The Science and Medicine of Acute Coronary Syndrome The Emergence of Consistent and Unified Management Strategies for STEMI and NSTEMI The Science and.

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 Moderator Sunil V. Rao, MD, FACC Host, Duke University Medical Center Cardiac Catheterization Conference Assistant Professor of Medicine Duke University Medical Center Director, Cardiac Catheterization Laboratories Durham VA Medical Center Durham, North Carolina Program Moderator Sunil V. Rao, MD, FACC Host, Duke University Medical Center Cardiac Catheterization Conference Assistant Professor of Medicine Duke University Medical Center Director, Cardiac Catheterization Laboratories Durham VA Medical Center Durham, North Carolina A Year 2008 Update

CME-accredited symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from The Medicines Company Mission statement: Improve patient care through evidence-based education, expert analysis, and case study-based management Processes: Strives for fair balance, clinical relevance, on-label indications for agents discussed, and emerging evidence and information from recent studies COI: Full faculty disclosures provided in syllabus and at the beginning of the program Welcome and Program Overview

Program 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 Faculty Program Moderator Sunil V. Rao, MD, FACC Host, Duke University Medical Center Cardiac Catheterization Conference Assistant Professor of Medicine | Duke University Medical Center | Director, Cardiac Catheterization Laboratories | Durham VA Medical Center | Durham, NC Distinguished Faculty Presenters Deepak L. Bhatt, MD, FACC, FSCAI, FESC, FAHA Associate Director, Cardiovascular Coordinating Center | Staff, Cardiac, Peripheral, and Carotid Intervention | Associate Professor of Medicine | Department of Cardiovascular Medicine | Cleveland Clinic Program Moderator Sunil V. Rao, MD, FACC Host, Duke University Medical Center Cardiac Catheterization Conference Assistant Professor of Medicine | Duke University Medical Center | Director, Cardiac Catheterization Laboratories | Durham VA Medical Center | Durham, NC Distinguished Faculty Presenters Deepak L. Bhatt, MD, FACC, FSCAI, FESC, FAHA Associate Director, Cardiovascular Coordinating Center | Staff, Cardiac, Peripheral, and Carotid Intervention | Associate Professor of Medicine | Department of Cardiovascular Medicine | Cleveland Clinic Harold L. Dauerman, MD Director, Cardiovascular Catheterization Laboratories | Professor of Medicine | University of Vermont/Fletcher Allen Health Care | Burlington, VT Gregg W. Stone, MD Professor of Medicine | Director of Cardiovascular Research and Education | Center for Interventional Vascular Therapy | Columbia University Medical Center | Chairman, The Cardiovascular Research Foundation | New York, NY Ron Waksman, MD, FACC Associate Director, Division of Cardiology | Washington Hospital Center | Director of Experimental Angioplasty and Vascular Brachytherapy | Cardiovascular Research Institute | Washington Hospital Center | Clinical Professor of Medicine | Georgetown University | Washington, DC Harold L. Dauerman, MD Director, Cardiovascular Catheterization Laboratories | Professor of Medicine | University of Vermont/Fletcher Allen Health Care | Burlington, VT Gregg W. Stone, MD Professor of Medicine | Director of Cardiovascular Research and Education | Center for Interventional Vascular Therapy | Columbia University Medical Center | Chairman, The Cardiovascular Research Foundation | New York, NY Ron Waksman, MD, FACC Associate Director, Division of Cardiology | Washington Hospital Center | Director of Experimental Angioplasty and Vascular Brachytherapy | Cardiovascular Research Institute | Washington Hospital Center | Clinical Professor of Medicine | Georgetown University | Washington, DC

Faculty Disclosures Sunil V. Rao, MD, FACC Grant/Research Support: Cordis Consultant: Sanofi-Aventis, The Medicines Company Speakers Bureau: Sanofi-Aventis, The Medicines Company, Cordis Deepak L. Bhatt, MD, FACC, FSCAI, FESC, FAHA Grant/Research Support: The Medicines Co., BMS, Sanofi-Aventis, Eisai, Ethicon Consultant: Astra Zeneca, BMS, Cardax, Centocor, Daiichi-Sankyo, Eisai, Eli Lilly, GSK, Millennium, Otsuka, Paringenix, PDL, Sanofi-Aventis, Schering Plough, The Medicines Co., tns Healthcare Speakers Bureau: BMS, Sanofi-Aventis, The Medicines Co Harold L. Dauerman, MD Consultant: The Medicines Company, Abbott Vascular Research Grants: Abbott Vascular and Boston Scientific Fellowship Support: Boston Scientific, Cordis/JNJ and Medtronic Gregg W. Stone, MD Grant/Research Support: The Medicines Co. and Boston Scientific Ron Waksman, MD, FACC Consultant and speaker or research grant support: Medtronic, Boston Scientific, Biotronik, GSK, Sanofi, BMS Sunil V. Rao, MD, FACC Grant/Research Support: Cordis Consultant: Sanofi-Aventis, The Medicines Company Speakers Bureau: Sanofi-Aventis, The Medicines Company, Cordis Deepak L. Bhatt, MD, FACC, FSCAI, FESC, FAHA Grant/Research Support: The Medicines Co., BMS, Sanofi-Aventis, Eisai, Ethicon Consultant: Astra Zeneca, BMS, Cardax, Centocor, Daiichi-Sankyo, Eisai, Eli Lilly, GSK, Millennium, Otsuka, Paringenix, PDL, Sanofi-Aventis, Schering Plough, The Medicines Co., tns Healthcare Speakers Bureau: BMS, Sanofi-Aventis, The Medicines Co Harold L. Dauerman, MD Consultant: The Medicines Company, Abbott Vascular Research Grants: Abbott Vascular and Boston Scientific Fellowship Support: Boston Scientific, Cordis/JNJ and Medtronic Gregg W. Stone, MD Grant/Research Support: The Medicines Co. and Boston Scientific Ron Waksman, MD, FACC Consultant and speaker or research grant support: Medtronic, Boston Scientific, Biotronik, GSK, Sanofi, BMS

Challenges and Uncertainties in Managing Acute Coronary Syndrome (ACS) Connecting Evidence Across All the Streams: How and Why Bleeding Matters The Science and Medicine of Acute Coronary Syndrome Program Moderator Sunil V. Rao, MD, FACC Host, Duke University Medical Center Cardiac Catheterization Conference Assistant Professor of Medicine Duke University Medical Center Director, Cardiac Catheterization Laboratories Durham VA Medical Center Durham, North Carolina Program Moderator Sunil V. Rao, MD, FACC Host, Duke University Medical Center Cardiac Catheterization Conference Assistant Professor of Medicine Duke University Medical Center Director, Cardiac Catheterization Laboratories Durham VA Medical Center Durham, North Carolina

Is there a consistent approach to care of STEMI and NSTEMI patients that can be use across the ACS risk spectrum? Across institutional needs in patients undergoing PCI? Is there a consistent approach to care of STEMI and NSTEMI patients that can be use across the ACS risk spectrum? Across institutional needs in patients undergoing PCI? How should recent ACC/AHA 2007 NSTEMI Guidelines impact our choices for upstream antithrombotic therapy? How should recent ACC/AHA 2007 NSTEMI Guidelines impact our choices for upstream antithrombotic therapy? What is the relationship between bleeding avoidance and mortality in ACS patents? Should bleeding avoidance be primary driver for selection of antithrombotic therapy? In all patients? In some? What is the relationship between bleeding avoidance and mortality in ACS patents? Should bleeding avoidance be primary driver for selection of antithrombotic therapy? In all patients? In some? How should recent STEMI trials impact our approach to upstream care for STEMI? For NSTEMI? How should recent STEMI trials impact our approach to upstream care for STEMI? For NSTEMI? Questions We Will Illuminate and Debate

What do know about changing anticoagulant therapy midstream? Problematic? Safe? Agent- specific? What do know about changing anticoagulant therapy midstream? Problematic? Safe? Agent- specific? What is the ideal alignment between oral antiplatelet therapy and anticoagulation in STEMI and NSTEMI? What is the ideal alignment between oral antiplatelet therapy and anticoagulation in STEMI and NSTEMI? What does a consistent and unified approach to upstream care look like in an institutional setting? A university-based case study. What does a consistent and unified approach to upstream care look like in an institutional setting? A 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 at Rest No ST-segment Elevation Non-Q-wave MI Unstable Angina Q-wave MI ST-segment Elevation + + + + ( : positive cardiac biomarker) EmergencyDepartmentEmergencyDepartment In-hospital6-24hrsIn-hospital6-24hrs PresentationPresentation Acute Coronary Syndromes Clinical Spectrum and Presentation NSTEMI Adapted from AHA/ACC NSTEMI Guidelines

SYNERGYLMWHESSENCE 1994199519961997199819992000200220032004200520062001 CUREClopidogrel Bleeding risk Ischemic risk GP IIb/IIIa blockers PRISM-PLUS PURSUIT ACUITY TACTICS TIMI-18 Early invasive PCI ~ 5% stents ~85% stents Drug-eluting stents ISAR-REACT 2 Milestones in ACS Management OASIS-5 [ Fondaparinux ] Anti-Thrombin Rx Anti-Platelet Rx Treatment Strategy Heparin Aspirin Conservative ICTUSBivalirudin REPLACE 2 Adapted from and with the courtesy of Steven Manoukian, MD.

Algorithm for Patients With UA/NSTEMI Managed by an Initial Invasive Strategy: ACC/AHA 2007 Guidelines Diagnosis of UA/NSTEMI is Likely or Definite ASA (Class I, LOE:A)* Clopidogrel if ASA intolerant (Class I, LOE: A) ASA (Class I, LOE:A)* Clopidogrel if ASA intolerant (Class I, LOE: A) Select Management Strategy Select Management Strategy Invasive Strategy Initiate anticoagulant therapy (Class I, LOE: A): Acceptable options*: enoxaparin or UFH (Class I, LOE: A), bivalirudin or fondaparinux are preferable (Class I, LOE: B) Invasive Strategy Initiate anticoagulant therapy (Class I, LOE: A): Acceptable options*: enoxaparin or UFH (Class I, LOE: A), bivalirudin or fondaparinux are preferable (Class I, LOE: B) InitialConservativeStrategyInitialConservativeStrategy AA B1B1 ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.

Algorithm for Patients With UA/NSTEMI Managed by an Initial Invasive Strategy Prior to Angiography Initiate at least one (Class I, LOE: A) or 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 and GP IIb/IIIa inhibitor include: Delay to angiography High risk features Early recurrent ischemic discomfort Prior to Angiography Initiate at least one (Class I, LOE: A) or 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 and GP IIb/IIIa inhibitor include: Delay to angiography High risk features Early recurrent ischemic discomfort Diagnostic Angiography B2B2 ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.

Considerations in the Modern Era of ACS/PCI 55-year-old male with 3 hours of chest pain 55-year-old male with 3 hours of chest pain Hx of HTN, lipids Hx of HTN, lipids Marked ST-segment depression leads II, III, aVL Marked ST-segment depression leads II, III, aVL Elevated serum troponin T, CKMB 4 X ULN Elevated serum troponin T, CKMB 4 X ULN Normal renal function Normal renal function 55-year-old male with 3 hours of chest pain 55-year-old male with 3 hours of chest pain Hx of HTN, lipids Hx of HTN, lipids Marked ST-segment depression leads II, III, aVL Marked ST-segment depression leads II, III, aVL Elevated serum troponin T, CKMB 4 X ULN Elevated serum troponin T, CKMB 4 X ULN Normal renal function Normal renal function 86-year-old female with 3 hours of chest pain 86-year-old female with 3 hours of chest pain Hx of DM, HTN, lipids Hx of DM, HTN, lipids ECG non-specific (no prior study for comparison) ECG non-specific (no prior study for comparison) Elevated troponin, normal CKMB Elevated troponin, normal CKMB Est. GFR 45 ml/min Est. GFR 45 ml/min

Ischemia vs. Bleeding: NSTE ACS vs. STEMI 30-Day Mortality (%) 47%47% 41%41% Stone GW NEJM 2007 Stone GW. TCT 2007 Stone GW NEJM 2007 Stone GW. TCT 2007 HORIZONS AMI ACUITYACUITY Major Bleeding (%) Heparin + IIb/IIIa Bivalirudin Heparin + IIb/IIIa Bivalirudin Heparin + IIb/IIIa Bivalirudin Heparin + IIb/IIIa Bivalirudin P=NS P=0.047

0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 Days After Randomization Primary Efficacy End Point (%) 876543210876543210 876543210876543210 Clopidogrel Prasugrel P=0.003 6.9 5.6 Wiviott SD, et al. NEJM 2007 Nov 15;357(20):2001-15 Is the Bleeding Issue Still Relevant in 2008?

3 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450 Key Safety End Point Prasugrel Clopidogrel 2.4 1.8 Days After Randomization 35 Events Hazard ratio, 1.32; 95% CI, 1/03-1.68; P=0.03 35 Events Hazard ratio, 1.32; 95% CI, 1/03-1.68; P=0.03 4321043210 4321043210 Wiviott SD, et al. NEJM 2007 Nov 15;357(20):2001-15 Even in 2008, the balance between efficacy and safety is paramount Even in 2008, the balance between efficacy and safety is paramount Is the Bleeding Issue Still Relevant in 2008?

*p<0.0001 ISAR-REACT 3: Results Kastrati A, et al. ACC 2008 Endpoint Bivalirudin (%) UFH (%) p Primary8.38.70.57 Secondary5.95.00.23 Major bleeding* 3.14.60.008 Minor bleeding* 6.89.90.0001 Transfusion1.31.80.15 TIMI major 0.51.00.04 TIMI minor 1.32.20.01 * as per ISAR-REACT 3 definition

ACS-related BleedingRelevant Questions Who bleeds? Can we risk stratify? Who bleeds? Can we risk stratify? Should bleeding risk affect upstream antithrombotic care? If so, how? Should bleeding risk affect upstream 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 with bleeding? Can blood transfusion correct risks associated with bleeding? Does bleeding affect resource use? Does bleeding affect resource use? Who bleeds? Can we risk stratify? Who bleeds? Can we risk stratify? Should bleeding risk affect upstream antithrombotic care? If so, how? Should bleeding risk affect upstream 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 with bleeding? Can blood transfusion correct risks associated with bleeding? Does bleeding affect resource use? Does bleeding affect resource use?

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 ACS Older Age Older Age Female Gender Female Gender Renal Failure Renal Failure History of Bleeding History of Bleeding Right Heart Catheterization Right Heart Catheterization GPIIb-IIIa Antagonists GPIIb-IIIa Antagonists Older Age Older Age Female Gender Female Gender Renal Failure Renal Failure History of Bleeding History of Bleeding Right Heart Catheterization Right Heart Catheterization GPIIb-IIIa Antagonists GPIIb-IIIa Antagonists

P-value RR (95% CI) Risk ratio ± 95% CI Predictors of Major Bleeding Age >75 (vs. 55-75) Anemia CrCl <60mL/min Diabetes Female gender High-risk (ST / biomarkers) Hypertension No prior PCI Prior antithrombotic therapy Heparin(s) + GPI (vs. Bivalirudin) 1.56 (1.19-2.04) 0.0009 1.89 (1.48-2.41) <0.0001 1.68 (1.29-2.18) <0.0001 1.30 (1.03-1.63) 0.0248 2.08 (1.68-2.57) <0.0001 1.42 (1.06-1.90) 0.0178 1.33 (1.03-1.70) 0.0287 1.47 (1.15-1.88) 0.0019 1.23 (0.98-1.55) 0.0768 2.08 (1.56-2.76) <0.0001 Manoukian SV, Voeltz MD, Feit F et al. TCT 2006. Results: The ACUITY Trial PCI Population

P-value RR (95% CI) Age >75 (vs. 55-75) Anemia CrCl <60mL/min Diabetes Female gender High-risk (ST / biomarkers) Hypertension Heparin(s) + GPI (vs. Bivalirudin) 1.420 (1.055-1.910) 0.0060 3.764 (2.919-4.855) <0.0001 2.097 (1.568-2.803) <0.0001 1.560 (1.209-2.014) 0.0060 2.233 (1.739-2.867) <0.0001 1.754 (1.297-2.372) 0.0003 1.457 (1.051-2.020) 0.0241 1.728 (1.256-2.379) 0.0007 Predictors of Transfusion Risk ratio ± 95% CI Results: The ACUITY Trial Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

Older age, chronic kidney disease, female gender are consistently associated with bleeding and blood transfusion Older age, chronic kidney disease, female gender are consistently associated with bleeding and blood transfusion Analysis of large randomized trials have also identified novel risk factors for bleeding such as diabetes and anemia Analysis of large randomized trials have also identified novel risk factors for bleeding such as diabetes and anemia Older age, chronic kidney disease, female gender are consistently associated with bleeding and blood transfusion Older age, chronic kidney disease, female gender are consistently associated with bleeding and blood transfusion Analysis of large randomized trials have also identified novel risk factors for bleeding such as diabetes and anemia Analysis of large randomized trials have also identified novel risk factors for bleeding such as diabetes and anemia Bleeding Predictors Conclusions

log rank p-value for all four categories <0.0001 log-rank p-value for no bleeding vs. mild bleeding = 0.02 log-rank p-value for mild vs. moderate bleeding <0.0001 log-rank p-value for moderate vs. severe <0.001 Bleeding 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 Severity N=26,452 ACS patients from GUSTO IIb, PARAGON A, PARAGON B, & PURSUIT Kaplan Meier Curves for 30-Day Death, Stratified by Bleed Severity N=26,452 ACS patients from GUSTO IIb, PARAGON A, PARAGON B, & PURSUIT None Mild Moderate Severe None Mild Moderate Severe 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 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 death *p<0.0001 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 Severity 30d Death 30d Death/MI 6 mo. Death Mild*1.61.31.4 Moderate*2.73.32.1 Severe*10.65.67.5 *Bleeding as a time-dependent covariate

Mortality (%) Days from Randomization 0306090120150180210240270300330360390 0 5 15 30 10 25 20 1 year Estimate 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 the First 30 Days on Risk of Death Over 1 Year 28.9% 12.5% 8.6% 3.4% Stone GW. TCT 2007 ACUITY

Day 0 – 2 after MI 12.6 (7.8-20.4) 29 (37.6) <0.0001 Day 3 – 7 after MI 5.3 (2.7-10.4) 11 (14.3) <0.0001 Day 8 – 35 after MI 1.6 (0.8-3.1) 12 (15.6) 0.18 Day > 35 after MI 1.2 (0.8-1.9) 25 (32.5) 0.34 Day 0 – 2 after Major Bleed 3.0 (1.6-5.6) 12 (12.9) 0.0009 Day 3 – 7 after Major Bleed 4.0 (2.1-7.5) 15 (16.1) <0.0001 Day 8 – 35 after Major Bleed 4.5 (2.8-7.4) 25 (26.9) <0.0001 Day > 35 after Major Bleed 2.2 (1.5-3.2) 41 (44.1) <0.0001 P-valueP-value Deaths (n/%) HR ± 95% CI 0.5 1 2 4 8 16 HR (CI) Impact of MI and Major Bleeding (non-CABG) in the First 30 Days on Risk of Death Over 1 Year ACUITY TRIALCox model adjusted for baseline predictors: Bleeding and MI as time updated covariates Stone, ACC 2007

Bleeding is associated with adverse short- and long- term outcomes among patients with ACS and those undergoing PCI Bleeding is associated with adverse short- and long- term outcomes among patients with ACS and those undergoing PCI Mortality rates are higher among those who bleed Mortality rates are higher among those who bleed MI rates are higher among those who bleed MI rates are higher among those who bleed Worse bleeding associated with worse outcomes Worse bleeding associated with worse outcomes This relationship is persistent after robust statistical adjustment for confounders This relationship is persistent after robust statistical adjustment for confounders Bleeding is associated with adverse short- and long- term outcomes among patients with ACS and those undergoing PCI Bleeding is associated with adverse short- and long- term outcomes among patients with ACS and those undergoing PCI Mortality rates are higher among those who bleed Mortality rates are higher among those who bleed MI rates are higher among those who bleed MI rates are higher among those who bleed Worse bleeding associated with worse outcomes Worse bleeding associated with worse outcomes This relationship is persistent after robust statistical adjustment for confounders This relationship is persistent after robust statistical adjustment for confounders Bleeding and Outcomes Conclusions

30-Day Survival By Transfusion Group Rao SV, et. al., JAMA 2004;292:1555–1562. Transfusion in ACS N=24,111N=24,111

*Transfusion as a time-dependent covariate Cox Model for 30-day Death N=24,111N=24,111 Rao SV, et. al., JAMA 2004;292:1555–1562. PRBC Transfusion Among NSTE ACS Patients PRBC Transfusion Among NSTE ACS Patients Adjusted for transfusion propensity Adjusted for baseline characteristics Adjusted for baseline characteristics, bleeding propensity, transfusion propensity, and nadir HCT Adjusted for transfusion propensity Adjusted for baseline characteristics Adjusted for baseline characteristics, bleeding propensity, transfusion propensity, and nadir HCT 3.77 (3.13, 4.52 3.54 (2.96, 4.23) 3.94 (3.26, 4.75) -4.01.0 10.0

Adjusted Risk of In-Hospital Outcomes By Transfusion Status* Adjusted Risk of In-Hospital Outcomes By Transfusion Status* *Non-CABG patients only Yang X, J Am Coll Cardiol 2005;46:1490–5. N=74,271 ACS patients from CRUSADE Death Death or Re-MI 1.0 2.0

Transfusion, Ischemic Endpoints, and Mortality in ACUITY Trial P<0.0001 for all Manoukian SV, Voeltz MD, Feit F et al. TCT 2006. Results: The ACUITY Trial (N=13,819)

Blood transfusion is independently associated with death and recurrent MI Blood transfusion is independently associated with death and recurrent MI Transfusion does not correct the adverse impact bleeding and is not an insurance policy against adverse outcomes associated with bleeding Transfusion does not correct the adverse impact bleeding and is not an insurance policy against adverse outcomes associated with bleeding Blood transfusion is best avoided in ACS patients whenever possible Blood transfusion is best avoided in ACS patients whenever possible Blood transfusion is independently associated with death and recurrent MI Blood transfusion is independently associated with death and recurrent MI Transfusion does not correct the adverse impact bleeding and is not an insurance policy against adverse outcomes associated with bleeding Transfusion does not correct the adverse impact bleeding and is not an insurance policy against adverse outcomes associated with bleeding Blood transfusion is best avoided in ACS patients whenever possible Blood transfusion is best avoided in ACS patients whenever possible Blood Transfusion Conclusions

What are the bleeding consequences of switching anticoagulation in midstream? What are the bleeding consequences of switching anticoagulation in midstream? Are there switching strategies that mitigate against or reduce risk of bleeding in ACS patients? What are they? Are there switching strategies that mitigate against or reduce risk of bleeding in ACS patients? What are they? Should routine switching be advocated as a strategy for bleeding minimization? In NSTE- ACS? In STEMI? Should routine switching be advocated as a strategy for bleeding minimization? In NSTE- ACS? In STEMI? What are the bleeding consequences of switching anticoagulation in midstream? What are the bleeding consequences of switching anticoagulation in midstream? Are there switching strategies that mitigate against or reduce risk of bleeding in ACS patients? What are they? Are there switching strategies that mitigate against or reduce risk of bleeding in ACS patients? What are they? Should routine switching be advocated as a strategy for bleeding minimization? In NSTE- ACS? In STEMI? Should routine switching be advocated as a strategy for bleeding minimization? In NSTE- ACS? In STEMI? Bleeding in ACSThe Big Switch

*Bivalirudin monotherapy with GP IIb/IIIa reserved for severe breakthrough ischemia and procedural complications during PCI. P =.47 P <.001 48% Adverse events (%) 30-day 9.0% 3.5% 8.2% 6.7% 0 5 10 15 Composite ischemiaNon-CABG major bleeding P =.75 Adverse events (%) 1-year 2.7% 2.9% 0 1 2 3 4 5 Mortality Data on file. The Medicines Company, Parsippany, NJ. Switch to bivalirudin* vs consistent heparin + GP IIb/IIIa outcomes Switching to Bivalirudin Improves Bleeding Outcomes Ischemic suppression was maintained and bleeding significantly reduced at 30 days Ischemic suppression was maintained and bleeding significantly reduced at 30 days Long-term efficacy in both groups was consistent at 1 year Long-term efficacy in both groups was consistent at 1 year Ischemic suppression was maintained and bleeding significantly reduced at 30 days Ischemic suppression was maintained and bleeding significantly reduced at 30 days Long-term efficacy in both groups was consistent at 1 year Long-term efficacy in both groups was consistent at 1 year Bivalirudin* (n=1,292) switch arm UFH/enoxaparin + GP IIb/IIIa (n=1,236) consistent arm PCI Subgroup

Bivalirudin* (n=1,014) switch arm P =.36 P =.003 45% *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. 9.3% 3.9% 8.1% 7.1% UFH/enoxaparin + GP IIb/IIIa (n=974) consistent arm 0 5 10 15 P =.97 3.1%3.1% 0 1 2 3 4 5 30-day Composite ischemia Non-CABG major bleeding 1-year Mortality Adverse events (%) Data on file. The Medicines Company, Parsippany, NJ. In High-Risk Patient Subset, Switching to Bivalirudin Also Improves Bleeding Outcomes Ischemic suppression was maintained and major bleeding significantly reduced at 30 days Ischemic suppression was maintained and major bleeding significantly reduced at 30 days Long-term efficacy in both groups was consistent at 1 year Long-term efficacy in both groups was consistent at 1 year Ischemic suppression was maintained and major bleeding significantly reduced at 30 days Ischemic suppression was maintained and major bleeding significantly reduced at 30 days Long-term efficacy in both groups was consistent at 1 year Long-term efficacy in both groups was consistent at 1 year Switch to bivalirudin* vs consistent heparin + GP IIb/IIIa outcomes PCI Subgroup

Bleeding and Resource Use Predictors of Total Costs Moderate/severe bleed Per patient cost - $530 Transfusion - $2,080, P < 0.01 Per patient cost - $287 Moderate/severe bleed Per patient cost - $530 Transfusion - $2,080, P < 0.01 Per patient cost - $287 Model C-index=0.87 Adjusted for patient characteristics Model C-index=0.87 Adjusted for patient characteristics Rao SV, et. al. AHJ 2008. N=1235 pts from GUSTO IIb

ACUITY: Hospital Index Costs ACUITY: Hospital Index Costs p<0.001 for comparison across the five groups Heparin + Upstream GPI Heparin + Cath Lab GPI Bivalirudin + Upstream GPI Bivalirudin + Cath Lab GPI Bivalirudin Monotherapy Pinto D et al. ACC 2008 Hospital Index Costs

The available costs data clearly show that a balance must be struck between ischemia reduction and bleeding The available costs data clearly show that a balance must be struck between ischemia reduction and bleeding Both ischemic complications and bleeding are associated with increased costs such that any cost savings realized by reducing one is offset by cost increases associated with the other Both ischemic complications and bleeding are associated with increased costs such that any cost savings realized by reducing one is offset by cost increases associated with the other The available costs data clearly show that a balance must be struck between ischemia reduction and bleeding The available costs data clearly show that a balance must be struck between ischemia reduction and bleeding Both ischemic complications and bleeding are associated with increased costs such that any cost savings realized by reducing one is offset by cost increases associated with the other Both ischemic complications and bleeding are associated with increased costs such that any cost savings realized by reducing one is offset by cost increases associated with the other Bleeding and Costs Conclusions

X Xa II IIa (Thrombin) (Prothrombin) TFVIIa IX IXa Direct Thrombin InhibitorsBivalirudin Va Targets for Intervention Better Options, Worse Options Xa Inhibitors Fondaparinux Xa Inhibitors Fondaparinux Direct Thrombin InhibitorsBivalirudin

Bivalent direct thrombin inhibitorBivalent direct thrombin inhibitor High specificity and potencyHigh specificity and potency Lack of dependence on antithrombin-IIILack of dependence on antithrombin-III Effect on clot-bound & free thrombinEffect on clot-bound & free thrombin No platelet activationNo platelet activation No inhibition by PF4 and othersNo inhibition by PF4 and others ReversibleReversible Bivalent direct thrombin inhibitorBivalent direct thrombin inhibitor High specificity and potencyHigh specificity and potency Lack of dependence on antithrombin-IIILack of dependence on antithrombin-III Effect on clot-bound & free thrombinEffect on clot-bound & free thrombin No platelet activationNo platelet activation No inhibition by PF4 and othersNo inhibition by PF4 and others ReversibleReversible ( Gly ) 4 Bivalirudin Pharmacology Gly-Pro-Arg-Pro (active site binding region) C-terminal dodecapeptide (exosite 1-binding region)

Addressing the Challenges of Selecting an Anticoagulation Strategy Bleeding Risk Ischemic Risk Renal function AgeAge Time to cath CostCost Ease of use PCI vs CABG vs Med Rx

Bleeding Among Patients with ACSConclusions There are several therapeutic pathways for ACS care There are several therapeutic pathways for ACS care Choices for therapy must take into account: Choices for therapy must take into account: Ischemic complications Ischemic complications Bleeding complications Bleeding complications The risk for bleeding and ischemia increases from NSTE-ACS to STEMI The risk for bleeding and ischemia increases from NSTE-ACS to STEMI There are several therapeutic pathways for ACS care There are several therapeutic pathways for ACS care Choices for therapy must take into account: Choices for therapy must take into account: Ischemic complications Ischemic complications Bleeding complications Bleeding complications The risk for bleeding and ischemia increases from NSTE-ACS to STEMI The risk for bleeding and ischemia increases from NSTE-ACS to STEMI

ConclusionsBleeding in ACS Certain patient and PCI procedure characteristics predict bleeding Certain patient and PCI procedure characteristics predict bleeding Age, female gender, CKD Age, female gender, CKD Diabetes and anemia are newly identified risk factors for bleeding among ACS patients Diabetes and anemia are newly identified risk factors for bleeding among ACS patients Bleeding is associated with worse short and long- term outcomes including death and MI Bleeding is associated with worse short and long- term outcomes including death and MI Blood transfusion is associated with increased mortality in ACS patients Blood transfusion is associated with increased mortality in ACS patients In addition to an adverse impact on clinical outcomes, bleeding is associated with increased cost of care In addition to an adverse impact on clinical outcomes, bleeding is associated with increased cost of care

Conclusions Bleeding in ACS ACC/AHA guidelines now recognize the value of bleeding reduction in ACS care ACC/AHA guidelines now recognize the value of bleeding reduction in ACS care Bivalirudin is a Class I (Level of evidence: B) Bivalirudin is a Class I (Level of evidence: B) recommended antithrombin agent for NSTE-ACS patients undergoing an invasive strategy We now have evidence for a bleeding reduction strategy with bivalirudin that is consistent across the spectrum of risk for NSTE-ACS and STEMI We now have evidence for a bleeding reduction strategy with bivalirudin that is consistent across the spectrum of risk for NSTE-ACS and STEMI

Acute Coronary Syndromes A Year 2008 Status Report The Guidelines: Many Streams Runs Through Deepak L. Bhatt MD, FACC, FSCAI, FESC, FACP, FCCP, FAHA Associate Director, Cleveland Clinic Cardiovascular Coordinating Center Staff, Cardiac, Peripheral, and Carotid Intervention Associate Professor of Medicine Deepak L. Bhatt MD, FACC, FSCAI, FESC, FACP, FCCP, FAHA Associate Director, Cleveland Clinic Cardiovascular Coordinating Center Staff, Cardiac, Peripheral, and Carotid Intervention Associate Professor of Medicine Getting in the Stream of Things

Mechanisms 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 Myonecrosis Cardiovascular Morbidity and Mortality Arterial Inflammation Arterial Inflammation Aspirin Resistance InterventionalDeviceInterventionalDevice

Mortality Major Bleeding TransfusionHypotension Cessation of ASA/Clopidogrel Ischemia Stent Thrombosis Inflammation Bhatt DL et al. In Braunwald: Harrisons Online 2005. Potential Relationship Between Bleeding and Mortality

The Big Picture: Early Invasive vs. Initial Conservative Therapy An early invasive strategy (i.e., diagnostic angiography with intent to perform revascularization) is indicated in initially stabilized UA/NSTEMI patients (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events. In initially stabilized patients, an initially conservative (i.e., a selectively invasive) strategy may be considered as a treatment strategy for UA/NSTEMI patients (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events, including those who are troponin positive. The decision to implement an initial conservative (vs. initial invasive) strategy in these patients may be made by considering physician and patient preference. The Big Picture: Early Invasive vs. Initial Conservative Therapy An early invasive strategy (i.e., diagnostic angiography with intent to perform revascularization) is indicated in initially stabilized UA/NSTEMI patients (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events. In initially stabilized patients, an initially conservative (i.e., a selectively invasive) strategy may be considered as a treatment strategy for UA/NSTEMI patients (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events, including those who are troponin positive. The decision to implement an initial conservative (vs. initial invasive) strategy in these patients may be made by considering physician and patient preference. UA/NSTEMI Strategy Overview ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.

Big Picture: Antiplatelet Agents Support for thienopyridine use (primarily with clopidogrel) continues to grow, including higher loading-dose options, earlier (upstream) administration, and longer administration (especially after drug-eluting stent placement). The question of how best to integrate thienopyridine use with parenteral glycoprotein (GP) IIb/IIIa antagonists to provide optimal antiplatelet therapy early in the course of UA/NSTEMI therapy, including cardiac catheterization, is an evolving area. Big Picture: Antiplatelet Agents Support for thienopyridine use (primarily with clopidogrel) continues to grow, including higher loading-dose options, earlier (upstream) administration, and longer administration (especially after drug-eluting stent placement). The question of how best to integrate thienopyridine use with parenteral glycoprotein (GP) IIb/IIIa antagonists to provide optimal antiplatelet therapy early in the course of UA/NSTEMI therapy, including cardiac catheterization, is an evolving area. UA/NSTEMI Strategy Overview ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.

Big Picture: Anticoagulants Two new anticoagulants, fondaparinux and bivalirudin, have undergone favorable testing in clinical trials and are recommended as alternatives to unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs) for specific or more general applications. Big Picture: Anticoagulants Two new anticoagulants, fondaparinux and bivalirudin, have undergone favorable testing in clinical trials and are recommended as alternatives to unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs) for specific or more general applications. ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation. UA/NSTEMI Strategy Overview

Pivotal Trials Focus on Anticoagulation Pivotal Trials Focus on Anticoagulation ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation. UA/NSTEMI Strategy Overview

OASIS-5: Efficacy at Day 9 EnoxFonda % Death/MI/RI5.85.9 Death/MI4.14.1 Death1.91.8 MI2.72.7 Refract Isch 1.92.05 0.81 1.2 Non-inferiority Margin = 1.185 Non-inferiority Margin = 1.185 Hazard Ratio Fonda Better Enox Better Yusuf S, et al. N Engl J Med. 2006;354(14):1464-76

OASIS-5: Bleeding Rates at Day 9 Yusuf S, et al. N Engl J Med. 2006;354(14):1464-76 OutcomeEnoxaparinFondaparinux HR (95% CI) P No. Randomized 10,02110,057 Total Bleed (%) 7.03.2 0.44 (0.39 – 0.51) < 0.0001 Major Bleed (%) 4.02.1 0.53 (0.45 – 0.62) < 0.0001 TIMI Major Bleed (%) 1.30.7 0.54 (0.41 – 0.73) < 0.0001 Minor Bleed (%) 3.11.1 0.35 (0.28 – 0.43) < 0.0001

OASIS-5 Efficacy End Points at 6 Months End point EnoxaparinFondaparinux P value Death/MI/ refractory ischemia 13.2%12.3%0.06 Death/MI11.4%10.5%0.05 Death6.5%5.8%0.05 MI6.6%6.3%NS Stroke1.7%1.3%0.04 Death/MI/stroke*12.5%11.3%0.007 Yusuf S, et al. N Engl J Med. 2006;354(14):1464-76

PCI Procedural Complications Events (30 Days) Enoxaparin n=3089 Fondaparinux n=3118 P value Any UFH during PCI 53.8%18.8% Any procedural complication 8.6%9.6%0.18 Abrupt closure 1.1%1.5%0.20 Catheter thrombus 0.5%1.3%0.001 Vascular access 8.1%3.3%<0.0001 Pseudo-aneurysm1.6%1.0%0.39 Large hematoma 4.4%1.6%<0.0001 Yusuf S, et al. N Engl J Med. 2006;354(14):1464-76

ACUITYIschemic Composite Endpoint 0 5 10 15 05101520253035 Cumulative Events (%) Days from Randomization Estimate P (log rank) 7.3% UFH/Enoxaparin + IIb/IIIa (N=4603) Bivalirudin + IIb/IIIa (N=4604) 0.37 7.7% Bivalirudin alone (N=4612) 0.30 7.8% Stone GW, et al. NEJM. 2006 Nov 23;355(21):2203-16.

ACUITYMajor Bleeding Endpoint 0 5 10 15 05101520253035 Cumulative Events (%) Days from Randomization Estimate P (log rank) 5.7% UFH/Enoxaparin + IIb/IIIa (N=4603) Bivalirudin + IIb/IIIa (N=4604) 0.41 5.3% Bivalirudin alone (N=4612) <0.0001 3.0% Stone GW, et al. NEJM. 2006 Nov 23;355(21):2203-16.

0306090120150180210240270300330360390 0 4 5 Mortality (%) Days from Randomization 2 1 ACUITY Mortality at One Year UFH/Enoxaparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone Estimate P (log rank) 1.4% 0.53 1.6% 0.39 1.6% Estimate P (log rank) 4.4% 0.93 4.2% 0.66 3.8% 1 year p=0.90 Bivalirudin+GPI vs. Hep+GPI HR [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+GPI HR [95% CI] = 0.95 (0.77-1.18) Bivalirudin alone vs. Hep+GPI HR [95% CI] = 0.95 (0.77-1.18) Stone GW, ACC 2007

Antiplatelet Agents Mechanisms and Current Trials Antiplatelet Agents Mechanisms and Current Trials UA/NSTEMI Strategy Overview

Meadows TA, Bhatt DL. Circ Res. 2007;100:1261-1275. Platelet and Thrombus Formation Vascular Injury

Meadows TA, Bhatt DL. Circ Res. 2007;100:1261-1275.

ADP Receptors Bhatt DL et al. Nature Reviews Drug Discovery 2003; 2:15-28.

CURRENT OASIS 7 Study Design RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE RANDOMIZERANDOMIZE PCI: Percutaneous coronary intervention UA/NSTEMI: Unstable angina/non-ST-segment elevation myocardial infarction Slide courtesy of Dr. Shamir Mehta N = ~14, 000 Patients with UA/NSTEMI planned for early invasive strategy, i.e. intend for PCI as early as possible within 24 hrs Patients with UA/NSTEMI planned for early invasive strategy, i.e. intend for PCI as early as possible within 24 hrs Clopidogrel High Dose Group Clopidogrel 600mg loading dose Day 1 followed by 150mg from Day 2 to Day 7; 75mg from Day 8 to 30 Clopidogrel High Dose Group Clopidogrel 600mg loading dose Day 1 followed by 150mg from Day 2 to Day 7; 75mg from Day 8 to 30 Clopidogrel Standard Dose Group Clopidogrel 300mg (+placebo) Day 1 followed by 75mg (+placebo) from Day 2 to Day 7; 75mg from Day 8 to 30 Clopidogrel Standard Dose Group Clopidogrel 300mg (+placebo) Day 1 followed by 75mg (+placebo) from Day 2 to Day 7; 75mg from Day 8 to 30 ASA high dose group At least 300mg Day1; 300mg–325mg from D2 to D30 ASA high dose group At least 300mg Day1; 300mg–325mg from D2 to D30 ASA low dose group At least 300mg Day1; 75–100mg from D2 to D30 ASA low dose group At least 300mg Day1; 75–100mg from D2 to D30 ASA low dose group At least 300mg Day1; 75–100mg from D2 to D30 ASA low dose group At least 300mg Day1; 75–100mg from D2 to D30 ASA high dose group At least 300mg Day1; 300mg–325mg from D2 to D30 ASA high dose group At least 300mg Day1; 300mg–325mg from D2 to D30

Cangrelor (AR-C69931MX) Parenteral ADP-P2Y12 receptor antagonist ATP analogue ATP analogue Molecular weight 800 Daltons Molecular weight 800 Daltons Plasma half-life of 5-9 minutes Plasma half-life of 5-9 minutes 20 minutes for return to normal platelet function 20 minutes for return to normal platelet function Parenteral ADP-P2Y12 receptor antagonist ATP analogue ATP analogue Molecular weight 800 Daltons Molecular weight 800 Daltons Plasma half-life of 5-9 minutes Plasma half-life of 5-9 minutes 20 minutes for return to normal platelet function 20 minutes for return to normal platelet function N N N N NH S CF 3 OH OH O O P O O P P O O O Cl O O O S 4Na +

CHAMPION Platform Trial uRevasc, urgent revascularization PCI for ACS ~4400) (N~4400) PCI for ACS ~4400) (N~4400) 1:1 Double -blind, double-dummy Cangrelor bolus (30 µg/kg) & infusion (4 µg/kg/min) Clopidogrel capsules (600 mg) Placebo capsules (to match) Placebo bolus and infusion (to match) Index Procedure Study drug infusion (for at least 2 hours or the duration of the procedure, whichever is longer) Index Procedure Study drug infusion (for at least 2 hours or the duration of the procedure, whichever is longer) Placebo capsules (to match) Clopidogrel capsules (600 mg) 1º Endpoint: Death, MI, and UTVR at 48 hours 2 º Endpoints: Death, MI, uRevasc at 30 days Death at 6 months and 1 year 2 º Endpoints: Death, MI, uRevasc at 30 days Death at 6 months and 1 year

The Inflammatory Interfaces Focus on Statins The Inflammatory Interfaces Focus on Statins NSTE-ACS Strategy Overview

Statins as Anti-Inflammatory Drugs? Inhibit Isoprenylation Rac, Rho, RA 1 Rac, Rho, RA 1 Upregulate eNOS Activate AKT pathway Inhibit caveolin Statins ROS ROS Oxidized LDL Oxidized LDL Angiotensin 1 Angiotensin 1 Endothelin 1 Endothelin 1 Inflammatory cells Inflammatory cells CRP, IL-6 CRP, IL-6 Endothelial nitric oxide Endothelial nitric oxide production & improves endothelial function production & improves endothelial function Foam cell Foam cell Inflammatory macrophages & T-cells Inflammatory macrophages & T-cells Cytokines Cytokines Adhesion molecules Adhesion molecules P- and C-selectin P- and C-selectin Smooth muscle cell proliferation Smooth muscle cell proliferation Matrix metalloproteinases Matrix metalloproteinases Platelet activation Platelet activation Tissue factor Tissue factor Plasminogen activator inhibitor-1 Plasminogen activator inhibitor-1 CD40/CD40L CD40/CD40L Platelet/thrombus formation Platelet/thrombus formation Inflammatory cells Inflammatory cells Cytokines, chemokines Cytokines, chemokines Vasoconstriction Vasoconstriction Cardiac remodeling Improve Autonomic Function Cardiac remodeling Improve Autonomic Function Acute Coronary Syndrome Patel T, Shishehbor MH, Bhatt DL. EHJ 2007.

Baseline hs-CRP and Outcome in PCI Chew DP, Bhatt DL, Robbins M, et al. Circulation 2001.

Statin Pretreatment Prior to PCI and CRP Chan AW, Bhatt DL, Chew DP, et al. Circulation 2003. P=0.26P=0.26 P=0.69P=0.69 P=0.97P=0.97 P=0.009P=0.009 3.4% vs. 6.9%, P=0.003 Preprocedural CRP (mg/dL) 1-Year Mortality (%)

Overall OR (95% CI) 0.74(0.61, 0.90) Statin Pretreatment Early in ACS Bavry, Mood, Kumbhani, Borek, Askari, Bhatt. AJCD 2006. MortalityIncidence (%) StudyOdds RatioStatin therapyLess-intensive L-CAD2.93.6 PTT2.58.1 Florida2.64.0 Colivicchi7.59.8 PROVE-IT2.23.2 ESTABLISH0.02.9 A to Z4.65.8 MortalityIncidence (%) StudyOdds RatioStatin therapyLess-intensive L-CAD2.93.6 PTT2.58.1 Florida2.64.0 Colivicchi7.59.8 PROVE-IT2.23.2 ESTABLISH0.02.9 A to Z4.65.8 0.1 1.0 10.0 Favors Statin Therapy Favors FavorsLess-intensive Lipid Therapy FavorsLess-intensive

Statin Pretreatment Prior to PCI and MI Mood G, Bavry AA, Roukoz H, Bhatt DL. AJC 2007. Odds ratio.1 1 1 10 Study % Weight % Weight Odds ratio Odds ratio (95% Confidence Interval) (95% Confidence Interval) 1.00 (0.25, 3.98) 1.00 (0.25, 3.98) PREDICT PREDICT 3.9 3.9 0.31 (0.09, 1.12) 0.31 (0.09, 1.12) FLARE FLARE 9.5 9.5 0.20 (0.01, 4.15) 0.20 (0.01, 4.15) GAIN GAIN 2.4 2.4 0.78 (0.49, 1.25) 0.78 (0.49, 1.25) LIPS LIPS 36.9 36.9 0.29 (0.10 0.84) 0.29 (0.10 0.84) ARMYDA ARMYDA 13.4 13.4 0.51 (0.30, 0.88) 0.51 (0.30, 0.88) Briguori Briguori 33.9 33.9 0.57 (0.42, 0.78) 0.57 (0.42, 0.78) Overall (95% Confidence Interval) Overall (95% Confidence Interval)

ECG and ASA within 10 minutes ECG and ASA within 10 minutes STEMI patients directed to their pathway STEMI patients directed to their pathway Risk stratification Risk stratification Focused history and physical, biomarkers, serial ECGs, risk score, and bleeding risk Focused history and physical, biomarkers, serial ECGs, risk score, and bleeding risk Patients with high ischemic risk should go for EIS (Class I) or, in a minority of cases, for ICS (Class IIa), but only after medical stabilization Patients with high ischemic risk should go for EIS (Class I) or, in a minority of cases, for ICS (Class IIa), but only after medical stabilization ECG and ASA within 10 minutes ECG and ASA within 10 minutes STEMI patients directed to their pathway STEMI patients directed to their pathway Risk stratification Risk stratification Focused history and physical, biomarkers, serial ECGs, risk score, and bleeding risk Focused history and physical, biomarkers, serial ECGs, risk score, and bleeding risk Patients with high ischemic risk should go for EIS (Class I) or, in a minority of cases, for ICS (Class IIa), but only after medical stabilization Patients with high ischemic risk should go for EIS (Class I) or, in a minority of cases, for ICS (Class IIa), but only after medical stabilization Summary 2007 Guidelines Upstream Management of Suspected ACS

Anticoagulation Strategies Anticoagulation 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 when bleeding risk is higher (screen for patients at higher risk for bleeding) Strong support for bivalirudin when time to lab is quick and/or when bleeding risk is higher (screen for patients at higher risk 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 more problematic if catheterization later required Strong support for fondaparinux when bleeding risk is higher, but more problematic if catheterization later required Individual patient characteristics (ischemic risk, bleeding risk, time to cath) should drive choices, Individual patient characteristics (ischemic risk, bleeding risk, time to cath) should drive choices, Anticoagulation Strategies Anticoagulation 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 when bleeding risk is higher (screen for patients at higher risk for bleeding) Strong support for bivalirudin when time to lab is quick and/or when bleeding risk is higher (screen for patients at higher risk 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 more problematic if catheterization later required Strong support for fondaparinux when bleeding risk is higher, but more problematic if catheterization later required Individual patient characteristics (ischemic risk, bleeding risk, time to cath) should drive choices, Individual patient characteristics (ischemic risk, bleeding risk, time to cath) should drive choices, Summary 2007 Guidelines Upstream Medical Stabilization

Year 2007 Guidelines: Good News, Bad News No (Up)Stream Strategy is Perfect Guideline Strategy Possible Limitation ASAAllergy Clopidogrel Resistance, CABG planned UFH Platelet activation, HIT UFH + GP IIb/IIIa Inhibitor Bleeding, cost Enoxaparin + GP IIb/IIIa Bleeding, renal dysfunction Bivalirudin Clopidogrel exposure

Conclusions New ACS guidelines provide considerable latitude as far as strategies of care New ACS guidelines provide considerable latitude as far as strategies of care Need to minimize ischemia and bleeding Need to minimize ischemia and bleeding Anticoagulation remains important Anticoagulation remains important Switching permitted with some agents Switching permitted with some agents Early antiplatelet therapy upgraded Early antiplatelet therapy upgraded Early statin use probably a good idea Early statin use probably a good idea Early invasive remains preferred Early invasive remains preferred New ACS guidelines provide considerable latitude as far as strategies of care New ACS guidelines provide considerable latitude as far as strategies of care Need to minimize ischemia and bleeding Need to minimize ischemia and bleeding Anticoagulation remains important Anticoagulation remains important Switching permitted with some agents Switching permitted with some agents Early antiplatelet therapy upgraded Early antiplatelet therapy upgraded Early statin use probably a good idea Early statin use probably a good idea Early invasive remains preferred Early invasive remains preferred

Ron Waksman, MD, FACC Associate Director, Division of Cardiology Washington Hospital Center, Washington Hospital Center Professor of Medicine - Georgetown University Washington, DC Associate Director, Division of Cardiology Washington Hospital Center, Washington Hospital Center Professor of Medicine - Georgetown University Washington, DC Ron Waksman, MD, FACC Associate Director, Division of Cardiology Washington Hospital Center, Washington Hospital Center Professor of Medicine - Georgetown University Washington, DC Associate Director, Division of Cardiology Washington Hospital Center, Washington Hospital Center Professor of Medicine - Georgetown University Washington, DC Getting in the Stream(s) of Antithrombotic Therapy for ACSWhat Do The Data Tell Us? To Switch or Not to Switch Therapy for ACSWhat Do The Data Tell Us? To Switch or Not to Switch Why, When, How, To What? Getting in the Stream(s) of Antithrombotic Therapy for ACSWhat Do The Data Tell Us? To Switch or Not to Switch Therapy for ACSWhat Do The Data Tell Us? To Switch or Not to Switch Why, When, How, To What? The Science and Medicine of Acute Coronary Syndrome

Overview of Presentation Why should switching to bivalirudin for PCI be reasonable? Why should switching to bivalirudin for PCI be reasonable? Mechanistic rationale for switching Mechanistic rationale for switching Why is there a concern about switching antithrombins in patients with ACS (lessons from SYNERGY) Why is there a concern about switching antithrombins in patients with ACS (lessons from SYNERGY) Clinical Evidence Clinical Evidence BAT BAT SWITCH SWITCH REPLACE 2 REPLACE 2 ACUITY ACUITY Why should switching to bivalirudin for PCI be reasonable? Why should switching to bivalirudin for PCI be reasonable? Mechanistic rationale for switching Mechanistic rationale for switching Why is there a concern about switching antithrombins in patients with ACS (lessons from SYNERGY) Why is there a concern about switching antithrombins in patients with ACS (lessons from SYNERGY) Clinical Evidence Clinical Evidence BAT BAT SWITCH SWITCH REPLACE 2 REPLACE 2 ACUITY ACUITY

Background Issues and Concerns ACS patients ACS patients 87% of patients receive either UFH, enoxaparin, or fondaparinux within 24 hours after admission 1 87% of patients receive either UFH, enoxaparin, or fondaparinux within 24 hours after admission 1 72% of patients in SYNERGY and 50 % of patients in OASIS- 5 received prior antithrombin 2,3 72% of patients in SYNERGY and 50 % of patients in OASIS- 5 received prior antithrombin 2,3 Published studies and perceptions Published studies and perceptions Patients in SYNERGY who crossed over between UFH and enoxaparin had an increase in bleeding complications 2 Patients in SYNERGY who crossed over between UFH and enoxaparin had an increase in bleeding complications 2 This activity occurred at various times through the study period: At times in response to clinical or clinician perception This activity occurred at various times through the study period: At times in response to clinical or clinician perception Consistent therapy is better 4 Consistent therapy is better 4 ACS patients ACS patients 87% of patients receive either UFH, enoxaparin, or fondaparinux within 24 hours after admission 1 87% of patients receive either UFH, enoxaparin, or fondaparinux within 24 hours after admission 1 72% of patients in SYNERGY and 50 % of patients in OASIS- 5 received prior antithrombin 2,3 72% of patients in SYNERGY and 50 % of patients in OASIS- 5 received prior antithrombin 2,3 Published studies and perceptions Published studies and perceptions Patients in SYNERGY who crossed over between UFH and enoxaparin had an increase in bleeding complications 2 Patients in SYNERGY who crossed over between UFH and enoxaparin had an increase in bleeding complications 2 This activity occurred at various times through the study period: At times in response to clinical or clinician perception This activity occurred at various times through the study period: At times in response to clinical or clinician perception Consistent therapy is better 4 Consistent therapy is better 4 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 An Alternative to UFH/LMWH Advantages of the direct thrombin inhibitor bivalirudin Advantages of the direct thrombin inhibitor bivalirudin No requirement for antithrombin III No requirement for antithrombin III Effective on clot-bound thrombin Effective on clot-bound thrombin Inhibits thrombin-mediated platelet activation Inhibits thrombin-mediated platelet activation No interactions with PF- 4 No interactions with PF- 4 Plasma half-life 25 minutes Plasma half-life 25 minutes No requirement for anticoagulant monitoring No requirement for anticoagulant monitoring Clinical results with bivalirudin in PCI Clinical results with bivalirudin in PCI Similar protection from ischemic events as UFH + GP IIb/IIIa inhibitors, with markedly reduced bleeding 1 Similar protection from ischemic events as UFH + GP IIb/IIIa inhibitors, with markedly reduced bleeding 1 Not previously tested in contemporary ACS patients Not previously tested in contemporary ACS patients Advantages of the direct thrombin inhibitor bivalirudin Advantages of the direct thrombin inhibitor bivalirudin No requirement for antithrombin III No requirement for antithrombin III Effective on clot-bound thrombin Effective on clot-bound thrombin Inhibits thrombin-mediated platelet activation Inhibits thrombin-mediated platelet activation No interactions with PF- 4 No interactions with PF- 4 Plasma half-life 25 minutes Plasma half-life 25 minutes No requirement for anticoagulant monitoring No requirement for anticoagulant monitoring Clinical results with bivalirudin in PCI Clinical results with bivalirudin in PCI Similar protection from ischemic events as UFH + GP IIb/IIIa inhibitors, with markedly reduced bleeding 1 Similar protection from ischemic events as UFH + GP IIb/IIIa inhibitors, with markedly reduced bleeding 1 Not previously tested in contemporary ACS patients Not previously tested in contemporary ACS patients REPLACE 2. Lincoff AM et al. JAMA 2003;289:853-863.

Indirect 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. Bivalirudins 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. Bivalirudins 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 Clot-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 Antithrombins The SYNERGY trial suggested a switch in anthithrombins (from heparin to LMWH) can lead to increase in bleeding The SYNERGY trial suggested a switch in anthithrombins (from heparin to LMWH) can lead to increase in bleeding What outcomes are observed when switching from heparin, LMWH, or fondaparinux to bivalirudin in PCI? What outcomes are observed when switching from heparin, LMWH, or fondaparinux to bivalirudin in PCI? Is it better to switch or to stay on consistent therapy? Is it better to switch or to stay on consistent therapy? The SYNERGY trial suggested a switch in anthithrombins (from heparin to LMWH) can lead to increase in bleeding The SYNERGY trial suggested a switch in anthithrombins (from heparin to LMWH) can lead to increase in bleeding What outcomes are observed when switching from heparin, LMWH, or fondaparinux to bivalirudin in PCI? What outcomes are observed when switching from heparin, LMWH, or fondaparinux to bivalirudin in PCI? Is it better to switch or to stay on consistent therapy? Is it better to switch or to stay on consistent therapy?

Bivalirudin Angioplasty Trial A double-blind randomized comparison of bivalirudin versus heparin in 4312 patients undergoing PTCA for new onset of severe, accelerating or rest angina or angina within 2 weeks of myocardial infarction BAT

Study Design HIGH RISK PATIENTS New onset severe, accelerating or rest angina New onset severe, accelerating or rest angina Symptoms in last month Symptoms in last month Suitable for PTCA Suitable for PTCA HIGH RISK PATIENTS New onset severe, accelerating or rest angina New onset severe, accelerating or rest angina Symptoms in last month Symptoms in last month Suitable for PTCA Suitable for PTCA HeparinpretreatmentHeparinpretreatment RandomizedRandomizedRandomizedRandomized PrimaryPrimaryPost-MIPost-MI Heparin BivalirudinBivalirudin BivalirudinBivalirudin ASA PTCA StratifyStratify BAT

6.2% % of patients with events at 7 days Heparin n = 2,151 Heparin n = 2,151 Bivalirudin n = 2,161 Bivalirudin n = 2,161 43% reduction p-value <0.001 43% reduction p-value <0.001 22% reduction p-value 0.039 22% reduction p-value 0.039 62% reduction p-value <0.001 62% reduction p-value <0.001 3.5% 9.7%7.9% HemorrhageHemorrhage Death, MI, Revascularization Death, MI, Revascularization Primary Endpoints BAT

Net Benefit By Risk Strata % of patients with events at 7 days HemorrhageHemorrhage Death, MI, revasc Heparin 16.5%14.0% Heparin 11.8%9.9% Bivalirudin 3.3%5.8% Bivalirudin 2.4%4.9% Bivalirudin 3.6%6.1% Bivalirudin 4.1%7.4% Heparin 11.9%10.3% Heparin 8.3%7.0% Heparin Unstable & post-MI n = 241 Unstable & post-MI n = 241 Unstable on heparin n = 1,006 Unstable on heparin n = 1,006 Post-MI n = 741 Post-MI n = 741 No risk factors n = 2,806 No risk factors n = 2,806 BAT

Switching from Enoxaparin to Bivalirudin in Patients with Acute Coronary Syndromes Without ST- Segment Elevation Undergoing Percutaneous Coronary Intervention (PCI) Ron Waksman, MD, FACC, FSCAI Associate Director Division of Cardiology Washington Hospital Center Washington, DC Ron Waksman, MD, FACC, FSCAI Associate Director Division of Cardiology Washington Hospital Center Washington, DC The study was sponsored in part by The Medicines Company SWITCH Study

31 30 Primary Endpoint BLEEDING BLEEDING 91 ACS patientsundergoingPCI (3 US sites) Open-label, prospective, 3-arm LMWH 1mg/kg SC 0-4 h before PCI LMWH 1mg/kg SC 4-8 h before PCI LMWH 1mg/kg SC 8-12 h before PCI Bivalirudin during PCI 0.75 mg/kg bolus 1.75 mg/kg/h IV infusion Arms Switched SWITCH: Study Design Waksman J Invasive Cardiol 2006;18:370-375.

Results: Study Drug- Related Bleeding Events Outcomes All, % N=91 Group 1,% n=30 Group 2,% N=30 Group 3,% N=31 p value All Major Bleed 7.7 (7) 13.3 (4) 13.3 (4) 3.2 (1) 6.5 (2) 0.39 Transfusion 2 units 4.4 (4) 3.2 (1) 6.5 (2) 1.0 Intracranial Bleed 0 (0) -- Retroperitoneal Bleed 0 (0) -- Spontaneous Hematuria or Hematemesis 1.1 (1) 3.2 (1) 0 (0) 0.66 Drop in Hg > 4g/dL, no site 2.2 (2) 6.7 (2) 0 (0) 0.21 Drop in Hg 3 g/dL 0 (0) -- All Transfusions 4.4 (4) 6.7 (2) 0 (0) 6.5 (2) 1.0 Minor Bleed 4.4 (4) 6.7 (2) 0 (0) 0.39 Waksman J Invasive Cardiol 2006;18:370-375.

SWITCH Conclusions SWITCH Conclusions Switching from LMWH to bivalirudin during PCI for patients with ACS was safe Switching from LMWH to bivalirudin during PCI for patients with ACS was safe Switching was not associated with major bleeding complications regardless of when LMWH was administered Switching was not associated with major bleeding complications regardless of when LMWH was administered The use of bivalirudin as the sole antithrombin agent during PCI can be extended for patients who were pretreated with enoxaparin 8 hours post the last dose of LMWH The use of bivalirudin as the sole antithrombin agent during PCI can be extended for patients who were pretreated with enoxaparin 8 hours post the last dose of LMWH Switching from LMWH to bivalirudin during PCI for patients with ACS was safe Switching from LMWH to bivalirudin during PCI for patients with ACS was safe Switching was not associated with major bleeding complications regardless of when LMWH was administered Switching was not associated with major bleeding complications regardless of when LMWH was administered The use of bivalirudin as the sole antithrombin agent during PCI can be extended for patients who were pretreated with enoxaparin 8 hours post the last dose of LMWH The use of bivalirudin as the sole antithrombin agent during PCI can be extended for patients who were pretreated with enoxaparin 8 hours post the last dose of LMWH

Association of Pre-Randomization Anticoagulant Switching with Bleeding in the Setting of Percutaneous Coronary Intervention: A REPLACE-2 Analysis Gibson CM, Am J Cardiol 2007. REPLACE-2 Trial: Switching 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, mortality Bivalirudin 0.75 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 65 U/kg with planned GP IIb/IIIa (n=3,008) (n=3,008) 1 Prior LMWH (n=258) 2 Naïve – no prior AT (n=2,325) 2 Prior UFH (n=349) 2 Prior LMWH (n=313) 2 REPLACE-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 SWITCH and Randomized Therapy Regardless of prior heparin or not, patients administered bivalirudin had decreased bleeding Regardless of prior heparin or not, patients administered bivalirudin had decreased bleeding There was a significant increase in major/minor protocol bleeding in patients administered UFH with prior heparin therapy There was a significant increase in major/minor protocol bleeding in patients administered UFH with prior heparin therapy Regardless of prior heparin or not, patients administered bivalirudin had decreased bleeding Regardless of prior heparin or not, patients administered bivalirudin had decreased bleeding There was a significant increase in major/minor protocol bleeding in patients administered UFH with prior heparin therapy There was a significant increase in major/minor protocol bleeding in 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. Protocol major/minor bleed Naïve Bivalirudin Naïve Bivalirudin (n=2,345) LMWH Bivalirudin (n=258) UFH Bivalirudin (n=287) LMWHUFH + GP IIb/IIIa (n=313) Naïve UFH + GP IIb/IIIa (n=2,325) UFHUFH + GP IIb/IIIa (n=349) * Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.

TIMI Major/Minor Bleed by SWITCH 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 switching between heparins Patients administered UFH had higher rates of bleeding, with highest rates in patients switching 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 switching between heparins Patients administered UFH had higher rates of bleeding, with highest rates in patients switching between heparins TIMI major/minor bleed Naïve Bivalirudin (n=2,345) LMWH Bivalirudin (n=258) UFH Bivalirudin (n=287) LMWHUFH + GP IIb/IIIa (n=313) NaïveUFH + GP IIb/IIIa (n=2,325) UFHUFH + GP IIb/IIIa (n=349) * *P=NS for all 3-way comparisons versus bivalirudin alone; naïve=no prior AT therapy in preceding 48 hours. Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.

Switching and 1-Year Mortality Cumulative events (mortality), % REPLACE-2 Subanalysis: 1-Year Mortality Results Consistent with Overall Trial Results Gibson CM, Am J Cardiol 2007 in press.

Moderate and high risk ACS (n=13,819) ACUITY Study Design – First Randomization Angiography within 72h Aspirin in all Clopidogrel dosing and timing per 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) Bivalirudin Alone (n=4,612) Bivalirudin Alone (n=4,612) R* *Stratified by pre-angiography thienopyridine use or administration Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy (N=13,819) Medicalmanagement PCI CABG

Scope of Analysis This analysis will address the question of the safety and efficacy of switching from indirect thrombin inhibition (UFH or enoxaparin) to direct thrombin inhibition (bivalirudin) in high risk ACS This analysis will address the question of the safety and efficacy of switching from indirect thrombin inhibition (UFH or enoxaparin) to direct thrombin inhibition (bivalirudin) in high risk ACS A protocol-driven activity of the ACUITY study at the time of randomization This analysis will address the question of the safety and efficacy of switching from indirect thrombin inhibition (UFH or enoxaparin) to direct thrombin inhibition (bivalirudin) in high risk ACS This analysis will address the question of the safety and efficacy of switching from indirect thrombin inhibition (UFH or enoxaparin) to direct thrombin inhibition (bivalirudin) in high risk ACS A protocol-driven activity of the ACUITY study at the time of randomization Harvey White. Presentation at AHA, 2006

ACUITY: Primary Results Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone P NI <0.001 P Sup = 0.015 P NI = 0.011 P NI = 0.011 P Sup = 0.32 P Sup = 0.32 P NI <0.001 P Sup <0.001 *Heparin=unfractionated or enoxaparin Harvey White. Presentation at AHA, 2006

Current Analysis and Questions Hypothesis Hypothesis Bivalirudin improves bleeding outcomes while preserving ischemic protection for ACS patients even if the patients are switched from either UFH or enoxaparin to bivalirudin (monotherapy) at the time of presentation. Bivalirudin improves bleeding outcomes while preserving ischemic protection for ACS patients even if the patients are switched from either UFH or enoxaparin to bivalirudin (monotherapy) at the time of presentation. Is it better to switch to bivalirudin or remain on consistent therapy? Is it better to switch to bivalirudin or remain on consistent therapy? Hypothesis Hypothesis Bivalirudin improves bleeding outcomes while preserving ischemic protection for ACS patients even if the patients are switched from either UFH or enoxaparin to bivalirudin (monotherapy) at the time of presentation. Bivalirudin improves bleeding outcomes while preserving ischemic protection for ACS patients even if the patients are switched from either UFH or enoxaparin to bivalirudin (monotherapy) at the time of presentation. Is it better to switch to bivalirudin or remain on consistent therapy? Is it better to switch to bivalirudin or remain on consistent therapy? Harvey White. Presentation at AHA, 2006

ACUITY Current Analysis Study Methods Study Methods Patients on prior antithrombin therapy Patients on prior antithrombin therapy Consistent: No switching from pre-randomization antithrombin agent to randomized therapy: Consistent: No switching from pre-randomization antithrombin agent to randomized therapy: –Enoxaparin Enoxaparin or UFH UFH Switch: Single switch to bivalirudin determined by randomization code Switch: Single switch to bivalirudin determined by randomization code –from Enoxaparin Bivalirudin or UFH Bivalirudin Event rates at 30-days Event rates at 30-days Net clinical outcome Net clinical outcome Ischemic composite Ischemic composite Major bleeding Major bleeding Study Methods Study Methods Patients on prior antithrombin therapy Patients on prior antithrombin therapy Consistent: No switching from pre-randomization antithrombin agent to randomized therapy: Consistent: No switching from pre-randomization antithrombin agent to randomized therapy: –Enoxaparin Enoxaparin or UFH UFH Switch: Single switch to bivalirudin determined by randomization code Switch: Single switch to bivalirudin determined by randomization code –from Enoxaparin Bivalirudin or UFH Bivalirudin Event rates at 30-days Event rates at 30-days Net clinical outcome Net clinical outcome Ischemic composite Ischemic composite Major bleeding Major bleeding Harvey White. Presentation at AHA, 2006

Consistent vs. Switch Comparison of Consistent therapy on UFH/Enox vs. Switch to Bivalirudin Alone Comparison of Consistent therapy on UFH/Enox vs. Switch to Bivalirudin Alone P=0.002 0.77 [0.63 – 0.91] P=0.601 0.95 [0.76 – 1.17] P<0.001 0.47 [0.35 – 0.64] Harvey White. Presentation at AHA, 2006

0.83 (0.67-1.02) OR (95% CI) Odds ratio ±95% CI Switch to Bivalirudin alone better Consistent UFH/Enox better Major Bleeding Ischemia Net Clinical Outcome 1.10 (0.86-1.41) 0.47 (0.34-0.65) P-value 0.073 0.464 <0.001 * Comparing consistent UFH/Enox vs Switch Bivalirudin Consistent vs. Switch All Patients Adjusted Harvey White. Presentation at AHA, 2006

0.86 (0.68-1.07) OR (95% CI) Odds ratio±95% CI Switch to Bivalirudin alone better Consistent UFH/Enox better Major Bleeding IschemiaIschemia Net Clinical Outcome 1.11 (0.85-1.46) 0.51 (0.36-0.72) P-valueP-value 0.1770.177 0.4450.445 <0.001<0.001 Consistent vs. Switch High Risk Adjusted Comparing Consistent UFH/Enox vs Switch Bivalirudin Comparing Consistent UFH/Enox vs Switch Bivalirudin Harvey White. Presentation at AHA, 2006

Consistent vs. Switch Comparing Consistent therapy on Enoxaparin vs. Switch from Enoxaparin to Bivalirudin Alone Comparing Consistent therapy on Enoxaparin vs. Switch from Enoxaparin to Bivalirudin Alone P=0.145 0.81 [0.61 – 1.07] P=0.626 0.92 [0.65 – 1.30] P=0.013 0.54 [0.34 – 0.88] Harvey White. Presentation at AHA, 2006

Consistent vs. Switch Comparing Consistent therapy on UFH vs. Comparing Consistent therapy on UFH vs. Switch from UFH to Bivalirudin Alone Comparing Consistent therapy on UFH vs. Comparing Consistent therapy on UFH vs. Switch from UFH to Bivalirudin Alone P=0.012 0.75[0.60 – 0.94] P=0.857 0.98[0.74 – 1.28] P<0.001 0.44[0.30 – 0.65] Harvey White. Presentation at AHA, 2006

ACUITY PCI: Switch from Prior Antithrombin Risk Ratio ±95% CI RR (95% CI) 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 PCI (n=2528) Composite ischemia 1.10 (0.85-1.42) Major bleeding 0.52 (0.36-0.74) PCI HIGH RISK* (n=1988) Composite ischemia 1.14 (0.86-1.52) Major bleeding 0.56 (0.38-0.81) PCI (n=2528) Mortality 0.93 (0.58-1.48) PCI HIGH RISK* (n=1988) Mortality 0.99 (0.60-1.63) * High risk = Tn, CKMB or ECG Δs 30-Day Results 1-Year Results

SWITCH III (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

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 III Study AIM SWITCH III ver 1.7

SWITCH III Study Design 1:1 Randomization All patients are followed through the duration of the hospitalization or until CABG 300 patients will be randomized SWITCH III ver 1.7

Pre-Randomization Anticoagulant Switching and Bleeding When switching to bivalirudin was undertaken across the risk spectrum of ACS, preceding therapy with either LMWH or UFH was not associated with an excess of bleeding or transfusions compared with bivalirudin therapy alone in the cardiac catheterization laboratory. When switching to bivalirudin was undertaken across the risk spectrum of ACS, preceding therapy with either LMWH or UFH was not associated with an excess of bleeding or transfusions compared with bivalirudin therapy alone in the cardiac catheterization laboratory. Overall Conclusion

How 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

Conclusions Switching to bivalirudin is safe Switching to bivalirudin is safe Switching from any heparin (either enoxaparin or UFH) to bivalirudin monotherapy is not associated with an increased risk for ischemic events. Switching from any heparin (either enoxaparin or UFH) to bivalirudin monotherapy is not associated with an increased risk for ischemic events. Furthermore Furthermore Switching to bivalirudin provides patients the 50% bleeding advantage of bivalirudin compared with consistent therapy on UFH or enoxaparin, while preserving anti-ischemic efficacy. Switching to bivalirudin provides patients the 50% bleeding advantage of bivalirudin compared with consistent therapy on UFH or enoxaparin, while preserving anti-ischemic efficacy.

Translating Advances in NSTEMI and STEMI into Real World Institutional Practice Harold L. Dauerman, MD Director, Cardiovascular Catheterization Laboratories Professor of Medicine University of Vermont Fletcher Allen Health Care Harold L. Dauerman, MD Director, Cardiovascular Catheterization Laboratories Professor of Medicine University of Vermont Fletcher Allen Health Care The Science and Medicine of ACS

University of Vermont Post-PCI Bleeding and Vascular Complication Rates NNE Rate: 2.0% in 2006 Any Transfusion, RPH or Repair = Bleeding Complication Introduction of Bivalirudin to Cath Lab Bivalirudin to Cath Lab Introduction of Bivalirudin to Cath Lab Bivalirudin to Cath Lab Introduction of Upstream Bivalirudin

Incorporation of Bivalirudin in Cath Lab for NSTEMI in 2003A Cautious Beginning Bivalirudin GP IIb/IIIa Inhibitor UFH alone Bivalirudin GP IIb/IIIa Inhibitor UFH alone

P < 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 2004 Dauerman, Applegate and Cohen, JACC 2007

How We Introduced Upstream and Downstream Bivalirudin: The UVMC Time Line 2003: Put bivalirudin on the cath lab shelf as an option for NSTEMI 2003: Put bivalirudin on the cath lab shelf as an option for NSTEMI 2007: Educational programs for fellows, floor staff and attendings 2007: Educational programs for fellows, floor staff and attendings We did not remove GPI option We did not remove GPI option We did NOT involve community hospitals in this decision. They can do whatever they want as long as they transfer and dont overdose patients. We did NOT involve community hospitals in this decision. They can do whatever they want as long as they transfer and dont overdose patients. 2008: A standardized STEMI bivalirudin approach 2008: A standardized STEMI bivalirudin approach For upstream AMI utilization, bivalirudin ordered from pharmacy For upstream AMI utilization, bivalirudin ordered from pharmacy In collaboration with ED (EDICT for ACS Strategy) In collaboration with ED (EDICT for ACS Strategy) 2003: Put bivalirudin on the cath lab shelf as an option for NSTEMI 2003: Put bivalirudin on the cath lab shelf as an option for NSTEMI 2007: Educational programs for fellows, floor staff and attendings 2007: Educational programs for fellows, floor staff and attendings We did not remove GPI option We did not remove GPI option We did NOT involve community hospitals in this decision. They can do whatever they want as long as they transfer and dont overdose patients. We did NOT involve community hospitals in this decision. They can do whatever they want as long as they transfer and dont overdose patients. 2008: A standardized STEMI bivalirudin approach 2008: A standardized STEMI bivalirudin approach For upstream AMI utilization, bivalirudin ordered from pharmacy For upstream AMI utilization, bivalirudin ordered from pharmacy 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 Non ST-Elevation Myocardial Infarction

What We Really Do With Transfers? September 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. DNRreverse 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. DNRreverse POLST (wants a cath, but no CABG). Echo today, cath tomorrow (or today if unstable). Thanks, Harry

Protocol Major/Minor Bleed by SWITCH 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. Protocol major/minor bleed Naïve Bivalirudin Naïve Bivalirudin (n=2,345) LMWH Bivalirudin (n=258) UFH Bivalirudin (n=287) LMWHUFH + GP IIb/IIIa (n=313) Naïve UFH + GP IIb/IIIa (n=2,325) UFHUFH + GP IIb/IIIa (n=349) * Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.

4.13.6 2.9 2.3 1.4 1.5 1.5 6.94.3 3.9 3.0 2.6 1.86.8 *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=2,553) REPLACE-2 One-Year Cumulative Mortality in Prespecified High-Risk Subgroups Cumulative mortality at 1 year 0 2 4 6 8 DiabetesUA* UA* or ACS UA* or ACS ACS ACS (n=2,489) (n=1,606) (n=2,046) Lincoff AM et al. JAMA. 2004;292:696-703. Stone GW. J Invasive Cardiol. 2004;16(suppl G):12-17. Heparin + GP IIb/IIIa Bivalirudin with provisional GP IIb/IIIa Percentage (%) (n=1,010) CrCl 60 Age >75 Age >65 (n=795)

Transfer to Cardiology Floor Enoxaparin heldwait 8 hours from community hospital last dose. Enoxaparin heldwait 8 hours from community hospital last dose. Then, start upstream bivalirudin Then, start upstream bivalirudin Patient pain free1 st case next A.M Patient pain free1 st case next A.M DES, no eptifibatide, closure device, 150 mg clopidogrel DES, no eptifibatide, closure device, 150 mg clopidogrel Ambulate at 6 hours Ambulate at 6 hours D/C following 0900 A.M. D/C following 0900 A.M. Enoxaparin heldwait 8 hours from community hospital last dose. Enoxaparin heldwait 8 hours from community hospital last dose. Then, start upstream bivalirudin Then, start upstream bivalirudin Patient pain free1 st case next A.M Patient pain free1 st case next A.M DES, no eptifibatide, closure device, 150 mg clopidogrel DES, no eptifibatide, closure device, 150 mg clopidogrel Ambulate at 6 hours Ambulate at 6 hours D/C following 0900 A.M. D/C following 0900 A.M.

The University of Vermont ExperienceGPI Trigger Strategy Impact of REPLACE 2 and ACUITY Trials: 91% Bivalirudin Use Elective PCI24% Elective PCI24% Urgent PCI30% Urgent PCI30% Emergent PCI30% Emergent PCI30% Pre-Load Clopidgrel in 60% and Switching in 45% of Patients Pre-Load Clopidgrel in 60% and Switching in 45% of Patients Note: Increasing utilization of bivalirudin but with maintained trigger-induced adjunctive use of GP IIb/IIIa antagonist Note: Increasing utilization of bivalirudin but with maintained trigger-induced adjunctive use of GP IIb/IIIa antagonist Elective PCI24% Elective PCI24% Urgent PCI30% Urgent PCI30% Emergent PCI30% Emergent PCI30% Pre-Load Clopidgrel in 60% and Switching in 45% of Patients Pre-Load Clopidgrel in 60% and Switching in 45% of Patients Note: Increasing utilization of bivalirudin but with maintained trigger-induced adjunctive use of GP IIb/IIIa antagonist Note: Increasing utilization of bivalirudin but with maintained trigger-induced adjunctive use of GP IIb/IIIa antagonist Ahmed B and Dauerman HL, Submitted ESC 2008 REPLACE 2 ACUITY

Not 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] 0.81 (0.68-0.96) RR [95%CI] 0.96 (0.77-1.20) RR [95%CI] 0.50 (0.37-0.67) RR [95%CI] 1.07 (0.83-1.39) RR [95%CI] 1.37 (1.00-1.88) RR [95%CI] 0.61 (0.39-0.97) Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16 Thienopyridine 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 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] p interaction = 0.35 0 0 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 Timing of Clopidogrel Administration and 30-Day Risk of Ischemic Outcomes S. Steinhubl TCT 2007

1.07 (0.66-1.73) 1.09 (0.46-2.58) 0.56 (0.17-1.93) 3.07 (0.32-29.49) ACUITY PCI: Impact of Clopidogrel PCI troponin+ patients 1-year Mortality Hazard Ratio ±95% CI HR (95% CI) Bivalirudin Alone Better UFH/Enox + IIb/IIIa Better H.White ESC 2007 Clopidogrel at any time prior to hospitalization, randomization or end of angiography (n=1,891) Clopidogrel after end of angiography to 30 post PCI (n=649) Clopidogrel after 30 post PCI (n=307) No clopidogrel (n=51) 0.1110

Does Periprocedural Infarct Increase With Upstream and Downstream Bivalirudin? No! Outcome2005 1 st 6 months N=3732007 1 st 6 Months N=361 P value Any Transfusion (%) 2.01.0NS Death (%) 3.01.00.08 Urgent revascularization (%) 2.01.0NS MI, 50% CK-MB Rise (%) MI, 50% CK-MB Rise (%)4.01.00.02 Mechanical Complication (%) 8.06.0NS Clopidogrel preload in approx 60% of PCI patients CK-MB on all patients the day after PCI (University of Vermont data)

STEMI Switching, Clopidogrel and Stent Thrombosis ST-Elevation Myocardial Infarction

Dauerman and French, Coronary Artery Disease, 2006 The Standard of Care for STEMI PCI in 2005: National Registry of Myocardial Infarction-5

Implementation of HORIZONS AMI PCI Pharmacologic Aspects of Management Unfractionated heparin Unfractionated heparin 60 U/kg IV*; subsequent boluses titrated by nomogram to ACT 200-250 secs; terminated at procedure end unless prolonged antithrombin needed 60 U/kg IV*; subsequent boluses titrated by nomogram to ACT 200-250 secs; terminated at procedure end unless prolonged antithrombin needed Bivalirudin at the REPLACE-2 Dosing (NOT ACUITY) Bivalirudin at the REPLACE-2 Dosing (NOT ACUITY) Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated to ACT; terminated at procedure end unless prolonged antithrombin needed (0.25 mg/kg/hr infusion) Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated to ACT; terminated at procedure end unless prolonged antithrombin needed (0.25 mg/kg/hr infusion) Glycoprotein IIb/IIIa inhibitors Glycoprotein IIb/IIIa inhibitors Routine use in UFH arm; recommended only for giant thrombus or refractory no reflow in bivalirudin arm Routine use in UFH arm; recommended only for giant thrombus or refractory no reflow in bivalirudin arm Abciximab or double bolus eptifibatide as per investigator discretion – dosing per FDA label, renal adjusted; continued for 12 (abciximab) or 12-18 (eptifibatide) Abciximab or double bolus eptifibatide as per investigator discretion – dosing per FDA label, renal adjusted; continued for 12 (abciximab) or 12-18 (eptifibatide) Unfractionated heparin Unfractionated heparin 60 U/kg IV*; subsequent boluses titrated by nomogram to ACT 200-250 secs; terminated at procedure end unless prolonged antithrombin needed 60 U/kg IV*; subsequent boluses titrated by nomogram to ACT 200-250 secs; terminated at procedure end unless prolonged antithrombin needed Bivalirudin at the REPLACE-2 Dosing (NOT ACUITY) Bivalirudin at the REPLACE-2 Dosing (NOT ACUITY) Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated to ACT; terminated at procedure end unless prolonged antithrombin needed (0.25 mg/kg/hr infusion) Bolus 0.75 mg/kg IV**, infusion 1.75 mg/kg/h, not titrated to ACT; terminated at procedure end unless prolonged antithrombin needed (0.25 mg/kg/hr infusion) Glycoprotein IIb/IIIa inhibitors Glycoprotein IIb/IIIa inhibitors Routine use in UFH arm; recommended only for giant thrombus or refractory no reflow in bivalirudin arm Routine use in UFH arm; recommended only for giant thrombus or refractory no reflow in bivalirudin arm Abciximab or double bolus eptifibatide as per investigator discretion – dosing per FDA label, renal adjusted; continued for 12 (abciximab) or 12-18 (eptifibatide) Abciximab or double bolus eptifibatide as per investigator discretion – dosing per FDA label, renal adjusted; continued for 12 (abciximab) or 12-18 (eptifibatide) * If pre randomization UFH administered, ACT is checked first ** If pre randomization UFH administered, started 30 after last bolus

Primary PCI for STEMI: Community Hospital Algorithm ASA, 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 highway

UFH + GP IIb/IIIa (N=1802)Bivalirudin(N=1800) UFH pre randomization UFH pre randomization65.6%65.6% Antithrombin in CCL Antithrombin in CCL UFH UFH98.9%4.1% Bivalirudin Bivalirudin0.4%96.9% Peak ACT Peak ACT 264 [228, 320] 357 [300, 402] GP IIb/IIIa in CCL GP IIb/IIIa in CCL94.5%*7.2%* Bail-out per protocol** Bail-out per protocol**-4.4% Abciximab Abciximab49.9%4.0% Eptifibatide Eptifibatide44.4%3.1% Tirofiban Tirofiban0.2%0.1% Do I Have to Load Bivalirudin in the ED or Can I Start in the Cath Lab? The HORIZONS AMI Switching Perspective *97.7% and 7.5% during PCI. ** For giant thrombus or refractory no reflow after PCI. CCL = cardiac catheterization laboratory G Stone TCT 2007

Bivalirudin Improves Mortality in STEMI Bivalirudin Improves Mortality in STEMI Death (%) Time in Days 3.1% 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) Bivalirudin monotherapy (n=1800) G Stone TCT 2007

The UVM STEMI Order Sheet One Pathway for Primary PCI and ED Collaboration TESTS AND MEDICATIONS EKG: EKG for diagnosis performed within 10 minutes of ED arrival. No further EKG required. LABORATORY: 7. CBC,lytes, BUN, CR, PT, PTT, Lipids, LFTs, CK, CK-MB and TnI sent immediately on arrival: STAT 8. Other labs: MEDICATIONS: Weight: __kg Estimated / Actual (Circle one) Check patient not allergic to aspirin 9. Aspirin Non- Enteric Coated 325 mg PO Daily 10. Clopidogrel 600 mg PO x one 11. 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 MEDICATIONS EKG: EKG for diagnosis performed within 10 minutes of ED arrival. No further EKG required. LABORATORY: 7. CBC,lytes, BUN, CR, PT, PTT, Lipids, LFTs, CK, CK-MB and TnI sent immediately on arrival: STAT 8. Other labs: MEDICATIONS: Weight: __kg Estimated / Actual (Circle one) Check patient not allergic to aspirin 9. Aspirin Non- Enteric Coated 325 mg PO Daily 10. Clopidogrel 600 mg PO x one 11. 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 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 UFH + GP IIb/IIIa (N=1553)Bivalirudin(N=1571)PValue ARC definite or probable* 1.9%2.5%0.33 Definite Definite1.4%2.2%0.11 Probable Probable0.5%0.3%0.26 Acute (24 hrs) Acute (24 hrs)0.3%1.3%0.0009 Subacute (>24 hrs – 30d) Subacute (>24 hrs – 30d)1.7%1.2%0.30 G Stone TCT 2007

Sianos, G. et al. J Am Coll Cardiol 2007;50:573-583 Risk Stratification For STEMI Stent Thrombosis The Importance of Thrombus Burden 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 Burden: Modifying Strategy In Highest Risk Patients Drug Eluting Stent Thrombosis and Large Thrombus Burden: Modifying Strategy In Highest Risk Patients Large Thrombus Large Thrombus Burden> 5 fold Burden> 5 fold Increased Risk of 30 Day Stent Thrombosis Increased Risk of 30 Day Stent Thrombosis Large Thrombus Large Thrombus Burden> 5 fold Burden> 5 fold Increased Risk of 30 Day Stent Thrombosis Increased Risk of 30 Day Stent Thrombosis Thrombectomy Prolonged Bivalirudin GPI Thrombectomy Prolonged Bivalirudin GPI LTB vs. STB, p<0.001 Total Population STB LTB 2.7% 3.2% 5.8% 8.2% 1.1% 1.4% 2.1% 3.2% 0.5% 0.7% 1.3% 0 1 3 6 9 12 15 18 21 24 15 12 9 6 3 0 15 12 9 6 3 0 Months of follow-up Cumulative IRA-ST Rate (%)

ACUITYHeparin + IIb/IIIa + IIb/IIIa(N=222) Bivalirudin + IIb/IIIa (N=241) Bivalirudin alone (N=249) P value 3-way Any thrombotic complication post PCI 8.6%3.7%5.6%0.09 Final TIMI flow 3 90.5%93.7%90.7%0.37 Final blush grade 3 81.5%79.0%79.5%0.78 ACUITY and Large Thrombus Data The Rationale for Selective Adjunctive GPI * New or thrombus, abrupt closure, no reflow, or distal embolization G. Stone AHA 2006

The Data on GPI and Bivalirudin for Large Thrombus Patients is Favorable (ACUITY) p=0.37p=0.58 p=0.22p=0.61 p=0.67p=0.03 G. Stone et al. Lancet 2007; 369: 907–19

Projecting What Happens if You Use GPI in 25% of Your Bivalirudin STEMI Patients Assumes Bival + GPI bleeding rate of 6.8% P < 0.001 Still P < 0.001 HORIZONS 7% UVM Implemented HORIZONS25% UVM Implemented HORIZONS25%

Incorporation of HORIZONS AMI and Large Thrombus DataSTEMI Algorithm ED STEMI25% of Patients ED STEMI25% of Patients ASA/clopidogrel 600 mg po load and bivalirudin ASA/clopidogrel 600 mg po load and bivalirudin Bolus and infusion of eptifibatide after wiring vessel shows Large Thrombus Burden Bolus and infusion of eptifibatide after wiring vessel shows Large Thrombus Burden Angiojet and Bare Metal Stent Angiojet and Bare Metal Stent 150 mg clopidogrel and 18 hours of eptifibatide 150 mg clopidogrel and 18 hours of eptifibatide No ambulation until eptifibatide off (18 hours) No ambulation until eptifibatide off (18 hours) D/C on Day 3 post MI D/C on Day 3 post MI ED STEMI25% of Patients ED STEMI25% of Patients ASA/clopidogrel 600 mg po load and bivalirudin ASA/clopidogrel 600 mg po load and bivalirudin Bolus and infusion of eptifibatide after wiring vessel shows Large Thrombus Burden Bolus and infusion of eptifibatide after wiring vessel shows Large Thrombus Burden Angiojet and Bare Metal Stent Angiojet and Bare Metal Stent 150 mg clopidogrel and 18 hours of eptifibatide 150 mg clopidogrel and 18 hours of eptifibatide No ambulation until eptifibatide off (18 hours) No ambulation until eptifibatide off (18 hours) D/C on Day 3 post MI D/C on Day 3 post MI

STEMI: Within 24 Hours CP UFH (60 U/Kg) Beta Blockers only if HTN UFH or Bivalirudin: UFH or Bivalirudin: GPI Optional: Avoid if High Bleed Risk B Blockers ONLY if HTN PCI Capability or < 60 minute Transfer Time No PCI Capability and > 60 minute Transfer Time Primary PCI with Stenting: GPI/Thrombectomy if Large Thrombus or as Bailout; Otherwise, Bivalirudin Alone 90 minutes To Open Artery Lytic LyticContraindicated Emergent Transfer TNK and UFH Transfer from Community ER To PCI Site If no CP and less than 50% ST Elevations, PCI at 12-24 Hours with Stent If Reperfusion Fails, Emergent PCI with stent ASA/ClopidogrelStatin Groin Closure Cardiac Rehab Lopressor 12.5 bid Transfer Rescue PCI: Class I Indication The NSTEMI Paradigm of 4-48 Hours ASA 325 po Clopidogrel 600 po Clopidogrel 300 po Continue bivalirudin for 2 hours after PCI

Conclusions Key Implementation Points Bivalirudin can be safely instituted across the spectrum of PCI patients, including those with NSTE-ACS and STEMI. Bivalirudin can be safely instituted across the spectrum of PCI patients, including those with NSTE-ACS and STEMI. Clopidogrel 600 mg po load may be done in ED or immediately after PCI. Clopidogrel 600 mg po load may be done in ED or immediately after PCI. Community referring hospitals may use antithrombotic therapy of choicethen switch to bivalirudin on arrival to PCI institution. Community referring hospitals may use antithrombotic therapy of choicethen switch to bivalirudin on arrival to PCI institution. STEMI requires an algorithm for care and bivalirudin is the baseline strategy. But, bivalirudin may be instituted in the ED or the cath lab, depending upon local issues. STEMI requires an algorithm for care and bivalirudin is the baseline strategy. But, bivalirudin may be instituted in the ED or the cath lab, depending upon local issues. Enhanced management of large thrombus burden should be considered especially during the most vulnerable 2 hours after PCI. Enhanced management of large thrombus burden should be considered especially during the most vulnerable 2 hours after PCI.

The Science and Medicine of Acute Coronary Syndrome The Emergence of Consistent and Unified Management Strategies for STEMI and NSTEMI The Science and.

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The Science and Medicine of Acute Coronary Syndrome The Emergence of Consistent and Unified Management Strategies for STEMI and NSTEMI The Science and.

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Presentation on theme: "The Science and Medicine of Acute Coronary Syndrome The Emergence of Consistent and Unified Management Strategies for STEMI and NSTEMI The Science and."— Presentation transcript:

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