E. Magnus Ohman, MD, FRCPI, FACC Program Chairman Professor of Medicine Director, Program for Advanced Coronary Disease Division of Cardiology Duke University.

E. Magnus Ohman, MD, FRCPI, FACC Program Chairman Professor of Medicine Director, Program for Advanced Coronary Disease Division of Cardiology Duke University Medical Center Durham, North Carolina E. Magnus Ohman, MD, FRCPI, FACC Program Chairman Professor of Medicine Director, Program for Advanced Coronary Disease Division of Cardiology Duke University Medical Center Durham, North Carolina Critical Challenges in Cardiovascular Medicine Translating Landmark Trials and AHA/ACC Guidelines into the Front Lines of Cardiovascular Care for Acute, Ischemic Heart Disease Getting in the ACS (Up)Stream of Things

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 (ACS) and related ischemic conditions, and their implications for invasive vascular management. Learn to identify signs, symptoms, and prognostic features of acute coronary syndrome (ACS) and related ischemic conditions, and their implications for invasive vascular management. Learn how recently issued 2007 AHA/ACC Guidelines for UA/Non ST- Elevation Myocardial Infarction are best applied to appropriately risk- stratified patients with UA and NSTEMI. Learn how recently issued 2007 AHA/ACC Guidelines for UA/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 and related conditions. Learn to assess and implement optimal pharmacologic interventions, especially antithrombotic therapy, in the upstream setting, for patients presenting with manifestations of UA, NSTEMI 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. 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 (ACS) and related ischemic conditions, and their implications for invasive vascular management. Learn to identify signs, symptoms, and prognostic features of acute coronary syndrome (ACS) and related ischemic conditions, and their implications for invasive vascular management. Learn how recently issued 2007 AHA/ACC Guidelines for UA/Non ST- Elevation Myocardial Infarction are best applied to appropriately risk- stratified patients with UA and NSTEMI. Learn how recently issued 2007 AHA/ACC Guidelines for UA/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 and related conditions. Learn to assess and implement optimal pharmacologic interventions, especially antithrombotic therapy, in the upstream setting, for patients presenting with manifestations of UA, NSTEMI 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. 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 Educational Objectives As a result of this educational activity, physicians will: Learn to characterize, identify, and evaluate the safety, efficacy, and side effects of myriad therapeutic options used for acute ischemic coronary syndromes including: Aspirin, antiplatelet agents, direct thrombin inhibitors, UFH, LMWHs, and factor Xa inhibitors. Learn to characterize, identify, and evaluate the safety, efficacy, and side effects of myriad therapeutic options used for acute ischemic coronary syndromes including: Aspirin, antiplatelet agents, direct thrombin inhibitors, UFH, LMWHs, and factor Xa inhibitors. Learn to understand the specific advantages and potential disadvantages of pharmacologic agents currently used to reduce ischemic and bleeding end points in the setting of cardiovascular emergencies. Learn to understand the specific advantages and potential disadvantages of pharmacologic agents currently used to reduce ischemic and bleeding end points in the setting of cardiovascular emergencies. Learn to identify the ideal properties of antithrombotic agents used in conjunction with stent insertion. Learn to identify the ideal properties of antithrombotic agents used in conjunction with stent insertion. Learn to discuss and assess the impact that new trials and Year 2007 AHA/ACC Guidelines are likely to have on future invasive management of patients with UA and NSTEMI. Learn to discuss and assess the impact that new trials and Year 2007 AHA/ACC Guidelines are likely to have on future invasive management of patients with UA and NSTEMI. Learn to apply national guidelines and expert, consensus-based recommendations in order to optimize invasive vascular management of patients with acute, ischemic heart disease. Learn to apply national guidelines and expert, consensus-based recommendations in order to optimize invasive vascular management of patients with acute, ischemic heart disease. As a result of this educational activity, physicians will: Learn to characterize, identify, and evaluate the safety, efficacy, and side effects of myriad therapeutic options used for acute ischemic coronary syndromes including: Aspirin, antiplatelet agents, direct thrombin inhibitors, UFH, LMWHs, and factor Xa inhibitors. Learn to characterize, identify, and evaluate the safety, efficacy, and side effects of myriad therapeutic options used for acute ischemic coronary syndromes including: Aspirin, antiplatelet agents, direct thrombin inhibitors, UFH, LMWHs, and factor Xa inhibitors. Learn to understand the specific advantages and potential disadvantages of pharmacologic agents currently used to reduce ischemic and bleeding end points in the setting of cardiovascular emergencies. Learn to understand the specific advantages and potential disadvantages of pharmacologic agents currently used to reduce ischemic and bleeding end points in the setting of cardiovascular emergencies. Learn to identify the ideal properties of antithrombotic agents used in conjunction with stent insertion. Learn to identify the ideal properties of antithrombotic agents used in conjunction with stent insertion. Learn to discuss and assess the impact that new trials and Year 2007 AHA/ACC Guidelines are likely to have on future invasive management of patients with UA and NSTEMI. Learn to discuss and assess the impact that new trials and Year 2007 AHA/ACC Guidelines are likely to have on future invasive management of patients with UA and NSTEMI. Learn to apply national guidelines and expert, consensus-based recommendations in order to optimize invasive vascular management of patients with acute, ischemic heart disease. Learn to apply national guidelines and expert, consensus-based recommendations in order to optimize invasive vascular management of patients with acute, ischemic heart disease.

Program Faculty Program Chairman E. Magnus Ohman, MD, FRCPI, FACC Professor of Medicine Director, Program for Advanced Coronary Disease Disease Division of Cardiology Duke University Medical Center Durham, North Carolina Distinguished Faculty C. Michael Gibson, MS, MD Director, TIMI Core Laboratories and Data Coordinating Center Associate Professor Harvard Medical School Boston, Massachusetts Program Chairman E. Magnus Ohman, MD, FRCPI, FACC Professor of Medicine Director, Program for Advanced Coronary Disease Disease Division of Cardiology Duke University Medical Center Durham, North Carolina Distinguished Faculty C. Michael Gibson, MS, MD Director, TIMI Core Laboratories and Data Coordinating Center Associate Professor Harvard Medical School Boston, Massachusetts A. Michael Lincoff, MD Vice Chairman for Research Department of Cardiovascular Medicine Director, Cleveland Clinic Cardiovascular Coordinating Center Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Case Western Reserve University The Cleveland Clinic Foundation Cleveland, Ohio Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Chairman, Department of Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine University of Pennsylvania School of Medicine Philadelphia, Pennsylvania Philadelphia, Pennsylvania A. Michael Lincoff, MD Vice Chairman for Research Department of Cardiovascular Medicine Director, Cleveland Clinic Cardiovascular Coordinating Center Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Case Western Reserve University The Cleveland Clinic Foundation Cleveland, Ohio Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Chairman, Department of Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine University of Pennsylvania School of Medicine Philadelphia, Pennsylvania Philadelphia, Pennsylvania

Faculty COI Disclosures Faculty COI Disclosures E. Magnus Ohman, MD, FRCPI, FACC Research Grants: Berlex, sanofi-aventis, Schering-Plough Corporation, Bristol Meyer Squibb, and Millennium. Stockholder: Medtronic. Consultant: Response Biomedical, Liposcience, and Inovise Medical C. Michael Gibson, MS, MD Present Research/Grant Funding: CardioKinetix, Eli Lilly, KAI Pharmaceuticals, Nuvelo, Schering Plough Corporation, Sanofi-Aventis, St. Jude Medical, Baxter, Novartis, FoldRx, INO Therapeutics, LLC Speakers Bureau: Genentech, Inc., GlaxoSmithKline, Schering Plough Corporation, The Medicines Company Consultant: Angel Medical Systems, The Medicines Company. HeartScape Technologies, Inc., Ascenta Therapeutics, Inc., Archemix Corp., PDL Pharmaceuticals, Atrium Medical Corporation, TIMI3 Systems, Biogen IDEC Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Grant/Research Support: GlaxoSmithKline Consultant: The Medicines Co., Schering-Plough, Sanofi-Aventis, BMS, Genentech Speakers Bureau: Schering-Plough, Sanofi-Aventis, BMS, Genentech E. Magnus Ohman, MD, FRCPI, FACC Research Grants: Berlex, sanofi-aventis, Schering-Plough Corporation, Bristol Meyer Squibb, and Millennium. Stockholder: Medtronic. Consultant: Response Biomedical, Liposcience, and Inovise Medical C. Michael Gibson, MS, MD Present Research/Grant Funding: CardioKinetix, Eli Lilly, KAI Pharmaceuticals, Nuvelo, Schering Plough Corporation, Sanofi-Aventis, St. Jude Medical, Baxter, Novartis, FoldRx, INO Therapeutics, LLC Speakers Bureau: Genentech, Inc., GlaxoSmithKline, Schering Plough Corporation, The Medicines Company Consultant: Angel Medical Systems, The Medicines Company. HeartScape Technologies, Inc., Ascenta Therapeutics, Inc., Archemix Corp., PDL Pharmaceuticals, Atrium Medical Corporation, TIMI3 Systems, Biogen IDEC Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Grant/Research Support: GlaxoSmithKline Consultant: The Medicines Co., Schering-Plough, Sanofi-Aventis, BMS, Genentech Speakers Bureau: Schering-Plough, Sanofi-Aventis, BMS, Genentech

Abraxis Abraxis Alexion Pharma Alexion Pharma AstraZeneca AstraZeneca Atherogenics Atherogenics Aventis Aventis Biosense Webster Biosense Webster Biosite Biosite Boehringer Ingelheim Boehringer Ingelheim Boston Scientific Boston Scientific Bristol-Myers Squibb (BMS) Bristol-Myers Squibb (BMS) Cardionet Cardionet Centocor Centocor Converge Medical Inc. Converge Medical Inc. Cordis Cordis Dr. Reddys Laboratory Dr. Reddys Laboratory Novartis Novartis Novo Nordisk Novo Nordisk Orphan Therapeutics Orphan Therapeutics P&G Pharma P&G Pharma Pfizer Pfizer Roche Roche Sankyo Sankyo Sanofi-Aventis Sanofi-Aventis Schering-Plough Schering-Plough Scios Scios St. Jude Medical St. Jude Medical Takeda Takeda VasoGenix VasoGenix Viacor Viacor Abraxis Abraxis Alexion Pharma Alexion Pharma AstraZeneca AstraZeneca Atherogenics Atherogenics Aventis Aventis Biosense Webster Biosense Webster Biosite Biosite Boehringer Ingelheim Boehringer Ingelheim Boston Scientific Boston Scientific Bristol-Myers Squibb (BMS) Bristol-Myers Squibb (BMS) Cardionet Cardionet Centocor Centocor Converge Medical Inc. Converge Medical Inc. Cordis Cordis Dr. Reddys Laboratory Dr. Reddys Laboratory Novartis Novartis Novo Nordisk Novo Nordisk Orphan Therapeutics Orphan Therapeutics P&G Pharma P&G Pharma Pfizer Pfizer Roche Roche Sankyo Sankyo Sanofi-Aventis Sanofi-Aventis Schering-Plough Schering-Plough Scios Scios St. Jude Medical St. Jude Medical Takeda Takeda VasoGenix VasoGenix Viacor Viacor Edwards Lifesciences Edwards Lifesciences Esperion Esperion GE Medical GE Medical Genentech Genentech Gilford Gilford GSK GSK Guidant Guidant J&J J&J Kensey-Nash Kensey-Nash Lilly Lilly Medicines Company Medicines Company Medtronic Medtronic Merck Merck Mytogen Mytogen Novartis Novartis Novo Nordisk Novo Nordisk Orphan Therapeutics Orphan Therapeutics P&G Pharma P&G Pharma Pfizer Pfizer Roche Roche Sankyo Sankyo Sanofi-Aventis Sanofi-Aventis Schering-Plough Schering-Plough Scios Scios St. Jude Medical St. Jude Medical Takeda Takeda VasoGenix VasoGenix Viacor Viacor Edwards Lifesciences Edwards Lifesciences Esperion Esperion GE Medical GE Medical Genentech Genentech Gilford Gilford GSK GSK Guidant Guidant J&J J&J Kensey-Nash Kensey-Nash Lilly Lilly Medicines Company Medicines Company Medtronic Medtronic Merck Merck Mytogen Mytogen Novartis Novartis Novo Nordisk Novo Nordisk Orphan Therapeutics Orphan Therapeutics P&G Pharma P&G Pharma Pfizer Pfizer Roche Roche Sankyo Sankyo Sanofi-Aventis Sanofi-Aventis Schering-Plough Schering-Plough Scios Scios St. Jude Medical St. Jude Medical Takeda Takeda VasoGenix VasoGenix Viacor Viacor Novartis Novartis Novo Nordisk Novo Nordisk Orphan Therapeutics Orphan Therapeutics P&G Pharma P&G Pharma Pfizer Pfizer Roche Roche Sankyo Sankyo Sanofi-Aventis Sanofi-Aventis Schering-Plough Schering-Plough Scios Scios St. Jude Medical St. Jude Medical Takeda Takeda VasoGenix VasoGenix Viacor Viacor Novartis Novartis Novo Nordisk Novo Nordisk Orphan Therapeutics Orphan Therapeutics P&G Pharma P&G Pharma Pfizer Pfizer Roche Roche Sankyo Sankyo Sanofi-Aventis Sanofi-Aventis Schering-Plough Schering-Plough Scios Scios St. Jude Medical St. Jude Medical Takeda Takeda VasoGenix VasoGenix Viacor Viacor A. Michael Lincoff, MD Relationships with Industry Research Sponsors C5Research C5Research Faculty COI Disclosures Faculty COI Disclosures

Critical Challenges in Acute Ischemic Heart Disease Overview Where Metal Meets Thrombus, Drugs, and Vascular Endothelium: A State of the Union Synthesis E. Magnus Ohman MD, FRCPI, FACC Program Chairman Professor of Medicine | Director, Program for Advanced Coronary Disease | Division of Cardiology | Duke University Medical Center | Durham, North Carolina Critical Challenges in Acute Ischemic Heart Disease Overview Where Metal Meets Thrombus, Drugs, and Vascular Endothelium: A State of the Union Synthesis E. Magnus Ohman MD, FRCPI, FACC Program Chairman Professor of Medicine | Director, Program for Advanced Coronary Disease | Division of Cardiology | Duke University Medical Center | Durham, North Carolina Getting in the ACS (Up)Stream of Things

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

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

Issues We Will Address Tonight GUIDELINES Do we need them? If so, why? In what situations? And how do we adapt to new evidence presented after guidelines are released? GUIDELINES Do we need them? If so, why? In what situations? And how do we adapt to new evidence presented after guidelines are released? UPSTREAM THERAPYHow do we identify optimal strategies? UPSTREAM THERAPYHow do we identify optimal strategies? COLLABORATIONHow do we facilitate collaboration among ED physicians and CV specialists? COLLABORATIONHow do we facilitate collaboration among ED physicians and CV specialists? CASE STUDIESTranslating science and evidence to practice CASE STUDIESTranslating science and evidence to practice Issues We Will Address Tonight GUIDELINES Do we need them? If so, why? In what situations? And how do we adapt to new evidence presented after guidelines are released? GUIDELINES Do we need them? If so, why? In what situations? And how do we adapt to new evidence presented after guidelines are released? UPSTREAM THERAPYHow do we identify optimal strategies? UPSTREAM THERAPYHow do we identify optimal strategies? COLLABORATIONHow do we facilitate collaboration among ED physicians and CV specialists? COLLABORATIONHow do we facilitate collaboration among ED physicians and CV specialists? CASE STUDIESTranslating science and evidence to practice CASE STUDIESTranslating science and evidence to practice Getting in the ACS (Up)Stream of Things

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 Snapshot of Trial Results that Supported Addition of Bivalirudin and Fondaparinux to Year 2007 AHA/ACC UA/NSTEMI Guidelines PIVOTAL TRIALS Snapshot of Trial Results that Supported Addition of Bivalirudin and Fondaparinux to Year 2007 AHA/ACC UA/NSTEMI Guidelines ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation. UA/NSTEMI Pivotal Trials

OASIS-5: Efficacy at Day 9 EnoxFonda % Death/MI/RI5.85.9 Death/MI4.14.1 Death1.91.8 MI2.72.7 Refractory Ischemia 1.92.05 0.81 1.2 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 OutcomeEnoxFonda 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 Yusuf S, et al. N Engl J Med. 2006;354(14):1464-76

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, McLaurin BT. 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, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16.

ACUITY Net Clinical Outcome 0 5 10 15 05101520253035 Cumulative Events (%) Days from Randomization Estimate P (log rank) 11.7% UFH/Enoxaparin + IIb/IIIa (N=4603) Bivalirudin + IIb/IIIa (N=4604) 0.89 11.8% Bivalirudin alone (N=4612) 0.014 10.1% Stone GW, McLaurin BT. 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) 30 day 3 Bivalirudin alone vs. Hep+GPI HR [95% CI] = 0.95 (0.77-1.18) Stone GW, ACC 2007

Addressing the Challenge 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

Sea and Stream Changes in ACS The 2007 Guidelines have created a Sea Change in the care of patients with UA/NSTEMI The 2007 Guidelines have created a Sea Change in the care of patients with UA/NSTEMI New Streams of care, with new anticoagulants, are in play New Streams of care, with new anticoagulants, are in play Clopidogrel use has been liberalized Clopidogrel use has been liberalized Bleeding end points play a more important role in drug selection Bleeding end points play a more important role in drug selection Dogmatism is out, customization is in Dogmatism is out, customization is in Collaboration is emphasized Collaboration is emphasized The 2007 Guidelines have created a Sea Change in the care of patients with UA/NSTEMI The 2007 Guidelines have created a Sea Change in the care of patients with UA/NSTEMI New Streams of care, with new anticoagulants, are in play New Streams of care, with new anticoagulants, are in play Clopidogrel use has been liberalized Clopidogrel use has been liberalized Bleeding end points play a more important role in drug selection Bleeding end points play a more important role in drug selection Dogmatism is out, customization is in Dogmatism is out, customization is in Collaboration is emphasized Collaboration is emphasized

C. Michael Gibson, M.S., M.D., FACC C. Michael Gibson, M.S., M.D., FACC Director, TIMI Core Laboratories and Data Coordinating Center Associate Professor, Harvard Medical School Boston, Massachusetts C. Michael Gibson, M.S., M.D., FACC C. Michael Gibson, M.S., M.D., FACC Director, TIMI Core Laboratories and Data Coordinating Center Associate Professor, Harvard Medical School Boston, Massachusetts Getting in the Stream(s) of Antithrombotic Therapy for ACS: What Do The Trials Tell Us? To Switch or Not to Switch What Do The Trials Tell Us? To Switch or Not to Switch If, When, How, To What? Getting in the Stream(s) of Antithrombotic Therapy for ACS: What Do The Trials Tell Us? To Switch or Not to Switch What Do The Trials Tell Us? To Switch or Not to Switch If, When, How, To What? Getting in the ACS Stream of Things

Overview of Presentation Mechanistic rational for switching Mechanistic rational 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) Why should switching to bivalirudin for PCI be reasonable? Why should switching to bivalirudin for PCI be reasonable? Clinical evidence in support of switching Clinical evidence in support of switching l SWITCH l REPLACE 2 l ACUITY Mechanistic rational for switching Mechanistic rational 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) Why should switching to bivalirudin for PCI be reasonable? Why should switching to bivalirudin for PCI be reasonable? Clinical evidence in support of switching Clinical evidence in support of switching l SWITCH l REPLACE 2 l ACUITY

Background Issues and Concerns ACS patients ACS patients l 87% of patients receive either UFH, enoxaparin, or fondaparinux within 24 hours after admission 1 l 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 l 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 perceptionThis activity occurred at various times through the study period: At times in response to clinical or clinician perception l Consistent therapy is better 4 ACS patients ACS patients l 87% of patients receive either UFH, enoxaparin, or fondaparinux within 24 hours after admission 1 l 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 l 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 perceptionThis activity occurred at various times through the study period: At times in response to clinical or clinician perception l 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: A Guidelines-Supported Alternative to UFH/LMWH in ACS Advantages of the direct thrombin inhibitor bivalirudin Advantages of the direct thrombin inhibitor bivalirudin l No requirement for antithrombin III l Effective on clot-bound thrombin l Inhibits thrombin-mediated platelet activation l No interactions with PF- 4 l Plasma half-life 25 minutes l No requirement for anticoagulant monitoring Clinical results with bivalirudin in PCI Clinical results with bivalirudin in PCI l 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 l No requirement for antithrombin III l Effective on clot-bound thrombin l Inhibits thrombin-mediated platelet activation l No interactions with PF- 4 l Plasma half-life 25 minutes l No requirement for anticoagulant monitoring Clinical results with bivalirudin in PCI Clinical results with bivalirudin in PCI l 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.

Switching Antithrombins: SYNERGY 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?

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 The SWITCH Study

31 30 Primary Endpoint BLEEDING Primary Endpoint BLEEDING 91 ACS patientsundergoingPCI (3 US sites) Open-label, prospective, 3-arm study 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 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

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 The goal of this analysis was to evaluate whether a hazard existed when either UFH or LMWH were administered prior to study medication in the REPLACE-2 trial C. Michael Gibson, Yuli Ten, Sabina A. Murphy, Lauren N. Ciaglo, Matthew C. Southard, A. Michael Lincoff, and Ron Waksman Gibson CM, Am J Cardiol. 2007 Jun 15;99(12):1687-90. REPLACE-2 Trial: Impact of Antithrombin Switching

Pre-Randomization Anticoagulant Switching and Bleeding The present study compared bleeding among patients treated either with preceding antithrombin therapy or no preceding antithrombin therapy in the prior 48 hours. Gibson CM, Am J Cardiol. 2007 Jun 15;99(12):1687-90.

The method of switching or transition involved administration of bivalirudin as follows: >8 hours after last low molecular weight heparin (LMWH) dose (LMWH) doseOR > 6 hours after unfractionated heparin, unless in the case of UFH therapy the activated partial thromboplastin time was 50 seconds or the activated clotting time was 175 seconds The method of switching or transition involved administration of bivalirudin as follows: >8 hours after last low molecular weight heparin (LMWH) dose (LMWH) doseOR > 6 hours after unfractionated heparin, unless in the case of UFH therapy the activated partial thromboplastin time was 50 seconds or the activated clotting time was 175 seconds Pre-Randomization Anticoagulant Switching and Bleeding Gibson CM, Am J Cardiol. 2007 Jun 15;99(12):1687-90.

Variable Naive BIV* (n=2,345)UFHBIV(n=287)LMWHBIV(n=258)Naive GP IIbIIIa /UFH(n=2,325)UFH GP IIbIIIa/U FH (n=349)LMWH (n=313) Protocol Major Bleed 2.3%*1.7%2.7%3.6%4.9%5.8% Protocol Minor Bleed 13.4%*13.6%14.0%25.0%28.9%29.1% Protocol Major/Minor Bleed 15.6%*15.3%16.7%28.6%**33.8%34.8% TIMI Major/Minor Bleed 1.9%*1.4%1.9%3.5%4.3%5.4% 2 Non-CABG Transfusions 0.8%*1.1%1.2%1.0%**2.3%2.9% Bleeding and Switching in REPLACE-2 * p=NS for all 3-way comparisons vs BIV alone ** p<0.05 for 3-way comparison vs glycoprotein IIbIIIa (GP IIbIIIa), unfractionated heparin (UFH) naïve as well as 2- way comparisons of unfractionated heparin (UFH) naïve vs either preceding unfractionated heparin (UFH) or preceding low molecular weight heparin (LMWH) Gibson CM, Am J Cardiol. 2007 Jun 15;99(12):1687-90.

Time to PCI (hours) NO BLEED Median = 18 hrs IQ 14.5 – 24 hrs N=228 Time from Last Dose of LMWH to PCI in Bivalirudin Patients by Presence of Protocol Major/Minor Bleed BLEED Median = 18.5 hrs IQ 12.6 – 24.5 N=51 p = 0.91 Gibson CM, Am J Cardiol. 2007 Jun 15;99(12):1687-90.

Switching and One Year Mortality Cumulative events (mortality), % REPLACE-2 Subanalysis: 1-Year Mortality Results Consistent with Overall Trial Results Gibson CM, Am J Cardiol. 2007 Jun 15;99(12):1687-90.

Pre-Randomization Anticoagulant Switching and Bleeding When switching to bivalirudin was undertaken in this fashion, 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 in this fashion, 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. Gibson CM, Am J Cardiol. 2007 Jun 15;99(12):1687-90.

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 Gibson CM, Am J Cardiol. 2007 Jun 15;99(12):1687-90.

UF Heparin EnoxaparinBivalirudin U/Kgmg/Kgmg/kg Bolus60 1.0 sc bid 0.1 iv Infusion/h 12 1 0.25 iv PCIACT200-250s 0.30 iv bolus 2 0.75 iv bolus 3 0.50 bolus iv 1.75/h infusion iv 4 CABG Per institution Per institution 5 Medical mgt None 6 ACUITY: Study Medications Antithrombin Agents Started Pre-angiography Antithrombin Agents Started Pre-angiography 1 Target aPTT 50-75 seconds. 2 If last enoxaparin dose 8h - <16h before PCI. 3 If maintenance dose discontinued or 16h from last dose. 4 Discontinued at end of PCI with option to continue at 0.25mg/kg for 4-12h if GPIIb/IIIa inhibitor not used. 5 Bivalirudin option for off-pump same as PCI dose. For on-pump bivalirudin discontinued 2 hours before. 6 Option to continue with pre-PCI anti-thrombotic regimen at physician discretion.

Switching Hypothesis and Question 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. Question: Question: Is it better to switch to bivalirudin or remain on consistent therapy with the antithrombin originally started? 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. Question: Question: Is it better to switch to bivalirudin or remain on consistent therapy with the antithrombin originally started?

ACUITY: Switching Analysis Study Methods Study Methods l 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 codeSwitch: Single switch to bivalirudin determined by randomization code –from Enoxaparin Bivalirudin or UFH Bivalirudin l Event rates at 30-days Net clinical outcomeNet clinical outcome Ischemic compositeIschemic composite Major bleedingMajor bleeding Study Methods Study Methods l 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 codeSwitch: Single switch to bivalirudin determined by randomization code –from Enoxaparin Bivalirudin or UFH Bivalirudin l Event rates at 30-days Net clinical outcomeNet clinical outcome Ischemic compositeIschemic composite Major bleedingMajor bleeding

ACUITY Primary Endpoints at 30 Days Net Clinical Endpoint Net Clinical Endpoint l Composite ischemic and non-CABG major bleeding endpoints Ischemic Endpoint Ischemic Endpoint l Death, MI, or unplanned revascularization Non-CABG Major Bleeding Endpoint Non-CABG Major Bleeding Endpoint l Intracranial, intraocular, or retroperitoneal bleeding l Access site bleed requiring intervention/surgery l Hematoma 5 cm l Hgb 3g/dL with an overt source or 4g/dL w/o overt source l Blood transfusion Net Clinical Endpoint Net Clinical Endpoint l Composite ischemic and non-CABG major bleeding endpoints Ischemic Endpoint Ischemic Endpoint l Death, MI, or unplanned revascularization Non-CABG Major Bleeding Endpoint Non-CABG Major Bleeding Endpoint l Intracranial, intraocular, or retroperitoneal bleeding l Access site bleed requiring intervention/surgery l Hematoma 5 cm l Hgb 3g/dL with an overt source or 4g/dL w/o overt source l Blood transfusion

Switching Consort Diagram ACUITY ACUITY 13819 CONSISTENT CONSISTENT UFH/Enox N = 2223 SWITCH SWITCH Bivalirudin* N = 2237 UFHUFH N = 1294 EnoxEnox N = 929 UFHBiv N = 1313 EnoxBiv N = 857 Patients on Prior AT N = 6606 Patients on Prior AT N = 6606 * Includes 67 pts. who had UFH and Enox excludes Arm B and pts. with multiple crossovers, missing data

Baseline Characteristics Consistent UFH/Enox vs. Switch to Bivalirudin ConsistentUFH/Enox N = 2223 SwitchBivalirudin N = 2237 P-value Age (median [range], yrs) 63 [23, 91] 62 [20, 92] 0.02 Male (%) 71.670.0NS Weight (median [IQR], kg) 83 [73, 96] 84 [73, 96] NS Diabetes(%)27.625.00.05 Hypertension (%) 64.563.8NS Hyperlipidemia (%) 54.654.0NS Current smoker (%) 29.530.7NS Prior MI (%) 31.030.4NS Prior PCI (%) 36.836.8NS Prior CABG (%) 18.418.1NS Thienopyridine exposure 63.866.1NS Renal insufficiency* (%) 19.617.4NS High Risk* (%) 77.674.60.02 Troponin + (%) 65.463.6NS * creatinine clearance <60 mL/min *Elevated cardiac markers and/or ST changes

Results: Consistent vs. Switch Comparison of Consistent therapy on UFH/Enox Comparison of Consistent therapy on UFH/Enox vs. Switch to Bivalirudin Alone Comparison of Consistent therapy on UFH/Enox 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, ESC 2007

0.83 (0.67-1.02) OR (95% CI) Odds ratio ±95% CI Switch to Bivalirudin alone better Consistent UFH/Enox better Major Bleeding IschemiaIschemia Net Clinical Outcome 1.10 (0.86-1.41) 0.47 (0.34-0.65) P-valueP-value 0.0730.073 0.4640.464 <0.001<0.001 * Comparing consistent UFH/Enox vs Switch Bivalirudin Consistent vs. Switch MV Adjusted Results in all Patients

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 Patients Adjusted Analysis Comparing Consistent UFH/Enox vs Switch Bivalirudin Comparing Consistent UFH/Enox vs Switch Bivalirudin

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]

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] Consistent vs. Switch

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

NSTE Acute Coronary Syndromes The Year 2007 ACC/AHA Guidelines and Upstream Therapy How Do We Collaborate Across Best Evidence? Charles V. Pollack, Jr., M.A., M.D., FACEP, FAHA Professor and Chairman Emergency Medicine, Pennsylvania Hospital University of Pennsylvania Health System Philadelphia Charles V. Pollack, Jr., M.A., M.D., FACEP, FAHA Professor and Chairman Emergency Medicine, Pennsylvania Hospital University of Pennsylvania Health System Philadelphia Getting in the ACS (Up)Stream of Things

Anderson JL, Adams CD, Antman EM, et al. 2007 guidelines for the management of patients with unstable angina/non-ST-segment-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2007;50:e1-e157, and Circulation 2007;116:e148-e304, and at www.acc.org and at www.americanheart.org. Anderson JL, Adams CD, Antman EM, et al. 2007 guidelines for the management of patients with unstable angina/non-ST-segment-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2007;50:e1-e157, and Circulation 2007;116:e148-e304, and at www.acc.org and at www.americanheart.org. Pollack CV, Braunwald E: 2007 Update to the ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: Implications for emergency department practice. Ann Emerg Med 2007, in press. Pollack CV, Braunwald E: 2007 Update to the ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: Implications for emergency department practice. Ann Emerg Med 2007, in press. Anderson JL, Adams CD, Antman EM, et al. 2007 guidelines for the management of patients with unstable angina/non-ST-segment-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2007;50:e1-e157, and Circulation 2007;116:e148-e304, and at www.acc.org and at www.americanheart.org. Anderson JL, Adams CD, Antman EM, et al. 2007 guidelines for the management of patients with unstable angina/non-ST-segment-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2007;50:e1-e157, and Circulation 2007;116:e148-e304, and at www.acc.org and at www.americanheart.org. Pollack CV, Braunwald E: 2007 Update to the ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: Implications for emergency department practice. Ann Emerg Med 2007, in press. Pollack CV, Braunwald E: 2007 Update to the ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: Implications for emergency department practice. Ann Emerg Med 2007, in press. NSTE ACS: Optimal Therapy, 8/6/07

The Role of the Emergency Physician in the Management of Chest Pain Stabilization Stabilization l When required Recognition Recognition l Atypical is the new typical Prompt STEMI management Prompt STEMI management l ~ 15% of our ACS populationnew data to follow Risk Stratification of the rest Risk Stratification of the rest l > 50% dont have ACS l Of those who do, fewer than 30% are high (ischemic) risk in the ED Stabilization Stabilization l When required Recognition Recognition l Atypical is the new typical Prompt STEMI management Prompt STEMI management l ~ 15% of our ACS populationnew data to follow Risk Stratification of the rest Risk Stratification of the rest l > 50% dont have ACS l Of those who do, fewer than 30% are high (ischemic) risk in the ED

The Role of the Emergency Physician in the Management of Chest Pain Communication with Cardiology Communication with Cardiology l Often hospital medicine, PCP, and noninterventionalists as part of process-of-care in ACS Confluent Therapeutic Choices Considerations Include: Confluent Therapeutic Choices Considerations Include: l Ischemic risk l Bleeding risk l Choice of upstream therapy l Reversibility of upstream therapyre CABG and bleeding l Likely duration of upstream therapy Transition of care Transition of care l If patient going to cath, time frame increasingly compressed l If to tele/CCU, emergency physician has more impact Communication with Cardiology Communication with Cardiology l Often hospital medicine, PCP, and noninterventionalists as part of process-of-care in ACS Confluent Therapeutic Choices Considerations Include: Confluent Therapeutic Choices Considerations Include: l Ischemic risk l Bleeding risk l Choice of upstream therapy l Reversibility of upstream therapyre CABG and bleeding l Likely duration of upstream therapy Transition of care Transition of care l If patient going to cath, time frame increasingly compressed l If to tele/CCU, emergency physician has more impact

Patients with Chest Pain Syndrome Must Be Risk- Stratified in ED Three levels of risk stratification are pertinent to the ED: Three levels of risk stratification are pertinent to the ED: Low, intermediate, or high risk that ischemic symptoms are a result of CAD Low, intermediate, or high risk of short-term death or nonfatal MI from ACS Dynamic, ongoing risk-oriented evaluation of low- or intermediate-risk patients for conversion to high-risk status that is linked to intensity of treatment Three levels of risk stratification are pertinent to the ED: Three levels of risk stratification are pertinent to the ED: Low, intermediate, or high risk that ischemic symptoms are a result of CAD Low, intermediate, or high risk of short-term death or nonfatal MI from ACS Dynamic, ongoing risk-oriented evaluation of low- or intermediate-risk patients for conversion to high-risk status that is linked to intensity of treatment Risk Stratification

Dynamic Risk Stratification Tools History and PhysicalHistory and Physical Standard EKG and Non-standard EKG leadsStandard EKG and Non-standard EKG leads 15-lead ECGs should perhaps be standard in all but very-low-risk patients 15-lead ECGs should perhaps be standard in all but very-low-risk patients MarkersMarkers CPK-MB, Troponins I and T, Myoglobin CPK-MB, Troponins I and T, Myoglobin Markers of inflammation and ischemia Markers of inflammation and ischemia BNP BNP Non-Invasive ImagingNon-Invasive Imaging Echocardiogram Echocardiogram Stress testing Stress testing Technetium-99m-sestamibi Technetium-99m-sestamibi CT coronary angiography CT coronary angiography Predictive Indices/SchemesPredictive Indices/Schemes TIMI, GRACE, PURSUIT TIMI, GRACE, PURSUIT History and PhysicalHistory and Physical Standard EKG and Non-standard EKG leadsStandard EKG and Non-standard EKG leads 15-lead ECGs should perhaps be standard in all but very-low-risk patients 15-lead ECGs should perhaps be standard in all but very-low-risk patients MarkersMarkers CPK-MB, Troponins I and T, Myoglobin CPK-MB, Troponins I and T, Myoglobin Markers of inflammation and ischemia Markers of inflammation and ischemia BNP BNP Non-Invasive ImagingNon-Invasive Imaging Echocardiogram Echocardiogram Stress testing Stress testing Technetium-99m-sestamibi Technetium-99m-sestamibi CT coronary angiography CT coronary angiography Predictive Indices/SchemesPredictive Indices/Schemes TIMI, GRACE, PURSUIT TIMI, GRACE, PURSUIT

CRUSADE: A National Quality Improvement Initiative CRUSADE: A National Quality Improvement Initiative Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines 2002-2007 Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines 2002-2007 The CRUSADE Experience The CRUSADE Experience

January 2007 443 Participating Sites 205,528 Patients 443 Participating Sites 205,528 Patients AK (0) WA (5) OR (5) CA (34) ID (0) NV (2) MT (0) WY (0) CO (9) NM (1) ND (1) SD (3) NE (3) KS (3) OK (7) TX (13) MN (3) IA (6) MO (8) AR (2) LA (6) WI (5) MI (20) MI UT (1) AZ (8) HI (0) IL (17) IN (7) KY (8) TN (9) MS (6) AL (9) GA (14) FL (31) SC (7) NC (14) VA (17) OH (35) WV (2) PA (36) NY (34) MD (13) ME (0) VT (1) NH (1) NJ (12) MA (10) CT (7) DE (3) RI (1) DC (1) The CRUSADE Experience The CRUSADE Experience Data on file, Duke Clinical Research Institute.

Quality and Outcomes

Invasive Procedures 2006 (Among Patients Without Contraindications to Cath Median Times Cath - 22 hrs Cath - 22 hrs PCI - 21 hrs PCI - 21 hrs CABG - 69 hrs CABG - 69 hrs

Management Strategies: 2007 Early Invasive versus Selectively Invasive Early Invasive: Diagnostic angiography with intent to perform revascularization Early Invasive: Diagnostic angiography with intent to perform revascularization l Cath anticipated within 4-24 hours l Follows a foundation of risk-directed medical therapy Selectively Invasive (or Early Conservative): Invasive evaluation only if optimal medical management fails Selectively Invasive (or Early Conservative): Invasive evaluation only if optimal medical management fails Note: From the ED perspective, both strategies involve risk-directed, evidence-based medical therapy Note: From the ED perspective, both strategies involve risk-directed, evidence-based medical therapy Early Invasive: Diagnostic angiography with intent to perform revascularization Early Invasive: Diagnostic angiography with intent to perform revascularization l Cath anticipated within 4-24 hours l Follows a foundation of risk-directed medical therapy Selectively Invasive (or Early Conservative): Invasive evaluation only if optimal medical management fails Selectively Invasive (or Early Conservative): Invasive evaluation only if optimal medical management fails Note: From the ED perspective, both strategies involve risk-directed, evidence-based medical therapy Note: From the ED perspective, both strategies involve risk-directed, evidence-based medical therapy

What Is Risk-Directed Medical Management? ASA ASA Antithrombin therapy Antithrombin therapy l I-A: Enoxaparin or UFH l I-B: Bivalirudin or fondaparinux Antiplatelet therapy Antiplatelet therapy l Oral anti-activation therapy l Parenteral anti-aggregation therapy ASA ASA Antithrombin therapy Antithrombin therapy l I-A: Enoxaparin or UFH l I-B: Bivalirudin or fondaparinux Antiplatelet therapy Antiplatelet therapy l Oral anti-activation therapy l Parenteral anti-aggregation therapy As number of therapies increases, bleeding risk generally increases As number of therapies increases, bleeding risk generally increases

The Upstream Antithrombin Challenge: Collaboration Across Many Choices Bleeding Risk Ischemic Risk Renal function AgeAge Time to Cath CostCost Ease of use PCI vs CABG vs Med Rx Low: Enox, Bival, UFH Mod: Enox, Bival, UFH High: Enox, Fonda, Bival? Low: Enox, Bival, UFH Mod: Enox, Bival, UFH High: Enox, Fonda, Bival? Low: Enox, UFH, Bival Mod: Bival, Fonda, UFH High: Bival, Fonda, UFH Low: Enox, UFH, Bival Mod: Bival, Fonda, UFH High: Bival, Fonda, UFH Elderly: ??? Normal: Enox, Bival, Fonda, UFH CKD: Bival, UFH Normal: Enox, Bival, Fonda, UFH CKD: Bival, UFH Enox, UFH Fonda? Bival? Enox, UFH Fonda? Bival? Enox, Bival, Fonda Rapid: Bival, UFH Early: Enox, UFH, Bival? Delayed: Enox Rapid: Bival, UFH Early: Enox, UFH, Bival? Delayed: Enox PCI: Enox, Bival, UFH CABG: UFH Med Rx: Enox, Fonda, Bival? PCI: Enox, Bival, UFH CABG: UFH Med Rx: Enox, Fonda, Bival? Courtesy Dr. Sunil Rao, DCRI

Recent ACS Trials Forging A New Paradigm for Upstream Management ISCHEMIA BLEEDING ISCHEMIA: The traditional, primary concern of the emergency physician ISCHEMIA: The traditional, primary concern of the emergency physician BLEEDING: Newer, important concern for the cardiologist A novel issue for the emergency physician

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

Recent ACS Trials Forging A New Paradigm for Upstream Management ISCHEMIA BLEEDING TIME TO CATH

Invasive Procedures 2006 (Among Patients Without Contraindications to Cath Median Times Cath - 22 hrs Cath - 22 hrs PCI - 21 hrs PCI - 21 hrs CABG - 69 hrs CABG - 69 hrs

Management Strategies: 2007 Early Invasive versus Selectively Invasive Early Invasive: Diagnostic angiography with intent to perform revascularization Early Invasive: Diagnostic angiography with intent to perform revascularization l Cath anticipated within 4-24 hours l Follows a foundation of risk-directed medical therapy Selectively Invasive (or Early Conservative): Invasive evaluation only if optimal medical management fails Selectively Invasive (or Early Conservative): Invasive evaluation only if optimal medical management fails Note: From the ED perspective, both strategies involve risk-directed, evidence-based medical therapy Note: From the ED perspective, both strategies involve risk-directed, evidence-based medical therapy Early Invasive: Diagnostic angiography with intent to perform revascularization Early Invasive: Diagnostic angiography with intent to perform revascularization l Cath anticipated within 4-24 hours l Follows a foundation of risk-directed medical therapy Selectively Invasive (or Early Conservative): Invasive evaluation only if optimal medical management fails Selectively Invasive (or Early Conservative): Invasive evaluation only if optimal medical management fails Note: From the ED perspective, both strategies involve risk-directed, evidence-based medical therapy Note: From the ED perspective, both strategies involve risk-directed, evidence-based medical therapy

Case Studies in Upstream Management How Many Ways Can We Cut the Cake? Consider Case Scenario 1: Consider Case Scenario 1: l 55 year-old man with chest pain syndrome for 4 hours l Smoker, diabetic, normal renal function l Troponin not elevated; nonspecific ST-T wave changes l Unless he deteriorates, not likely to go to cath before tomorrow Optimal Upstream Therapy in Emergency Department: Optimal Upstream Therapy in Emergency Department: l Enoxaparin or UFH l Strongly consider clopidogrel l GPI if troponin overnight Consider Case Scenario 1: Consider Case Scenario 1: l 55 year-old man with chest pain syndrome for 4 hours l Smoker, diabetic, normal renal function l Troponin not elevated; nonspecific ST-T wave changes l Unless he deteriorates, not likely to go to cath before tomorrow Optimal Upstream Therapy in Emergency Department: Optimal Upstream Therapy in Emergency Department: l Enoxaparin or UFH l Strongly consider clopidogrel l GPI if troponin overnight

Case Studies in Upstream Management How Many Ways Can We Cut the Cake? Consider Case Scenario 2: Consider Case Scenario 2: l 55 year-old man with chest pain syndrome for 4 hours l Smoker, diabetic, normal renal function l Troponin not elevated; Non-specific ST-T wave changes l Going to cath later today Optimal Upstream Therapy in Emergency Department: Optimal Upstream Therapy in Emergency Department: l Bivalirudin or UFH l Stronger support for clopidogrel Consider Case Scenario 2: Consider Case Scenario 2: l 55 year-old man with chest pain syndrome for 4 hours l Smoker, diabetic, normal renal function l Troponin not elevated; Non-specific ST-T wave changes l Going to cath later today Optimal Upstream Therapy in Emergency Department: Optimal Upstream Therapy in Emergency Department: l Bivalirudin or UFH l Stronger support for clopidogrel

Case Studies in Upstream Management How Many Ways Can We Cut the Cake? Consider Case Scenario 3: Consider Case Scenario 3: 80 year-old woman with chest pain syndrome for 4 hours 80 year-old woman with chest pain syndrome for 4 hours l Smoker, diabetic, Cr Cl 40 ml/min l Troponin elevated; ST-T Wave changes l Going to cath later today Optimal Upstream Therapy in Emergency Department: Optimal Upstream Therapy in Emergency Department: l Bivalirudin l Consider clopidogrel, but CABG risk may be higher here Consider Case Scenario 3: Consider Case Scenario 3: 80 year-old woman with chest pain syndrome for 4 hours 80 year-old woman with chest pain syndrome for 4 hours l Smoker, diabetic, Cr Cl 40 ml/min l Troponin elevated; ST-T Wave changes l Going to cath later today Optimal Upstream Therapy in Emergency Department: Optimal Upstream Therapy in Emergency Department: l Bivalirudin l Consider clopidogrel, but CABG risk may be higher here

Case Studies in Upstream Management How Many Ways Can We Cut the Cake? Consider Case Scenario 4: Consider Case Scenario 4: l 80 year-old woman with chest pain syndrome for 4 hours l Smoker, diabetic, Cr Cl 40 ml/min l Troponin elevated, NSSTTΔs l No catheterization lab in hospital; transfer time uncertain Optimal Upstream Therapy: Optimal Upstream Therapy: l Enoxaparin or fondaparinux l Strongly consider clopidogrel l Consider renal-adjusted small-molecule GPI Consider Case Scenario 4: Consider Case Scenario 4: l 80 year-old woman with chest pain syndrome for 4 hours l Smoker, diabetic, Cr Cl 40 ml/min l Troponin elevated, NSSTTΔs l No catheterization lab in hospital; transfer time uncertain Optimal Upstream Therapy: Optimal Upstream Therapy: l Enoxaparin or fondaparinux l Strongly consider clopidogrel l Consider renal-adjusted small-molecule GPI

Recent ACS Trials Forging A New Paradigm for Upstream Management ISCHEMIA BLEEDING

Optimal Upstream Management Ischemic Risk Assessment Basis for Assessment: Basis for Assessment: l Pain story l Background ASCVD risk l ECG l Troponin in pertinent time frame l Predictive score Options: Options: l UFH and enoxaparin established l Bivalirudin and fondaparinux: New options that are non-inferior l Antiplatelet therapy increasingly more important as ischemic risk increases Basis for Assessment: Basis for Assessment: l Pain story l Background ASCVD risk l ECG l Troponin in pertinent time frame l Predictive score Options: Options: l UFH and enoxaparin established l Bivalirudin and fondaparinux: New options that are non-inferior l Antiplatelet therapy increasingly more important as ischemic risk increases

Recent ACS Trials Forging A New Paradigm for Upstream Management ISCHEMIA BLEEDING

Optimal Upstream Management Bleeding Risk Assessment Basis for Assessment: Basis for Assessment: l Female > male l Old > young l CKD > normal renal function l Anemic > normal H/H l Diabetic > nondiabetic Options: Options: l Bivalirudin and fondaparinux associated with less bleeding than UFH and enoxaparin l Clopidogrel not reversible l GPIs increase bleeding risk but with renal-adjusted doses seem to have reasonable safety margin Basis for Assessment: Basis for Assessment: l Female > male l Old > young l CKD > normal renal function l Anemic > normal H/H l Diabetic > nondiabetic Options: Options: l Bivalirudin and fondaparinux associated with less bleeding than UFH and enoxaparin l Clopidogrel not reversible l GPIs increase bleeding risk but with renal-adjusted doses seem to have reasonable safety margin

A New Paradigm in Upstream Management ISCHEMIA BLEEDING TIME TO CATH

Optimal Upstream Management Time to Catheterization Basis for Assessment: Basis for Assessment: l Time to catheterization is frequently an unknown variable in the ED for UA/NSTEMI patients: May have impact on initial antithrombin selection l Improved collaboration among CV specialists and ED physicians and perhaps, development of EDICT for ACS therapeutic teams would lead to more consistent management of ACS and predictability of time to catheterization Options: Options: l With shorter times to catheterization, increasing support for bivalirudin l With longer times to catheterization or medical management, increasing support for enoxaparin and UFH l Role of fondaparinux in patients going to cath may be problematic and not adequately tested l Note Dr. Gibsons switch data re: bivalirudin Basis for Assessment: Basis for Assessment: l Time to catheterization is frequently an unknown variable in the ED for UA/NSTEMI patients: May have impact on initial antithrombin selection l Improved collaboration among CV specialists and ED physicians and perhaps, development of EDICT for ACS therapeutic teams would lead to more consistent management of ACS and predictability of time to catheterization Options: Options: l With shorter times to catheterization, increasing support for bivalirudin l With longer times to catheterization or medical management, increasing support for enoxaparin and UFH l Role of fondaparinux in patients going to cath may be problematic and not adequately tested l Note Dr. Gibsons switch data re: bivalirudin

Chest Pain or ACS Committee Chest Pain or ACS Committee Meets quarterly or PRN Meets quarterly or PRN l PRN means after... Pertinent, practice-changing new study publishedPertinent, practice-changing new study published ACC / AHA / TCT meetingsACC / AHA / TCT meetings M & M or sentinel eventM & M or sentinel event New guidelines publishedNew guidelines published Chest Pain or ACS Committee Chest Pain or ACS Committee Meets quarterly or PRN Meets quarterly or PRN l PRN means after... Pertinent, practice-changing new study publishedPertinent, practice-changing new study published ACC / AHA / TCT meetingsACC / AHA / TCT meetings M & M or sentinel eventM & M or sentinel event New guidelines publishedNew guidelines published Optimal Management of NSTE ACS: ED to Cardiology A Functional Model

Chest Pain or ACS Committee comprised of: Chest Pain or ACS Committee comprised of: l Emergency physicians l Interventional cardiologists l Medical cardiologists l Hospitalists l CT surgeons l ED nursing l Cath lab nursing l CCU nursing l Lab l Imaging Chest Pain or ACS Committee comprised of: Chest Pain or ACS Committee comprised of: l Emergency physicians l Interventional cardiologists l Medical cardiologists l Hospitalists l CT surgeons l ED nursing l Cath lab nursing l CCU nursing l Lab l Imaging Optimal Management of NSTE ACS ED to Cardiology A Functional Model

Chest Pain or ACS Committee discusses: Chest Pain or ACS Committee discusses: l Protocols and standing orders l Practice variations versus evidence l Time to catheterization predictability l Reduction of medical errors in ACS care l DTB times l QI issues (CRUSADE / NRMI / ACTION) l Transfers in, transfers out l New data: How should it impact our protocols? Chest Pain or ACS Committee discusses: Chest Pain or ACS Committee discusses: l Protocols and standing orders l Practice variations versus evidence l Time to catheterization predictability l Reduction of medical errors in ACS care l DTB times l QI issues (CRUSADE / NRMI / ACTION) l Transfers in, transfers out l New data: How should it impact our protocols? Optimal Management of NSTE ACS ED to Cardiology A Functional Model

ED physicians should be using optimal, evidence- based, guideline-consistent medical therapy for NSTE ACS ED physicians should be using optimal, evidence- based, guideline-consistent medical therapy for NSTE ACS ED physicians must work with their colleagues in cardiology to develop pathways and approaches (EDICT for ACS) for proper use of antithrombotic and antiplatelet therapy at all levels ED physicians must work with their colleagues in cardiology to develop pathways and approaches (EDICT for ACS) for proper use of antithrombotic and antiplatelet therapy at all levels ED physicians should facilitate early invasive management of ACS whenever feasible and appropriate ED physicians should facilitate early invasive management of ACS whenever feasible and appropriate ED physicians should address issues related to bleeding risk as well as ischemic risk. ED physicians should address issues related to bleeding risk as well as ischemic risk. A seamless transition of care is most likely to result in good outcomes. A seamless transition of care is most likely to result in good outcomes. ED physicians should be using optimal, evidence- based, guideline-consistent medical therapy for NSTE ACS ED physicians should be using optimal, evidence- based, guideline-consistent medical therapy for NSTE ACS ED physicians must work with their colleagues in cardiology to develop pathways and approaches (EDICT for ACS) for proper use of antithrombotic and antiplatelet therapy at all levels ED physicians must work with their colleagues in cardiology to develop pathways and approaches (EDICT for ACS) for proper use of antithrombotic and antiplatelet therapy at all levels ED physicians should facilitate early invasive management of ACS whenever feasible and appropriate ED physicians should facilitate early invasive management of ACS whenever feasible and appropriate ED physicians should address issues related to bleeding risk as well as ischemic risk. ED physicians should address issues related to bleeding risk as well as ischemic risk. A seamless transition of care is most likely to result in good outcomes. A seamless transition of care is most likely to result in good outcomes. Optimal Management of NSTE ACS ED to Cardiology Summary and Game Plan

UPSTREAM ACS CARE Collaborations, Models, and Protocols UPSTREAM ACS CARE Collaborations, Models, and Protocols The Mandate to Cooperate and Collaborate ED EmergencyDepartment IC InterventionalCardiology + + T TherapeuticTeams + + ACS for

UPSTREAM ACS CARE Collaborations, Models, and Protocols UPSTREAM ACS CARE Collaborations, Models, and Protocols The Mandate to Cooperate and Collaborate ED EmergencyDepartment IC InterventionalCardiology + + T TherapeuticTeams + + ACS for Same model applies to STEMI care: Its not just a discussion of D2B time Same model applies to STEMI care: Its not just a discussion of D2B time

A Prospective, Randomized Comparison of Bivalirudin vs. Heparin Plus Glycoprotein IIb/IIIa Inhibitors During Primary Angioplasty in Acute Myocardial Infarction – 30 Day Results – Gregg W. Stone MD For the HORIZONS AMI Investigators TCT 2007 HORIZONS AMI

Harmonizing Outcomes with Revascularization and Stents in AMI 3400* pts with STEMI with symptom onset 12 hours UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide) Bivalirudin monotherapy (± provisional GP IIb/IIIa) Aspirin, thienopyridine R 1:1 Pharmacology Arm Primary Endpoints* 30 Day Intention to Treat Population * All stent randomization results are still blinded HORIZONS AMI Emergent angiography, followed by triage to… Primary PCI CABG– Medical Rx –

Inclusion Criteria STEMI >20 mins and 20 mins and <12 hours in duration l ST-segment elevation of 1 mm in 2 contiguous leads; or l Presumably new left bundle branch block; or l True posterior MI with ST depression of 1 mm in 2 contiguous anterior leads l Patients with cardiogenic shock, left main disease, etc., were not excluded Age 18 years Age 18 years Written, informed consent Written, informed consent STEMI >20 mins and 20 mins and <12 hours in duration l ST-segment elevation of 1 mm in 2 contiguous leads; or l Presumably new left bundle branch block; or l True posterior MI with ST depression of 1 mm in 2 contiguous anterior leads l Patients with cardiogenic shock, left main disease, etc., were not excluded Age 18 years Age 18 years Written, informed consent Written, informed consent

Principal Exclusion Criteria Contraindication to any of the study medications Contraindication to any of the study medications Prior administration of thrombolytic therapy, bivalirudin, GP IIb/IIIa inhibitors, LMWH or fondaparinux for the present admission (prior UFH allowed) Prior administration of thrombolytic therapy, bivalirudin, GP IIb/IIIa inhibitors, LMWH or fondaparinux for the present admission (prior UFH allowed) Current use of coumadin Current use of coumadin History of bleeding diathesis or known coagulopathy (including HIT), or will refuse blood transfusions History of bleeding diathesis or known coagulopathy (including HIT), or will refuse blood transfusions History of intracerebral mass, aneurysm, AVM, or hemorrhagic stroke; stroke or TIA within 6 months or any permanent neurologic deficit; GI or GU bleed within 2 months, or major surgery within 6 weeks; recent or known platelet count <100,000 cells/mm 3 or hgb <10 g/dL History of intracerebral mass, aneurysm, AVM, or hemorrhagic stroke; stroke or TIA within 6 months or any permanent neurologic deficit; GI or GU bleed within 2 months, or major surgery within 6 weeks; recent or known platelet count <100,000 cells/mm 3 or hgb <10 g/dL Planned elective surgical procedure that would necessitate interruption of thienopyridines during the first 6 months post enrollment Planned elective surgical procedure that would necessitate interruption of thienopyridines during the first 6 months post enrollment Contraindication to any of the study medications Contraindication to any of the study medications Prior administration of thrombolytic therapy, bivalirudin, GP IIb/IIIa inhibitors, LMWH or fondaparinux for the present admission (prior UFH allowed) Prior administration of thrombolytic therapy, bivalirudin, GP IIb/IIIa inhibitors, LMWH or fondaparinux for the present admission (prior UFH allowed) Current use of coumadin Current use of coumadin History of bleeding diathesis or known coagulopathy (including HIT), or will refuse blood transfusions History of bleeding diathesis or known coagulopathy (including HIT), or will refuse blood transfusions History of intracerebral mass, aneurysm, AVM, or hemorrhagic stroke; stroke or TIA within 6 months or any permanent neurologic deficit; GI or GU bleed within 2 months, or major surgery within 6 weeks; recent or known platelet count <100,000 cells/mm 3 or hgb <10 g/dL History of intracerebral mass, aneurysm, AVM, or hemorrhagic stroke; stroke or TIA within 6 months or any permanent neurologic deficit; GI or GU bleed within 2 months, or major surgery within 6 weeks; recent or known platelet count <100,000 cells/mm 3 or hgb <10 g/dL Planned elective surgical procedure that would necessitate interruption of thienopyridines during the first 6 months post enrollment Planned elective surgical procedure that would necessitate interruption of thienopyridines during the first 6 months post enrollment

Study Medications (i) Unfractionated heparin Unfractionated heparin l 60 U/kg IV*; subsequent boluses titrated by nomogram to ACT 200-250 secs; terminated at procedure end unless prolonged antithrombin needed Bivalirudin Bivalirudin l 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 l Routine use in UFH arm; recommended only for giant thrombus or refractory no reflow in bivalirudin arm l Abciximab or double bolus eptifibatide as per investigator discretion – dosing per FDA label, renal adjusted; continued for 12 (abcx) or 12-18 (eptif) Unfractionated heparin Unfractionated heparin l 60 U/kg IV*; subsequent boluses titrated by nomogram to ACT 200-250 secs; terminated at procedure end unless prolonged antithrombin needed Bivalirudin Bivalirudin l 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 l Routine use in UFH arm; recommended only for giant thrombus or refractory no reflow in bivalirudin arm l Abciximab or double bolus eptifibatide as per investigator discretion – dosing per FDA label, renal adjusted; continued for 12 (abcx) or 12-18 (eptif) * If pre randomization UFH administered, ACT is checked first ** If pre randomization UFH administered, started 30 after last bolus

Study Medications (ii) Aspirin Aspirin l 324 mg chewed non enteric coated or 500 mg IV in the ER, followed by 300-325 mg/day in-hospital and 75-81 mg/day as out patient indefinitely Thienopyridines Thienopyridines l Clopidogrel 300 mg or 600 mg loading dose (per investigator discretion) in the ER followed by 75 mg PO QD for at least 6 months (1 year or longer recommended) Ticlopidine load + daily dose permissible if clopiodgrel is unavailable or patient is allergicTiclopidine load + daily dose permissible if clopiodgrel is unavailable or patient is allergic Other Other l Beta blockers: IV pre procedure followed by PO QD in the absence of contraindications; ACE inhibitors for HTN, CHF or LVEF 100 mg/dl Aspirin Aspirin l 324 mg chewed non enteric coated or 500 mg IV in the ER, followed by 300-325 mg/day in-hospital and 75-81 mg/day as out patient indefinitely Thienopyridines Thienopyridines l Clopidogrel 300 mg or 600 mg loading dose (per investigator discretion) in the ER followed by 75 mg PO QD for at least 6 months (1 year or longer recommended) Ticlopidine load + daily dose permissible if clopiodgrel is unavailable or patient is allergicTiclopidine load + daily dose permissible if clopiodgrel is unavailable or patient is allergic Other Other l Beta blockers: IV pre procedure followed by PO QD in the absence of contraindications; ACE inhibitors for HTN, CHF or LVEF 100 mg/dl

2 Primary Endpoints (at 30 Days) 1) Net Adverse Clinical Events 2) Major Bleeding (non CABG) Intracranial bleeding intraocular bleeding Retroperitoneal bleeding Access site bleed requiring intervention/surgery Hematoma 5 cm Hgb 3g/dL with an overt source Hgb 4g/dL w/o overt source Reoperation for bleeding Blood product transfusion and

2 Primary Endpoints (at 30 Days) 1) Net Adverse Clinical Events 2) Major Bleeding (non CABG) = or All cause death All cause death Reinfarction Reinfarction Ischemic TVR Ischemic TVR Stroke Stroke Major adverse cardiovascular events (major secondary endpoint)

Baseline Characteristics UFH + GP IIb/IIIa (N=1802)Bivalirudin(N=1800) Age (years) 60.7 [52.9, 70.1] 59.8 [51.9, 69.5] Male76.1%77.1% Diabetes17.3%15.6% Hypertension55.2%51.8% Hyperlipidemia42.7%43.4% Current smoking 45.0%47.2% Prior MI 11.4%10.4% Prior PCI 11.0%10.5% Prior CABG 2.6%3.3% *P=0.04 *

Diff = Diff = 0.0% [-1.6, 1.5] RR = 0.99 RR = 0.99 [0.76, 1.30] P sup = 1.00 Primary Outcome Measures (ITT) Diff = Diff = -3.3% [-5.0, -1.6] RR = RR = 0.60 [0.46, 0.77] P NI 0.0001 P sup 0.0001 Diff = Diff = -2.9% [-4.9, -0.8] RR = RR = 0.76 [0.63, 0.92] P NI 0.0001 P sup = 0.006 1 endpoint *Not related to CABG **MACE = All cause death, reinfarction, ischemic TVR or stroke

30 Day Net Adverse Clinical Events *MACE or major bleeding (non CABG) Number at risk Bivalirudin1800166016331626162016071544 Heparin + GPIIb/IIIa1802163515911578156915521482 Primary Endpoint Net adverse clinical events (%)* Primary Endpoint Net adverse clinical events (%)* Time in Days 12.2% 9.3% HR [95%CI] = 0.75 [0.62, 0.92] P=0.006 HR [95%CI] = 0.75 [0.62, 0.92] P=0.006 Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800)

Number at risk Bivalirudin1800169716751668166416531590 Heparin + GPIIb/IIIa1802165116171606159815811511 Primary Endpoint Major Bleeding (%) Primary Endpoint Major Bleeding (%) Time in Days 8.4% 5.0% HR [95%CI] = 0.59 [0.45, 0.76] P<0.0001 HR [95%CI] = 0.59 [0.45, 0.76] P<0.0001 Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800) 30 Day Major Bleeding (non-CABG)

30 Day Bleeding Endpoints UFH + GP IIb/IIIa (N=1802)Bivalirudin(N=1800) P Value Protocol Major, non CABG* 8.3%4.9%<0.0001 Protocol Major, All 10.8%6.8%<0.0001 Protocol Minor 15.4%8.6%<0.0001 Blood transfusion 3.5%2.1%0.01 TIMI Major 5.0%3.1%0.003 TIMI Minor 4.6%2.8%0.008 TIMI Major or Minor 9.6%5.9%<0.0001 GUSTO LT** or Severe 0.6%0.4%0.65 GUSTO Moderate 5.0%3.1%0.003 GUSTO LT or Sev or Mod 5.6%3.5%0.003 *Primary endpoint; **Life threatening

30 Day Major Adverse CV Events Number at risk Bivalirudin1800171617011695 1689 16731608 Heparin + GPIIb/IIIa180217441712 169916881668 1590 Major adverse CV events (%)* Time in Days 5.5% HR [95%CI] = 1.00 [0.75, 1.32] P=0.98 HR [95%CI] = 1.00 [0.75, 1.32] P=0.98 Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800) *MACE = All cause death, reinfarction, ischemic TVR or stroke

30 Day MACE Components* UFH + GP IIb/IIIa (N=1802)Bivalirudin(N=1800) P Value Death3.1%2.1%0.058 - Cardiac - Cardiac2.9%1.8%0.035 - Non cardiac - Non cardiac0.2%0.3%0.75 Reinfarction1.8%1.8%0.90 - Q-wave - Q-wave1.2%1.4%0.66 - Non Q-wave - Non Q-wave0.7%0.4%0.50 Ischemic TVR 1.9%2.6%0.18 - Ischemic TLR - Ischemic TLR1.8%2.5%0.14 - Ischemic remote TVR - Ischemic remote TVR0.3%0.3%1.0 Stroke0.6%0.7%0.69 *CEC adjudicated

30 Day Mortality: Cardiac and Non Cardiac Number at risk Bivalirudin 1800175817511746174217291666 Heparin + GPIIb/IIIa 1802176417481736172817071630 Death (%) Time in Days 2.9% 1.8% Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800) 0.3% 0.2% Cardiac Non cardiac HR [95%CI] = 0.62 [0.40, 0.96] P=0.029 HR [95%CI] = 0.62 [0.40, 0.96] P=0.029

Primary Management Strategy* UFH + GP IIb/IIIa Inhibitor N=1802 Bivalirudin Monotherapy N=1800 Primary PCI Deferred PCI CABG Medical Rx *Primary ITT analysis includes all pts regardless of treatment

Primary PCI Cohort (N=3,340; 92.7%) Diff = - Diff = -0.1% [-1.6, 1.5] RR = 0.99 RR = 0.99 [0.75, 1.32] P sup = 1.00 Diff = Diff = -3.5% [-5.2, -1.7] RR = RR = 0.59 [0.46, 0.77] P NI 0.0001 P sup 0.0001 Diff = Diff = -3.0% [-5.2, -2.9] RR = RR = 0.75 [0.62, 0.92] P NI 0.0001 P sup = 0.005 *Not related to CABG **MACE = All cause death, reinfarction, ischemic TVR or stroke

30 Day Net Clinical Events: PCI Cohort *MACE or major bleeding (non CABG) Number at risk Bivalirudin1678155415281521151615051448 Heparin + GPIIb/IIIa1662151014671456144814361372 Net Adverse Clinical Events (%)* Time in Days 12.3% 9.2% HR [95%CI] = 0.74 [0.60, 0.92] P=0.005 HR [95%CI] = 0.74 [0.60, 0.92] P=0.005 Heparin + GPIIb/IIIa inhibitor (n=1662) Bivalirudin monotherapy (n=1678)

30 Day Major Bleeding: PCI Cohort Number at risk Bivalirudin1678159015681561155815481490 Heparin + GPIIb/IIIa1662152514921482147514631399 Major Bleeding (Non-CABG) (%) Time in Days 8.6% 5.1% HR [95%CI] = 0.58 [0.44, 0.76] P<0.0001 HR [95%CI] = 0.58 [0.44, 0.76] P<0.0001 Heparin + GPIIb/IIIa inhibitor (n=1662) Bivalirudin monotherapy (n=1678)

30 Day Major Adverse CV Events: PCI Cohort *MACE = All cause death, reinfarction, ischemic TVR or stroke Number at risk Bivalirudin1678160615921585158115671509 Heparin + GPIIb/IIIa1662161315811570156115461474 Major Adverse CV Events (%)* Time in Days 5.5% 5.4% Heparin + GPIIb/IIIa inhibitor (n=1662) Bivalirudin monotherapy (n=1678) HR [95%CI] = 1.00 [0.74, 1.33] P=0.98 HR [95%CI] = 1.00 [0.74, 1.33] P=0.98

Number at risk Bivalirudin 1678164716401635163216201563 Heparin + GPIIb/IIIa 1662163116151604159815831512 Death (%) Time in days 1.8% Heparin + GPIIb/IIIa inhibitor (n=1662) Bivalirudin monotherapy (n=1678) 0.2% 0.1% Cardiac Non cardiac 30 Day Mortality: PCI Cohort 2.8% HR [95%CI] = 0.63 [0.40, 0.99] P=0.049 HR [95%CI] = 0.63 [0.40, 0.99] P=0.049

30 Day Stent Thrombosis (N=3,124) 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 *Protocol definition of stent thrombosis, CEC adjudicated

Conclusions In this large scale, prospective, randomized trial of pts with STEMI undergoing a primary PCI management strategy, compared to UFH plus the routine use of GP IIb/IIIa inhibitors, bivalirudin monotherapy with GP IIb/IIIa inhibitors reserved for suboptimal PCI outcomes resulted in: In this large scale, prospective, randomized trial of pts with STEMI undergoing a primary PCI management strategy, compared to UFH plus the routine use of GP IIb/IIIa inhibitors, bivalirudin monotherapy with GP IIb/IIIa inhibitors reserved for suboptimal PCI outcomes resulted in: l A significant 24% reduction in the 30 day primary endpoint of net adverse clinical events l A significant 40% reduction in the 30 day primary endpoint of major bleeding In this large scale, prospective, randomized trial of pts with STEMI undergoing a primary PCI management strategy, compared to UFH plus the routine use of GP IIb/IIIa inhibitors, bivalirudin monotherapy with GP IIb/IIIa inhibitors reserved for suboptimal PCI outcomes resulted in: In this large scale, prospective, randomized trial of pts with STEMI undergoing a primary PCI management strategy, compared to UFH plus the routine use of GP IIb/IIIa inhibitors, bivalirudin monotherapy with GP IIb/IIIa inhibitors reserved for suboptimal PCI outcomes resulted in: l A significant 24% reduction in the 30 day primary endpoint of net adverse clinical events l A significant 40% reduction in the 30 day primary endpoint of major bleeding

Risk Stratification is an essential function of the ED evaluation. Risk Stratification is an essential function of the ED evaluation. Treatment stratification must be coupled to risk stratification. Treatment stratification must be coupled to risk stratification. Risk stratification must be considered for bleeding as well as ischemia. Risk stratification must be considered for bleeding as well as ischemia. Time issues also direct therapeutic choices, but management of these issues must be multidisciplinary. Time issues also direct therapeutic choices, but management of these issues must be multidisciplinary. We now have evidence across the ACS spectrum that bivalirudin is associated with superior bleeding outcomes. We now have evidence across the ACS spectrum that bivalirudin is associated with superior bleeding outcomes. A seamless transition of care is most likely to result in good outcomes. A seamless transition of care is most likely to result in good outcomes. Risk Stratification is an essential function of the ED evaluation. Risk Stratification is an essential function of the ED evaluation. Treatment stratification must be coupled to risk stratification. Treatment stratification must be coupled to risk stratification. Risk stratification must be considered for bleeding as well as ischemia. Risk stratification must be considered for bleeding as well as ischemia. Time issues also direct therapeutic choices, but management of these issues must be multidisciplinary. Time issues also direct therapeutic choices, but management of these issues must be multidisciplinary. We now have evidence across the ACS spectrum that bivalirudin is associated with superior bleeding outcomes. We now have evidence across the ACS spectrum that bivalirudin is associated with superior bleeding outcomes. A seamless transition of care is most likely to result in good outcomes. A seamless transition of care is most likely to result in good outcomes. Optimal Management of ACS ED to Cardiology Summary and Game Plan

Chairman and Distinguished Faculty Where Metal Meets Thrombus and Vascular Endothelium A Case Study Analysis of Upstream Interventions Getting in the ACS Stream of Things

ACS Case Presentation #1 77 year old female presents to ED with 2 weeks of progressive angina, one episode lasting 90 minutes 77 year old female presents to ED with 2 weeks of progressive angina, one episode lasting 90 minutes l History of Type 2 DM, HTN, cigarette smoking l Weight 65 kg ECG non-specific, POS TnI 0.79 (ULN 0.5), nl CKMB, CrCL 40 ml/min, Hgb 9.7 g/dl ECG non-specific, POS TnI 0.79 (ULN 0.5), nl CKMB, CrCL 40 ml/min, Hgb 9.7 g/dl Given ASA, 300 mg clopidogrel, 5 mg IV metoprolol, IV NTG Given ASA, 300 mg clopidogrel, 5 mg IV metoprolol, IV NTG Continued chest pain Continued chest pain l Anticoagulation options in the ED? l Risk stratification strategy? l Which upstream strategy makes most sense? l Collaboration with cardiology colleagues? 77 year old female presents to ED with 2 weeks of progressive angina, one episode lasting 90 minutes 77 year old female presents to ED with 2 weeks of progressive angina, one episode lasting 90 minutes l History of Type 2 DM, HTN, cigarette smoking l Weight 65 kg ECG non-specific, POS TnI 0.79 (ULN 0.5), nl CKMB, CrCL 40 ml/min, Hgb 9.7 g/dl ECG non-specific, POS TnI 0.79 (ULN 0.5), nl CKMB, CrCL 40 ml/min, Hgb 9.7 g/dl Given ASA, 300 mg clopidogrel, 5 mg IV metoprolol, IV NTG Given ASA, 300 mg clopidogrel, 5 mg IV metoprolol, IV NTG Continued chest pain Continued chest pain l Anticoagulation options in the ED? l Risk stratification strategy? l Which upstream strategy makes most sense? l Collaboration with cardiology colleagues?

Decision made to pursue rapid invasive risk stratification Decision made to pursue rapid invasive risk stratification l High-risk features Elevated troponinElevated troponin Ongoing chest pain despite medical therapyOngoing chest pain despite medical therapy Antithrombin therapy choices Antithrombin therapy choices l Risk for bleeding Age, Female sex, renal insufficiency, anemiaAge, Female sex, renal insufficiency, anemia l Bivalirudin bolus and drip initiated Angiography Angiography Decision made to pursue rapid invasive risk stratification Decision made to pursue rapid invasive risk stratification l High-risk features Elevated troponinElevated troponin Ongoing chest pain despite medical therapyOngoing chest pain despite medical therapy Antithrombin therapy choices Antithrombin therapy choices l Risk for bleeding Age, Female sex, renal insufficiency, anemiaAge, Female sex, renal insufficiency, anemia l Bivalirudin bolus and drip initiated Angiography Angiography ACS Case Presentation #1

A 76 year-old white male with h/o stent to LAD 1 year ago A 76 year-old white male with h/o stent to LAD 1 year ago Presents with multiple episodes of recurrent chest pain including rest pain over 2 days Presents with multiple episodes of recurrent chest pain including rest pain over 2 days Pain similar to time of PCI in past Pain similar to time of PCI in past Symptoms relieved in ED with sl NTG Symptoms relieved in ED with sl NTG PMH: IDDM, HTN, CHOL elevation PMH: IDDM, HTN, CHOL elevation PE: benign (weight 84 kg). PE: benign (weight 84 kg). Labs: Hgb 10.7, Cr 1.9, CK 173/2, Tr <0.03. Labs: Hgb 10.7, Cr 1.9, CK 173/2, Tr <0.03. ECG (next slide) ECG (next slide) A 76 year-old white male with h/o stent to LAD 1 year ago A 76 year-old white male with h/o stent to LAD 1 year ago Presents with multiple episodes of recurrent chest pain including rest pain over 2 days Presents with multiple episodes of recurrent chest pain including rest pain over 2 days Pain similar to time of PCI in past Pain similar to time of PCI in past Symptoms relieved in ED with sl NTG Symptoms relieved in ED with sl NTG PMH: IDDM, HTN, CHOL elevation PMH: IDDM, HTN, CHOL elevation PE: benign (weight 84 kg). PE: benign (weight 84 kg). Labs: Hgb 10.7, Cr 1.9, CK 173/2, Tr <0.03. Labs: Hgb 10.7, Cr 1.9, CK 173/2, Tr <0.03. ECG (next slide) ECG (next slide) ACS Case Presentation #2

New anterior and lateral ST / T changes. Case #2: ECG

Based on your clinical assessment, this patients risk of short-term (30-Day) ischemic events is: A.Low B.Moderate C.High D.Very high A.Low B.Moderate C.High D.Very high ACS Case Presentation #2

Which of this patients baseline factors do you consider most important for determining this patients ischemic risk? A. Advanced age B. Anginal pattern C. ECG findings D. Biomarkers A. Advanced age B. Anginal pattern C. ECG findings D. Biomarkers * ACS Case Presentation #2

Based on your clinical assessment, this patients risk of incurring a short-term (30-Day) hemorrhagic event related to PCI is: A.Low B.Moderate C.High D.Very high A.Low B.Moderate C.High D.Very high ACS Case Presentation #2

Which of this patients baseline factors do you consider most important for determining hemorrhagic risk? A. Advanced age B. Hypertension C. Impaired creatinine clearance D. Anemia A. Advanced age B. Hypertension C. Impaired creatinine clearance D. Anemia * ACS Case Presentation #2

In ACS patients, do you alter your choice of anticoagulant/ antithrombotic therapy based upon an assessment of the individual patients risk of hemorrhagic complications? A. Yes B. No A. Yes B. No * ACS Case Presentation #2

Among those of you who would alter or customize antithrombotic therapy based on an ACS patients risk for hemorrhage in the setting of PCI, which of the following baseline characteristics would you consider most important in supporting the use of a hemorrhage-minimizing anithrombotic regimen: A. Elderly and female B. Renal insufficiency and positive biomarkers C. Anemia and high risk ischemic features A. Elderly and female B. Renal insufficiency and positive biomarkers C. Anemia and high risk ischemic features * ACS Case Presentation #2

What would you likely use for anticoagulation in this patient, prior to catheterization, if you anticipated catheterization would occur in 4 hours or less? A. Unfractionated heparin alone B. Enoxaparin alone C. Bivalirudin alone D. A heparin with a GP IIb/IIIa inhibitor E. Fondaparinux A. Unfractionated heparin alone B. Enoxaparin alone C. Bivalirudin alone D. A heparin with a GP IIb/IIIa inhibitor E. Fondaparinux * ACS Case Presentation #2

What would your choice of upstream anticoagulation therapy be, if you anticipated cardiac catheterization the same day (within 12 hours)? A. Unfractionated heparin alone B. Enoxaparin alone C. Bivalirudin alone D. A heparin with a GP IIb/IIIa inhibitor E. Fondaparinux A. Unfractionated heparin alone B. Enoxaparin alone C. Bivalirudin alone D. A heparin with a GP IIb/IIIa inhibitor E. Fondaparinux * ACS Case Presentation #2

What would your choice of upstream anticoagulation therapy be, if you anticipated cardiac catheterization the next day (within 24 hours)? A. Unfractionated heparin alone B. Enoxaparin alone C. Bivalirudin alone D. A heparin with a GP IIb/IIIa inhibitor E. Fondaparinux A. Unfractionated heparin alone B. Enoxaparin alone C. Bivalirudin alone D. A heparin with a GP IIb/IIIa inhibitor E. Fondaparinux * ACS Case Presentation #2

At this point, your anticoagulation regimen for PCI in this patient would be? A. Additional heparin B. Switch to enoxaparin C. Switch to bivalirudin D. Additional heparin plus GP IIb/IIIa inhibitor A. Additional heparin B. Switch to enoxaparin C. Switch to bivalirudin D. Additional heparin plus GP IIb/IIIa inhibitor * ACS Case Presentation #2

E. Magnus Ohman, MD, FRCPI, FACC Program Chairman Professor of Medicine Director, Program for Advanced Coronary Disease Division of Cardiology Duke University.

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E. Magnus Ohman, MD, FRCPI, FACC Program Chairman Professor of Medicine Director, Program for Advanced Coronary Disease Division of Cardiology Duke University.

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Presentation on theme: "E. Magnus Ohman, MD, FRCPI, FACC Program Chairman Professor of Medicine Director, Program for Advanced Coronary Disease Division of Cardiology Duke University."— Presentation transcript:

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