95
0.90
0.85
0.80
0.75
0.70
Days to DeathDays to Death
26,452 patients from PURSUIT, PARAGON A, PARAGON B, GUSTO IIb NST
26,452 patients from PURSUIT, PARAGON A, PARAGON B, GUSTO IIb NST
Bleeding severity and adjusted hazard of deathBleeding severity and adjusted hazard of death
*p<0.0001*p<0.0001
Bleeding and Outcomes in NSTE-ACS Bleeding and Outcomes in NSTE-ACS
Rao SV, et al. Am J Cardiol. 2005 Nov 1;96(9):1200-6. Epub 2005 Sep 12.
Bleeding Bleeding SeveritySeverity 30d Death30d Death 30d Death/MI30d Death/MI 6 mo. Death6 mo. Death
Mild*Mild* 1.61.6 1.31.3 1.41.4
Moderate*Moderate* 2.72.7 3.33.3 2.12.1
Severe*Severe* 10.610.6 5.65.6 7.57.5
*Bleeding as a time-dependent covariate*Bleeding as a time-dependent covariate*Bleeding as a time-dependent covariate*Bleeding as a time-dependent covariate
Mor
talit
y (%
)M
orta
lity
(%)
Days from RandomizationDays from Randomization
0 30 60 90 120 150 180 210 240 270 300 330 360 3900
5
15
30
10
25
20
1 yearEstimate
Major Bleed only (without MI) (N=551) 12.5%28.9%Both MI and Major Bleed (N=94)
3.4%No MI or Major Bleed (N=12,557)MI only (without Major Bleed) (N=611) 8.6%
Impact of MI and Major Bleeding (non-CABG) in Impact of MI and Major Bleeding (non-CABG) in the First 30 Days on Risk of Death Over 1 Yearthe First 30 Days on Risk of Death Over 1 Year
28.9%
12.5%
8.6%
3.4%
Stone GW. Stone GW. TCTTCT 2007 2007Stone GW. Stone GW. TCTTCT 2007 2007
ACUITYACUITY
Day 0 – 2 after MIDay 0 – 2 after MI 12.6 (7.8-20.4)12.6 (7.8-20.4) 29 (37.6)29 (37.6) <0.0001<0.0001
Day 3 – 7 after MIDay 3 – 7 after MI 5.3 (2.7-10.4)5.3 (2.7-10.4) 11 (14.3)11 (14.3) <0.0001<0.0001
Day 8 – 35 after MIDay 8 – 35 after MI 1.6 (0.8-3.1)1.6 (0.8-3.1) 12 (15.6)12 (15.6) 0.180.18
Day > 35 after MIDay > 35 after MI 1.2 (0.8-1.9)1.2 (0.8-1.9) 25 (32.5)25 (32.5) 0.340.34
Day 0 – 2 after Major BleedDay 0 – 2 after Major Bleed 3.0 (1.6-5.6)3.0 (1.6-5.6) 12 (12.9)12 (12.9) 0.00090.0009
Day 3 – 7 after Major BleedDay 3 – 7 after Major Bleed 4.0 (2.1-7.5)4.0 (2.1-7.5) 15 (16.1)15 (16.1) <0.0001<0.0001
Day 8 – 35 after Major BleedDay 8 – 35 after Major Bleed 4.5 (2.8-7.4)4.5 (2.8-7.4) 25 (26.9)25 (26.9) <0.0001<0.0001
Day > 35 after Major BleedDay > 35 after Major Bleed 2.2 (1.5-3.2)2.2 (1.5-3.2) 41 (44.1)41 (44.1) <0.0001<0.0001
P-valueP-valueP-valueP-valueDeaths (n/%)Deaths (n/%)Deaths (n/%)Deaths (n/%)HR ± 95% CIHR ± 95% CIHR ± 95% CIHR ± 95% CI
0.5 1 2 4 8 16
HR (CI)HR (CI)HR (CI)HR (CI)
Impact of MI and Major Bleeding (non-CABG) in Impact of MI and Major Bleeding (non-CABG) in the First 30 Days on Risk of Death Over 1 Yearthe First 30 Days on Risk of Death Over 1 Year
ACUITY TRIAL—Cox model adjusted for baseline predictors: Bleeding and MI as time updated covariates ACUITY TRIAL—Cox model adjusted for baseline predictors: Bleeding and MI as time updated covariates
Stone, ACC 2007Stone, ACC 2007
► Bleeding is associated with adverse short- and long-Bleeding is associated with adverse short- and long-term outcomes among patients with ACS and those term outcomes among patients with ACS and those undergoing PCIundergoing PCI
● Mortality rates are higher among those who bleedMortality rates are higher among those who bleed
● MI rates are higher among those who bleedMI rates are higher among those who bleed
► Worse bleeding associated with worse outcomesWorse bleeding associated with worse outcomes
► This relationship is persistent after robust statistical This relationship is persistent after robust statistical adjustment for confoundersadjustment for confounders
Bleeding and Outcomes — Conclusions
30-Day Survival By Transfusion Group30-Day Survival By Transfusion Group
Rao SV, et. al., JAMA 2004;292:1555–1562.
Transfusion in ACSTransfusion in ACS
N=24,111N=24,111N=24,111N=24,111
*Transfusion as a time-dependent covariate*Transfusion as a time-dependent covariate
Cox Model for 30-day DeathCox Model for 30-day Death
N=24,111N=24,111N=24,111N=24,111
Rao SV, et. al., JAMA 2004;292:1555–1562.
PRBC Transfusion Among NSTE ACS PatientsPRBC Transfusion Among NSTE ACS Patients
Adjusted fortransfusion propensity
Adjusted for baseline characteristics
Adjusted for baseline characteristics, bleeding propensity, transfusion propensity, and nadir HCT
Adjusted fortransfusion propensity
Adjusted for baseline characteristics
Adjusted for baseline characteristics, bleeding propensity, transfusion propensity, and nadir HCT
3.77 (3.13, 4.523.77 (3.13, 4.523.77 (3.13, 4.523.77 (3.13, 4.52
3.54 (2.96, 4.23)3.54 (2.96, 4.23)3.54 (2.96, 4.23)3.54 (2.96, 4.23)
3.94 (3.26, 4.75)3.94 (3.26, 4.75)3.94 (3.26, 4.75)3.94 (3.26, 4.75)
-4.0-4.0 1.0 1.0 10.0 10.0-4.0-4.0 1.0 1.0 10.0 10.0
Adjusted Risk of In-Hospital Outcomes Adjusted Risk of In-Hospital Outcomes By Transfusion Status*By Transfusion Status*
*Non-CABG patients only
Yang X, J Am Coll Cardiol 2005;46:1490–5.
N=74,271 ACS patients from CRUSADE N=74,271 ACS patients from CRUSADE
DeathDeath
Death or Re-MIDeath or Re-MI
1.01.0 2.02.0
9.4%
2.3%
18.8%
11.0%
29.2%
4.8%7.1%
1.3%
IschemicComposite
Death MI (all) UnplannedRevasc
30 d
ay e
vent
s (%
)
Transfusion (N=319, 2.3%) No Transfusion (N=13500, 97.7%)
9.4%
2.3%
18.8%
11.0%
29.2%
4.8%7.1%
1.3%
IschemicComposite
Death MI (all) UnplannedRevasc
30 d
ay e
vent
s (%
)
Transfusion (N=319, 2.3%) No Transfusion (N=13500, 97.7%)
Transfusion, Ischemic Endpoints,Transfusion, Ischemic Endpoints,and Mortality in ACUITY Trialand Mortality in ACUITY Trial
9.4%
2.3%
18.8%
11.0%
29.2%
4.8%7.1%
1.3%
IschemicComposite
Death MI (all) UnplannedRevasc
30
da
y e
ve
nts
(%
)
Transfusion (N=319, 2.3%) No Transfusion (N=13500, 97.7%)
P<0.0001 for all
Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.
Results: The ACUITY Trial (N=13,819)Results: The ACUITY Trial (N=13,819)Results: The ACUITY Trial (N=13,819)Results: The ACUITY Trial (N=13,819)
► Blood transfusion is independently associated Blood transfusion is independently associated with death and recurrent MIwith death and recurrent MI
► Transfusion does not correct the adverse Transfusion does not correct the adverse impact bleeding and is not an “insurance impact bleeding and is not an “insurance policy” against adverse outcomes associated policy” against adverse outcomes associated with bleedingwith bleeding
► Blood transfusion is best avoided in ACS Blood transfusion is best avoided in ACS patients whenever possiblepatients whenever possible
Blood Transfusion — Conclusions
► What are the bleeding consequences of What are the bleeding consequences of switching anticoagulation in midstream?switching anticoagulation in midstream?
► Are there switching strategies that mitigate Are there switching strategies that mitigate against or reduce risk of bleeding in ACS against or reduce risk of bleeding in ACS patients? What are they?patients? What are they?
► Should routine switching be advocated as a Should routine switching be advocated as a strategy for bleeding minimization? In NSTE-strategy for bleeding minimization? In NSTE-ACS? In STEMI?ACS? In STEMI?
Bleeding in ACS—The Big Switch
Bivalirudin* (n=1,014)Bivalirudin* (n=1,014)switch armswitch arm
PP=.36=.36 PP=.003=.003
45%45%
*Bivalirudin monotherapy with GP IIb/IIIa reserved for severe breakthrough ischemia and procedural complications during PCI. *Bivalirudin monotherapy with GP IIb/IIIa reserved for severe breakthrough ischemia and procedural complications during PCI. ††76% of ACUITY PCI patients had raised cardiac biomarkers and/or ST-segment deviation at baseline.76% of ACUITY PCI patients had raised cardiac biomarkers and/or ST-segment deviation at baseline.
9.3%9.3%
3.9%3.9%
8.1%8.1%7.1%7.1%
UFH/enoxaparin + GP IIb/IIIa (n=974)UFH/enoxaparin + GP IIb/IIIa (n=974)consistent armconsistent arm
00
55
1010
1515
PP=.97=.97
3.1%3.1% 3.1%3.1%
00
11
22
33
44
55
30-day30-dayComposite ischemiaComposite ischemia Non-CABG major bleedingNon-CABG major bleeding
1-year1-yearMortalityMortality
Adv
erse
eve
nts
(%)
Adv
erse
eve
nts
(%)
Adv
erse
eve
nts
(%)
Adv
erse
eve
nts
(%)
Data on file. The Medicines Company, Parsippany, NJ.Data on file. The Medicines Company, Parsippany, NJ.
In In High-Risk Patient SubsetHigh-Risk Patient Subset, Switching to , Switching to Bivalirudin Also Improves Bleeding OutcomesBivalirudin Also Improves Bleeding Outcomes
► Ischemic suppression was maintained and major bleeding significantly reduced at 30 daysIschemic suppression was maintained and major bleeding significantly reduced at 30 days
► Long-term efficacy in both groups was consistent at 1 yearLong-term efficacy in both groups was consistent at 1 year
► Ischemic suppression was maintained and major bleeding significantly reduced at 30 daysIschemic suppression was maintained and major bleeding significantly reduced at 30 days
► Long-term efficacy in both groups was consistent at 1 yearLong-term efficacy in both groups was consistent at 1 year
Switch to bivalirudin* vs consistent heparin + GP IIb/IIIa outcomes†Switch to bivalirudin* vs consistent heparin + GP IIb/IIIa outcomes†
PCI Subgroup
Bleeding and Resource Use Bleeding and Resource Use Predictors of Total CostsPredictors of Total Costs
$3,370
$1,158
$2,164
$7,188
$12,409
$2,488
$5,255
$2,436
$1,336
0
2,000
4,000
6,000
8,000
10,000
12,000
14,000
Mod/SevBld
UA Cath PCI CABG Pacemaker IABP ICU day Non-ICUday
$
$3,370
$1,158
$2,164
$7,188
$12,409
$2,488
$5,255
$2,436
$1,336
0
2,000
4,000
6,000
8,000
10,000
12,000
14,000
Mod/SevBld
UA Cath PCI CABG Pacemaker IABP ICU day Non-ICUday
$
Moderate/severe bleedModerate/severe bleedPer patient cost - $530Per patient cost - $530
Transfusion - $2,080, P < 0.01Transfusion - $2,080, P < 0.01Per patient cost - $287Per patient cost - $287
Moderate/severe bleedModerate/severe bleedPer patient cost - $530Per patient cost - $530
Transfusion - $2,080, P < 0.01Transfusion - $2,080, P < 0.01Per patient cost - $287Per patient cost - $287
Model C-index=0.87Model C-index=0.87
Adjusted for patient characteristicsAdjusted for patient characteristics
Model C-index=0.87Model C-index=0.87
Adjusted for patient characteristicsAdjusted for patient characteristicsRao SV, et. al. AHJ 2008.
N=1235 pts from GUSTO IIbN=1235 pts from GUSTO IIbN=1235 pts from GUSTO IIbN=1235 pts from GUSTO IIb
$14,416$14,028
$14,925
$14,153$13,844
$8,000
$12,000
$16,000
$14,416$14,028
$14,925
$14,153$13,844
$8,000
$12,000
$16,000
ACUITY: Hospital Index CostsACUITY: Hospital Index Costs
p<0.001 for comparison p<0.001 for comparison across across
the five groupsthe five groups
Heparin + Heparin + Upstream GPIUpstream GPI
Heparin + Heparin + Cath Lab GPICath Lab GPI
Bivalirudin + Bivalirudin + Upstream GPIUpstream GPI
Bivalirudin + Bivalirudin + Cath Lab GPICath Lab GPI
Bivalirudin Bivalirudin MonotherapyMonotherapy
Pinto D et al. ACC 2008
Hospital Index CostsHospital Index CostsHospital Index CostsHospital Index Costs
► The available costs data clearly show that a The available costs data clearly show that a balance must be struck between ischemia balance must be struck between ischemia reduction and bleedingreduction and bleeding
● Both ischemic complications and bleeding are Both ischemic complications and bleeding are associated with increased costs such that any cost associated with increased costs such that any cost savings realized by reducing one is offset by cost savings realized by reducing one is offset by cost increases associated with the otherincreases associated with the other
Bleeding and Costs — Conclusions
X
Xa
II
IIa
(Thrombin)
(Prothrombin)TF VIIa
IX IXa
Direct Thrombin Inhibitors—Bivalirudin
Direct Thrombin Inhibitors—Bivalirudin
Va
Targets for InterventionTargets for InterventionBetter Options, Worse OptionsBetter Options, Worse Options
Xa Inhibitors—FondaparinuxXa Inhibitors—Fondaparinux
Direct Thrombin Inhibitors—Bivalirudin
Direct Thrombin Inhibitors—Bivalirudin
• Bivalent direct thrombin Bivalent direct thrombin inhibitorinhibitor
• High specificity and potencyHigh specificity and potency
• Lack of dependence on Lack of dependence on antithrombin-IIIantithrombin-III
• Effect on clot-bound & free Effect on clot-bound & free thrombinthrombin
• No platelet activation No platelet activation
• No inhibition by PF4 and No inhibition by PF4 and othersothers
• ReversibleReversible
• Bivalent direct thrombin Bivalent direct thrombin inhibitorinhibitor
• High specificity and potencyHigh specificity and potency
• Lack of dependence on Lack of dependence on antithrombin-IIIantithrombin-III
• Effect on clot-bound & free Effect on clot-bound & free thrombinthrombin
• No platelet activation No platelet activation
• No inhibition by PF4 and No inhibition by PF4 and othersothers
• ReversibleReversible
(Gly)4(Gly)4
Bivalirudin PharmacologyBivalirudin Pharmacology
Gly-Pro-Arg-Pro (active site binding region)Gly-Pro-Arg-Pro (active site binding region)
C-terminal dodecapeptide(exosite 1-binding region)C-terminal dodecapeptide(exosite 1-binding region)
Addressing the Challenges of Addressing the Challenges of Selecting an Anticoagulation StrategySelecting an Anticoagulation Strategy
Bleeding RiskBleeding RiskBleeding RiskBleeding Risk
Ischemic RiskIschemic RiskIschemic RiskIschemic Risk
Renal functionRenal functionRenal functionRenal functionAgeAgeAgeAge
Time to cathTime to cathTime to cathTime to cath
CostCostCostCost
Ease of useEase of useEase of useEase of use
PCI vs CABG vs Med RxPCI vs CABG vs Med RxPCI vs CABG vs Med RxPCI vs CABG vs Med Rx
Bleeding Among Patients with ACS—Conclusions
► There are several therapeutic pathways for There are several therapeutic pathways for ACS careACS care
► Choices for therapy must take into account:Choices for therapy must take into account:● Ischemic complicationsIschemic complications● Bleeding complicationsBleeding complications
► The risk for bleeding and ischemia increases The risk for bleeding and ischemia increases from NSTE-ACS to STEMIfrom NSTE-ACS to STEMI
Conclusions—Bleeding in ACS
► Certain patient and PCI procedure characteristics Certain patient and PCI procedure characteristics predict bleedingpredict bleeding
● Age, female gender, CKD Age, female gender, CKD ● Diabetes and anemia are newly identified risk factors for Diabetes and anemia are newly identified risk factors for
bleeding among ACS patientsbleeding among ACS patients
► Bleeding is associated with worse short and long-Bleeding is associated with worse short and long-term outcomes including death and MIterm outcomes including death and MI
► Blood transfusion is associated with increased Blood transfusion is associated with increased mortality in ACS patients mortality in ACS patients
► In addition to an adverse impact on clinical In addition to an adverse impact on clinical outcomes, bleeding is associated with increased cost outcomes, bleeding is associated with increased cost of careof care
Conclusions — Bleeding in ACS
► ACC/AHA guidelines ACC/AHA guidelines now recognize the value now recognize the value of bleeding reduction in ACS careof bleeding reduction in ACS care
Bivalirudin is a Class I (Bivalirudin is a Class I (Level of evidence: B)Level of evidence: B)recommended antithrombin agent for NSTE-ACSrecommended antithrombin agent for NSTE-ACSpatients undergoing an invasive strategypatients undergoing an invasive strategy
► We now have evidence for a bleeding We now have evidence for a bleeding reduction strategy with bivalirudin that is reduction strategy with bivalirudin that is consistent across the spectrum of risk for consistent across the spectrum of risk for NSTE-ACS and STEMINSTE-ACS and STEMI
Acute CoronaryAcute CoronarySyndromes — A Year 2008Syndromes — A Year 2008
Status ReportStatus ReportThe Guidelines: Many Streams Runs ThroughThe Guidelines: Many Streams Runs Through
Acute CoronaryAcute CoronarySyndromes — A Year 2008Syndromes — A Year 2008
Status ReportStatus ReportThe Guidelines: Many Streams Runs ThroughThe Guidelines: Many Streams Runs Through
Deepak L. Bhatt MD, FACC, FSCAI, FESC,Deepak L. Bhatt MD, FACC, FSCAI, FESC,FACP, FCCP, FAHAFACP, FCCP, FAHA
Associate Director, Cleveland Clinic Cardiovascular CoordinatingAssociate Director, Cleveland Clinic Cardiovascular CoordinatingCenter Staff, Cardiac, Peripheral, and Carotid InterventionCenter Staff, Cardiac, Peripheral, and Carotid Intervention
Associate Professor of MedicineAssociate Professor of Medicine
Deepak L. Bhatt MD, FACC, FSCAI, FESC,Deepak L. Bhatt MD, FACC, FSCAI, FESC,FACP, FCCP, FAHAFACP, FCCP, FAHA
Associate Director, Cleveland Clinic Cardiovascular CoordinatingAssociate Director, Cleveland Clinic Cardiovascular CoordinatingCenter Staff, Cardiac, Peripheral, and Carotid InterventionCenter Staff, Cardiac, Peripheral, and Carotid Intervention
Associate Professor of MedicineAssociate Professor of Medicine
Getting in the Stream of ThingsGetting in the Stream of Things
Mechanisms Behind Periprocedural MIMechanisms Behind Periprocedural MI
Bhatt DL et al. Circulation 2005; 112:906-923.
↑ Atheroma Burden↑ Plaque Vulnerability↓ Statins
↑ Atheroma Burden↑ Plaque Vulnerability↓ Statins
↓ Antithrombotics Clopidogrel GP IIb/IIIa Enoxaparin Bivalirudin
↓ Antithrombotics Clopidogrel GP IIb/IIIa Enoxaparin Bivalirudin
↑ Atherectomy↓ EPD↑ Atherectomy↓ EPD
Perioprocedural MyonecrosisPerioprocedural MyonecrosisPerioprocedural MyonecrosisPerioprocedural Myonecrosis
Cardiovascular Morbidity and MortalityCardiovascular Morbidity and MortalityCardiovascular Morbidity and MortalityCardiovascular Morbidity and Mortality
Arterial InflammationArterial Inflammation Arterial InflammationArterial Inflammation Aspirin ResistanceAspirin ResistanceAspirin ResistanceAspirin Resistance InterventionalInterventionalDeviceDevice
InterventionalInterventionalDeviceDevice
MortalityMortality
Major BleedingMajor Bleeding
TransfusionTransfusionHypotensionHypotension Cessation of Cessation of ASA/ClopidogrelASA/Clopidogrel
IschemiaIschemia Stent ThrombosisStent Thrombosis InflammationInflammation
Bhatt DL et al. In Braunwald: Harrison’s Online 2005.
Potential Relationship BetweenPotential Relationship BetweenBleeding and MortalityBleeding and Mortality
The Big Picture: Early Invasive vs. The Big Picture: Early Invasive vs. Initial Conservative TherapyInitial Conservative Therapy
““An early invasive strategy (i.e., diagnostic angiography with intent to perform An early invasive strategy (i.e., diagnostic angiography with intent to perform revascularization) is indicated in initially stabilized UA/NSTEMI patients revascularization) is indicated in initially stabilized UA/NSTEMI patients (without serious comorbidities or contraindications to such procedures) (without serious comorbidities or contraindications to such procedures) who who have an elevated risk for clinical eventshave an elevated risk for clinical events.”.”
““In initially stabilized patients, an In initially stabilized patients, an initially conservative (i.e., a selectively initially conservative (i.e., a selectively invasive) strategy may be consideredinvasive) strategy may be considered as a treatment strategy for UA/NSTEMI as a treatment strategy for UA/NSTEMI patients (without serious comorbidities or contraindications to such patients (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events, procedures) who have an elevated risk for clinical events, including those who including those who are troponin positiveare troponin positive.”.”
““The decision to implement an initial conservative (vs. initial invasive) strategy The decision to implement an initial conservative (vs. initial invasive) strategy in these patients may be made by in these patients may be made by considering physician and patient considering physician and patient preferencepreference.” .”
The Big Picture: Early Invasive vs. The Big Picture: Early Invasive vs. Initial Conservative TherapyInitial Conservative Therapy
““An early invasive strategy (i.e., diagnostic angiography with intent to perform An early invasive strategy (i.e., diagnostic angiography with intent to perform revascularization) is indicated in initially stabilized UA/NSTEMI patients revascularization) is indicated in initially stabilized UA/NSTEMI patients (without serious comorbidities or contraindications to such procedures) (without serious comorbidities or contraindications to such procedures) who who have an elevated risk for clinical eventshave an elevated risk for clinical events.”.”
““In initially stabilized patients, an In initially stabilized patients, an initially conservative (i.e., a selectively initially conservative (i.e., a selectively invasive) strategy may be consideredinvasive) strategy may be considered as a treatment strategy for UA/NSTEMI as a treatment strategy for UA/NSTEMI patients (without serious comorbidities or contraindications to such patients (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events, procedures) who have an elevated risk for clinical events, including those who including those who are troponin positiveare troponin positive.”.”
““The decision to implement an initial conservative (vs. initial invasive) strategy The decision to implement an initial conservative (vs. initial invasive) strategy in these patients may be made by in these patients may be made by considering physician and patient considering physician and patient preferencepreference.” .”
UA/NSTEMI Strategy OverviewUA/NSTEMI Strategy Overview
ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.Circulation.ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.Circulation.
Big Picture: Antiplatelet AgentsBig Picture: Antiplatelet Agents
““Support for thienopyridine use (primarily with clopidogrel) Support for thienopyridine use (primarily with clopidogrel) continues to grow, including higher loading-dose options, continues to grow, including higher loading-dose options, earlier (upstream) administrationearlier (upstream) administration, and longer administration , and longer administration (especially after drug-eluting stent placement).” (especially after drug-eluting stent placement).”
““The question of how best to integrate thienopyridine use The question of how best to integrate thienopyridine use with parenteral glycoprotein (GP) IIb/IIIa antagonists to with parenteral glycoprotein (GP) IIb/IIIa antagonists to provide optimal antiplatelet therapy early in the course of provide optimal antiplatelet therapy early in the course of UA/NSTEMI therapy, including cardiac catheterization, UA/NSTEMI therapy, including cardiac catheterization, is an is an evolving areaevolving area.”.”
Big Picture: Antiplatelet AgentsBig Picture: Antiplatelet Agents
““Support for thienopyridine use (primarily with clopidogrel) Support for thienopyridine use (primarily with clopidogrel) continues to grow, including higher loading-dose options, continues to grow, including higher loading-dose options, earlier (upstream) administrationearlier (upstream) administration, and longer administration , and longer administration (especially after drug-eluting stent placement).” (especially after drug-eluting stent placement).”
““The question of how best to integrate thienopyridine use The question of how best to integrate thienopyridine use with parenteral glycoprotein (GP) IIb/IIIa antagonists to with parenteral glycoprotein (GP) IIb/IIIa antagonists to provide optimal antiplatelet therapy early in the course of provide optimal antiplatelet therapy early in the course of UA/NSTEMI therapy, including cardiac catheterization, UA/NSTEMI therapy, including cardiac catheterization, is an is an evolving areaevolving area.”.”
UA/NSTEMI Strategy OverviewUA/NSTEMI Strategy Overview
ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.
Big Picture: AnticoagulantsBig Picture: Anticoagulants
““Two new anticoagulants, Two new anticoagulants, fondaparinux and bivalirudinfondaparinux and bivalirudin, , have undergone have undergone favorable testing in clinical trialsfavorable testing in clinical trials and and are recommendedare recommended as alternatives to unfractionated as alternatives to unfractionated heparin (UFH) and low-molecular-weight heparins heparin (UFH) and low-molecular-weight heparins (LMWHs) for specific or more general applications.”(LMWHs) for specific or more general applications.”
Big Picture: AnticoagulantsBig Picture: Anticoagulants
““Two new anticoagulants, Two new anticoagulants, fondaparinux and bivalirudinfondaparinux and bivalirudin, , have undergone have undergone favorable testing in clinical trialsfavorable testing in clinical trials and and are recommendedare recommended as alternatives to unfractionated as alternatives to unfractionated heparin (UFH) and low-molecular-weight heparins heparin (UFH) and low-molecular-weight heparins (LMWHs) for specific or more general applications.”(LMWHs) for specific or more general applications.”
ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.
UA/NSTEMI Strategy OverviewUA/NSTEMI Strategy Overview
Pivotal TrialsPivotal TrialsFocus on AnticoagulationFocus on AnticoagulationPivotal TrialsPivotal Trials
Focus on AnticoagulationFocus on Anticoagulation
ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.
UA/NSTEMI Strategy OverviewUA/NSTEMI Strategy Overview
OASIS-5: Efficacy at Day 9OASIS-5: Efficacy at Day 9
EnoxEnox FondaFonda————%——%——
Death/MI/RIDeath/MI/RI 5.85.8 5.95.9
Death/MIDeath/MI 4.14.1 4.14.1
DeathDeath 1.91.9 1.81.8
MIMI 2.72.7 2.72.7
Refract IschRefract Isch 1.91.9 2.052.05
0.80.8 11 1.21.2
Non-inferiorityMargin = 1.185Non-inferiorityMargin = 1.185
Hazard RatioHazard RatioHazard RatioHazard Ratio
Fonda BetterFonda BetterFonda BetterFonda Better Enox BetterEnox BetterEnox BetterEnox Better
Yusuf S, et al. N Engl J Med. 2006;354(14):1464-76Yusuf S, et al. N Engl J Med. 2006;354(14):1464-76
OASIS-5: Bleeding Rates at Day 9OASIS-5: Bleeding Rates at Day 9
Yusuf S, et al. N Engl J Med. 2006;354(14):1464-76Yusuf S, et al. N Engl J Med. 2006;354(14):1464-76
OutcomeOutcome EnoxaparinEnoxaparin FondaparinuxFondaparinux HR (95% CI)HR (95% CI) PP
No. RandomizedNo. Randomized 10,02110,021 10,05710,057
Total Bleed (%)Total Bleed (%) 7.07.0 3.23.2 0.44 (0.39 – 0.51)0.44 (0.39 – 0.51) < 0.0001< 0.0001
Major Bleed (%)Major Bleed (%) 4.04.0 2.12.1 0.53 (0.45 – 0.62)0.53 (0.45 – 0.62) < 0.0001< 0.0001
TIMI Major TIMI Major Bleed (%)Bleed (%) 1.31.3 0.70.7 0.54 (0.41 – 0.73)0.54 (0.41 – 0.73) < 0.0001< 0.0001
Minor Bleed (%)Minor Bleed (%) 3.13.1 1.11.1 0.35 (0.28 – 0.43)0.35 (0.28 – 0.43) < 0.0001< 0.0001
OASIS-5OASIS-5 Efficacy End Points at 6 MonthsEfficacy End Points at 6 Months
End point End point EnoxaparinEnoxaparin FondaparinuxFondaparinux P valueP value
Death/MI/ refractory ischemia Death/MI/ refractory ischemia 13.2%13.2% 12.3%12.3% 0.060.06
Death/MI Death/MI 11.4%11.4% 10.5%10.5% 0.050.05
Death Death 6.5%6.5% 5.8%5.8% 0.050.05
MI MI 6.6%6.6% 6.3%6.3% NSNS
Stroke Stroke 1.7%1.7% 1.3%1.3% 0.040.04
Death/MI/stroke*Death/MI/stroke* 12.5%12.5% 11.3%11.3% 0.0070.007
Yusuf S, et al. N Engl J Med. 2006;354(14):1464-76Yusuf S, et al. N Engl J Med. 2006;354(14):1464-76
PCI — Procedural ComplicationsPCI — Procedural Complications
Events (30 Days)Events (30 Days) Enoxaparin Enoxaparin n=3089n=3089
Fondaparinux Fondaparinux n=3118n=3118
P valueP value
Any UFH during PCI Any UFH during PCI 53.8%53.8% 18.8%18.8%
Any procedural Any procedural complication complication 8.6%8.6% 9.6%9.6% 0.180.18
Abrupt closureAbrupt closure 1.1%1.1% 1.5%1.5% 0.200.20
Catheter thrombus Catheter thrombus 0.5%0.5% 1.3%1.3% 0.0010.001
Vascular access Vascular access 8.1%8.1% 3.3%3.3% <0.0001<0.0001
Pseudo-aneurysmPseudo-aneurysm 1.6%1.6% 1.0%1.0% 0.390.39
Large hematomaLarge hematoma 4.4%4.4% 1.6%1.6% <0.0001<0.0001
Yusuf S, et al. N Engl J Med. 2006;354(14):1464-76Yusuf S, et al. N Engl J Med. 2006;354(14):1464-76
ACUITY—Ischemic Composite EndpointACUITY—Ischemic Composite Endpoint
0
5
10
15
0 5 10 15 20 25 30 35
Cum
ulat
ive
Eve
nts
(%)
Cum
ulat
ive
Eve
nts
(%)
Days from RandomizationDays from Randomization
EstimateEstimatePP
(log rank)(log rank)
7.3%7.3%UFH/Enoxaparin + IIb/IIIa (N=4603)UFH/Enoxaparin + IIb/IIIa (N=4603)
Bivalirudin + IIb/IIIa (N=4604)Bivalirudin + IIb/IIIa (N=4604) 0.370.377.7%7.7%
Bivalirudin alone (N=4612)Bivalirudin alone (N=4612) 0.300.307.8%7.8%
Stone GW, et al. NEJM. 2006 Nov 23;355(21):2203-16. Stone GW, et al. NEJM. 2006 Nov 23;355(21):2203-16.
ACUITY—Major Bleeding EndpointACUITY—Major Bleeding Endpoint
0
5
10
15
0 5 10 15 20 25 30 35
Cum
ulat
ive
Eve
nts
(%)
Cum
ulat
ive
Eve
nts
(%)
Days from RandomizationDays from Randomization
EstimateEstimate PP
(log rank)(log rank)
5.7%5.7%UFH/Enoxaparin + IIb/IIIa (N=4603)UFH/Enoxaparin + IIb/IIIa (N=4603)
Bivalirudin + IIb/IIIa (N=4604)Bivalirudin + IIb/IIIa (N=4604) 0.410.415.3%5.3%
Bivalirudin alone (N=4612)Bivalirudin alone (N=4612) <0.0001<0.00013.0%3.0%
Stone GW, et al. NEJM. 2006 Nov 23;355(21):2203-16.
0 30 60 90 120 150 180 210 240 270 300 330 360 3900
4
5
Mor
talit
y (%
)M
orta
lity
(%)
Days from RandomizationDays from Randomization
2
1
ACUITY Mortality at One YearACUITY Mortality at One Year
UFH/Enoxaparin + IIb/IIIaBivalirudin + IIb/IIIaBivalirudin alone
EstimateP
(log rank)
1.4%0.531.6%0.391.6%
—
EstimateP
(log rank)
4.4%0.934.2%0.663.8%
1 year
—
p=0.90
Bivalirudin+GPI vs. Hep+GPIHR [95% CI] = 0.99 (0.80-1.22)Bivalirudin+GPI vs. Hep+GPI
HR [95% CI] = 0.99 (0.80-1.22)
30 day
3
Bivalirudin alone vs. Hep+GPIHR [95% CI] = 0.95 (0.77-1.18)Bivalirudin alone vs. Hep+GPIHR [95% CI] = 0.95 (0.77-1.18)
Stone GW, ACC 2007 Stone GW, ACC 2007
Antiplatelet AgentsAntiplatelet AgentsMechanisms and Current TrialsMechanisms and Current TrialsAntiplatelet AgentsAntiplatelet Agents
Mechanisms and Current TrialsMechanisms and Current Trials
UA/NSTEMI Strategy OverviewUA/NSTEMI Strategy Overview
Meadows TA, Bhatt DL. Circ Res. 2007;100:1261-1275.
Platelet and Thrombus FormationVascular Injury
Platelet and Thrombus FormationVascular Injury
Meadows TA, Bhatt DL. Circ Res. 2007;100:1261-1275.
ADP ReceptorsADP Receptors
Bhatt DL et al. Nature Reviews Drug Discovery 2003; 2:15-28.
CURRENT OASIS 7 Study DesignCURRENT OASIS 7 Study Design
RANDOMIZERANDOMIZERANDOMIZERANDOMIZE RANDOMIZERANDOMIZERANDOMIZERANDOMIZE
RANDOMIZERANDOMIZERANDOMIZERANDOMIZE
PCI: Percutaneous coronary interventionUA/NSTEMI: Unstable angina/non-ST-segment elevation myocardial infarction
Slide courtesy of Dr. Shamir Mehta
N = ~14, 000N = ~14, 000
Patients with UA/NSTEMI planned for early invasivestrategy, i.e. intend for PCI as early as possible within 24 hrs
Patients with UA/NSTEMI planned for early invasivestrategy, i.e. intend for PCI as early as possible within 24 hrs
Clopidogrel High Dose GroupClopidogrel 600mg loading dose Day 1 followed by
150mg from Day 2 to Day 7; 75mg from Day 8 to 30
Clopidogrel High Dose GroupClopidogrel 600mg loading dose Day 1 followed by
150mg from Day 2 to Day 7; 75mg from Day 8 to 30
Clopidogrel Standard Dose GroupClopidogrel 300mg (+placebo) Day 1 followed
by 75mg (+placebo) from Day 2 to Day 7;75mg from Day 8 to 30
Clopidogrel Standard Dose GroupClopidogrel 300mg (+placebo) Day 1 followed
by 75mg (+placebo) from Day 2 to Day 7;75mg from Day 8 to 30
ASA high dose groupAt least 300mg Day1;
300mg–325mgfrom D2 to D30
ASA high dose groupAt least 300mg Day1;
300mg–325mgfrom D2 to D30
ASA low dose groupAt least 300mg Day1;
75–100mgfrom D2 to D30
ASA low dose groupAt least 300mg Day1;
75–100mgfrom D2 to D30
ASA low dose groupAt least 300mg Day1;
75–100mgfrom D2 to D30
ASA low dose groupAt least 300mg Day1;
75–100mgfrom D2 to D30
ASA high dose groupAt least 300mg Day1;
300mg–325mgfrom D2 to D30
ASA high dose groupAt least 300mg Day1;
300mg–325mgfrom D2 to D30
Cangrelor (AR-C69931MX)Cangrelor (AR-C69931MX)
Parenteral ADP-P2Y12 receptor antagonistParenteral ADP-P2Y12 receptor antagonist ● ATP analogue ATP analogue ● Molecular weight 800 DaltonsMolecular weight 800 Daltons● Plasma half-life of 5-9 minutesPlasma half-life of 5-9 minutes● 20 minutes for return to normal platelet 20 minutes for return to normal platelet
functionfunction
Parenteral ADP-P2Y12 receptor antagonistParenteral ADP-P2Y12 receptor antagonist ● ATP analogue ATP analogue ● Molecular weight 800 DaltonsMolecular weight 800 Daltons● Plasma half-life of 5-9 minutesPlasma half-life of 5-9 minutes● 20 minutes for return to normal platelet 20 minutes for return to normal platelet
functionfunction
NN
NN
NH
SCF
3
OHOH
OO
PO
O
PP
OO
OCl
Cl
OO
O
S
4Na+
CHAMPION — Platform TrialCHAMPION — Platform Trial
uRevasc, urgent revascularizationuRevasc, urgent revascularization
PCI for ACS(N~4400)~4400)
PCI for ACS(N~4400)~4400)
1:1 Double -blind, double-dummy1:1 Double -blind, double-dummy1:1 Double -blind, double-dummy1:1 Double -blind, double-dummy
Cangrelorbolus (30 µg/kg) &
infusion (4 µg/kg/min)
Cangrelorbolus (30 µg/kg) &
infusion (4 µg/kg/min)
Clopidogrelcapsules(600 mg)
Clopidogrelcapsules(600 mg)
Placebo Placebo capsules (to capsules (to
match)match)
Placebo Placebo capsules (to capsules (to
match)match)
Placebo bolus Placebo bolus and infusion and infusion (to match)(to match)
Placebo bolus Placebo bolus and infusion and infusion (to match)(to match)
Index ProcedureIndex Procedure
Study drug infusion (for at least 2 hours orStudy drug infusion (for at least 2 hours orthe duration of the procedure, whichever is longer)the duration of the procedure, whichever is longer)
Index ProcedureIndex Procedure
Study drug infusion (for at least 2 hours orStudy drug infusion (for at least 2 hours orthe duration of the procedure, whichever is longer)the duration of the procedure, whichever is longer)
Placebo Placebo capsules (to capsules (to
match)match)
Placebo Placebo capsules (to capsules (to
match)match)
Clopidogrel Clopidogrel capsules capsules (600 mg)(600 mg)
Clopidogrel Clopidogrel capsules capsules (600 mg)(600 mg)
1º Endpoint: Death, MI, and UTVR at 48 hours1º Endpoint: Death, MI, and UTVR at 48 hours1º Endpoint: Death, MI, and UTVR at 48 hours1º Endpoint: Death, MI, and UTVR at 48 hours
2 º Endpoints:Death, MI, uRevasc at 30 daysDeath at 6 months and 1 year
2 º Endpoints:Death, MI, uRevasc at 30 daysDeath at 6 months and 1 year
The Inflammatory InterfacesThe Inflammatory InterfacesFocus on StatinsFocus on Statins
The Inflammatory InterfacesThe Inflammatory InterfacesFocus on StatinsFocus on Statins
NSTE-ACS Strategy OverviewNSTE-ACS Strategy Overview
Statins as Anti-Inflammatory Drugs?Statins as Anti-Inflammatory Drugs?
Inhibit IsoprenylationInhibit Isoprenylation Rac, Rho, RA 1Rac, Rho, RA 1Upregulate eNOSUpregulate eNOSActivate AKT pathwayActivate AKT pathwayInhibit caveolinInhibit caveolin
StatinsStatins
ROSROS Oxidized LDLOxidized LDL Angiotensin 1Angiotensin 1 Endothelin 1Endothelin 1 Inflammatory cellsInflammatory cells CRP, IL-6CRP, IL-6 Endothelial nitric oxideEndothelial nitric oxide production & improves production & improves
endothelial functionendothelial function
Foam cellFoam cell Inflammatory Inflammatory
macrophages & T-cellsmacrophages & T-cells CytokinesCytokines Adhesion moleculesAdhesion molecules P- and C-selectinP- and C-selectin Smooth muscle cellSmooth muscle cell
proliferationproliferation
Matrix metalloproteinasesMatrix metalloproteinases Platelet activationPlatelet activation Tissue factorTissue factor Plasminogen activator Plasminogen activator
inhibitor-1inhibitor-1 CD40/CD40LCD40/CD40L Platelet/thrombusPlatelet/thrombus
formationformation
Inflammatory cellsInflammatory cells Cytokines, Cytokines, chemokines chemokines VasoconstrictionVasoconstriction Cardiac remodelingCardiac remodeling
Improve Autonomic FunctionImprove Autonomic Function
AcuteAcuteCoronary SyndromeCoronary SyndromePatel T, Shishehbor MH, Bhatt DL. EHJ 2007.
Baseline hs-CRP and Outcome in PCIBaseline hs-CRP and Outcome in PCI
Chew DP, Bhatt DL, Robbins M, et al. Circulation 2001.
Statin Pretreatment Prior toStatin Pretreatment Prior toPCI and CRPPCI and CRP
Chan AW, Bhatt DL, Chew DP, et al. Circulation 2003.Chan AW, Bhatt DL, Chew DP, et al. Circulation 2003.
1.21.8
5.6 5.7
3.1 2.8
6.3
14.8
0
2
4
6
8
10
12
14
16
1st Quartile 2nd Quartile 3rd Quartile 4th Quartile
Statin No Statin
1.21.8
5.6 5.7
3.1 2.8
6.3
14.8
0
2
4
6
8
10
12
14
16
1st Quartile 2nd Quartile 3rd Quartile 4th Quartile
Statin No Statin
P=0.26P=0.26P=0.26P=0.26P=0.69P=0.69P=0.69P=0.69
P=0.97P=0.97P=0.97P=0.97
P=0.009P=0.009P=0.009P=0.009
3.4% vs. 6.9%, P=0.0033.4% vs. 6.9%, P=0.0033.4% vs. 6.9%, P=0.0033.4% vs. 6.9%, P=0.003
Preprocedural CRP (mg/dL)Preprocedural CRP (mg/dL)Preprocedural CRP (mg/dL)Preprocedural CRP (mg/dL)
1-Y
ear
Mor
talit
y (%
)1-
Yea
r M
orta
lity
(%)
1-Y
ear
Mor
talit
y (%
)1-
Yea
r M
orta
lity
(%)
Overall OR (95% CI) 0.74(0.61, 0.90)Overall OR (95% CI) 0.74(0.61, 0.90)Overall OR (95% CI) 0.74(0.61, 0.90)Overall OR (95% CI) 0.74(0.61, 0.90)
Statin Pretreatment Early in ACSStatin Pretreatment Early in ACS
Bavry, Mood, Kumbhani, Borek, Askari, Bhatt. AJCD 2006.
Mortality Incidence (%)Study Odds Ratio Statin therapy Less-intensive
L-CAD 2.9 3.6
PTT 2.5 8.1
Florida 2.6 4.0
Colivicchi 7.5 9.8
PROVE-IT 2.2 3.2
ESTABLISH 0.0 2.9
A to Z 4.6 5.8
Mortality Incidence (%)Study Odds Ratio Statin therapy Less-intensive
L-CAD 2.9 3.6
PTT 2.5 8.1
Florida 2.6 4.0
Colivicchi 7.5 9.8
PROVE-IT 2.2 3.2
ESTABLISH 0.0 2.9
A to Z 4.6 5.8
0.1 1.0 10.00.1 1.0 10.0
FavorsFavorsStatin TherapyStatin Therapy
FavorsFavorsStatin TherapyStatin Therapy
FavorsFavorsLess-intensiveLess-intensiveLipid TherapyLipid Therapy
FavorsFavorsLess-intensiveLess-intensiveLipid TherapyLipid Therapy
Statin Pretreatment Prior to PCI and MIStatin Pretreatment Prior to PCI and MI
Mood G, Bavry AA, Roukoz H, Bhatt DL. AJC 2007.
Odds ratioOdds ratioOdds ratioOdds ratio
.1.1 11 1010
StudyStudy % Weight% Weight % Weight% Weight Odds ratioOdds ratio Odds ratioOdds ratio
(95% Confidence (95% Confidence Interval)Interval)
(95% Confidence (95% Confidence Interval)Interval)
1.00 (0.25, 3.98)1.00 (0.25, 3.98) 1.00 (0.25, 3.98)1.00 (0.25, 3.98) PREDICTPREDICT PREDICTPREDICT 3.93.9 3.93.9
0.31 (0.09, 1.12)0.31 (0.09, 1.12) 0.31 (0.09, 1.12)0.31 (0.09, 1.12) FLAREFLARE FLAREFLARE 9.59.5 9.59.5
0.20 (0.01, 4.15)0.20 (0.01, 4.15) 0.20 (0.01, 4.15)0.20 (0.01, 4.15) GAINGAIN GAINGAIN 2.42.4 2.42.4
0.78 (0.49, 1.25)0.78 (0.49, 1.25) 0.78 (0.49, 1.25)0.78 (0.49, 1.25) LIPSLIPS LIPSLIPS 36.936.9 36.936.9
0.29 (0.10 0.84)0.29 (0.10 0.84) 0.29 (0.10 0.84)0.29 (0.10 0.84) ARMYDAARMYDA ARMYDAARMYDA 13.413.4 13.413.4
0.51 (0.30, 0.88)0.51 (0.30, 0.88) 0.51 (0.30, 0.88)0.51 (0.30, 0.88) BriguoriBriguori BriguoriBriguori 33.933.9 33.933.9
0.57 (0.42, 0.78)0.57 (0.42, 0.78) 0.57 (0.42, 0.78)0.57 (0.42, 0.78) Overall (95% Confidence Overall (95% Confidence Interval)Interval) Overall (95% Confidence Overall (95% Confidence Interval)Interval)
► ECG and ASA within 10 minutesECG and ASA within 10 minutes● STEMI patients directed to their pathwaySTEMI patients directed to their pathway
► Risk stratificationRisk stratification● Focused history and physical, biomarkers, serial ECGs, risk Focused history and physical, biomarkers, serial ECGs, risk
score, and bleeding riskscore, and bleeding risk
► Patients with high ischemic risk should go for EIS Patients with high ischemic risk should go for EIS (Class I) or, in a minority of cases, for ICS (Class (Class I) or, in a minority of cases, for ICS (Class IIa), but only IIa), but only after medical stabilizationafter medical stabilization
► ECG and ASA within 10 minutesECG and ASA within 10 minutes● STEMI patients directed to their pathwaySTEMI patients directed to their pathway
► Risk stratificationRisk stratification● Focused history and physical, biomarkers, serial ECGs, risk Focused history and physical, biomarkers, serial ECGs, risk
score, and bleeding riskscore, and bleeding risk
► Patients with high ischemic risk should go for EIS Patients with high ischemic risk should go for EIS (Class I) or, in a minority of cases, for ICS (Class (Class I) or, in a minority of cases, for ICS (Class IIa), but only IIa), but only after medical stabilizationafter medical stabilization
Summary 2007 GuidelinesSummary 2007 GuidelinesUpstream Management of Suspected ACSUpstream Management of Suspected ACS
► Anticoagulation StrategiesAnticoagulation Strategies● EIS: Enoxaparin (I-A), UFH (I-A), or bivalirudin (I-B)EIS: Enoxaparin (I-A), UFH (I-A), or bivalirudin (I-B)
• Strong support for bivalirudin when time to lab is quick and/or Strong support for bivalirudin when time to lab is quick and/or when bleeding risk is higher (screen for patients at higher risk when bleeding risk is higher (screen for patients at higher risk for bleeding)for bleeding)
● ECS: Enoxaparin (I-A), UFH (I-A), or fondaparinux ECS: Enoxaparin (I-A), UFH (I-A), or fondaparinux
(I-B)(I-B)• Strong support for fondaparinux when bleeding risk is higher, but Strong support for fondaparinux when bleeding risk is higher, but
more problematic if catheterization later requiredmore problematic if catheterization later required
● Individual patient characteristics (ischemic risk, Individual patient characteristics (ischemic risk, bleeding risk, time to cath) should drive choices, bleeding risk, time to cath) should drive choices,
► Anticoagulation StrategiesAnticoagulation Strategies● EIS: Enoxaparin (I-A), UFH (I-A), or bivalirudin (I-B)EIS: Enoxaparin (I-A), UFH (I-A), or bivalirudin (I-B)
• Strong support for bivalirudin when time to lab is quick and/or Strong support for bivalirudin when time to lab is quick and/or when bleeding risk is higher (screen for patients at higher risk when bleeding risk is higher (screen for patients at higher risk for bleeding)for bleeding)
● ECS: Enoxaparin (I-A), UFH (I-A), or fondaparinux ECS: Enoxaparin (I-A), UFH (I-A), or fondaparinux
(I-B)(I-B)• Strong support for fondaparinux when bleeding risk is higher, but Strong support for fondaparinux when bleeding risk is higher, but
more problematic if catheterization later requiredmore problematic if catheterization later required
● Individual patient characteristics (ischemic risk, Individual patient characteristics (ischemic risk, bleeding risk, time to cath) should drive choices, bleeding risk, time to cath) should drive choices,
Summary 2007 GuidelinesSummary 2007 GuidelinesUpstream Medical StabilizationUpstream Medical Stabilization
Year 2007 Guidelines: Year 2007 Guidelines: Good News, Bad NewsGood News, Bad News
No (Up)Stream Strategy is PerfectNo (Up)Stream Strategy is Perfect
Guideline StrategyGuideline Strategy Possible LimitationPossible Limitation
ASAASA AllergyAllergy
ClopidogrelClopidogrel Resistance, CABG plannedResistance, CABG planned
UFHUFH Platelet activation, HITPlatelet activation, HIT
UFH + GP IIb/IIIa InhibitorUFH + GP IIb/IIIa Inhibitor Bleeding, costBleeding, cost
Enoxaparin + GP IIb/IIIa Enoxaparin + GP IIb/IIIa Bleeding, renal dysfunctionBleeding, renal dysfunction
BivalirudinBivalirudin Clopidogrel exposureClopidogrel exposure
Conclusions Conclusions
► New ACS guidelines provide considerableNew ACS guidelines provide considerablelatitude as far as strategies of carelatitude as far as strategies of care
► Need to minimize ischemia and bleedingNeed to minimize ischemia and bleeding
► Anticoagulation remains importantAnticoagulation remains important
► Switching permitted with some agentsSwitching permitted with some agents
► Early antiplatelet therapy upgradedEarly antiplatelet therapy upgraded
► Early statin use probably a good ideaEarly statin use probably a good idea
► Early invasive remains preferredEarly invasive remains preferred
► New ACS guidelines provide considerableNew ACS guidelines provide considerablelatitude as far as strategies of carelatitude as far as strategies of care
► Need to minimize ischemia and bleedingNeed to minimize ischemia and bleeding
► Anticoagulation remains importantAnticoagulation remains important
► Switching permitted with some agentsSwitching permitted with some agents
► Early antiplatelet therapy upgradedEarly antiplatelet therapy upgraded
► Early statin use probably a good ideaEarly statin use probably a good idea
► Early invasive remains preferredEarly invasive remains preferred
Ron Waksman, MD, FACCRon Waksman, MD, FACC Associate Director, Division of CardiologyAssociate Director, Division of Cardiology
Washington Hospital Center, Washington Hospital Center Washington Hospital Center, Washington Hospital Center Professor of Medicine - Georgetown University Washington, DCProfessor of Medicine - Georgetown University Washington, DC
Ron Waksman, MD, FACCRon Waksman, MD, FACC Associate Director, Division of CardiologyAssociate Director, Division of Cardiology
Washington Hospital Center, Washington Hospital Center Washington Hospital Center, Washington Hospital Center Professor of Medicine - Georgetown University Washington, DCProfessor of Medicine - Georgetown University Washington, DC
Getting in the Stream(s) of Antithrombotic Getting in the Stream(s) of Antithrombotic Therapy for ACS—What Do TheTherapy for ACS—What Do The
Data Tell Us?Data Tell Us?
To Switch or Not to Switch —To Switch or Not to Switch —
Why, When, How, To What?Why, When, How, To What?
Getting in the Stream(s) of Antithrombotic Getting in the Stream(s) of Antithrombotic Therapy for ACS—What Do TheTherapy for ACS—What Do The
Data Tell Us?Data Tell Us?
To Switch or Not to Switch —To Switch or Not to Switch —
Why, When, How, To What?Why, When, How, To What?
The Science and Medicine of Acute Coronary SyndromeThe Science and Medicine of Acute Coronary Syndrome
Overview of PresentationOverview of Presentation
► Why should switching to bivalirudin for PCI be Why should switching to bivalirudin for PCI be reasonable?reasonable?
► Mechanistic rationale for switchingMechanistic rationale for switching
► Why is there a concern about switching Why is there a concern about switching antithrombins in patients with ACS (lessons from antithrombins in patients with ACS (lessons from SYNERGY)SYNERGY)
► Clinical EvidenceClinical Evidence● BATBAT● SWITCHSWITCH● REPLACE 2REPLACE 2● ACUITYACUITY
► Why should switching to bivalirudin for PCI be Why should switching to bivalirudin for PCI be reasonable?reasonable?
► Mechanistic rationale for switchingMechanistic rationale for switching
► Why is there a concern about switching Why is there a concern about switching antithrombins in patients with ACS (lessons from antithrombins in patients with ACS (lessons from SYNERGY)SYNERGY)
► Clinical EvidenceClinical Evidence● BATBAT● SWITCHSWITCH● REPLACE 2REPLACE 2● ACUITYACUITY
Background — Issues and ConcernsBackground — Issues and Concerns
► ACS patientsACS patients● 87% of patients receive either UFH, enoxaparin, or 87% of patients receive either UFH, enoxaparin, or
fondaparinux within 24 hours after admissionfondaparinux within 24 hours after admission11
● 72% of patients in SYNERGY and 50 % of patients in 72% of patients in SYNERGY and 50 % of patients in OASIS- 5OASIS- 5 received prior antithrombinreceived prior antithrombin2,32,3
► Published studies and perceptionsPublished studies and perceptions● Patients in SYNERGY who crossed over between Patients in SYNERGY who crossed over between
UFH and enoxaparin had an increase in bleeding UFH and enoxaparin had an increase in bleeding complicationscomplications22
• This activity occurred at various times through the study period: This activity occurred at various times through the study period: At times in response to clinical or clinician perceptionAt times in response to clinical or clinician perception
● Consistent therapy is betterConsistent therapy is better44
► ACS patientsACS patients● 87% of patients receive either UFH, enoxaparin, or 87% of patients receive either UFH, enoxaparin, or
fondaparinux within 24 hours after admissionfondaparinux within 24 hours after admission11
● 72% of patients in SYNERGY and 50 % of patients in 72% of patients in SYNERGY and 50 % of patients in OASIS- 5OASIS- 5 received prior antithrombinreceived prior antithrombin2,32,3
► Published studies and perceptionsPublished studies and perceptions● Patients in SYNERGY who crossed over between Patients in SYNERGY who crossed over between
UFH and enoxaparin had an increase in bleeding UFH and enoxaparin had an increase in bleeding complicationscomplications22
• This activity occurred at various times through the study period: This activity occurred at various times through the study period: At times in response to clinical or clinician perceptionAt times in response to clinical or clinician perception
● Consistent therapy is betterConsistent therapy is better44
1 CRUSADE( 1Q-2006 results); 2 Synergy results; JAMA 2004; 3 OASIS -5; Yusuf et al,NEJM 2006; 4 Cohen et al, JACC 2006.
Bivalirudin Bivalirudin An Alternative to UFH/LMWHAn Alternative to UFH/LMWH
► Advantages of the direct thrombin inhibitor Advantages of the direct thrombin inhibitor bivalirudinbivalirudin
● No requirement for antithrombin IIINo requirement for antithrombin III● Effective on clot-bound thrombinEffective on clot-bound thrombin● Inhibits thrombin-mediated platelet activationInhibits thrombin-mediated platelet activation● No interactions with PF- 4No interactions with PF- 4● Plasma half-life 25 minutesPlasma half-life 25 minutes● No requirement for anticoagulant monitoringNo requirement for anticoagulant monitoring
► Clinical results with bivalirudin in PCIClinical results with bivalirudin in PCI● Similar protection from ischemic events as UFH + GP IIb/IIIa Similar protection from ischemic events as UFH + GP IIb/IIIa
inhibitors, with markedly reduced bleedinginhibitors, with markedly reduced bleeding11
► Not previously tested in contemporary ACS Not previously tested in contemporary ACS patientspatients
► Advantages of the direct thrombin inhibitor Advantages of the direct thrombin inhibitor bivalirudinbivalirudin
● No requirement for antithrombin IIINo requirement for antithrombin III● Effective on clot-bound thrombinEffective on clot-bound thrombin● Inhibits thrombin-mediated platelet activationInhibits thrombin-mediated platelet activation● No interactions with PF- 4No interactions with PF- 4● Plasma half-life 25 minutesPlasma half-life 25 minutes● No requirement for anticoagulant monitoringNo requirement for anticoagulant monitoring
► Clinical results with bivalirudin in PCIClinical results with bivalirudin in PCI● Similar protection from ischemic events as UFH + GP IIb/IIIa Similar protection from ischemic events as UFH + GP IIb/IIIa
inhibitors, with markedly reduced bleedinginhibitors, with markedly reduced bleeding11
► Not previously tested in contemporary ACS Not previously tested in contemporary ACS patientspatients
REPLACE 2. Lincoff AM et al. JAMA 2003;289:853-863.
Indirect vs Direct Thrombin InhibitionIndirect vs Direct Thrombin Inhibition
Indirect inhibition by heparin requires the presence of antithrombin (AT), the actual inhibitor.
Heparin (long yellow strand) binds to AT, causing a shape change that increases the ability of AT to inhibit thrombin.
Indirect inhibition by heparin requires the presence of antithrombin (AT), the actual inhibitor.
Heparin (long yellow strand) binds to AT, causing a shape change that increases the ability of AT to inhibit thrombin.
Direct inhibition with bivalirudin inhibits thrombin directly with high affinity and specificity.
It requires no cofactor, and acts alone.
Bivalirudin’s effectiveness is not affected by variability in the concentration of a co-factor like AT.
Direct inhibition with bivalirudin inhibits thrombin directly with high affinity and specificity.
It requires no cofactor, and acts alone.
Bivalirudin’s effectiveness is not affected by variability in the concentration of a co-factor like AT.
Hirsh J et al. Chest. 2001;119(1 suppl):64S-94S.Weitz JI et al. Thromb Res. 2002;106:V275-V284. Gibson CM, 2006.
Bivalirudin Inhibits Bivalirudin Inhibits Clot-Bound ThrombinClot-Bound Thrombin
The heparin-AT complex “bounces” off and is not effective against clot-bound thrombin.
This reservoir of active thrombin continues to activate platelets and trigger further clotting.
The heparin-AT complex “bounces” off and is not effective against clot-bound thrombin.
This reservoir of active thrombin continues to activate platelets and trigger further clotting.
Bivalirudin has a high affinity for and “sticks” to thrombin, which displaces thrombin from fibrin.
Bivalirudin effectively inhibits both clot-bound and circulating thrombin.
Bivalirudin has a high affinity for and “sticks” to thrombin, which displaces thrombin from fibrin.
Bivalirudin effectively inhibits both clot-bound and circulating thrombin.
Hirsh J et al. Chest. 2001;119(1 suppl):64S-94S.Weitz JI et al. Thromb Res. 2002;106:V275-V284. Gibson CM, 2006.
Switching AntithrombinsSwitching Antithrombins
► The The SYNERGYSYNERGY trial suggested a switch in trial suggested a switch in anthithrombins (from heparin to LMWH) can lead anthithrombins (from heparin to LMWH) can lead to increase in bleeding to increase in bleeding
► What outcomes are observed when switching from What outcomes are observed when switching from heparin, LMWH, or fondaparinux heparin, LMWH, or fondaparinux to bivalirudinto bivalirudin in in PCI?PCI?
► Is it better to switch or to stay on consistent Is it better to switch or to stay on consistent therapy?therapy?
► The The SYNERGYSYNERGY trial suggested a switch in trial suggested a switch in anthithrombins (from heparin to LMWH) can lead anthithrombins (from heparin to LMWH) can lead to increase in bleeding to increase in bleeding
► What outcomes are observed when switching from What outcomes are observed when switching from heparin, LMWH, or fondaparinux heparin, LMWH, or fondaparinux to bivalirudinto bivalirudin in in PCI?PCI?
► Is it better to switch or to stay on consistent Is it better to switch or to stay on consistent therapy?therapy?
Bivalirudin Angioplasty TrialBivalirudin Angioplasty Trial
A double-blind randomized A double-blind randomized comparison of comparison of bivalirudin bivalirudin versusversus
heparinheparin in 4312 patients undergoing in 4312 patients undergoing PTCA for new onset of severe, PTCA for new onset of severe, accelerating or rest angina or accelerating or rest angina or
angina within 2 weeks of myocardial angina within 2 weeks of myocardial infarctioninfarction
A double-blind randomized A double-blind randomized comparison of comparison of bivalirudin bivalirudin versusversus
heparinheparin in 4312 patients undergoing in 4312 patients undergoing PTCA for new onset of severe, PTCA for new onset of severe, accelerating or rest angina or accelerating or rest angina or
angina within 2 weeks of myocardial angina within 2 weeks of myocardial infarctioninfarction
B•A•T
Study DesignStudy Design
HIGH RISK PATIENTSHIGH RISK PATIENTS• • New onset severe, accelerating or rest anginaNew onset severe, accelerating or rest angina
• • Symptoms in last monthSymptoms in last month• • Suitable for PTCASuitable for PTCA
HIGH RISK PATIENTSHIGH RISK PATIENTS• • New onset severe, accelerating or rest anginaNew onset severe, accelerating or rest angina
• • Symptoms in last monthSymptoms in last month• • Suitable for PTCASuitable for PTCA
HeparinHeparinpretreatmentpretreatmentHeparinHeparinpretreatmentpretreatment
RandomizedRandomizedRandomizedRandomized RandomizedRandomizedRandomizedRandomized
PrimaryPrimaryPrimaryPrimary Post-MIPost-MIPost-MIPost-MI
HeparinHeparinBivalirudinBivalirudinBivalirudinBivalirudin HeparinHeparinBivalirudinBivalirudinBivalirudinBivalirudin
ASAASAASAASA ASAASAASAASA
PTCAPTCAPTCAPTCA PTCAPTCAPTCAPTCA
StratifyStratifyStratifyStratify
B•A•T
6.2%
% of patients with events at 7 days% of patients with events at 7 days
Heparinn = 2,151Heparinn = 2,151
Bivalirudinn = 2,161 Bivalirudinn = 2,161
43% reductionp-value <0.001
43% reductionp-value <0.001
22% reductionp-value 0.039
22% reductionp-value 0.039
62% reductionp-value <0.001
62% reductionp-value <0.001
3.5%
9.7% 7.9%
HemorrhageHemorrhageHemorrhageHemorrhage Death, MI, RevascularizationDeath, MI, Revascularization Death, MI, RevascularizationDeath, MI, Revascularization
Primary EndpointsPrimary EndpointsB•A•T
Net Benefit By Risk StrataNet Benefit By Risk Strata
% of patients with events at 7 days% of patients with events at 7 days
HemorrhageHemorrhageHemorrhageHemorrhage Death, MI, revascDeath, MI, revascDeath, MI, revascDeath, MI, revasc
Heparin16.5% 14.0%
Heparin11.8% 9.9%
Bivalirudin3.3% 5.8%
Bivalirudin2.4% 4.9%
Bivalirudin3.6% 6.1%
Bivalirudin4.1% 7.4%
Heparin11.9% 10.3%
Heparin8.3% 7.0%Heparin
Unstable& post-MIn = 241
Unstable& post-MIn = 241
Unstable on heparinn = 1,006
Unstable on heparinn = 1,006
Post-MIn = 741Post-MIn = 741
No risk factorsn = 2,806
No risk factorsn = 2,806
B•A•T
Switching from Enoxaparin to Bivalirudin in Patients Switching from Enoxaparin to Bivalirudin in Patients with Acute Coronary Syndromes Without ST-with Acute Coronary Syndromes Without ST-Segment Elevation Undergoing Percutaneous Segment Elevation Undergoing Percutaneous
Coronary Intervention (PCICoronary Intervention (PCI) )
Switching from Enoxaparin to Bivalirudin in Patients Switching from Enoxaparin to Bivalirudin in Patients with Acute Coronary Syndromes Without ST-with Acute Coronary Syndromes Without ST-Segment Elevation Undergoing Percutaneous Segment Elevation Undergoing Percutaneous
Coronary Intervention (PCICoronary Intervention (PCI) )
Ron Waksman, MD, FACC, FSCAIRon Waksman, MD, FACC, FSCAIAssociate Director Division of CardiologyAssociate Director Division of Cardiology
Washington Hospital CenterWashington Hospital CenterWashington, DCWashington, DC
Ron Waksman, MD, FACC, FSCAIRon Waksman, MD, FACC, FSCAIAssociate Director Division of CardiologyAssociate Director Division of Cardiology
Washington Hospital CenterWashington Hospital CenterWashington, DCWashington, DC
The study was sponsored in part by The Medicines CompanyThe study was sponsored in part by The Medicines Company
SWITCH Study SWITCH Study
31
30
30
Primary Primary EndpointEndpoint
BLEEDINGBLEEDING
91 ACS91 ACSpatients patients
undergoing undergoing PCI PCI
(3 US(3 USsites)sites)
Open-label, prospective, 3-armOpen-label, prospective, 3-arm
LMWHLMWH1mg/kg SC 1mg/kg SC
0-4 h before PCI0-4 h before PCI
LMWHLMWH1mg/kg SC 1mg/kg SC
4-8 h before PCI4-8 h before PCI
LMWHLMWH1mg/kg SC 1mg/kg SC
8-12 h before8-12 h before PCI PCI
Bivalirudin during PCI
0.75 mg/kg bolus
1.75 mg/kg/h IV infusion
Arms Switched
SWITCH: Study DesignSWITCH: Study Design
Waksman J Invasive Cardiol 2006;18:370-375.
Results: Study Drug-Results: Study Drug-Related Bleeding Events Related Bleeding Events
OutcomesOutcomes All, %All, %N=91N=91
Group 1,%Group 1,%n=30n=30
Group 2,%Group 2,%N=30N=30
Group 3,%Group 3,%N=31N=31
p p valuevalue
All Major BleedAll Major Bleed 7.7 (7)7.7 (7) 13.3 (4) 13.3 (4) 3.2 (1)3.2 (1) 6.5 (2)6.5 (2) 0.390.39
Transfusion ≥2 units Transfusion ≥2 units 4.4 (4)4.4 (4) 3.2 (1)3.2 (1) 3.2 (1)3.2 (1) 6.5 (2)6.5 (2) 1.01.0
Intracranial BleedIntracranial Bleed 0 (0)0 (0) 0 (0)0 (0) 0 (0)0 (0) 0 (0)0 (0) ----
Retroperitoneal BleedRetroperitoneal Bleed 0 (0)0 (0) 0 (0)0 (0) 0 (0)0 (0) 0 (0)0 (0) ----
Spontaneous Hematuria or Spontaneous Hematuria or HematemesisHematemesis 1.1 (1)1.1 (1) 3.2 (1)3.2 (1) 0 (0)0 (0) 0 (0)0 (0) 0.660.66
Drop in Hg > 4g/dL, no siteDrop in Hg > 4g/dL, no site 2.2 (2)2.2 (2) 6.7 (2)6.7 (2) 0 (0)0 (0) 0 (0)0 (0) 0.210.21
Drop in Hg ≥ 3 g/dLDrop in Hg ≥ 3 g/dL 0 (0)0 (0) 0 (0)0 (0) 0 (0)0 (0) 0 (0)0 (0) ----
All TransfusionsAll Transfusions 4.4 (4)4.4 (4) 6.7 (2)6.7 (2) 0 (0)0 (0) 6.5 (2)6.5 (2) 1.01.0
Minor BleedMinor Bleed 4.4 (4)4.4 (4) 6.7 (2)6.7 (2) 6.7 (2)6.7 (2) 0 (0)0 (0) 0.390.39
Waksman J Invasive Cardiol 2006;18:370-375.
SWITCH — ConclusionsSWITCH — Conclusions
► Switching from LMWH to bivalirudin during Switching from LMWH to bivalirudin during PCI for patients with ACS was safe PCI for patients with ACS was safe
► Switching was not associated with major Switching was not associated with major bleeding complications regardless of when bleeding complications regardless of when LMWH was administeredLMWH was administered
► The use of bivalirudin as the sole antithrombin The use of bivalirudin as the sole antithrombin agent during PCI can be extended for patients agent during PCI can be extended for patients who were pretreated with enoxaparin 8 hours who were pretreated with enoxaparin 8 hours post the last dose of LMWHpost the last dose of LMWH
► Switching from LMWH to bivalirudin during Switching from LMWH to bivalirudin during PCI for patients with ACS was safe PCI for patients with ACS was safe
► Switching was not associated with major Switching was not associated with major bleeding complications regardless of when bleeding complications regardless of when LMWH was administeredLMWH was administered
► The use of bivalirudin as the sole antithrombin The use of bivalirudin as the sole antithrombin agent during PCI can be extended for patients agent during PCI can be extended for patients who were pretreated with enoxaparin 8 hours who were pretreated with enoxaparin 8 hours post the last dose of LMWHpost the last dose of LMWH
Association of Pre-Randomization Anticoagulant Association of Pre-Randomization Anticoagulant Switching with Bleeding in the Setting of Percutaneous Switching with Bleeding in the Setting of Percutaneous
Coronary Intervention: A REPLACE-2 AnalysisCoronary Intervention: A REPLACE-2 Analysis
Association of Pre-Randomization Anticoagulant Association of Pre-Randomization Anticoagulant Switching with Bleeding in the Setting of Percutaneous Switching with Bleeding in the Setting of Percutaneous
Coronary Intervention: A REPLACE-2 AnalysisCoronary Intervention: A REPLACE-2 Analysis
Gibson CM, Am J Cardiol 2007.
REPLACE-2 Trial: SwitchingREPLACE-2 Trial: Switching
C. Michael Gibson, Yuli Ten, Sabina A. Murphy, Lauren N. Ciaglo, Matthew C. Southard, A. Michael Lincoff, and Ron Waksman
C. Michael Gibson, Yuli Ten, Sabina A. Murphy, Lauren N. Ciaglo, Matthew C. Southard, A. Michael Lincoff, and Ron Waksman
Randomize
Protocol major/minor bleeding, TIMI bleeding, transfusion, mortalityProtocol major/minor bleeding, TIMI bleeding, transfusion, mortality
Bivalirudin0.75 mg/kg bolus/1.75 mg/kg/h infusion with
“provisional” GP IIb/IIIa (n=2,994)1
Prior UFH (n=287)2
Naïve – no prior AT
(n=2,345)2
Overall population: Urgent or elective PCI patients (N=6,002)1
Overall population: Urgent or elective PCI patients (N=6,002)1
UFH UFH 65 U/kg with planned GP IIb/IIIa65 U/kg with planned GP IIb/IIIa
(n=3,008)(n=3,008)1
Prior LMWH
(n=258)2
Naïve – no Naïve – no prior ATprior AT
(n=2,325)(n=2,325)22
Prior UFH Prior UFH (n=349)(n=349)22
Prior Prior LMWHLMWH
(n=313)(n=313)22
REPLACE-2: SWITCH AnalysisREPLACE-2: SWITCH Analysis
AT=antithrombin.
1. Lincoff ML et al. JAMA. 2004;292:696-703.2. Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.
Protocol Major/Minor Bleed by Protocol Major/Minor Bleed by SWITCH and Randomized TherapySWITCH and Randomized Therapy
► Regardless of prior heparin or not, patients administered bivalirudin Regardless of prior heparin or not, patients administered bivalirudin had decreased bleedinghad decreased bleeding
► There was a significant increase in major/minor protocol bleeding There was a significant increase in major/minor protocol bleeding in patients administered UFH with prior heparin therapyin patients administered UFH with prior heparin therapy
► Regardless of prior heparin or not, patients administered bivalirudin Regardless of prior heparin or not, patients administered bivalirudin had decreased bleedinghad decreased bleeding
► There was a significant increase in major/minor protocol bleeding There was a significant increase in major/minor protocol bleeding in patients administered UFH with prior heparin therapyin patients administered UFH with prior heparin therapy
*P=NS for all 3-way comparisons versus bivalirudin alone; †P<.05 vs prior treatment with UFH or enoxaparin; ‡naïve=no prior AT therapy in preceding 48 hours.
Pro
toc
ol
ma
jor/
min
or
ble
ed
15.6% 15.3%16.7%
28.6%
33.8% 34.8%
0%
5%
10%
15%
20%
25%
30%
35%
15.6% 15.3%16.7%
28.6%
33.8% 34.8%
0%
5%
10%
15%
20%
25%
30%
35%
Naïve→Naïve→BivalirudinBivalirudin‡‡
(n=2,345)(n=2,345)
LMWH→LMWH→Bivalirudin Bivalirudin
(n=258)(n=258)
UFH→UFH→BivalirudinBivalirudin
(n=287)(n=287)
LMWH→UFH LMWH→UFH + GP IIb/IIIa+ GP IIb/IIIa
(n=313)(n=313)
Naïve→ Naïve→ UFH + UFH +
GP IIb/IIIaGP IIb/IIIa‡ ‡
(n=2,325)(n=2,325)
UFH→UFH UFH→UFH + GP IIb/IIIa + GP IIb/IIIa
(n=349)(n=349)
*
†
Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.
TIMI Major/Minor Bleed byTIMI Major/Minor Bleed bySWITCH and Randomized TherapySWITCH and Randomized Therapy
► Patients switched from UFH or enoxaparin to bivalirudin had the lowest rates of TIMI bleeding Patients switched from UFH or enoxaparin to bivalirudin had the lowest rates of TIMI bleeding
► Patients administered UFH had higher rates of bleeding, with highest rates in patients Patients administered UFH had higher rates of bleeding, with highest rates in patients switching between heparinsswitching between heparins
► Patients switched from UFH or enoxaparin to bivalirudin had the lowest rates of TIMI bleeding Patients switched from UFH or enoxaparin to bivalirudin had the lowest rates of TIMI bleeding
► Patients administered UFH had higher rates of bleeding, with highest rates in patients Patients administered UFH had higher rates of bleeding, with highest rates in patients switching between heparinsswitching between heparins
TIM
I m
ajo
r/m
ino
r b
lee
d
1.9%1.4%
4.3%
5.4%
1.9%
3.5%
0%
1%
2%
3%
4%
5%
6%
1.9%1.4%
4.3%
5.4%
1.9%
3.5%
0%
1%
2%
3%
4%
5%
6%
Naïve→Naïve→BivalirudinBivalirudin††
(n=2,345)(n=2,345)
LMWH →LMWH → Bivalirudin Bivalirudin
(n=258)(n=258)
UFH→UFH→BivalirudinBivalirudin
(n=287)(n=287)
LMWH→UFHLMWH→UFH+ GP IIb/IIIa+ GP IIb/IIIa
(n=313)(n=313)
Naïve→UFH Naïve→UFH + GP IIb/IIIa+ GP IIb/IIIa††
(n=2,325)(n=2,325)
UFH→UFH UFH→UFH + GP IIb/IIIa + GP IIb/IIIa
(n=349)(n=349)
*
*P=NS for all 3-way comparisons versus bivalirudin alone; †naïve=no prior AT therapy in preceding 48 hours.
Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.
Switching and 1-Year MortalitySwitching and 1-Year Mortality
2.2 2.1 2.1
3.3
4.9
3.8
0
1
2
3
4
5
6
UFHpretreatment
LMWHpretreatment
Any heparinpretreatment
Bivalirudin with "provisional" GP IIb/IIIa Heparin + GP IIb/IIIa
2.2 2.1 2.1
3.3
4.9
3.8
0
1
2
3
4
5
6
UFHpretreatment
LMWHpretreatment
Any heparinpretreatment
Bivalirudin with "provisional" GP IIb/IIIa Heparin + GP IIb/IIIa
Cu
mu
lati
ve e
ven
ts (
mo
rtal
ity)
, %C
um
ula
tive
eve
nts
(m
ort
alit
y), %
Cu
mu
lati
ve e
ven
ts (
mo
rtal
ity)
, %C
um
ula
tive
eve
nts
(m
ort
alit
y), %
REPLACE-2 Subanalysis: 1-Year Mortality Results REPLACE-2 Subanalysis: 1-Year Mortality Results Consistent with Overall Trial ResultsConsistent with Overall Trial Results
REPLACE-2 Subanalysis: 1-Year Mortality Results REPLACE-2 Subanalysis: 1-Year Mortality Results Consistent with Overall Trial ResultsConsistent with Overall Trial Results
Gibson CM, Am J Cardiol 2007 in press.
ModerateModerateand highand highrisk ACSrisk ACS(n=13,819)(n=13,819)
ACUITY Study Design – First ACUITY Study Design – First RandomizationRandomization
An
gio
gra
ph
y w
ithin
72
hA
ngi
ogr
ap
hy
with
in 7
2h
Aspirin in allClopidogrel
dosing and timingper local practice
UFH/Enox+ GP IIb/IIIa(n=4,603)
UFH/Enox+ GP IIb/IIIa(n=4,603)
Bivalirudin+ GP IIb/IIIa(n=4,604)
Bivalirudin+ GP IIb/IIIa(n=4,604)
BivalirudinAlone
(n=4,612)
BivalirudinAlone
(n=4,612)
R*
*Stratified by pre-angiography thienopyridine use or administration
Moderate and high risk unstable angina or NSTEMIModerate and high risk unstable angina or NSTEMIundergoing an invasive strategy (N=13,819)undergoing an invasive strategy (N=13,819)
MedicalMedicalmanagementmanagement
PCIPCI
CABGCABG
Scope of AnalysisScope of Analysis
This analysis will address the question of the This analysis will address the question of the safety and efficacy of switching from indirect safety and efficacy of switching from indirect
thrombin inhibition (UFH or enoxaparin) to direct thrombin inhibition (UFH or enoxaparin) to direct thrombin inhibition (bivalirudin) in high risk ACSthrombin inhibition (bivalirudin) in high risk ACS
A protocol-driven activity of the ACUITY A protocol-driven activity of the ACUITY
study at the time of randomizationstudy at the time of randomization
This analysis will address the question of the This analysis will address the question of the safety and efficacy of switching from indirect safety and efficacy of switching from indirect
thrombin inhibition (UFH or enoxaparin) to direct thrombin inhibition (UFH or enoxaparin) to direct thrombin inhibition (bivalirudin) in high risk ACSthrombin inhibition (bivalirudin) in high risk ACS
A protocol-driven activity of the ACUITY A protocol-driven activity of the ACUITY
study at the time of randomizationstudy at the time of randomization
Harvey White. Presentation at AHA, 2006Harvey White. Presentation at AHA, 2006Harvey White. Presentation at AHA, 2006Harvey White. Presentation at AHA, 2006
ACUITY: Primary ResultsACUITY: Primary Results
7.3%5.7%
11.7%
7.7%
11.8%
5.3%
3.0%
10.1%
7.8%
Net clinical outcome Composite ischemia Major bleeding (non-CABG)
30 d
ay e
ven
ts (
%)
Heparin+IIb/IIIa (N=4603) Bivalirudin+IIb/IIIa (N=4604) Bivalirudin alone (N=4612)
7.3%5.7%
11.7%
7.7%
11.8%
5.3%
3.0%
10.1%
7.8%
Net clinical outcome Composite ischemia Major bleeding (non-CABG)
30 d
ay e
ven
ts (
%)
Heparin+IIb/IIIa (N=4603) Bivalirudin+IIb/IIIa (N=4604) Bivalirudin alone (N=4612)
► Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin AloneHeparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone► Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin AloneHeparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone
PPNINI <0.001 <0.001
PPSupSup = 0.015 = 0.015 PPNINI = 0.011 = 0.011
PPSupSup = 0.32 = 0.32 PPNINI <0.001 <0.001
PPSupSup <0.001 <0.001
*Heparin=unfractionated or enoxaparin
Harvey White. Presentation at AHA, 2006Harvey White. Presentation at AHA, 2006Harvey White. Presentation at AHA, 2006Harvey White. Presentation at AHA, 2006
Current Analysis and QuestionsCurrent Analysis and Questions
► HypothesisHypothesis● Bivalirudin improves bleeding outcomes while Bivalirudin improves bleeding outcomes while
preserving ischemic protection for ACS preserving ischemic protection for ACS patients patients even if the patients are switched from even if the patients are switched from either UFH or enoxaparin to bivalirudin either UFH or enoxaparin to bivalirudin (monotherapy) at the time of presentation.(monotherapy) at the time of presentation.
► Is it better to switch to bivalirudin or Is it better to switch to bivalirudin or remain on consistent therapyremain on consistent therapy??
► HypothesisHypothesis● Bivalirudin improves bleeding outcomes while Bivalirudin improves bleeding outcomes while
preserving ischemic protection for ACS preserving ischemic protection for ACS patients patients even if the patients are switched from even if the patients are switched from either UFH or enoxaparin to bivalirudin either UFH or enoxaparin to bivalirudin (monotherapy) at the time of presentation.(monotherapy) at the time of presentation.
► Is it better to switch to bivalirudin or Is it better to switch to bivalirudin or remain on consistent therapyremain on consistent therapy??
Harvey White. Presentation at AHA, 2006Harvey White. Presentation at AHA, 2006Harvey White. Presentation at AHA, 2006Harvey White. Presentation at AHA, 2006
ACUITY — Current AnalysisACUITY — Current Analysis
► Study MethodsStudy Methods● Patients on prior antithrombin therapyPatients on prior antithrombin therapy
• Consistent:Consistent: No switchingNo switching from pre-randomization from pre-randomization antithrombin agent to randomized therapy: antithrombin agent to randomized therapy:
– Enoxaparin Enoxaparin →→Enoxaparin or UFH Enoxaparin or UFH →→ UFH UFH
• Switch:Switch: Single switchSingle switch to bivalirudin determined by to bivalirudin determined by randomization code randomization code
– from Enoxaparin from Enoxaparin →→ Bivalirudin or UFH Bivalirudin or UFH → → BivalirudinBivalirudin
● Event rates at 30-daysEvent rates at 30-days• Net clinical outcome Net clinical outcome • Ischemic compositeIschemic composite• Major bleedingMajor bleeding
► Study MethodsStudy Methods● Patients on prior antithrombin therapyPatients on prior antithrombin therapy
• Consistent:Consistent: No switchingNo switching from pre-randomization from pre-randomization antithrombin agent to randomized therapy: antithrombin agent to randomized therapy:
– Enoxaparin Enoxaparin →→Enoxaparin or UFH Enoxaparin or UFH →→ UFH UFH
• Switch:Switch: Single switchSingle switch to bivalirudin determined by to bivalirudin determined by randomization code randomization code
– from Enoxaparin from Enoxaparin →→ Bivalirudin or UFH Bivalirudin or UFH → → BivalirudinBivalirudin
● Event rates at 30-daysEvent rates at 30-days• Net clinical outcome Net clinical outcome • Ischemic compositeIschemic composite• Major bleedingMajor bleeding
Harvey White. Presentation at AHA, 2006Harvey White. Presentation at AHA, 2006Harvey White. Presentation at AHA, 2006Harvey White. Presentation at AHA, 2006
Consistent vs. SwitchConsistent vs. Switch
11.9%
7.3%5.8%
6.9%
9.1%
2.8%
Net Clinical Outcome Ischemic composite Major bleeding
30
da
y e
ve
nts
(%
)
Consistent UFH/Enox (N = 2223 )
Switch to Bivalirudin (N= 2237)
11.9%
7.3%5.8%
6.9%
9.1%
2.8%
Net Clinical Outcome Ischemic composite Major bleeding
30
da
y e
ve
nts
(%
)
Consistent UFH/Enox (N = 2223 )
Switch to Bivalirudin (N= 2237)
Comparison of Consistent therapy on UFH/Enoxvs. Switch to Bivalirudin Alone
Comparison of Consistent therapy on UFH/Enoxvs. Switch to Bivalirudin Alone
P=0.002
0.77 [0.63 – 0.91]
P=0.601
0.95 [0.76 – 1.17]
P<0.001
0.47 [0.35 – 0.64]
Harvey White. Presentation at AHA, 2006Harvey White. Presentation at AHA, 2006Harvey White. Presentation at AHA, 2006Harvey White. Presentation at AHA, 2006
0 1 20 1 2
0.83 (0.67-1.02)0.83 (0.67-1.02)
OR (95% CI)OR (95% CI)Odds ratio ±95% CIOdds ratio ±95% CI
Switch to Bivalirudin alone betterSwitch to Bivalirudin alone better Consistent UFH/Enox betterConsistent UFH/Enox better
Major BleedingMajor Bleeding
IschemiaIschemia
Net Clinical OutcomeNet Clinical Outcome
1.10 (0.86-1.41)1.10 (0.86-1.41)
0.47 (0.34-0.65)0.47 (0.34-0.65)
P-valueP-value
0.0730.073
0.4640.464
<0.001<0.001
* Comparing consistent UFH/Enox vs Switch Bivalirudin* Comparing consistent UFH/Enox vs Switch Bivalirudin
Consistent vs. SwitchConsistent vs. SwitchAll Patients — AdjustedAll Patients — Adjusted
Harvey White. Presentation at AHA, 2006Harvey White. Presentation at AHA, 2006Harvey White. Presentation at AHA, 2006Harvey White. Presentation at AHA, 2006
0 1 20 1 2
0.86 (0.68-1.07)0.86 (0.68-1.07)0.86 (0.68-1.07)0.86 (0.68-1.07)
OR (95% CI)OR (95% CI)OR (95% CI)OR (95% CI)Odds ratio±95% CIOdds ratio±95% CIOdds ratio±95% CIOdds ratio±95% CI
Switch to Bivalirudin alone betterSwitch to Bivalirudin alone better Consistent UFH/Enox betterConsistent UFH/Enox better
Major BleedingMajor BleedingMajor BleedingMajor Bleeding
IschemiaIschemiaIschemiaIschemia
Net Clinical OutcomeNet Clinical OutcomeNet Clinical OutcomeNet Clinical Outcome
1.11 (0.85-1.46)1.11 (0.85-1.46)1.11 (0.85-1.46)1.11 (0.85-1.46)
0.51 (0.36-0.72)0.51 (0.36-0.72)0.51 (0.36-0.72)0.51 (0.36-0.72)
P-valueP-valueP-valueP-value
0.1770.1770.1770.177
0.4450.4450.4450.445
<0.001<0.001<0.001<0.001
Consistent vs. SwitchConsistent vs. SwitchHigh Risk — AdjustedHigh Risk — Adjusted
Comparing Comparing ConsistentConsistent UFH/Enox vs UFH/Enox vs Switch Switch BivalirudinBivalirudin Comparing Comparing ConsistentConsistent UFH/Enox vs UFH/Enox vs Switch Switch BivalirudinBivalirudin
Harvey White. Presentation at AHA, 2006Harvey White. Presentation at AHA, 2006Harvey White. Presentation at AHA, 2006Harvey White. Presentation at AHA, 2006
Consistent vs. SwitchConsistent vs. Switch
11.2%
7.0%
5.2%6.4%
9.1%
2.8%
Net Clinical Outcome Ischemic composite Major bleeding
30
da
y e
ve
nts
(%
)
Consistent Enox (N = 929 )
Switch from Enox to Bivalirudin (N= 857)
11.2%
7.0%
5.2%6.4%
9.1%
2.8%
Net Clinical Outcome Ischemic composite Major bleeding
30
da
y e
ve
nts
(%
)
Consistent Enox (N = 929 )
Switch from Enox to Bivalirudin (N= 857)
Comparing Comparing ConsistentConsistent therapy on Enoxaparin vs. therapy on Enoxaparin vs. SwitchSwitch from from Enoxaparin to Bivalirudin AloneEnoxaparin to Bivalirudin Alone
Comparing Comparing ConsistentConsistent therapy on Enoxaparin vs. therapy on Enoxaparin vs. SwitchSwitch from from Enoxaparin to Bivalirudin AloneEnoxaparin to Bivalirudin Alone
P=0.145
0.81 [0.61 – 1.07]
P=0.626
0.92 [0.65 – 1.30]
P=0.013
0.54 [0.34 – 0.88]
Harvey White. Presentation at AHA, 2006Harvey White. Presentation at AHA, 2006Harvey White. Presentation at AHA, 2006Harvey White. Presentation at AHA, 2006
Consistent vs. SwitchConsistent vs. Switch
12.4%
7.6%6.3%
7.4%
9.4%
2.8%
Net Clinical Outcome Ischemic composite Major bleeding
30
da
y e
ve
nts
(%
)
( UFH +GP IIb/ IIIa) N =1294
( UFH to Bivalirudin)N =1313
12.4%
7.6%6.3%
7.4%
9.4%
2.8%
Net Clinical Outcome Ischemic composite Major bleeding
30
da
y e
ve
nts
(%
)
( UFH +GP IIb/ IIIa) N =1294
( UFH to Bivalirudin)N =1313
Comparing Comparing ConsistentConsistent therapy on UFH vs. therapy on UFH vs. SwitchSwitch from UFH to Bivalirudin Alone from UFH to Bivalirudin Alone
Comparing Comparing ConsistentConsistent therapy on UFH vs. therapy on UFH vs. SwitchSwitch from UFH to Bivalirudin Alone from UFH to Bivalirudin Alone
P=0.012
0.75[0.60 – 0.94]
P=0.857
0.98[0.74 – 1.28]
P<0.001
0.44[0.30 – 0.65]
Harvey White. Presentation at AHA, 2006Harvey White. Presentation at AHA, 2006Harvey White. Presentation at AHA, 2006Harvey White. Presentation at AHA, 2006
ACUITY PCI: Switch from Prior AntithrombinACUITY PCI: Switch from Prior Antithrombin
0.1 1 10
Risk Ratio±95% CI RR (95% CI)
0.1 1 10
Hazard Ratio±95% CI HR (95% CI)
Switch to Bivalirudin
better
Consistent UFH/Enox + IIb/IIIa better
Switch to Bivalirudin
better
Consistent UFH/Enox + IIb/IIIa better
PCIPCI (n=2528)(n=2528)
Composite Composite ischemiaischemia 1.10 (0.85-1.42)1.10 (0.85-1.42)
Major bleedingMajor bleeding 0.52 (0.36-0.74)0.52 (0.36-0.74)
PCI HIGH RISK*PCI HIGH RISK*(n=1988)(n=1988)
Composite Composite ischemiaischemia 1.14 (0.86-1.52)1.14 (0.86-1.52)
Major bleedingMajor bleeding 0.56 (0.38-0.81)0.56 (0.38-0.81)
PCI PCI (n=2528)(n=2528)
MortalityMortality 0.93 (0.58-1.48)0.93 (0.58-1.48)
PCI HIGH RISK*PCI HIGH RISK*(n=1988)(n=1988)
MortalityMortality 0.99 (0.60-1.63)0.99 (0.60-1.63)
* High risk = ↑Tn, CKMB or ECG Δ’s
30-Day Results30-Day Results 1-Year Results1-Year Results
SWITCH IIISWITCH III
(Switching from fondaparinux to bivalirudin or unfractionated heparin in patients with acute
coronary syndromes without ST-segment elevation undergoing percutaneous coronary
intervention (PCI))
(Switching from fondaparinux to bivalirudin or unfractionated heparin in patients with acute
coronary syndromes without ST-segment elevation undergoing percutaneous coronary
intervention (PCI))
Principal Investigator: Ron Waksman, MD Principal Investigator: Ron Waksman, MD
► The primary objective of this clinical trial is to evaluate safety of switching from fondaparinux to either unfractionated heparin or bivalirudin for patients experiencing acute coronary syndrome undergoing percutaneous coronary angioplasty.
► The primary objective of this clinical trial is to evaluate safety of switching from fondaparinux to either unfractionated heparin or bivalirudin for patients experiencing acute coronary syndrome undergoing percutaneous coronary angioplasty.
SWITCH IIISWITCH III Study AIM Study AIM
SWITCH III ver 1.7
SWITCH III Study DesignSWITCH III Study Design
Patient Presents to Patient Presents to ED/Cath LabED/Cath Lab
Patient Presents to Patient Presents to ED/Cath LabED/Cath Lab
Fondaparinux AdministrationFondaparinux Administration2.5 mg SubQ QD2.5 mg SubQ QD
Fondaparinux AdministrationFondaparinux Administration2.5 mg SubQ QD2.5 mg SubQ QD
CatheterizationCatheterization≤ ≤ 24 hours of fondaparinux24 hours of fondaparinux
CatheterizationCatheterization≤ ≤ 24 hours of fondaparinux24 hours of fondaparinux
Requires PCIRequires PCIRequires PCIRequires PCINo PCINo PCI
““Screen Failure”Screen Failure”No PCINo PCI
““Screen Failure”Screen Failure”
UFHUFHUFHUFHBivalirudinBivalirudinBivalirudinBivalirudin1:1
Randomization
All patients are followed through the duration of the
hospitalization or until CABG
All patients are followed through the duration of the
hospitalization or until CABG
300 patients will be randomized 300 patients will be randomized
SWITCH III ver 1.7
Pre-Randomization Anticoagulant Pre-Randomization Anticoagulant Switching and BleedingSwitching and Bleeding
► When switching to bivalirudin was undertaken When switching to bivalirudin was undertaken across the risk spectrum of ACS, preceding across the risk spectrum of ACS, preceding therapy with either LMWH or UFH was therapy with either LMWH or UFH was notnot associated with an excess of bleeding or associated with an excess of bleeding or transfusions compared with bivalirudin therapy transfusions compared with bivalirudin therapy alone in the cardiac catheterization laboratory. alone in the cardiac catheterization laboratory.
► When switching to bivalirudin was undertaken When switching to bivalirudin was undertaken across the risk spectrum of ACS, preceding across the risk spectrum of ACS, preceding therapy with either LMWH or UFH was therapy with either LMWH or UFH was notnot associated with an excess of bleeding or associated with an excess of bleeding or transfusions compared with bivalirudin therapy transfusions compared with bivalirudin therapy alone in the cardiac catheterization laboratory. alone in the cardiac catheterization laboratory.
Overall ConclusionOverall Conclusion
How to Switch — Science to PracticeHow to Switch — Science to Practice
From UFH to Bivalirudin
• Discontinue UFH for 30 minutes before starting bivalirudin for PCI
From UFH to Bivalirudin
• Discontinue UFH for 30 minutes before starting bivalirudin for PCI
From LMWH to Bivalirudin
• Discontinue LMWH for 8 hours before starting bivalirudin for PCI
From LMWH to Bivalirudin
• Discontinue LMWH for 8 hours before starting bivalirudin for PCI
ConclusionsConclusions
► Switching to bivalirudin is safeSwitching to bivalirudin is safe● Switching from any heparin (either enoxaparin Switching from any heparin (either enoxaparin
or UFH) to bivalirudin monotherapy is not or UFH) to bivalirudin monotherapy is not associated with an increased risk for ischemic associated with an increased risk for ischemic events.events.
► FurthermoreFurthermore● Switching to bivalirudin provides patients the Switching to bivalirudin provides patients the
50% bleeding advantage of bivalirudin 50% bleeding advantage of bivalirudin compared with consistent therapy on UFH or compared with consistent therapy on UFH or enoxaparin, while preserving anti-ischemic enoxaparin, while preserving anti-ischemic efficacy.efficacy.
► Switching to bivalirudin is safeSwitching to bivalirudin is safe● Switching from any heparin (either enoxaparin Switching from any heparin (either enoxaparin
or UFH) to bivalirudin monotherapy is not or UFH) to bivalirudin monotherapy is not associated with an increased risk for ischemic associated with an increased risk for ischemic events.events.
► FurthermoreFurthermore● Switching to bivalirudin provides patients the Switching to bivalirudin provides patients the
50% bleeding advantage of bivalirudin 50% bleeding advantage of bivalirudin compared with consistent therapy on UFH or compared with consistent therapy on UFH or enoxaparin, while preserving anti-ischemic enoxaparin, while preserving anti-ischemic efficacy.efficacy.
Translating Advances in NSTEMI Translating Advances in NSTEMI and STEMI into Real World and STEMI into Real World
Institutional PracticeInstitutional Practice
Translating Advances in NSTEMI Translating Advances in NSTEMI and STEMI into Real World and STEMI into Real World
Institutional PracticeInstitutional Practice
Harold L. Dauerman, MDHarold L. Dauerman, MDDirector, Cardiovascular Catheterization LaboratoriesDirector, Cardiovascular Catheterization Laboratories
Professor of MedicineProfessor of MedicineUniversity of VermontUniversity of Vermont
Fletcher Allen Health CareFletcher Allen Health Care
Harold L. Dauerman, MDHarold L. Dauerman, MDDirector, Cardiovascular Catheterization LaboratoriesDirector, Cardiovascular Catheterization Laboratories
Professor of MedicineProfessor of MedicineUniversity of VermontUniversity of Vermont
Fletcher Allen Health CareFletcher Allen Health Care
The Science and Medicine of ACSThe Science and Medicine of ACS
0
0.5
1
1.5
2
2.5
3
3.5
4
2001 2002 2003 2004 2005 2006 2007
Blee
ding C
ompli
catio
n, %
University of Vermont Post-PCI Bleeding University of Vermont Post-PCI Bleeding and Vascular Complication Ratesand Vascular Complication Rates
NNE Rate: 2.0% in 2006
Any Transfusion, RPH or Repair = Bleeding ComplicationAny Transfusion, RPH or Repair = Bleeding Complication Any Transfusion, RPH or Repair = Bleeding ComplicationAny Transfusion, RPH or Repair = Bleeding Complication
Introduction ofIntroduction of Bivalirudin to Cath LabBivalirudin to Cath Lab
Introduction ofIntroduction of Bivalirudin to Cath LabBivalirudin to Cath Lab
Introduction of Introduction of Upstream BivalirudinUpstream Bivalirudin
Introduction of Introduction of Upstream BivalirudinUpstream Bivalirudin
Incorporation of Bivalirudin in Cath Lab for Incorporation of Bivalirudin in Cath Lab for NSTEMI in 2003—A Cautious BeginningNSTEMI in 2003—A Cautious Beginning
82%18%
Drug Eluting Bare Metal
82%18%
Drug Eluting Bare Metal
42%
25% 33%
Bivalirudin
GP IIb/IIIa Inhibitor
UFH alone
Bivalirudin
GP IIb/IIIa Inhibitor
UFH alone
3.2
2.51
2.111.96
3.37
0
0.5
1
1.5
2
2.5
3
3.5
4
2002 2003 2004 2005 2006
Maj
or V
ascu
lar C
ompl
icat
ions
, %*
P < 0.001 for temporal trendP < 0.001 for temporal trend
• Arterial injury and/or arterial injury related bleeding• N= 36,631 Patients Undergoing PCI, NNE Registry• Arterial injury and/or arterial injury related bleeding• N= 36,631 Patients Undergoing PCI, NNE Registry
Signs of Hope Since 2004Signs of Hope Since 2004
Dauerman, Applegate and Cohen, JACC 2007
How We Introduced Upstream and Downstream How We Introduced Upstream and Downstream Bivalirudin: The UVMC Time LineBivalirudin: The UVMC Time Line
► 2003:2003: Put bivalirudin on the cath lab shelf as an option for Put bivalirudin on the cath lab shelf as an option for NSTEMINSTEMI
► 2007:2007: Educational programs for fellows, floor staff and Educational programs for fellows, floor staff and attendingsattendings
► We did not remove GPI optionWe did not remove GPI option
► We did NOT involve community hospitals in this decision. We did NOT involve community hospitals in this decision. They can do whatever they want as long as they transfer and They can do whatever they want as long as they transfer and don’t overdose patients.don’t overdose patients.
► 20082008:: A standardized STEMI bivalirudin approach A standardized STEMI bivalirudin approach
► For upstream AMI utilization, bivalirudin ordered from For upstream AMI utilization, bivalirudin ordered from pharmacypharmacy
► In collaboration with ED (EDICT for ACS Strategy)In collaboration with ED (EDICT for ACS Strategy)
► 2003:2003: Put bivalirudin on the cath lab shelf as an option for Put bivalirudin on the cath lab shelf as an option for NSTEMINSTEMI
► 2007:2007: Educational programs for fellows, floor staff and Educational programs for fellows, floor staff and attendingsattendings
► We did not remove GPI optionWe did not remove GPI option
► We did NOT involve community hospitals in this decision. We did NOT involve community hospitals in this decision. They can do whatever they want as long as they transfer and They can do whatever they want as long as they transfer and don’t overdose patients.don’t overdose patients.
► 20082008:: A standardized STEMI bivalirudin approach A standardized STEMI bivalirudin approach
► For upstream AMI utilization, bivalirudin ordered from For upstream AMI utilization, bivalirudin ordered from pharmacypharmacy
► In collaboration with ED (EDICT for ACS Strategy)In collaboration with ED (EDICT for ACS Strategy)
NSTEMI Transfers, Upstream Strategies, and
Results of Clinical Trials
NSTEMI Transfers, Upstream Strategies, and
Results of Clinical Trials
Non ST-Elevation Myocardial InfarctionNon ST-Elevation Myocardial Infarction
What We Really Do With Transfers? What We Really Do With Transfers? September 24, 2007 email from meSeptember 24, 2007 email from me
To: Sullivan, Claudia A.Cc: Ades, Philip A.Subject: Transfer of John XXXXX, DOB 11/08/25
81M with NSTEMI/old LBBB, Tn 3.0 Pain free, but with NSVT. ASA/clopidogrel 300 po/enoxaparin. From Adirondack Medical Center.
Class I transfer. Change to bivalirudin on arrival. DNR—reverse POLST (wants a cath, but no CABG). Echo today, cath tomorrow (or today if unstable).
Thanks,Harry
To: Sullivan, Claudia A.Cc: Ades, Philip A.Subject: Transfer of John XXXXX, DOB 11/08/25
81M with NSTEMI/old LBBB, Tn 3.0 Pain free, but with NSVT. ASA/clopidogrel 300 po/enoxaparin. From Adirondack Medical Center.
Class I transfer. Change to bivalirudin on arrival. DNR—reverse POLST (wants a cath, but no CABG). Echo today, cath tomorrow (or today if unstable).
Thanks,Harry
Protocol Major/Minor Bleed by Protocol Major/Minor Bleed by SWITCH and Randomized TherapySWITCH and Randomized Therapy
*P=NS for all 3-way comparisons versus bivalirudin alone; †P<.05 vs prior treatment with UFH or enoxaparin; ‡naïve=no prior AT therapy in preceding 48 hours.
Pro
toco
l maj
or/m
inor
ble
edP
roto
col m
ajor
/min
or b
leed
15.6% 15.3%16.7%
28.6%
33.8% 34.8%
0%
5%
10%
15%
20%
25%
30%
35%
15.6% 15.3%16.7%
28.6%
33.8% 34.8%
0%
5%
10%
15%
20%
25%
30%
35%
NaïveNaïve→→BivalirudinBivalirudin‡‡
(n=2,345)(n=2,345)
LMWH→LMWH→Bivalirudin Bivalirudin
(n=258)(n=258)
UFH→UFH→BivalirudinBivalirudin
(n=287)(n=287)
LMWH→UFH LMWH→UFH + GP IIb/IIIa+ GP IIb/IIIa
(n=313)(n=313)
Naïve→ UFH + Naïve→ UFH +
GP IIb/IIIaGP IIb/IIIa‡ ‡
(n=2,325)(n=2,325)
UFH→UFH UFH→UFH + GP IIb/IIIa + GP IIb/IIIa
(n=349)(n=349)
*
†
Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.
44..1133..66
22..9922..33
11..44 11..55 11..55
66..99
44..3333..99
33..0022..66
11..88
66..88
*UA at any time, within preceding 48 hours or before.†ACS defined as UA within preceding 48 hours or MI within prior 7 days.
CrCl= creatinine clearance.
(n=1,330)(n=1,330)
(n=2,553)(n=2,553)
REPLACE-2 One-Year Cumulative Mortality in REPLACE-2 One-Year Cumulative Mortality in Prespecified High-Risk SubgroupsPrespecified High-Risk Subgroups
Cumulative mortality at 1 yearCumulative mortality at 1 year
00
22
44
66
88
DDiiaabbeetteess UUA*A* UA* or UA* or ACSACS†† ACSACS††
(n=2,489)(n=2,489) (n=1,606)(n=1,606) (n=2,046)(n=2,046)
Lincoff AM et al. Lincoff AM et al. JAMAJAMA. 2004;292:696-703. . 2004;292:696-703. Stone GW. Stone GW. J Invasive Cardiol.J Invasive Cardiol. 2004;16(suppl G):12-17. 2004;16(suppl G):12-17.
Heparin + GP IIb/IIIaHeparin + GP IIb/IIIa
Bivalirudin with Bivalirudin with “provisional” GP IIb/IIIa “provisional” GP IIb/IIIa
Per
cent
age
(%)
Per
cent
age
(%)
(n=1,010)(n=1,010)CrCl ≤60CrCl ≤60 Age >75Age >75 Age >65Age >65
(n=795)(n=795)
Transfer to Cardiology FloorTransfer to Cardiology Floor
► Enoxaparin held—wait 8 Enoxaparin held—wait 8 hours from community hours from community hospital last dose.hospital last dose.
► Then, start upstream Then, start upstream bivalirudinbivalirudin
► Patient pain free—1Patient pain free—1stst case next A.Mcase next A.M
► DES, no eptifibatide, DES, no eptifibatide, closure device, 150 mg closure device, 150 mg clopidogrelclopidogrel
► Ambulate at 6 hoursAmbulate at 6 hours
► D/C following 0900 A.M.D/C following 0900 A.M.
► Enoxaparin held—wait 8 Enoxaparin held—wait 8 hours from community hours from community hospital last dose.hospital last dose.
► Then, start upstream Then, start upstream bivalirudinbivalirudin
► Patient pain free—1Patient pain free—1stst case next A.Mcase next A.M
► DES, no eptifibatide, DES, no eptifibatide, closure device, 150 mg closure device, 150 mg clopidogrelclopidogrel
► Ambulate at 6 hoursAmbulate at 6 hours
► D/C following 0900 A.M.D/C following 0900 A.M.
The University of Vermont Experience—GPI Trigger StrategyThe University of Vermont Experience—GPI Trigger Strategy Impact of REPLACE 2 and ACUITY Trials: 91% Bivalirudin UseImpact of REPLACE 2 and ACUITY Trials: 91% Bivalirudin Use
0
10
20
30
40
50
60
70
80
90
100
2005 2007
PC
I P
atie
nts
, %
Eptifibatide
Bivalirudin
► Elective PCI—24%Elective PCI—24%► Urgent PCI—30%Urgent PCI—30%► Emergent PCI—30%Emergent PCI—30%► Pre-Load Clopidgrel in Pre-Load Clopidgrel in
60% and Switching in 60% and Switching in 45% of Patients45% of Patients
► Note: Increasing Note: Increasing utilization of bivalirudin utilization of bivalirudin but with maintained but with maintained trigger-induced trigger-induced adjunctive use of GP adjunctive use of GP IIb/IIIa antagonistIIb/IIIa antagonist
► Elective PCI—24%Elective PCI—24%► Urgent PCI—30%Urgent PCI—30%► Emergent PCI—30%Emergent PCI—30%► Pre-Load Clopidgrel in Pre-Load Clopidgrel in
60% and Switching in 60% and Switching in 45% of Patients45% of Patients
► Note: Increasing Note: Increasing utilization of bivalirudin utilization of bivalirudin but with maintained but with maintained trigger-induced trigger-induced adjunctive use of GP adjunctive use of GP IIb/IIIa antagonistIIb/IIIa antagonist
Ahmed B and Dauerman HL, Submitted ESC 2008
REPLACE 2 ACUITYREPLACE 2 ACUITY
13.8%
8.4%7.2%
8.1%
11.1%
3.6%
Net clinicaloutcomes
Ischemiccomposite
Major bleeding
UFH/Enoxaparin + IIb/IIIa (N=1722)
Bivalirudin Alone (N=1789)
11.8%
7.5%
5.7%
3.5%
12.7%
10.3%
Net clinicaloutcomes
Ischemiccomposite
Major bleeding
UFH/Enoxaparin + IIb/IIIa (N=811)
Bivalirudin Alone (N=804)
11.8%
7.5%
5.7%
3.5%
12.7%
10.3%
Net clinicaloutcomes
Ischemiccomposite
Major bleeding
UFH/Enoxaparin + IIb/IIIa (N=811)
Bivalirudin Alone (N=804)
Not Thienopyridine ExposedNot Thienopyridine Exposed
If Patient is not Clopidogrel Exposed, Do We Use Bivalirudin? Definitions?
If Patient is not Clopidogrel Exposed, Do We Use Bivalirudin? Definitions?
RR [95%CI]RR [95%CI]
0.81 (0.68-0.96)0.81 (0.68-0.96)
RR [95%CI] RR [95%CI]
0.96 (0.77-1.20)0.96 (0.77-1.20)
RR [95%CI] RR [95%CI]
0.50 (0.37-0.67)0.50 (0.37-0.67)
RR [95%CI] RR [95%CI]
1.07 (0.83-1.39)1.07 (0.83-1.39)
RR [95%CI] RR [95%CI]
1.37 (1.00-1.88)1.37 (1.00-1.88)
RR [95%CI] RR [95%CI]
0.61 (0.39-0.97)0.61 (0.39-0.97)
Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16 Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16
Thienopyridine ExposedThienopyridine Exposed
Risk ratio (RR) ±95% CI for the triple ischemic endpoint(death, MI, unplanned revascularization)
Risk ratio (RR) ±95% CI for the triple ischemic endpoint(death, MI, unplanned revascularization)
Bivalirudin alone betterBivalirudin alone better Heparin + GPIIb/IIIa better Heparin + GPIIb/IIIa better
Peri-PCI Clopidogrel N=1044, RR 1.26 [95% CI 0.82,1.92]
Peri-PCI Clopidogrel N=1044, RR 1.26 [95% CI 0.82,1.92]
Post-PCI Clopidgrel(> 30 minutes After PCI)
N=519 RR 1.48 [95% CI 0.89, 2.47]
Post-PCI Clopidgrel(> 30 minutes After PCI)
N=519 RR 1.48 [95% CI 0.89, 2.47]
Pre-PCI clopidogrel N=3429, RR 0.92 [95% CI 0.74,1.15]
Pre-PCI clopidogrel N=3429, RR 0.92 [95% CI 0.74,1.15]
No Clopidogrel N=88 RR 2.62 [95% CI 0.89, 7.72]
No Clopidogrel N=88 RR 2.62 [95% CI 0.89, 7.72]
pinteraction = 0.35pinteraction = 0.35
00 11 22 33 44 55 66 77 88
Timing of Clopidogrel Administration andTiming of Clopidogrel Administration and 30-Day Risk of Ischemic Outcomes 30-Day Risk of Ischemic Outcomes
S. Steinhubl TCT 2007S. Steinhubl TCT 2007
1.07 (0.66-1.73) 1.07 (0.66-1.73)
1.09 (0.46-2.58) 1.09 (0.46-2.58)
0.56 (0.17-1.93) 0.56 (0.17-1.93)
3.07 (0.32-29.49) 3.07 (0.32-29.49)
ACUITY PCI: Impact of ClopidogrelACUITY PCI: Impact of Clopidogrel
PCI troponin+ patientsPCI troponin+ patients 1-year Mortality1-year MortalityHazard Ratio ±95% CIHazard Ratio ±95% CI
HR (95% CI)HR (95% CI)
Bivalirudin Alone BetterBivalirudin Alone Better UFH/Enox + IIb/IIIa BetterUFH/Enox + IIb/IIIa Better
H.White ESC 2007
Clopidogrel at any time prior to Clopidogrel at any time prior to hospitalization, randomization or end hospitalization, randomization or end of angiographyof angiography (n=1,891)(n=1,891)
Clopidogrel at any time prior to Clopidogrel at any time prior to hospitalization, randomization or end hospitalization, randomization or end of angiographyof angiography (n=1,891)(n=1,891)
Clopidogrel after end of angio-Clopidogrel after end of angio-graphy to 30’ post PCIgraphy to 30’ post PCI (n=649)(n=649)
Clopidogrel after end of angio-Clopidogrel after end of angio-graphy to 30’ post PCIgraphy to 30’ post PCI (n=649)(n=649)
Clopidogrel after 30’ Clopidogrel after 30’ post PCIpost PCI (n=307)(n=307)
Clopidogrel after 30’ Clopidogrel after 30’ post PCIpost PCI (n=307)(n=307)
No clopidogrelNo clopidogrel (n=51)(n=51)No clopidogrelNo clopidogrel (n=51)(n=51)
0.1 1 10
Does Periprocedural Infarct Increase With Does Periprocedural Infarct Increase With Upstream and Downstream Bivalirudin? No!Upstream and Downstream Bivalirudin? No!
OutcomeOutcome20052005
11stst 6 months 6 monthsN=373N=373
2007200711stst 6 Months 6 Months
N=361N=361P valueP value
Any Transfusion (%)Any Transfusion (%) 2.02.0 1.01.0 NSNS
Death (%)Death (%) 3.03.0 1.01.0 0.080.08
Urgent revascularization (%)Urgent revascularization (%) 2.02.0 1.01.0 NSNS
MI, 50% CK-MB Rise (%)MI, 50% CK-MB Rise (%) 4.04.0 1.01.0 0.020.02
Mechanical Complication (%)Mechanical Complication (%) 8.08.0 6.06.0 NSNS
Clopidogrel preload in approx 60% of PCI patientsCK-MB on all patients the day after PCI (University of Vermont data)
STEMI Switching, Clopidogrel and Stent
Thrombosis
STEMI Switching, Clopidogrel and Stent
Thrombosis
ST-Elevation Myocardial Infarction ST-Elevation Myocardial Infarction
Primary PCI for STEMI N= 7,629
Bivalirudin and GPIIbIIIa PCIN=177 (55%)
No Bivalirudin PCI N= 7,309
ClopidogrelN=171 (97%)
GP IIbIIIa Inhibitor useN=6,873 (94%)
Prior to PCI N=37 (21%)
Not Prior to PCI N= 140 (79%)
Prior to PCI N=2,489 (36%)
Not Prior to PCI N= 4,384 (64%)
Abciximab N=64 (36%)Eptifibatide N=93 (52%)Tirofiban N=1 (1%)Unkown N=19 (11%)
Abciximab N=2,283 (33%)Eptifibatide N=3,551 (52%)Tirofiban N=154 (2%)Unknown N= 885 (13%)
Abciximab N=8 (22%)Eptifibatide N=27 (73%)Tirofiban N=1 (3%)Unknown N=1 (2%)
Abciximab N=622 (25%)Eptifibatide N=1621 (65%)Tirofiban N=99 (4%)Unknown N=147 (6%)
Abciximab N=56 (40%)Eptifibatide N=66 (47%)Tirofiban N=0 (0%)Unknown N=18 (13%)
Abciximab N=1661 (38%)Eptifibatide N=1930 (44%)Tirofiban N=55 (1%)Unknown N=738 (17%)
Bivalirudin Alone N=143 (45%)
ClopidogrelPrior to PCI N=41 (24%)
ClopidogrelN=137 (96%)
Prior to PCI N=31 (23%)
ClopidogrelN=6878 (94%)
Clopidogrel Prior to PCI
N=1466 (21%)
Bivalirudin PCIN=320 (4%)
Dauerman and French, Coronary Artery Disease, 2006
The Standard of Care for STEMI PCI in 2005:The Standard of Care for STEMI PCI in 2005:National Registry of Myocardial Infarction-5National Registry of Myocardial Infarction-5
Implementation of HORIZONS AMI PCI Implementation of HORIZONS AMI PCI Pharmacologic Aspects of ManagementPharmacologic Aspects of Management
► Unfractionated heparinUnfractionated heparin● 60 U/kg IV*; subsequent boluses titrated by nomogram to ACT 200-250 60 U/kg IV*; subsequent boluses titrated by nomogram to ACT 200-250
secs; terminated at procedure end unless prolonged antithrombin secs; terminated at procedure end unless prolonged antithrombin neededneeded
► Bivalirudin at the REPLACE-2 Dosing (NOT ACUITYBivalirudin at the REPLACE-2 Dosing (NOT ACUITY))● Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated to ACT; Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated to ACT;
terminated at procedure end unless prolonged antithrombin needed terminated at procedure end unless prolonged antithrombin needed (0.25 mg/kg/hr infusion(0.25 mg/kg/hr infusion))
► Glycoprotein IIb/IIIa inhibitorsGlycoprotein IIb/IIIa inhibitors● Routine use in UFH arm; recommended only for giant thrombus or Routine use in UFH arm; recommended only for giant thrombus or
refractory no reflowrefractory no reflow in bivalirudin arm in bivalirudin arm● Abciximab or double bolus eptifibatide as per investigator discretion – Abciximab or double bolus eptifibatide as per investigator discretion –
dosing per FDA label, renal adjusted; continued for 12dosing per FDA label, renal adjusted; continued for 12 (abciximab) or (abciximab) or 12-1812-18 (eptifibatide) (eptifibatide)
► Unfractionated heparinUnfractionated heparin● 60 U/kg IV*; subsequent boluses titrated by nomogram to ACT 200-250 60 U/kg IV*; subsequent boluses titrated by nomogram to ACT 200-250
secs; terminated at procedure end unless prolonged antithrombin secs; terminated at procedure end unless prolonged antithrombin neededneeded
► Bivalirudin at the REPLACE-2 Dosing (NOT ACUITYBivalirudin at the REPLACE-2 Dosing (NOT ACUITY))● Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated to ACT; Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated to ACT;
terminated at procedure end unless prolonged antithrombin needed terminated at procedure end unless prolonged antithrombin needed (0.25 mg/kg/hr infusion(0.25 mg/kg/hr infusion))
► Glycoprotein IIb/IIIa inhibitorsGlycoprotein IIb/IIIa inhibitors● Routine use in UFH arm; recommended only for giant thrombus or Routine use in UFH arm; recommended only for giant thrombus or
refractory no reflowrefractory no reflow in bivalirudin arm in bivalirudin arm● Abciximab or double bolus eptifibatide as per investigator discretion – Abciximab or double bolus eptifibatide as per investigator discretion –
dosing per FDA label, renal adjusted; continued for 12dosing per FDA label, renal adjusted; continued for 12 (abciximab) or (abciximab) or 12-1812-18 (eptifibatide) (eptifibatide)
* If pre randomization UFH administered, ACT is checked first* If pre randomization UFH administered, ACT is checked first** If pre randomization UFH administered, started 30’ after last bolus** If pre randomization UFH administered, started 30’ after last bolus
Primary PCI for STEMI: Community Hospital AlgorithmPrimary PCI for STEMI: Community Hospital AlgorithmASA, Clopidogrel and UFH and then Switch to Bivalirudin at UVMASA, Clopidogrel and UFH and then Switch to Bivalirudin at UVM
Time from ED Presentation at NWMC to Open Artery at FAHC: 88 Minutes
Time from ED Presentation at NWMC to Open Artery at FAHC: 88 Minutes
27 miles, on interstate highway27 miles, on interstate highway
UFH + GP IIb/IIIaUFH + GP IIb/IIIa(N=1802)(N=1802)
BivalirudinBivalirudin(N=1800)(N=1800)
UFH pre randomizationUFH pre randomization 65.6%65.6% 65.6%65.6%
Antithrombin in CCLAntithrombin in CCL
► UFHUFH 98.9%98.9% 4.1%4.1%► BivalirudinBivalirudin 0.4%0.4% 96.9%96.9%► Peak ACTPeak ACT 264 [228, 320]264 [228, 320] 357 [300, 402]357 [300, 402]
GP IIb/IIIa in CCLGP IIb/IIIa in CCL 94.5%*94.5%* 7.2%*7.2%*► Bail-out per protocol**Bail-out per protocol** -- 4.4%4.4%► AbciximabAbciximab 49.9%49.9% 4.0%4.0%► EptifibatideEptifibatide 44.4%44.4% 3.1%3.1%► TirofibanTirofiban 0.2%0.2% 0.1%0.1%
Do I Have to Load Bivalirudin in the ED or Can I Start in the Do I Have to Load Bivalirudin in the ED or Can I Start in the Cath Lab? The HORIZONS AMI Switching PerspectiveCath Lab? The HORIZONS AMI Switching Perspective
*97.7% and 7.5% during PCI. ** For giant thrombus or refractory no reflow after *97.7% and 7.5% during PCI. ** For giant thrombus or refractory no reflow after PCI. CCL = cardiac catheterization laboratoryPCI. CCL = cardiac catheterization laboratory
G Stone TCT 2007G Stone TCT 2007
Bivalirudin Improves Mortality in STEMIBivalirudin Improves Mortality in STEMI
Dea
th (
%)
Dea
th (
%)
Dea
th (
%)
Dea
th (
%)
Time in DaysTime in DaysTime in DaysTime in Days
3.1%3.1%
2.1%2.1%
HR [95%CI] =0.66 [0.44, 1.00]
P=0.048
HR [95%CI] =0.66 [0.44, 1.00]
P=0.048
Heparin + GPIIb/IIIa inhibitor (n=1802)Heparin + GPIIb/IIIa inhibitor (n=1802)
Bivalirudin monotherapy (n=1800)Bivalirudin monotherapy (n=1800)
G Stone TCT 2007G Stone TCT 2007
The UVM STEMI Order SheetThe UVM STEMI Order SheetOne Pathway for Primary PCI and ED CollaborationOne Pathway for Primary PCI and ED Collaboration
TESTS AND MEDICATIONSEKG: EKG for diagnosis performed within 10 minutes of ED arrival. No further EKG required.
LABORATORY:7. CBC,lytes, BUN, CR, PT, PTT, Lipids, LFT’s, CK, CK-MB and TnI sent immediately on arrival: STAT8. Other labs: MEDICATIONS: Weight: __kg Estimated / Actual (Circle one) Check patient not allergic to aspirin9. Aspirin Non- Enteric Coated 325 mg PO Daily 10. Clopidogrel 600 mg PO x one11. Bivalirudin bolus 0.75 mg/kg IV, then infusion 1.75 mg/kg/hr (STAT from Pharmacy)12. Saline Lock with routine flushes every 8 hours
OPTIONAL:13. Nitroglycerin infusion: 400 mcg/ml infusion at _______ mcg/kg/min IV Titrate to chest pain, keep systolic BP >90. 14. Lopressor 5 mg IVP x 1 if HR > 80 and SBP > 140
TESTS AND MEDICATIONSEKG: EKG for diagnosis performed within 10 minutes of ED arrival. No further EKG required.
LABORATORY:7. CBC,lytes, BUN, CR, PT, PTT, Lipids, LFT’s, CK, CK-MB and TnI sent immediately on arrival: STAT8. Other labs: MEDICATIONS: Weight: __kg Estimated / Actual (Circle one) Check patient not allergic to aspirin9. Aspirin Non- Enteric Coated 325 mg PO Daily 10. Clopidogrel 600 mg PO x one11. Bivalirudin bolus 0.75 mg/kg IV, then infusion 1.75 mg/kg/hr (STAT from Pharmacy)12. Saline Lock with routine flushes every 8 hours
OPTIONAL:13. Nitroglycerin infusion: 400 mcg/ml infusion at _______ mcg/kg/min IV Titrate to chest pain, keep systolic BP >90. 14. Lopressor 5 mg IVP x 1 if HR > 80 and SBP > 140
The Bivalirudin Strategy for STEMI PCIThe Bivalirudin Strategy for STEMI PCI
ASA, clopidogrel 600 po x 1, bivalirudin and stent
What About The Stent Thrombosis Risk?What About The Stent Thrombosis Risk?
*Protocol definition of stent thrombosis, CEC adjudicated*Protocol definition of stent thrombosis, CEC adjudicated*Protocol definition of stent thrombosis, CEC adjudicated*Protocol definition of stent thrombosis, CEC adjudicated
UFH + GP IIb/IIIaUFH + GP IIb/IIIa(N=1553)(N=1553)
BivalirudinBivalirudin(N=1571)(N=1571)
PPValueValue
ARC definite ARC definite or probable*or probable* 1.9%1.9% 2.5%2.5% 0.330.33
DefiniteDefinite 1.4%1.4% 2.2%2.2% 0.110.11
ProbableProbable 0.5%0.5% 0.3%0.3% 0.260.26
Acute Acute (≤24 hrs)(≤24 hrs) 0.3%0.3% 1.3%1.3% 0.00090.0009
Subacute Subacute (>24 hrs – 30d)(>24 hrs – 30d) 1.7%1.7% 1.2%1.2% 0.300.30
G Stone TCT 2007G Stone TCT 2007
Sianos, G. et al. J Am Coll Cardiol 2007;50:573-583
Risk Stratification For STEMI Stent ThrombosisRisk Stratification For STEMI Stent ThrombosisThe Importance of Thrombus BurdenThe Importance of Thrombus Burden
Large thrombus burden (LTB), defined as thrombus burden > 2 vessel diameters: Approx 25% of STEMI
Large thrombus burden (LTB), defined as thrombus burden > 2 vessel diameters: Approx 25% of STEMI
Sianos, G. et al. J Am Coll Cardiol 2007;50:573-583
Drug Eluting Stent Thrombosis and Large Thrombus Drug Eluting Stent Thrombosis and Large Thrombus Burden: Modifying Strategy In Highest Risk PatientsBurden: Modifying Strategy In Highest Risk Patients
► Large ThrombusLarge Thrombus
► Burden> 5 fold Burden> 5 fold
► Increased Risk of Increased Risk of 30 Day Stent 30 Day Stent ThrombosisThrombosis
► Large ThrombusLarge Thrombus
► Burden> 5 fold Burden> 5 fold
► Increased Risk of Increased Risk of 30 Day Stent 30 Day Stent ThrombosisThrombosis
ThrombectomyProlonged BivalirudinGPI
ThrombectomyProlonged BivalirudinGPI
LTB vs. STB, p<0.001LTB vs. STB, p<0.001
Total PopulationTotal Population
STBSTB
LTBLTB
2.7%2.7%3.2%3.2%
5.8%5.8%
8.2%8.2%
1.1%1.1% 1.4%1.4%2.1%2.1% 3.2%3.2%
0.5%0.5% 0.7%0.7% 0.7%0.7%1.3%1.3%
0 1 3 6 9 12 15 18 21 240 1 3 6 9 12 15 18 21 24
15
12
9
6
3
0
15
12
9
6
3
0
Months of follow-upMonths of follow-up
Cum
ulat
ive
IRA
-ST
Rat
e (%
)C
umul
ativ
e IR
A-S
T R
ate
(%)
ACUITYACUITYHeparinHeparin + IIb/IIIa+ IIb/IIIa
(N=222)(N=222)
Bivalirudin Bivalirudin + + IIb/IIIaIIb/IIIa(N=241)(N=241)
Bivalirudin Bivalirudin
alonealone(N=249)(N=249)
P valueP value3-way3-way
Any thrombotic Any thrombotic complication post PCIcomplication post PCI 8.6%8.6% 3.7%3.7% 5.6%5.6% 0.090.09
Final TIMI flow 3Final TIMI flow 3 90.5%90.5% 93.7%93.7% 90.7%90.7% 0.370.37
Final blush grade 3Final blush grade 3 81.5%81.5% 79.0%79.0% 79.5%79.5% 0.780.78
ACUITY and Large Thrombus DataACUITY and Large Thrombus DataThe Rationale for Selective Adjunctive GPIThe Rationale for Selective Adjunctive GPIACUITY and Large Thrombus DataACUITY and Large Thrombus Data
The Rationale for Selective Adjunctive GPIThe Rationale for Selective Adjunctive GPI
* New or ↑ thrombus, abrupt closure, no reflow, or distal embolization * New or ↑ thrombus, abrupt closure, no reflow, or distal embolization
G. Stone AHA 2006G. Stone AHA 2006
The Data on GPI and Bivalirudin for Large The Data on GPI and Bivalirudin for Large Thrombus Patients is Favorable (ACUITY)Thrombus Patients is Favorable (ACUITY)
17.1%
11.7%
7.2%8.3%
14.1%
6.2%
2.8%
15.3%13.3%
Net clinical outcome Composite ischemia Major bleeding (non-CABG)
30 d
ay e
vent
s (%
)
Heparin+IIb/IIIa (N=222) Bivalirudin+IIb/IIIa (N=241) Bivalirudin alone (N=249)
17.1%
11.7%
7.2%8.3%
14.1%
6.2%
2.8%
15.3%13.3%
Net clinical outcome Composite ischemia Major bleeding (non-CABG)
30 d
ay e
vent
s (%
)
Heparin+IIb/IIIa (N=222) Bivalirudin+IIb/IIIa (N=241) Bivalirudin alone (N=249)
p=0.37 p=0.58 p=0.22 p=0.61 p=0.67 p=0.03
G. Stone et al. Lancet 2007; 369: 907–19G. Stone et al. Lancet 2007; 369: 907–19
Projecting What Happens if You Use GPI in Projecting What Happens if You Use GPI in 25% of Your Bivalirudin STEMI Patients 25% of Your Bivalirudin STEMI Patients
4.9 5.2
8.38.3
0
1
2
3
4
5
6
7
8
9
Maj
or B
leed
ing,
%
Bival +UFH + GPI
4.9 5.2
8.38.3
0
1
2
3
4
5
6
7
8
9
Maj
or B
leed
ing,
%
Bival +UFH + GPI
Assumes Bival + GPI bleeding rate of 6.8%Assumes Bival + GPI bleeding rate of 6.8%
P < 0.001
Still P < 0.001Still P < 0.001
HORIZONS 7%HORIZONS 7% UVM Implemented HORIZONS—25%UVM Implemented HORIZONS—25%
Incorporation of HORIZONS AMI and Large Incorporation of HORIZONS AMI and Large Thrombus Data—STEMI AlgorithmThrombus Data—STEMI Algorithm
► ED STEMI—25% of PatientsED STEMI—25% of Patients
► ASA/clopidogrel 600 mg po ASA/clopidogrel 600 mg po load and bivalirudinload and bivalirudin
► Bolus and infusion of Bolus and infusion of eptifibatide after wiring eptifibatide after wiring vessel shows Large vessel shows Large Thrombus BurdenThrombus Burden
► Angiojet and Bare Metal Angiojet and Bare Metal StentStent
► 150 mg clopidogrel and 18 150 mg clopidogrel and 18 hours of eptifibatidehours of eptifibatide
► No ambulation until No ambulation until eptifibatide off (18 hours)eptifibatide off (18 hours)
► D/C on Day 3 post MID/C on Day 3 post MI
STEMI:STEMI:Within 24 Hours CPWithin 24 Hours CP
UFH (60 U/Kg)UFH (60 U/Kg)Beta Blockers only if HTNBeta Blockers only if HTN
UFH or Bivalirudin:UFH or Bivalirudin:GPI Optional: Avoid if High Bleed RiskGPI Optional: Avoid if High Bleed Risk
B Blockers ONLY if HTNB Blockers ONLY if HTN
PCI Capability or < 60 minute Transfer Time
No PCI Capability and > 60 minute Transfer Time
Primary PCI with Stenting:Primary PCI with Stenting:GPI/Thrombectomy if Large ThrombusGPI/Thrombectomy if Large Thrombus
or as Bailout; Otherwise, Bivalirudin Aloneor as Bailout; Otherwise, Bivalirudin Alone
90 minutesTo Open
Artery Lytic Lytic ContraindicatedContraindicated
Emergent Transfer
TNK and UFHTNK and UFH
Transfer Transfer from from Community ERCommunity ER
To PCI SiteTo PCI Site
If no CP and less than 50% If no CP and less than 50% ST Elevations, PCI at 12-24ST Elevations, PCI at 12-24
Hours with StentHours with Stent
If Reperfusion Fails,If Reperfusion Fails,Emergent PCI with stentEmergent PCI with stent
ASA/ClopidogrelASA/ClopidogrelStatinStatin
Groin ClosureGroin ClosureCardiac RehabCardiac Rehab
Lopressor 12.5 bidLopressor 12.5 bid
Transfer
Rescue PCI:
Class I Indication
The NSTEMI Paradigm
of 4-48 Hours
ASA 325 po
ClopidogrelClopidogrel600 po600 po
Clopidogrel Clopidogrel 300 po300 po
Continue bivalirudin for 2 hours after PCI
Conclusions Conclusions Key Implementation PointsKey Implementation Points
► Bivalirudin can be safely instituted across the spectrum of Bivalirudin can be safely instituted across the spectrum of PCI patients, including those with NSTE-ACS and STEMI.PCI patients, including those with NSTE-ACS and STEMI.
► Clopidogrel 600 mg po load may be done in ED or Clopidogrel 600 mg po load may be done in ED or immediately after PCI.immediately after PCI.
► Community referring hospitals may use antithrombotic Community referring hospitals may use antithrombotic therapy of choice—then switch to bivalirudin on arrival to PCI therapy of choice—then switch to bivalirudin on arrival to PCI institution.institution.
► STEMI requires an algorithm for care and bivalirudin is the STEMI requires an algorithm for care and bivalirudin is the baseline strategy. But, bivalirudin may be instituted in the ED baseline strategy. But, bivalirudin may be instituted in the ED or the cath lab, depending upon local issues.or the cath lab, depending upon local issues.
► Enhanced management of large thrombus burden should be Enhanced management of large thrombus burden should be considered especially during the most “vulnerable” 2 hours considered especially during the most “vulnerable” 2 hours after PCI.after PCI.
Recommended