The Science and Medicine of Acute Coronary Syndrome The Emergence of Consistent and Unified...

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

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0-D

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Mo

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(%)

30

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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

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din

g (

%)

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


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


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


► 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


30 d

ay e

vent

s (%

)


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


30

da

y e

ve

nts

(%

)


P<0.0001 for all


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


Va

Targets for InterventionTargets for InterventionBetter Options, Worse OptionsBetter Options, Worse Options

Xa Inhibitors—FondaparinuxXa Inhibitors—Fondaparinux



• 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.”.”


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.”



Pivotal TrialsPivotal TrialsFocus on AnticoagulationFocus on AnticoagulationPivotal TrialsPivotal Trials

Focus on AnticoagulationFocus on Anticoagulation



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


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


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


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

(%)


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

(%)


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

(%)


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


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 low dose groupAt least 300mg Day1;

75–100mgfrom 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)


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)


match)match)


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


22% reductionp-value 0.039

22% reductionp-value 0.039



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%




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


4-8 h before PCI4-8 h before PCI


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)


(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)


(n=349)(n=349)

*

*P=NS for all 3-way comparisons versus bivalirudin alone; †naïve=no prior AT therapy in preceding 48 hours.


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%


30 d

ay e

ven

ts (

%)


► 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


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??


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


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%


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]


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


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



11.2%

7.0%

5.2%6.4%

9.1%

2.8%


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%


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]



12.4%

7.6%6.3%

7.4%

9.4%

2.8%


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%


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]


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)


(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)


(n=349)(n=349)

*

†


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%


Ischemiccomposite

Major bleeding



11.8%

7.5%

5.7%

3.5%

12.7%

10.3%


Ischemiccomposite

Major bleeding



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%)




Bivalirudin Alone N=143 (45%)

ClopidogrelPrior to PCI N=41 (24%)


Prior to PCI N=31 (23%)


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)


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


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%


30 d

ay e

vent

s (%

)


17.1%

11.7%

7.2%8.3%

14.1%

6.2%

2.8%

15.3%13.3%


30 d

ay e

vent

s (%

)


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.

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