2. 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

3. 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

4. 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.

5. 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 Frederick Feit, MD, FACC Associate Professor of Medicine|New York University School of Medicine|Director, Interventional Cardiology|New York University School of Medicine|New York, NY Associate Professor of Medicine | New York University School of Medicine | Director, Interventional Cardiology | New York University School of Medicine | New York, NY 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 Frederick Feit, MD, FACC Associate Professor of Medicine|New York University School of Medicine|Director, Interventional Cardiology|New York University School of Medicine|New York, NY Associate Professor of Medicine | New York University School of Medicine | Director, Interventional Cardiology | New York University School of Medicine | New York, NY 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 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

6. Faculty Disclosures Sunil V. Rao, MD, FACC Grant/Research Support: Cordis Consultant: Sanofi-Aventis, The Medicines Company Speaker’s Bureau: Sanofi-Aventis, The Medicines Company, Cordis Frederick Feit, MD, FACC Consultant: The Medicines Company Major Shareholder: Johnson & Johnson, Millennium Pharmaceuticals, The Medicines Company 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 Sunil V. Rao, MD, FACC Grant/Research Support: Cordis Consultant: Sanofi-Aventis, The Medicines Company Speaker’s Bureau: Sanofi-Aventis, The Medicines Company, Cordis Frederick Feit, MD, FACC Consultant: The Medicines Company Major Shareholder: Johnson & Johnson, Millennium Pharmaceuticals, The Medicines Company 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

7. CME Program Agenda CME Program Agenda 9:15AM – 10:00AM Changing Anticoagulants in Midstream — To Switch or Not To Switch: That is the Question The How, Why, When, and In Whom of Switching Antithrombin Therapy in the Setting of ACS Frederick Feit, MD, FACC Associate Professor of Medicine|New York University School of Medicine|Director, Interventional Cardiology|New York University School of Medicine|New York, NY Associate Professor of Medicine | New York University School of Medicine | Director, Interventional Cardiology | New York University School of Medicine | New York, NY 10:00AM – 10:45AM Translating Advances in NSTEMI and STEMI Care Into Real World Cardiology Practice — When Evidence Drives the ACS Care Pathway: An Institutional Case Study A Unified and Consistent Management Strategy for ACS Care Harold L. Dauerman, MD Director, Cardiovascular Catheterization Laboratories | Professor of Medicine | University of Vermont/Fletcher Allen Health Care | Burlington, Vermont 9:15AM – 10:00AM Changing Anticoagulants in Midstream — To Switch or Not To Switch: That is the Question The How, Why, When, and In Whom of Switching Antithrombin Therapy in the Setting of ACS Frederick Feit, MD, FACC Associate Professor of Medicine|New York University School of Medicine|Director, Interventional Cardiology|New York University School of Medicine|New York, NY Associate Professor of Medicine | New York University School of Medicine | Director, Interventional Cardiology | New York University School of Medicine | New York, NY 10:00AM – 10:45AM Translating Advances in NSTEMI and STEMI Care Into Real World Cardiology Practice — When Evidence Drives the ACS Care Pathway: An Institutional Case Study A Unified and Consistent Management Strategy for ACS Care Harold L. Dauerman, MD Director, Cardiovascular Catheterization Laboratories | Professor of Medicine | University of Vermont/Fletcher Allen Health Care | Burlington, Vermont

8. 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

9. ► 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? ► 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? Questions We Will Illuminate and Debate

10. ► 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 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?

11. + + 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

12. 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.

13. 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 † 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.

14. 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* ‡ 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* ‡ 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.

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

16. 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

17. Is the Bleeding Issue Still Relevant in 2008? Wiviott SD, et al. NEJM 2007 Nov 15;357(20):2001-15

18. 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?

19. 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?

20. *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

21. ACS-related Bleeding—Relevant Questions ► Who bleeds? Can we risk stratify? ► Should bleeding risk affect upstream antithrombotic care? If so, how? ► Is bleeding bad or a necessary evil? ► Can blood transfusion “correct” risks associated with bleeding? ► Does bleeding affect resource use? ► Who bleeds? Can we risk stratify? ► Should bleeding risk affect upstream antithrombotic care? If so, how? ► Is bleeding bad or a necessary evil? ► Can blood transfusion “correct” risks associated with bleeding? ► Does bleeding affect resource use?

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

23. 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

24. 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.

25. ► 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 ► 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 Bleeding Predictors — Conclusions

26. 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

27. 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

28. 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

29. 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 TRIAL—Cox model adjusted for baseline predictors: Bleeding and MI as time updated covariates Stone, ACC 2007

30. ► 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 ● MI rates are higher among those who bleed ► Worse bleeding associated with worse outcomes ► 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 ● Mortality rates are higher among those who bleed ● MI rates are higher among those who bleed ► Worse bleeding associated with worse outcomes ► This relationship is persistent after robust statistical adjustment for confounders Bleeding and Outcomes — Conclusions

31. 30-Day Survival By Transfusion Group Rao SV, et. al., JAMA 2004;292:1555–1562. Transfusion in ACS N=24,111N=24,111

32. *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

33. 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

34. 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)

35. ► 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 ► Blood transfusion is best avoided in ACS patients whenever possible ► 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 ► Blood transfusion is best avoided in ACS patients whenever possible Blood Transfusion — Conclusions

36. ► 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? ► 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? ► 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? Bleeding in ACS—The Big Switch

37. *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 ► Long-term efficacy in both groups was consistent at 1 year ► Ischemic suppression was maintained and bleeding significantly reduced at 30 days ► 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

38. 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 ► Long-term efficacy in both groups was consistent at 1 year ► Ischemic suppression was maintained and major bleeding significantly reduced at 30 days ► Long-term efficacy in both groups was consistent at 1 year Switch to bivalirudin* vs consistent heparin + GP IIb/IIIa outcomes † PCI Subgroup

39. 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

40. 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

41. ► 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 ► 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 Bleeding and Costs — Conclusions

42. X Xa II IIa (Thrombin) (Prothrombin) TFVIIa IX IXa  Direct Thrombin Inhibitors—Bivalirudin Va Targets for Intervention Better Options, Worse Options Xa Inhibitors— Fondaparinux Xa Inhibitors— Fondaparinux Direct Thrombin Inhibitors—Bivalirudin

43. 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)

44. 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

45. 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

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

47. Conclusions—Bleeding in ACS ► Certain patient and PCI procedure characteristics predict bleeding ● Age, female gender, CKD ● 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 ► 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

48. Conclusions — Bleeding in ACS ► 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

49. Frederick Feit, MD, FACC Director, Interventional Cardiology Director, Interventional Cardiology NYU School of Medicine Frederick Feit, MD, FACC Director, Interventional Cardiology Director, Interventional Cardiology NYU School of Medicine Can We “Switch” From Enoxaparin or Unfractionated Heparin to Bivalirudin Monotherapy? The Science and Medicine of Acute Coronary Syndrome

50. Why Bivalirudin Monotherapy? ► Reliable anticoagulation ► Rapid onset and offset ► Protects from ischemic and bleeding complications ► Low long-term mortality ► Cost-effective ► Simple ► Seamless integration from ED to Cath Lab ► Reliable anticoagulation ► Rapid onset and offset ► Protects from ischemic and bleeding complications ► Low long-term mortality ► Cost-effective ► Simple ► Seamless integration from ED to Cath Lab

51. Switching ► Concern about switching antithrombins in patients with ACS (lessons from SYNERGY) ► Why should switching to bivalirudin monotherapy be reasonable? ► Mechanistic rationale for switching ► Clinical Evidence ● BAT ● REPLACE 2 ● ACUITY ► Concern about switching antithrombins in patients with ACS (lessons from SYNERGY) ► Why should switching to bivalirudin monotherapy be reasonable? ► Mechanistic rationale for switching ► Clinical Evidence ● BAT ● REPLACE 2 ● ACUITY

52. Background — Issues and Concerns ► ACS patients ● 87% receive UFH, enoxaparin, or fondaparinux within 24 hours of admission 1 ● 72% in SYNERGY and 50% of patients in OASIS- 5 received prior antithrombin 2,3 ► Published studies and perceptions ● Patients in SYNERGY who switched between UFH and enoxaparin had an increase in bleeding complications 2 ● Consistent therapy is better 4 ► ACS patients ● 87% receive UFH, enoxaparin, or fondaparinux within 24 hours of admission 1 ● 72% in SYNERGY and 50% of patients in OASIS- 5 received prior antithrombin 2,3 ► Published studies and perceptions ● Patients in SYNERGY who switched between UFH and enoxaparin had an increase in bleeding complications 2 ● 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.

53. Bivalirudin An Alternative to UFH/LMWH ► Advantages of the direct thrombin inhibitor bivalirudin ● No requirement for antithrombin III ● Effective on clot-bound thrombin ● Inhibits thrombin-mediated platelet activation ● No interactions with PF- 4 ● Plasma half-life 25 minutes ► Clinical results with bivalirudin in PCI ● Similar protection from ischemic events as UFH + GP IIb/IIIa inhibitors, with markedly reduced bleeding 1 ► Not previously extensively tested in contemporary ACS patients ► Advantages of the direct thrombin inhibitor bivalirudin ● No requirement for antithrombin III ● Effective on clot-bound thrombin ● Inhibits thrombin-mediated platelet activation ● No interactions with PF- 4 ● Plasma half-life 25 minutes ► Clinical results with bivalirudin in PCI ● Similar protection from ischemic events as UFH + GP IIb/IIIa inhibitors, with markedly reduced bleeding 1 ► Not previously extensively tested in contemporary ACS patients REPLACE 2. Lincoff AM et al. JAMA 2003;289:853-863.

54. 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. Bivalirudin’s effectiveness is not affected by variability in the concentration of a co-factor like AT. Direct inhibition with bivalirudin inhibits thrombin directly with high affinity and specificity. It requires no cofactor, and acts alone. Bivalirudin’s effectiveness is not affected by variability in the concentration of a co-factor like AT. Hirsh J et al. Chest. 2001;119(1 suppl):64S-94S. Weitz JI et al. Thromb Res. 2002;106:V275-V284. Gibson CM, 2006.

55. 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.

56. Switching Antithrombins ► The SYNERGY trial suggested a switch in anthithrombins (from heparin to LMWH) may lead to increase in bleeding ► What outcomes are observed when switching from heparin or LMWH, to bivalirudin in PCI? ► Is it better to switch or to stay on consistent therapy? ► The SYNERGY trial suggested a switch in anthithrombins (from heparin to LMWH) may lead to increase in bleeding ► What outcomes are observed when switching from heparin or LMWH, to bivalirudin in PCI? ► Is it better to switch or to stay on consistent therapy?

57. 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

58. 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

59. 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

60. 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

61. 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

62. 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.

63. Protocol Major/Minor Bleed by SWITCH and Randomized Therapy ► 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 ► 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 *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 ‡ (n=2,345) LMWH→ Bivalirudin (n=258) UFH→ Bivalirudin (n=287) LMWH→UFH + GP IIb/IIIa (n=313) Naïve→ UFH + GP IIb/IIIa ‡ (n=2,325) UFH→UFH + GP IIb/IIIa (n=349) * † Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.

64. 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 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 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) LMWH→UFH + GP IIb/IIIa (n=313) Naïve→UFH + GP IIb/IIIa † (n=2,325) UFH→UFH + 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.

65. 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.

66. 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

67. 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

68. Current Analysis and Questions ► 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. ► Is it better to switch to bivalirudin or remain on consistent therapy? ► 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. ► Is it better to switch to bivalirudin or remain on consistent therapy? Harvey White. Presentation at AHA, 2006

69. ACUITY — Current Analysis ► Study Methods ● 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 Net clinical outcome Net clinical outcome Ischemic composite Ischemic composite Major bleeding Major bleeding ► Study Methods ● 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 Net clinical outcome Net clinical outcome Ischemic composite Ischemic composite Major bleeding Major bleeding Harvey White. JACC – in press

70. ACUITY – Primary Results UFH/Enoxaparin + GPI vs. Bivalirudin Alone P NI <0.0001 P Sup = 0.015 P NI = 0.011 P Sup = 0.32 P NI <0.0001 P Sup <0.0001

71. 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

72. 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

73. 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

74. 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

75. 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 n=1,294n=1,294 n=1,313n=1,313

76. 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 Δ’s 30-Day Results 1-Year Results

77. How to Switch — Science to Practice From UFH to Bivalirudin Discontinue UFH for 30 minutes before starting bivalirudin From UFH to Bivalirudin Discontinue UFH for 30 minutes before starting bivalirudin From LMWH to Bivalirudin Discontinue LMWH for 8 hours before starting bivalirudin From LMWH to Bivalirudin Discontinue LMWH for 8 hours before starting bivalirudin

78. Conclusions ► Switching to bivalirudin is safe ● Switching from either LMWH or UFH to bivalirudin monotherapy is not associated with an increased risk for ischemic events ► Furthermore ● Switching to bivalirudin monotherapy preserves its 50% reduction in bleeding complications compared with consistent therapy with UFH/enoxaparin + GPI, while preserving anti-ischemic efficacy.

79. 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

80. 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

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

82. 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

83. How We Introduced Upstream and Downstream Bivalirudin: The UVMC Time Line ► 2003: Put bivalirudin on the cath lab shelf as an option for NSTEMI ► 2007: Educational programs for fellows, floor staff and attendings ► 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 don’t overdose patients. ► 2008: A standardized STEMI bivalirudin approach ► For upstream AMI utilization, bivalirudin ordered from pharmacy ► In collaboration with ED (EDICT for ACS Strategy) ► 2003: Put bivalirudin on the cath lab shelf as an option for NSTEMI ► 2007: Educational programs for fellows, floor staff and attendings ► 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 don’t overdose patients. ► 2008: A standardized STEMI bivalirudin approach ► For upstream AMI utilization, bivalirudin ordered from pharmacy ► In collaboration with ED (EDICT for ACS Strategy)

84. NSTEMI Transfers, Upstream Strategies, and Results of Clinical Trials Non ST-Elevation Myocardial Infarction

85. 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. DNR—reverse POLST (wants a cath, but no CABG). Echo today, cath tomorrow (or today if unstable). Thanks, Harry To:Sullivan, Claudia A. Cc:Ades, Philip A. Subject: Transfer of John XXXXX, DOB 11/08/25 81M with NSTEMI/old LBBB, Tn 3.0 Pain free, but with NSVT. ASA/clopidogrel 300 po/enoxaparin. From Adirondack Medical Center. Class I transfer. Change to bivalirudin on arrival. DNR—reverse POLST (wants a cath, but no CABG). Echo today, cath tomorrow (or today if unstable). Thanks, Harry

86. 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 ‡ (n=2,345) LMWH→ Bivalirudin (n=258) UFH→ Bivalirudin (n=287) LMWH→UFH + GP IIb/IIIa (n=313) Naïve→ UFH + GP IIb/IIIa ‡ (n=2,325) UFH→UFH + GP IIb/IIIa (n=349) * † Gibson CM et al. Am J Cardiol. 2007;99:1687-1690.

87. 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 † 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)

88. Transfer to Cardiology Floor ► Enoxaparin held—wait 8 hours from community hospital last dose. ► Then, start upstream bivalirudin ► Patient pain free—1 st case next A.M ► DES, no eptifibatide, closure device, 150 mg clopidogrel ► Ambulate at 6 hours ► D/C following 0900 A.M. ► Enoxaparin held—wait 8 hours from community hospital last dose. ► Then, start upstream bivalirudin ► Patient pain free—1 st case next A.M ► DES, no eptifibatide, closure device, 150 mg clopidogrel ► Ambulate at 6 hours ► D/C following 0900 A.M.

89. The University of Vermont Experience—GPI Trigger Strategy Impact of REPLACE 2 and ACUITY Trials: 91% Bivalirudin Use ► Elective PCI—24% ► Urgent PCI—30% ► Emergent PCI—30% ► 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 ► Elective PCI—24% ► Urgent PCI—30% ► Emergent PCI—30% ► 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 Ahmed B and Dauerman HL, Submitted ESC 2008 REPLACE 2 ACUITY

90. 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

91. 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

92. 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 angio- graphy to 30’ post PCI (n=649) Clopidogrel after 30’ post PCI (n=307) No clopidogrel (n=51) 0.1110

93. 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)

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

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

96. Implementation of HORIZONS AMI PCI Pharmacologic Aspects of Management ► Unfractionated heparin ● 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) ● 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 ● 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) ► Unfractionated heparin ● 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) ● 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 ● 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) * If pre randomization UFH administered, ACT is checked first ** If pre randomization UFH administered, started 30’ after last bolus

97. 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

98. 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 98.9%4.1% ► Bivalirudin 0.4%96.9% ► 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** -4.4% ► Abciximab 49.9%4.0% ► Eptifibatide 44.4%3.1% ► Tirofiban 0.2%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

99. 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

100. 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, LFT’s, 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, LFT’s, 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

101. The Bivalirudin Strategy for STEMI PCI ASA, clopidogrel 600 po x 1, bivalirudin and stent

102. 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

103. 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

104. 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 ► Burden> 5 fold ► Increased Risk of 30 Day Stent Thrombosis ► Large Thrombus ► Burden> 5 fold ► 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 (%)

105. 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

106. 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

107. 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 HORIZONS—25% UVM Implemented HORIZONS—25%

108. Incorporation of HORIZONS AMI and Large Thrombus Data—STEMI Algorithm ► ED STEMI—25% of Patients ► ASA/clopidogrel 600 mg po load and bivalirudin ► Bolus and infusion of eptifibatide after wiring vessel shows Large Thrombus Burden ► Angiojet and Bare Metal Stent ► 150 mg clopidogrel and 18 hours of eptifibatide ► No ambulation until eptifibatide off (18 hours) ► D/C on Day 3 post MI ► ED STEMI—25% of Patients ► ASA/clopidogrel 600 mg po load and bivalirudin ► Bolus and infusion of eptifibatide after wiring vessel shows Large Thrombus Burden ► Angiojet and Bare Metal Stent ► 150 mg clopidogrel and 18 hours of eptifibatide ► No ambulation until eptifibatide off (18 hours) ► D/C on Day 3 post MI

109. 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

110. Conclusions Key Implementation Points ► 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. ► Community referring hospitals may use antithrombotic therapy of choice—then 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. ► Enhanced management of large thrombus burden should be considered especially during the most “vulnerable” 2 hours after PCI.

111. Questions for the Panel ► Does a consistent, unified upstream strategy for anticoagulation across the STEMI and NSTE-ACS risk spectrum make sense? When does it? When doesn’t it? ► Given that bleeding appears to be a driver of MACE events, including mortality, in ACS and STEMI, and since switching to bivalirudin appears to decrease bleeding, should this switching strategy be promulgated in patients undergoing PCI? ► What are the best ways, from an institutional/process-of-care perspective, to establish a consistent antithrombotic strategy for this patient population? ► Other issues? We’ll answer your questions!