Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Program Chairman Chairman, Department of Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine.

Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Program Chairman Chairman, Department of Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine University of Pennsylvania School of Medicine Philadelphia, Pennsylvania Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Program Chairman Chairman, Department of Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine University of Pennsylvania School of Medicine Philadelphia, Pennsylvania Cardiovascular Emergencies New Dimensions and Critical Practice Advances Evidence-Based Management of Acute Coronary Syndromes: Optimizing Patient Outcomes in the Complex and Challenging Sphere of Cardiovascular Emergency Care Getting in the 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 and clinical relevance; stresses 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 session, emergency physicians will: As a result of this session, emergency physicians will: Learn to identify signs, symptoms, and prognostic features of acute coronary syndromes and related cardiovascular emergencies. Learn to identify signs, symptoms, and prognostic features of acute coronary syndromes and related cardiovascular emergencies. Learn to assess and implement optimal pharmacologic interventions, especially antithrombotic therapy in the upstream setting, for patients presenting with manifestations of ACS and related cardiovascular disease emergencies. Learn to assess and implement optimal pharmacologic interventions, especially antithrombotic therapy in the upstream setting, for patients presenting with manifestations of ACS and related cardiovascular disease emergencies. 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 with a focus on new 2007 ACC/AHA UA/NSTEMI Guidelines 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 with a focus on new 2007 ACC/AHA UA/NSTEMI Guidelines As a result of this session, emergency physicians will: As a result of this session, emergency physicians will: Learn to identify signs, symptoms, and prognostic features of acute coronary syndromes and related cardiovascular emergencies. Learn to identify signs, symptoms, and prognostic features of acute coronary syndromes and related cardiovascular emergencies. Learn to assess and implement optimal pharmacologic interventions, especially antithrombotic therapy in the upstream setting, for patients presenting with manifestations of ACS and related cardiovascular disease emergencies. Learn to assess and implement optimal pharmacologic interventions, especially antithrombotic therapy in the upstream setting, for patients presenting with manifestations of ACS and related cardiovascular disease emergencies. 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 with a focus on new 2007 ACC/AHA UA/NSTEMI Guidelines 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 with a focus on new 2007 ACC/AHA UA/NSTEMI Guidelines

Program Faculty Program Chairman Program Chairman Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Chairman, Department of Emergency Medicine Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine University of Pennsylvania School of Medicine of Medicine Philadelphia, Pennsylvania Program Chairman Program Chairman Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Chairman, Department of Emergency Medicine Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine University of Pennsylvania School of Medicine of Medicine Philadelphia, Pennsylvania Distinguished Presenters Judd E. Hollander, MD Professor and Clinical Research Director Department of Emergency Medicine University of Pennsylvania Philadelphia, Pennsylvania Sunil Rao, MD, FACC Director of Interventional Cardiology Veterans Administration Medical Center Assistant Professor Division of Cardiovascular Medicine Duke University Medical Center Durham, North Carolina Durham, North Carolina Distinguished Presenters Judd E. Hollander, MD Professor and Clinical Research Director Department of Emergency Medicine University of Pennsylvania Philadelphia, Pennsylvania Sunil Rao, MD, FACC Director of Interventional Cardiology Veterans Administration Medical Center Assistant Professor Division of Cardiovascular Medicine Duke University Medical Center Durham, North Carolina Durham, North Carolina

COI Faculty Disclosures 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 Judd E. Hollander, MD Grant/Research Support: Sanofi-Aventis, Biosite, Scios, The Medicines Company Consultant: Sanofi-Aventis, Biosite, Scios, The Medicines Company Speakers Bureau: Sanofi-Aventis, Biosite, Scios, The Medicines Company Sunil Rao, MD, FACC Grant/Research Support: Cordis Consultant: Sanofi-Aventis, The Medicines Company Speakers Bureau: Sanofi-Aventis, The Medicines Company, Cordis 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 Judd E. Hollander, MD Grant/Research Support: Sanofi-Aventis, Biosite, Scios, The Medicines Company Consultant: Sanofi-Aventis, Biosite, Scios, The Medicines Company Speakers Bureau: Sanofi-Aventis, Biosite, Scios, The Medicines Company Sunil Rao, MD, FACC Grant/Research Support: Cordis Consultant: Sanofi-Aventis, The Medicines Company Speakers Bureau: Sanofi-Aventis, The Medicines Company, Cordis

Acute Coronary Syndrome The 2007 ACC/AHA UA/NSTEMI Guidelines From the ED to CCU and Cath Lab Adherence Yields Better Outcomes Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Program Chairman Chairman, Department of Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine University of Pennsylvania School of Medicine Philadelphia, Pennsylvania Getting in the (Up)Stream of Things

Changing the Calculation Assessing Adherence to Guidelines Anderson HV, Bach RG, J Am Coll Cardiol 2005;46:1488-9. We need to invert the current equation to calculate an opportunity score for ACS patients rather than a risk score. Patients with higher baseline risks, such as the elderly, would have higher opportunity scores for benefit, even allowing for some of the greater risks from the treatment.

+ + Ischemic Discomfort at Rest No ST-segment Elevation Non-Q-wave MIUnstable Angina Q-wave MI ST-segment Elevation + + + + ( : positive cardiac biomarker) EmergencyDepartment In-hospital6-24hrs Presentation Acute Coronary Syndromes Clinical Spectrum and Presentation NSTEMI

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

We Must Risk Stratify Patients with Chest Pain Three levels of risk stratification are pertinent to Emergency Department Management Three levels of risk stratification are pertinent to Emergency Department Management 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 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 Emergency Department Management Three levels of risk stratification are pertinent to Emergency Department Management 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 Dynamic, ongoing risk-oriented evaluation of low- or intermediate-risk patients for conversion to high-risk status that is linked to intensity of treatment

Dynamic Risk Stratification Tools History and Physical History and Physical Standard EKG and non-standard EKG leads Standard 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 Biomarkers Biomarkers CPK-MB, Troponins I and T, Myoglobin CPK-MB, Troponins I and T, Myoglobin Ischemia-Modified Albumin Ischemia-Modified Albumin Non-Invasive Imaging Non-Invasive Imaging Echocardiogram Echocardiogram Stress testing Stress testing Technetium-99m-sestamibi Technetium-99m-sestamibi Predictive Indices/Schemes Predictive Indices/Schemes Better as research tools than for real-time clinical decision- making Better as research tools than for real-time clinical decision- making History and Physical History and Physical Standard EKG and non-standard EKG leads Standard 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 Biomarkers Biomarkers CPK-MB, Troponins I and T, Myoglobin CPK-MB, Troponins I and T, Myoglobin Ischemia-Modified Albumin Ischemia-Modified Albumin Non-Invasive Imaging Non-Invasive Imaging Echocardiogram Echocardiogram Stress testing Stress testing Technetium-99m-sestamibi Technetium-99m-sestamibi Predictive Indices/Schemes Predictive Indices/Schemes Better as research tools than for real-time clinical decision- making Better as research tools than for real-time clinical decision- making

Braunwald E, Antman EM, Beasley JW, et al: ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). J Am Coll Cardiol 2000;36:970-1062 (2002 update at www.acc.org; summary in Circulation 2002;106:1893-1900) Braunwald E, Antman EM, Beasley JW, et al: ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). J Am Coll Cardiol 2000;36:970-1062 (2002 update at www.acc.org; summary in Circulation 2002;106:1893-1900)www.acc.org Pollack CV, Roe MT, Peterson ED: 2002 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 2003;41:355-69 Pollack CV, Roe MT, Peterson ED: 2002 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 2003;41:355-69 Braunwald E, Antman EM, Beasley JW, et al: ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). J Am Coll Cardiol 2000;36:970-1062 (2002 update at www.acc.org; summary in Circulation 2002;106:1893-1900) Braunwald E, Antman EM, Beasley JW, et al: ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). J Am Coll Cardiol 2000;36:970-1062 (2002 update at www.acc.org; summary in Circulation 2002;106:1893-1900)www.acc.org Pollack CV, Roe MT, Peterson ED: 2002 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 2003;41:355-69 Pollack CV, Roe MT, Peterson ED: 2002 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 2003;41:355-69 NSTE ACS Optimal Therapy: 2002

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.www.acc.org www.americanheart.orgwww.acc.org 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, 2007

I I IIa IIb III The Guidelines Classes of Recommendations Intervention is useful and effective Evidence supportive; awaiting confirming data Evidence conflicts/opinions differ; neutral statement Intervention is not useful/effective and may be harmful Intervention is useful and effective Evidence supportive; awaiting confirming data Evidence conflicts/opinions differ; neutral statement Intervention is not useful/effective and may be harmful

Evidence-Based Approach to ACS Weighing the Evidence Class I: Benefit > > Risk Class I: Benefit > > Risk Class IIa: Benefit > Risk Class IIa: Benefit > Risk Class IIb: Benefit > Risk Class IIb: Benefit > Risk Class III: Risk > Benefit Class III: Risk > Benefit Class I: Benefit > > Risk Class I: Benefit > > Risk Class IIa: Benefit > Risk Class IIa: Benefit > Risk Class IIb: Benefit > Risk Class IIb: Benefit > Risk Class III: Risk > Benefit Class III: Risk > Benefit

The Guidelines Weighing the Evidence Weight of Evidence Grades Weight of Evidence Grades = Data from many large, randomized trials = Data from many large, randomized trials =Data from fewer, smaller randomized trials, careful analyses of nonrandomized studies, observational registries =Expert consensus

What Do The Guidelines Mean for Emergency Medicine Practice? Objective approach to risk stratification and treatment Objective approach to risk stratification and treatment Driven by risk, not patient geography Driven by risk, not patient geography Multidisciplinary Multidisciplinary Provides a foundation for communication, collaboration, and continuum of care from ED to cardiology service Provides a foundation for communication, collaboration, and continuum of care from ED to cardiology service 2007 Guidelines push for that continuum to be compressed in duration 2007 Guidelines push for that continuum to be compressed in duration Objective approach to risk stratification and treatment Objective approach to risk stratification and treatment Driven by risk, not patient geography Driven by risk, not patient geography Multidisciplinary Multidisciplinary Provides a foundation for communication, collaboration, and continuum of care from ED to cardiology service Provides a foundation for communication, collaboration, and continuum of care from ED to cardiology service 2007 Guidelines push for that continuum to be compressed in duration 2007 Guidelines push for that continuum to be compressed in duration

AcuteCoronarySyndromeAcuteCoronarySyndrome What Do The Guidelines Mean for Emergency Medicine Practice?

AcuteControversySyndromeAcuteControversySyndrome

AcuteConfusionalSyndromeAcuteConfusionalSyndrome

Acute Confounded Syndrome The Writing Committee believes that inadequate unconfounded, comparative information is available to recommend a preferred [anticoagulation] regimen when an early, invasive strategy is used for UA/NSTEMI, and physician and health care system preference, together with individualized patient application, is advised. The Writing Committee believes that inadequate unconfounded, comparative information is available to recommend a preferred [anticoagulation] regimen when an early, invasive strategy is used for UA/NSTEMI, and physician and health care system preference, together with individualized patient application, is advised. Acute Confounded Syndrome The Writing Committee believes that inadequate unconfounded, comparative information is available to recommend a preferred [anticoagulation] regimen when an early, invasive strategy is used for UA/NSTEMI, and physician and health care system preference, together with individualized patient application, is advised. The Writing Committee believes that inadequate unconfounded, comparative information is available to recommend a preferred [anticoagulation] regimen when an early, invasive strategy is used for UA/NSTEMI, and physician and health care system preference, together with individualized patient application, is advised. UA/NSTEMI Strategy Overview ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.

AcuteContentiousnessSyndromeAcuteContentiousnessSyndrome What Do The Guidelines Mean for Emergency Medicine Practice?

AcuteCollaborationSyndromeAcuteCollaborationSyndrome

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. 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.

Algorithm for Evaluation and Management of Patients Suspected of Having ACS ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation. A A Symptoms Suggestive of ACS NoncardiacDiagnosisNoncardiacDiagnosisUnstableAnginaUnstableAngina Treatment as indicated by alternative diagnosis See ACC/AHA Guidelines for Chronic Stable Angina BI B2 PossibleACSPossibleACS DefiniteACSDefiniteACS B3 B4

Algorithm for Evaluation and Management of Patients Suspected of Having ACS Possible ACS Nondiagnostic ECG Normal initial serum cardiac biomarkers Nondiagnostic ECG Normal initial serum cardiac biomarkers OBSERVE 12 hours or more from symptom onset OBSERVE No recurrent pain, negative follow-up studies Recurrent pain, positive follow-up studies Diagnosis OF ACS confirmed Recurrent pain, positive follow-up studies Diagnosis OF ACS confirmed Admit to hospital Manage via acute ischemia pathway Admit to hospital Manage via acute ischemia pathway Stress study to provoke ischemia Consider evaluation of LV function if ischemia is present (tests may be performed either prior to discharge or as outpatient Stress study to provoke ischemia Consider evaluation of LV function if ischemia is present (tests may be performed either prior to discharge or as outpatient D1 E1 F2 F1 G1 H3 ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.

Algorithm for Evaluation and Management of Patients Suspected of Having ACS Positive Diagnosis of ACS confirmed or highly likely Positive Admin to hospital Manage via acute ischemia pathway Admin to hospital Manage via acute ischemia pathway H2 H3 Stress study to provoke ischemia Consider evaluation of LV function if ischemia is present (tests may be performed either prior to discharge or as outpatient Stress study to provoke ischemia Consider evaluation of LV function if ischemia is present (tests may be performed either prior to discharge or as outpatient G1 Negative Potential diagnoses: Nonischemic discomfort; low-risk ACS Negative Potential diagnoses: Nonischemic discomfort; low-risk ACS Arrangements for outpatient follow-up H1 I1 ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.

Specific Recommendations, Class Designation, and Levels Of Evidence Initial Invasive Strategy: Whats New? Specific Recommendations, Class Designation, and Levels Of Evidence Initial Invasive Strategy: Whats New? UA/NSTEMI Strategy Overview

New Strategies: 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. New Strategies: 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. UA/NSTEMI Strategy Overview ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.

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

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

Welcome To This Program! Move from confusion, controversy, and contentiousness to collaboration and more evidence-based careMove from confusion, controversy, and contentiousness to collaboration and more evidence-based care Give emergency physicians familiarity they need with ACC/AHA 2007 UA/NSTEMI Guidelines in order to:Give emergency physicians familiarity they need with ACC/AHA 2007 UA/NSTEMI Guidelines in order to: l (1) Treat patients optimally and; l (2) Work effectively and collegially with their cardiology consultants Move from confusion, controversy, and contentiousness to collaboration and more evidence-based careMove from confusion, controversy, and contentiousness to collaboration and more evidence-based care Give emergency physicians familiarity they need with ACC/AHA 2007 UA/NSTEMI Guidelines in order to:Give emergency physicians familiarity they need with ACC/AHA 2007 UA/NSTEMI Guidelines in order to: l (1) Treat patients optimally and; l (2) Work effectively and collegially with their cardiology consultants

Recent Clinical Trials in STEMI and NSTEMI What New Evidence Tells Us and Implications for ED Cardiovascular Management Judd E. Hollander, MD Professor and Clinical Research Director Department of Emergency Medicine University of Pennsylvania Getting in the Stream of Things

ACS: Recent Clinical Trials in STEMI and NSTEMI Getting in the (Up)Stream of Things

PCI versus Fibrinolysis Systematic Overview Short term (4-6 weeks) Keeley EC, Boura JA, Grines CL. Lancet. 2003. P=0.0002 P=0.0003 P<0.0001 P<0.0001 P=0.0004 (23 RCTs, n=7,739)

Early Presenting Patients Primary PCI versus Fibrinolytics p=0.058p=0.47 CAPTIM p<0.02 PRAGUE-2 Widimsky P, et al. Eur Heart J. 2003;24(1):94-104. Steg PG, et al. Circulation. 2003;108(23):2851-2856.

Mortality Rates with Primary PCI as a Function of PCI Time Delay P=.006 Circle sizes =sample size of the study Solid line = weighted metaregression Nallamothu BK, Bates ER. Am J Cardiol. 2003;92:824-826. 62 min Benefit Favors PCI Harm Favors Lysis For every 10 min delay to PCI: 1% reduction in mortality difference towards lytics 5 10 15 0 Absolute risk difference in death (%) –5 020406080100 PCI-related time delay (door to balloon - door to needle)

Can We Improve STEMI Care With Fibrinolysis? Optimizing STEMI Outcomes

Adjunctive Medications No Effect in STEMI Double-bolus t-PA Double-bolus t-PA TNK TNK rPA rPA nPA nPA GP IIb/IIIa inhibition +lytic GP IIb/IIIa inhibition +lytic Oral GP IIb/IIIa Oral GP IIb/IIIa Double-bolus t-PA Double-bolus t-PA TNK TNK rPA rPA nPA nPA GP IIb/IIIa inhibition +lytic GP IIb/IIIa inhibition +lytic Oral GP IIb/IIIa Oral GP IIb/IIIa Hirudin Hirudin Pexulizamab Pexulizamab Magnesium Magnesium Adenosine Adenosine PSGL PSGL GIK GIK Hirudin Hirudin Pexulizamab Pexulizamab Magnesium Magnesium Adenosine Adenosine PSGL PSGL GIK GIK USEFUL ADJUNCTS Aspirin Enoxaparin Clopidogrel USEFUL ADJUNCTS Aspirin Enoxaparin Clopidogrel

CLARITY–TIMI 28 Double-blind, randomized, placebo-controlled trial in 3491 Patients, aged 18–75 yr, with STEMI <12 hr Fibrinolytic, ASA, heparin Clopidogrel 300 + 75 mg qd Coronary angiogram (2–8 days) Primary endpoint Occluded artery (TIMI flow grade 0/1) or death/MI by time of angio Randomized Placebo Studydrug 30-d clinical follow-up Open-labelclopidogrel per MD in both groups Sabatine MS, et al. N Engl J Med. 2005;352:1179-1189.

PlaceboClopidogrel P=.001 Odds Ratio: 0.64 (95% CI, 0.53-0.76) 1.00.40.60.81.21.6 Clopidogrel Better Placebo Better n=1752n=1739 36% Odds Reduction 15.0 21.7 Occluded Artery or Death/MI (%) 0 5 10 15 20 25 Sabatine MS, et al. N Engl J Med. 2005;352:1179-1189. CLARITY–TIMI 28

CV Death, MI, and Urgent Revascularization Days Endpoint (%) 0 5 10 15 0 5 1015 20 25 30 Placebo Clopidogrel Odds Ratio: 0.80 (95% CI, 0.65–0.97) P=.03 20% Sabatine MS, et al. N Engl J Med. 2005;352:1179-1189.

CLARITY–TIMI 28: Bleeding NS7.27.5 In those undergoing CABG NS7.9 9.1 CABG w/in 5 d of study med 0.9 1.7 0.7 0.5 1.1 Placebo (%) NS NS NS NS NS PP 1.9 TIMI major 1.6 0.5 1.0 1.3 Clopidogrel (%) TIMI minor ICH Through 30 days TIMI minor TIMI major Through angiography OutcomeOutcome Sabatine MS, et al. N Engl J Med. 2005;352:1179-1189.

STEMI < 6 hours Lytic eligible Lytic choice by MD (TNK, tPA, rPA, SK) ENOXAPARIN < 75 y: 30 mg IV bolus SC 1.0 mg / kg q 12 h (Hosp DC) 75 y: No bolus SC 0.75 mg / kg q 12 h (Hosp DC ) CrCl < 30: 1.0 mg / kg q 24 h Double-blind, double-dummy ASA Day 30 1° Efficacy Endpoint: Death or Nonfatal MI 1° Safety Endpoint: TIMI Major Hemorrhage EXTRACT: TIMI 25 UFH 60 U / kg bolus (4000 U) Inf 12 U / kg / h (1000 U / h) Duration: at least 48 h Contd at MD discretion

Primary End Point (ITT) Death or Nonfatal MI Primary End Point (%) Primary End Point (%) ENOX UFH Relative Risk 0.83 (0.77 to 0.90) P<0.0001 Days 9.9% 12.0% Lost to follow up = 3 17% RRR Antman EM, et al. NEJM 354:1477-1488

Death or Nonfatal MI Day 30 Medical Therapy vs Any PCI 0.0004 0.001 % Events N = 15,223 (75%) N = 4,676 (23%) P Value 9.7 RRR 16% 11.4 13.8 10.7 RRR 23% EnoxaparinUFHEnoxaparinUFH Antman EM, et al. NEJM 354:1477-1488

Death or Nonfatal MI Day 30 Clopidogrel Use 0.0005 0.0006 0.0006 % Events N = 14,752 (78%) N = 5,727 (28%) P Value 10.4 RRR 15% 12.2 11.4 8.7 RRR 24% * 2546 clopidogrel treated patients did not undergo PCI EnoxaparinUFHEnoxaparinUFH Antman EM, et al. NEJM 354:1477-1488

Net Clinical Benefit at 30 Days 11.250.90.8 Death or Nonfatal MI or Nonfatal ICH Death or Nonfatal MI or Nonfatal Major Bleed Death or Nonfatal MI or Nonfatal Disabl. Stroke ENOX Better UFH Better RR UFH (%) ENOX (%) RRR (%) 12.3 10.1 10.118 12.8 11.0 11.014 12.2 10.1 10.117 Prespecified Definitions P <0.0001 Antman EM, et al. NEJM 354:1477-1488

Trial Results In Perspective PCI vs Lysis for STEMI % Events (30-42 Days) Reinfarction Lytic Arms (UFH) PCI Arms ENOX Overview of 23 RCTs Overview of 23 RCTs The advance in adjunctive therapy with enoxaparin has narrowed the gap between PCI and Lysis as reperfusion for STEMI Keeley EC, Boura JA, Grines CL. Lancet. 2003.

12,000 Patients with STEMI 1.8, pregnancy, ICH<12 mo 4UFH4not4indicated UFHnot indicated Study Design: Randomized, Double Blind, Double Dummy Lytics (SK, TPA, TNK, RPA), Primary PCI or no reperfusion (eg. late) Stratification 4UFH indicated UFH indicated Randomization Fondaparinux 2.5 mg Placebo Fondaparinux 2.5 mg UFH Keeley EC, Boura JA, Grines CL. Lancet. 2003.

Primary Efficacy Outcome Death/MI at 30 Days Days Cumulative Hazard 0.0 0.02 0.04 0.06 0.08 0.10 0.12 036912151821242730 UFH/Placebo Fondaparinux HR 0.86 95% CI 0.77- 0.96 P=0.008 Keeley EC, Boura JA, Grines CL. Lancet. 2003.

Efficacy of Fondaparinux by Strata on Death/MI 0.76-1.020.8811.212.7 Stratum II (n = 6434) (Fonda vs. UFH) 0.76-0.990.8715.917.3 Stratum I (n = 5658) (Fonda vs. Placebo) 95% CI HRFondaControl No. of Events (%) Interaction P=0.88 Keeley EC, Boura JA, Grines CL. Lancet. 2003.

STEMI Conclusions There is still a role for fibrinolytic therapy in STEMI There is still a role for fibrinolytic therapy in STEMI Adjuvant clopidogrel and/or enoxaparin improve outcomes in combination with fibrinolytics Adjuvant clopidogrel and/or enoxaparin improve outcomes in combination with fibrinolytics Fondaparinux improves outcomes relative to placebo Fondaparinux improves outcomes relative to placebo

ACS: Recent Clinical Trials in STEMI and NSTEMI Getting in the (Up) Stream of Things

5.95 6.33 5.16 5.07 4.97 4.63 4.16 4.17 0 1 2 3 4 5 6 7 Hospital Composite Quality Quartiles % In-hospital Mortality Every 10% in guidelines adherence = 11% in mortality (OR=0.89, 95% CI, 0.81-0.98) Peterson ED et al. J Am Coll Cardiol. 2004;43(suppl A):406A. Abstract 1077-71. The Link Between Guideline Implementation and Mortality Is Clear 25% 25%–50%50%–75% 75% Adjusted Unadjusted

Antithrombotic and Antiplatelet Therapy in ACS ACC/AHA Guideline Update for UA and NSTEMI. 2002.

CURE: C lopidogrel in U nstable Angina to Prevent R ecurrent E vents

CURE: Primary End Point: MI/Stroke/CV Death (N=12,562*)

CURE Safety

SYNERGY Design At least 2 of 3 required: Age 60 ST (transient) or (+) CK-MB or troponin Primary endpoint: Death or MI at 30 days High-risk ACS Patients Early invasive strategy Other therapy per ACC/AHA guidelines (ASA, -blocker, ACE, clopidogrel, GP IIb/IIIa) EnoxaparinIV UFH Randomize (n = 10,000) 60 U/kg 12 U/kg/h (aPTT 50 – 70 sec) 1 mg/kg SC Q12 h SYNERGY Trial Investigators. JAMA 2004;292:45-54

Death and MI at 30 Days 1 Hazard Ratio (95% CI) EnoxaparinUFH BetterBetter 30-day Death/MI 0.81.01.2 HR 0.96 (0.86 – 1.06) 1.1 051015202530 0.8 0.9 0.95 1.0 Freedom from Death / MI Days from Randomization 0.85 Enoxaparin UFH SYNERGY Trial Investigators. JAMA 2004;292:45-54

6-Month Survival Death/MI (Intention-to-Treat) HR (95% CI) = 0.978 (0.891, 1.075) 0306090120150180 0.7 0.75 0.8 0.85 0.9 0.95 1 Freedom from Death / MI at 6 Months Days from Randomization UFH Enoxaparin SYNERGY Trial Investigators. JAMA 2004;292:45-54

Bleeding Events GUSTO severe2.72.20.08 TIMI major (clinical): 9.17.60.008 CABG-related6.85.90.08 Non-CABG-related2.41.80.03 Hb/HCT drop (algorithm)15.212.5< 0.001 Any RBC transfusion17.016.00.16 ICH< 0.1< 0.1NS EnoxaparinUFHP value (n = 4,993)(n = 4,985) % % SYNERGY Trial Investigators. JAMA 2004;292:45-54

Enoxaparin was not superior to unfractionated heparin but was noninferior for non–ST-segment elevation ACS Enoxaparin was not superior to unfractionated heparin but was noninferior for non–ST-segment elevation ACS More bleeding was observed with enoxaparin More bleeding was observed with enoxaparin Enoxaparin was an alternative to unfractionated heparin for non–ST-segment elevation ACS in high- risk patients being managed with a rapid transition to intervention Enoxaparin was an alternative to unfractionated heparin for non–ST-segment elevation ACS in high- risk patients being managed with a rapid transition to intervention Do not change from Do not change from l UFH to Enoxaparin, or l Enoxaparin to UFH Stay with the agent initiated in the ED Stay with the agent initiated in the ED l Collaboration l Pathways l Bivalirudin may be exception SYNERGY: Conclusions/Caveats

OASIS-5 Study Design Yusuf S, et al. N Engl J Med. 2006;354(14):1464-76 Patients w/ NSTE ACS Chest pain < 24 hours 2/3: Age > 60 ST-segment cardiac markers Chest pain < 24 hours 2/3: Age > 60 ST-segment cardiac markers ASA, clopidogrel, IIb/IIIa, planned cath per local practice Exclude Age < 21 Contraindication to enox Hemorrhagic stroke < 12 mo Creat > 3 mg/dL (265 umol/L) Exclude Age < 21 Contraindication to enox Hemorrhagic stroke < 12 mo Creat > 3 mg/dL (265 umol/L) Randomize n = 20,000 Fondaparinux 2.5 mg sc qd Fondaparinux 2.5 mg sc qd Enoxaparin 1 mg/kg sc bid Enoxaparin 1 mg/kg sc bid PCI < 6 h: IV fondaparinux 2.5 mg w/o IIb/IIIa, 0 w/ IIb/IIIa PCI > 6h: IV fondaparinux 5 mg w/o IIb/IIIa, 2.5 mg w/ IIb/IIIa PCI < 6 h: IV fondaparinux 2.5 mg w/o IIb/IIIa, 0 w/ IIb/IIIa PCI > 6h: IV fondaparinux 5 mg w/o IIb/IIIa, 2.5 mg w/ IIb/IIIa Primary Efficacy: Death, MI, refractory ischemia at 9 days Safety: Major bleeding at 9 days Risk/Benefit: Death, MI, refractory ischemia and major bleeding at 9 days Secondary Above and each component separately at day 30 and 6 months Primary Efficacy: Death, MI, refractory ischemia at 9 days Safety: Major bleeding at 9 days Risk/Benefit: Death, MI, refractory ischemia and major bleeding at 9 days Secondary Above and each component separately at day 30 and 6 months PCI < 6 h: no UFH PCI > 6h: IV UFH 100 U/kg w/o IIb/IIIa 60 U/kg w/ IIb/IIIa PCI < 6 h: no UFH PCI > 6h: IV UFH 100 U/kg w/o IIb/IIIa 60 U/kg w/ IIb/IIIa Outcomes

OASIS–5: Efficacy at Day 9 EnoxFonda % Death/MI/RI5.85.9 Death/MI4.14.1 Death1.91.8 MI2.72.7 Refract Isch 1.92.05 0.81 1.2 Non-inferiority Margin = 1.185 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

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

Moderate- high risk ACS ACUITY Study Design – First Randomization Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819) Angiography within 72h Aspirin in all Clopidogrel dosing and timing per local practice UFH or Enoxaparin + GP IIb/IIIa Bivalirudin + GP IIb/IIIa Bivalirudin Alone R* ACUITY Design. Stone GW et al. AHJ 2004;148:764–75 Medical management PCI CABG Primary endpoint: Net Clinical Composite Death, MI, TVR, Bleeding Primary endpoint: Net Clinical Composite Death, MI, TVR, Bleeding

Moderate- high risk ACS ACUITY Study Design – Second Randomization Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819) Angiography within 72h ACUITY Design. Stone GW et al. AHJ 2004;148:764–75 Aspirin in all Clopidogrel dosing and timing per local practice Medical management PCI CABG Bivalirudin Alone UFH or Enoxaparin Routine upstream GPI in all pts GPI started in CCL for PCI only R Bivalirudin R Routine upstream GPI in all pts GPI started in CCL for PCI only

1. Composite net clinical benefit = 2. Ischemic composite or 3. Major bleeding 3 Primary Endpoints (at 30 Days) Death from any cause Myocardial infarction - During medical Rx: Any biomarker elevation >ULN - Post PCI: CKMB >ULN with new Q waves or >3x ULN w/o Q waves - Post CABG: CKMB >5x ULN with new Q waves, >10x ULN w/o Q waves Unplanned revascularization for ischemia Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16.

1. Composite net clinical benefit = 2. Ischemic composite or 3. Major bleeding 3 Primary Endpoints (at 30 Days) Non CABG related bleeding – Intracranial bleeding or intraocular bleeding – Retroperitoneal bleeding – Access site bleed requiring intervention/surgery – Hematoma 5 cm – Hgb 3g/dL with an overt source or 4g/dL w/o overt source – Blood product transfusion -– Reoperation for bleeding Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16.

Ischemic 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.

Major 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.

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

Bivalirudin plus IIb/IIIa had similar ischemic outcomes, similar bleeding, and similar net clinical benefit to heparin plus IIb/IIIa Bivalirudin plus IIb/IIIa had similar ischemic outcomes, similar bleeding, and similar net clinical benefit to heparin plus IIb/IIIa Bivalirudin alone (with provisional IIb/IIIa use) had similar ischemic outcomes, less bleeding, and superior net clinical benefit to heparin plus IIb/IIIa Bivalirudin alone (with provisional IIb/IIIa use) had similar ischemic outcomes, less bleeding, and superior net clinical benefit to heparin plus IIb/IIIa Whether or not reductions in bleeding will translate into longer-term reductions in mortality is yet to be determined Whether or not reductions in bleeding will translate into longer-term reductions in mortality is yet to be determined Bivalirudin plus IIb/IIIa had similar ischemic outcomes, similar bleeding, and similar net clinical benefit to heparin plus IIb/IIIa Bivalirudin plus IIb/IIIa had similar ischemic outcomes, similar bleeding, and similar net clinical benefit to heparin plus IIb/IIIa Bivalirudin alone (with provisional IIb/IIIa use) had similar ischemic outcomes, less bleeding, and superior net clinical benefit to heparin plus IIb/IIIa Bivalirudin alone (with provisional IIb/IIIa use) had similar ischemic outcomes, less bleeding, and superior net clinical benefit to heparin plus IIb/IIIa Whether or not reductions in bleeding will translate into longer-term reductions in mortality is yet to be determined Whether or not reductions in bleeding will translate into longer-term reductions in mortality is yet to be determined ACUITY Conclusions

NSTEMI Conclusions Old and new options for ACS Old and new options for ACS l UFH or Enoxaparin l Bivalirudin l Fondaparinux (not tested adequately in cath lab) Balance ischemic efficacy and safety Balance ischemic efficacy and safety l Customize approach for patient and institution Many choices Many choices l Collaborate with IC and CARD on clinical pathways Adapt ACC/AHA 2007 Guidelines to Clinical Practice in ED (Endorsed by SAEM) Adapt ACC/AHA 2007 Guidelines to Clinical Practice in ED (Endorsed by SAEM) Old and new options for ACS Old and new options for ACS l UFH or Enoxaparin l Bivalirudin l Fondaparinux (not tested adequately in cath lab) Balance ischemic efficacy and safety Balance ischemic efficacy and safety l Customize approach for patient and institution Many choices Many choices l Collaborate with IC and CARD on clinical pathways Adapt ACC/AHA 2007 Guidelines to Clinical Practice in ED (Endorsed by SAEM) Adapt ACC/AHA 2007 Guidelines to Clinical Practice in ED (Endorsed by SAEM)

Acute Coronary Syndrome The 2007 ACC/AHA UA/NSTEMI Guidelines From the ED to the CCU and Cath Lab Adherence as the Road to Better Outcomes Getting in the (Up)Stream of Things 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 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

1990199219941996199820002002 1990 ACC/AHA AMI R. Gunnar 1994 AHCPR/NHLBI UA E. Braunwald 1996 1999 Revised Updated ACC/AHA AMI T. Ryan 1996 1999 Revised Updated ACC/AHA AMI T. Ryan 2004 2007 2004 2007 Revised Updated Revised Updated ACC/AHA STEMI ACC/AHA STEMI E. Antman E. Antman 2004 2007 2004 2007 Revised Updated Revised Updated ACC/AHA STEMI ACC/AHA STEMI E. Antman E. Antman 2000 2002 2007 2000 2002 2007 Revised Updated Revised Revised Updated Revised ACC/AHA UA/NSTEMI ACC/AHA UA/NSTEMI E. Braunwald J. Anderson E. Braunwald J. Anderson 2000 2002 2007 2000 2002 2007 Revised Updated Revised Revised Updated Revised ACC/AHA UA/NSTEMI ACC/AHA UA/NSTEMI E. Braunwald J. Anderson E. Braunwald J. Anderson 20042007 Evolution of Guidelines for ACS

Sea and Stream Changes in ACS The 2007 Guidelines have created a Sea Change in the ED and IC Therapeutic approach to care of patients with UA/NSTEMI The 2007 Guidelines have created a Sea Change in the ED and IC Therapeutic approach to 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

Class I Benefit >>> Risk Procedure/ Treatment SHOULD be performed/ administered Class IIa Benefit >> Risk Additional studies with focused objectives needed IT IS REASONABLE to perform procedure/administer treatment Class IIb Benefit Risk Additional studies with broad objectives needed; Additional registry data would be helpful Procedure/Treatment MAY BE CONSIDERED Class III Risk Benefit No additional studies needed Procedure/Treatment should NOT be performed/administered SINCE IT IS NOT HELPFUL AND MAY BE HARMFUL Should Is recommended Is indicated Is useful/effective/ beneficial Is reasonable Can be useful/effective/ beneficial Is probably recommended or indicated May/might be considered May/might be reasonable Usefulness/ effectiveness is unknown/unclear/ uncertain or not well established Is not recommended Is not indicated Should not Is not useful/effective/ beneficial May be harmful Applying Classification of Recommendations

CRUSADE: A National Quality Improvement Initiative C an R apid Risk Stratification of U nstable Angina Patients S uppress AD verse Outcomes with E arly Implementation of the ACC/AHA Guidelines 2002-2007 C an R apid Risk Stratification of U nstable Angina Patients S uppress AD verse Outcomes with E arly Implementation of the ACC/AHA Guidelines 2002-2007

Management Strategies: 2002 Guidelines Conservative versus Invasive Strategies Early (within 48h) invasive strategy in high-risk patients with any of the following: l Recurrent ischemia, despite meds l Elevated Troponin I or T l New ST-segment depression l New CHF symptoms l High-risk stress test findings l LV dysfunction (EF < 40%) l Hemodynamic instability, sustained VT l PCI within 6 months, prior CABG Early (within 48h) invasive strategy in high-risk patients with any of the following: l Recurrent ischemia, despite meds l Elevated Troponin I or T l New ST-segment depression l New CHF symptoms l High-risk stress test findings l LV dysfunction (EF < 40%) l Hemodynamic instability, sustained VT l PCI within 6 months, prior CABG I I IIa IIb III

Either strategy in low- to moderate-risk patients without contraindications to revascularization Early invasive strategy for patients with repeated ACS presentations, without high-risk features or ongoing ischemia Either strategy in low- to moderate-risk patients without contraindications to revascularization Early invasive strategy for patients with repeated ACS presentations, without high-risk features or ongoing ischemia I I IIa IIb III Management Strategies 2002 Guidelines Conservative versus Invasive Strategies

Invasive Procedures in 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 Initial Conservative 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 Early Conservative (or selectively invasive): Invasive evaluation only if optimal medical management fails Early Conservative (or selectively invasive): Invasive evaluation only if optimal medical management fails Note: from ED perspective, both strategies involve risk-directed, evidence-based medical therapy Note: from 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 Early Conservative (or selectively invasive): Invasive evaluation only if optimal medical management fails Early Conservative (or selectively invasive): Invasive evaluation only if optimal medical management fails Note: from ED perspective, both strategies involve risk-directed, evidence-based medical therapy Note: from ED perspective, both strategies involve risk-directed, evidence-based medical therapy

EIS is indicated in initially stabilized UA/NSTEMI patients (without contraindications) who have an elevated risk for clinical events EIS is indicated in UA/NSTEMI patients (without contraindications) who have refractory angina or hemodynamic or electrical instability ICS may be considered in initially stabilized patients who have an elevated risk for clinical events (including Tn) EIS is indicated in initially stabilized UA/NSTEMI patients (without contraindications) who have an elevated risk for clinical events EIS is indicated in UA/NSTEMI patients (without contraindications) who have refractory angina or hemodynamic or electrical instability ICS may be considered in initially stabilized patients who have an elevated risk for clinical events (including Tn) I I IIa IIb III Management Strategies 2007 Early Invasive versus Initial Conservative

EIS is indicated in initially stabilized UA/NSTEMI patients (without contraindications) who have an elevated risk for clinical events EIS is indicated in UA/NSTEMI patients (without contraindications) who have refractory angina or hemodynamic or electrical instability ICS may be considered in initially stabilized patients who have an elevated risk for clinical events (including Tn) EIS is indicated in initially stabilized UA/NSTEMI patients (without contraindications) who have an elevated risk for clinical events EIS is indicated in UA/NSTEMI patients (without contraindications) who have refractory angina or hemodynamic or electrical instability ICS may be considered in initially stabilized patients who have an elevated risk for clinical events (including Tn) I I IIa IIb III Management Strategies 2007 Early Invasive vs Initial Invasive

The decision to employ an EIS vs ICS may be made by considering physician and patient preference Invasive strategy may be preferable in patients with CKD EIS if patient: Will not consent to revascularization Will not consent to revascularization Has too many comorbidities Has too many comorbidities Is low risk Is low risk The decision to employ an EIS vs ICS may be made by considering physician and patient preference Invasive strategy may be preferable in patients with CKD EIS if patient: Will not consent to revascularization Will not consent to revascularization Has too many comorbidities Has too many comorbidities Is low risk Is low risk I I IIa IIb III Management Strategies 2007 Early Invasive versus Initial Conservative

Benefits of Early Catheterization by Risk Group Bhatt AHA 2002. % Inhospital Mortality

Invasive Procedure Use by Age Alexander KA, J Am Coll Cardiol 2005;46:1479-87.

Medical Management 2002 Guidelines Antithrombotic Therapy Immediate aspirin Clopidogrel, if aspirin contraindicated Heparin (IV unfractionated, LMW) with antiplatelet agents listed above Enoxaparin preferred over UFH unless CABG is planned within 24 hours Immediate aspirin Clopidogrel, if aspirin contraindicated Heparin (IV unfractionated, LMW) with antiplatelet agents listed above Enoxaparin preferred over UFH unless CABG is planned within 24 hours IIIIaIIaIIbIIbIIIIII

Acute (first 24 hours) Antithrombotic Therapies

Medical Management 2007 Guidelines AntiThrombotic Therapy In EIS: Enoxaparin or UFH Enoxaparin or UFH Bivalirudin* or fondaparinux Bivalirudin* or fondaparinux In ICS: In ICS: Enoxaparin or UFH Enoxaparin or UFH Fondaparinux Fondaparinux In ICS with risk of bleeding: Fondaparinux In ICS with risk of bleeding: Fondaparinux In EIS: Enoxaparin or UFH Enoxaparin or UFH Bivalirudin* or fondaparinux Bivalirudin* or fondaparinux In ICS: In ICS: Enoxaparin or UFH Enoxaparin or UFH Fondaparinux Fondaparinux In ICS with risk of bleeding: Fondaparinux In ICS with risk of bleeding: Fondaparinux IIIIaIIaIIbIIbIIIIII

If ICS selected, either enoxaparin or fondaparinux is preferred over UFH unless CABG is anticipated within 24 hours IIIIaIIaIIbIIbIIIIII Relevant new studies for antithrombotic therapy: SYNERGY, JAMA 2004 OASIS-5, NEJM 2006 ACUITY, NEJM 2006 Relevant new studies for antithrombotic therapy: SYNERGY, JAMA 2004 OASIS-5, NEJM 2006 ACUITY, NEJM 2006 Medical Management 2007 Guidelines Antithrombotic Therapy

SYNERGY: Primary Efficacy Outcome Enoxaparin is as effective as UFH in the treatment of high-risk patients with ACS undergoing a rapid invasive strategy SYNERGY Trial Investigators, JAMA 2004;292:45. 1 Hazard Ratio (95% CI) EnoxaparinUFH BetterBetter 30-day Death/MI 0.81.01.2 HR 0.96 (0.86 – 1.06) 1.1 051015202530 0.8 0.9 0.95 1.0 Freedom from Death / MI Days from Randomization 0.85 Enoxaparin UFH

OASIS-5 OASIS-5: Death/MI/RI at Day 9 Days Cumulative Hazard 0.0 0.01 0.02 0.03 0.04 0.05 0.06 0123456789 Enoxaparin Fondaparinux HR 1.01 95% CI 0.90 - 1.13

OASIS-5 Major Bleeding at 9 Days Days Cumulative Hazard 0.0 0.01 0.02 0.03 0.04 0123456789 HR 0.52 95% CI 0.44-0.61 P<0.001 Enoxaparin Fondaparinux OASIS-5OASIS-5

OASIS-5: 30-Day Mortality Days Cumulative Hazard 0.0 0.01 0.02 0.03 036912151821242730 HR 0.83 95% CI 0.71 - - 0.97 P=0.02 Enoxaparin Fondaparinux OASIS-5OASIS-5

Patients Undergoing PCI within the first 8 Days of Randomization

The ACUITY study, which tested bivalirudin for UA/NSTEMI, has led to a guidelines change to allow bivalirudin as an anticoagulant option. UA/NSTEMI Strategy Overview ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.

ACUITY: Primary Results – 30 days UFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone P NI <0.001 P Sup = 0.015 P NI = 0.011 P Sup = 0.32 P NI <0.001 P Sup <0.001 Stone GW et al. NEJM 2006;355:2203-16

0306090120150180210240270300330360390 0 5 15 25 Ischemic Composite (%) Days from Randomization 10 20 UFH/Enoxaparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone Estimate P (log rank) 30 day 7.4% 0.36 7.8% 0.34 7.9% Estimate P (log rank) 16.3% 0.38 16.5% 0.31 16.4% 1 year p=0.55 Bivalirudin alone vs. Hep+GPI HR [95% CI] = 1.05 (0.95-1.17) Bivalirudin+GPI vs. Hep+GPI HR [95% CI] = 1.05 (0.94-1.16) Ischemic Composite Endpoint (Death, MI, unplanned revascularization for ischemia) UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone Stone GW. ACC 2007 presentation

ACUITY Trial Troponin Positive PCI Subgroup (N= 2949) UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone Stone GW et al, www.thelancet.com Vol 369 March 17, 2007.www.thelancet.com RR [95%CI] 0.93 [0.77-1.12] RR [95%CI] 1.12 [0.88-1.42] RR [95%CI] 0.59 [0.44-0.80]

No Thienopyridine Exposure – PCI pts* 30 Day Primary Endpoint Adverse Events *Thienopyridine at any time, any dose, up to time of PCI (Including 87 patients not receiving thienopyridine at any time) RR [95%CI] 0.61 (0.39-0.97) RR [95%CI] 1.37 (1.00-1.88) RR [95%CI] 1.07 (0.83-1.39) ACUITY PCI as presented at TCT 2006.

Composite Ischemia at 1 Year Hazard ratio ±95% CI Hazard ratio ±95% CI Bival alone UFH/Enox + IIb/IIIa HR (95% CI) P int 0.67 Bivalirudin alone better UFH/Enox + IIb/IIIa better 19.8%19.2% 1.09 (0.96-1.23) 21.1%20.7% 1.04 (0.79-1.36) 9.0%9.6% 0.97 (0.76-1.24) Actual Treatment PCI (n=5179) CABG (n=1040) Medical (n=2994)17.7%14.6%16.4%16.1% 1.14 (0.99-1.30) 0.95 (0.80-1.14) 0.11 Biomarkers (CK/Trop) Elevated (n=5072) Normal (n=3402)16.2%16.4%17.2%14.3% 0.97 (0.86-1.11) 1.20 (1.01-1.44) 0.07 Pre Thienopyridine Yes (n=5751) No (n=3305) UFH/Enoxaparin + GPIIb/IIIa vs. Bivalirudin alone 1 yr KM estimate ACUITY 1-Year Data as presented at ACC 2007. P value interaction only between subgroups

Unfractionated Heparin (UFH) Unfractionated Heparin (UFH) l Pro: Familiarity, reversibility l Con: Adverse PK Enoxaparin Enoxaparin l Pro: Ease of use, predictability, familiarity l Con: Bleeding concerns, transition to cath lab, needs dose adjustment for CKD, increased bleeding risk noted especially in patients with renal dysfunction (OASIS-5) Unfractionated Heparin (UFH) Unfractionated Heparin (UFH) l Pro: Familiarity, reversibility l Con: Adverse PK Enoxaparin Enoxaparin l Pro: Ease of use, predictability, familiarity l Con: Bleeding concerns, transition to cath lab, needs dose adjustment for CKD, increased bleeding risk noted especially in patients with renal dysfunction (OASIS-5) Upstream Antithrombotic Therapy: IA

Fondaparinux Fondaparinux l Pro: Ease of use, once daily l Con: Need additional anticoagulant (UFH? bivalirudin?) in cath lab (clot on the wire), lack of familiarity in ED, label, not studied in CrCl < 30, not accepted by IC community for PCI despite Guidelines Bivalirudin Bivalirudin l Pro: Comfort level in cath lab, short half-life, can omit GP IIb/IIIas (more to follow) in most patients, reduced bleeding risk, can switch to bivalirudin from other anticoaglants and antithrombotics l Con: Lack of familiarity in ED, limited data on prolonged infusion, cost of prolonged infusion, label, not studied in CrCl < 30 Fondaparinux Fondaparinux l Pro: Ease of use, once daily l Con: Need additional anticoagulant (UFH? bivalirudin?) in cath lab (clot on the wire), lack of familiarity in ED, label, not studied in CrCl < 30, not accepted by IC community for PCI despite Guidelines Bivalirudin Bivalirudin l Pro: Comfort level in cath lab, short half-life, can omit GP IIb/IIIas (more to follow) in most patients, reduced bleeding risk, can switch to bivalirudin from other anticoaglants and antithrombotics l Con: Lack of familiarity in ED, limited data on prolonged infusion, cost of prolonged infusion, label, not studied in CrCl < 30 Upstream Antithrombotic Therapy: IB

Oral Antiplatelet Therapy 2002 Clopidogrel Guidance Aspirin + clopidogrel, for up to 1 month* Aspirin + clopidogrel, for up to 9 months* Withhold clopidogrel for 5-7 days for CABG Aspirin + clopidogrel, for up to 1 month* Aspirin + clopidogrel, for up to 9 months* Withhold clopidogrel for 5-7 days for CABG IIIIaIIaIIbIIbIIIIII * For patients managed with an early conservative strategy, and those who are planned to undergo early PCI those who are planned to undergo early PCI * For patients managed with an early conservative strategy, and those who are planned to undergo early PCI those who are planned to undergo early PCI Guidelines do not specify initial timing of using Guidelines do not specify initial timing of using clopidogrel when coronary anatomy is unknown clopidogrel when coronary anatomy is unknown Guidelines do not specify initial timing of using Guidelines do not specify initial timing of using clopidogrel when coronary anatomy is unknown clopidogrel when coronary anatomy is unknown

Acute (< 24 hrs) Antiplatelet Therapies for High-Risk NSTE ACS 43% 10% 20% 30% 40% 50% 60% 52% 34% GP IIb/IIIa Clopidogrel GP IIb/IIIa + Neither GP IIb/IIIa Clopidogrel GP IIb/IIIa + Neither Clopidogrel Clopidogrel CRUSADE Q4 2003 data. 29%

Antiplatelet Therapy Year 2007 Clopidogrel Guidance I I IIa IIb III Clopidogrel with full loading dose in ASA-allergic patients EIS: Clopidogrel or IIb/IIIa administered upstream ICS: Clopidogrel initiated as soon as possible and continued for at least one month...and preferably for one year Clopidogrel with full loading dose in ASA-allergic patients EIS: Clopidogrel or IIb/IIIa administered upstream ICS: Clopidogrel initiated as soon as possible and continued for at least one month...and preferably for one year

Antiplatelet Therapy: 2007 Platelet GP IIb/IIIa Inhibitors I I IIa IIb III ICS with recurrent ischemia on ASA, clopidogrel, and anticoag: Add IIb/IIIa upstream EIS: It is reasonable to give both clopidogrel and IIb/IIIa upstream EIS: Can omit IIb/IIIa if bivalirudin is anticoagulant and at least 300mg clopidogrel given > 6h prior to cath

Antiplatelet Drug Targets Platelet Thrombin ADP Thromboxane A 2 Epinephrine Serotonin Collagen PAR-1 PAR-4 P2Y 1 P2Y 12 TXA2-R 5HT 2 A Anionic phospholipid surfaces GP IIb GP IIIa GP VI Platelet GP IIIa GP IIb Fibrinogen GP Ia TRA Clopidogrel Prasugrel Aspirin Gp IIb/IIIa inhibitors PAR - 1 P2Y 12

Gurbel PA, et al. Circulation. 2005;111:1153-1159. Clear Platelets * Platelet Inhibition * Platelet Inhibition * 0 20% 40% 60% 80% 100% 0 20% 40% 60% 80% 100% Group A: Clopidogrel 300 mg (n = 30) Group B: Clopidogrel 600 mg (n = 30) Group C: Clopidogrel 300 mg + eptifibatide (n = 30)Group D: Clopidogrel 600 mg + eptifibatide (n = 30) 5 µmol/L ADP20 µmol/L ADP *(P 0.001), Group A vs B; (P 0.001), Group C or D vs Group A or B. *(P = 0.09), Group A vs B; (P = 0.01), Group A vs B; (P < 0.001), Groups C and D vs Group A and B; §(P -0.05), Groups C vs D. §

Choices between dual (ASA+clopidogrel), dual (ASA+IIb/IIIa) and triple (ASA+clopidogrel+IIb/IIIa) antiplatelet therapy are driven by risk and upon consideration of a bivalirudin only EIS: l Ischemic risk Conventional consideration in EDConventional consideration in ED Prefer triple therapy unless...Prefer triple therapy unless... l Bleeding risk In ED: Female, elderly, CKD, anemic, proper dosing, use of bivalirudin only EISIn ED: Female, elderly, CKD, anemic, proper dosing, use of bivalirudin only EIS l CABG risk In ED, cant accurately quantifyIn ED, cant accurately quantify Small-molecule IIb/IIIa is reversible; clopidogrel is notSmall-molecule IIb/IIIa is reversible; clopidogrel is not Choices between dual (ASA+clopidogrel), dual (ASA+IIb/IIIa) and triple (ASA+clopidogrel+IIb/IIIa) antiplatelet therapy are driven by risk and upon consideration of a bivalirudin only EIS: l Ischemic risk Conventional consideration in EDConventional consideration in ED Prefer triple therapy unless...Prefer triple therapy unless... l Bleeding risk In ED: Female, elderly, CKD, anemic, proper dosing, use of bivalirudin only EISIn ED: Female, elderly, CKD, anemic, proper dosing, use of bivalirudin only EIS l CABG risk In ED, cant accurately quantifyIn ED, cant accurately quantify Small-molecule IIb/IIIa is reversible; clopidogrel is notSmall-molecule IIb/IIIa is reversible; clopidogrel is not Antiplatelet Therapy Driven By Risk

Parenteral Antiplatelet Therapy: 2002 Platelet GP IIb/IIIa Inhibitors Any GP IIb/IIIa inhibitor + ASA/Heparin for all patients, if cath/PCI planned Eptifibatide or tirofiban + ASA/Heparin for high-risk* patients in whom early cath/PCI is not planned Any GP IIb/IIIa inhibitor for patients already on ASA + Heparin + clopidogrel, if cath/PCI is planned Any GP IIb/IIIa inhibitor + ASA/Heparin for all patients, if cath/PCI planned Eptifibatide or tirofiban + ASA/Heparin for high-risk* patients in whom early cath/PCI is not planned Any GP IIb/IIIa inhibitor for patients already on ASA + Heparin + clopidogrel, if cath/PCI is planned I I IIa IIb III * High-risk: Age > 75; prolonged, ongoing CP; hemodynamic instability; rest CP w/ ST ; VT; positive cardiac markers * High-risk: Age > 75; prolonged, ongoing CP; hemodynamic instability; rest CP w/ ST ; VT; positive cardiac markers

Eptifibatide or tirofiban + ASA/Heparin for patients without continuing ischemia in whom PCI is not planned Abciximab for patients in whom PCI is not planned Eptifibatide or tirofiban + ASA/Heparin for patients without continuing ischemia in whom PCI is not planned Abciximab for patients in whom PCI is not planned I I IIa IIb III Parenteral Antiplatelet Therapy: 2002 Platelet GP IIb/IIIa Inhibitors

Antiplatelet Therapy: 2007 Platelet GP IIb/IIIa Inhibitors I I IIa IIb III All patients receive ASA EIS: Upstream clopidogrel or IIb/IIIa EIS: Upstream IIb/IIIa should be small-molecule ICS: If medical management fails, add IIb/IIIa or clopidogrel... upstream

I I IIa IIb III ICS with recurrent ischemia on ASA, clopidogrel, and anticoagulant: Add IIb/IIIa upstream EIS: It is reasonable to give both clopidogrel and IIb/IIIa upstream EIS: Can omit IIb/IIIa if bivalirudin is anticoagulant and at least 300mg clopidogrel given > 6h prior to cath Antiplatelet Therapy: 2007 Platelet GP IIb/IIIa Inhibitors

ISAR-REACT-2, JAMA 2006 (ACUITY, NEJM 2006) Both of these studies have risk considerations that are important to upstream therapy ISAR-REACT-2, JAMA 2006 (ACUITY, NEJM 2006) Both of these studies have risk considerations that are important to upstream therapy Relevant New Studies Focusing on Antiplatelet Therapy

ISAR-REACT 2: Troponin Status Troponin negative ( <0.03µg/L, n=973) Primary Events p=0.98 Kastrati A, Mehilli J, et al. JAMA. 2006 Apr 5;295(13):1531-8. Troponin positive (>0.03 µg/L, n=1049) p=0.02

In-hospital Major and Minor Bleeding (%) p=NS ISAR-REACT 2 : Bleeding Kastrati A, Mehilli J, et al. JAMA. 2006 Apr 5;295(13):1531-8.

ACUITY Composite Ischemia at 1-Year ACUITY Composite Ischemia at 1-Year UFH/Enoxaparin + GPIIb/IIIa vs. Bivalirudin Alone Hazard ratio ±95% CI Hazard ratio ±95% CI Bival alone UFH/Enox + IIb/IIIa HR (95% CI)P int 0.67 Bivalirudin alone better UFH/Enox + IIb/IIIa better 19.8%19.2%1.09 (0.96-1.23) 21.1%20.7%1.04 (0.79-1.36) 9.0%9.6%0.97 (0.76-1.24) Actual Treatment PCI (n=5179) CABG (n=1040) Medical (n=2994) 17.7% 14.6% 16.4% 16.1% 1.14 (0.99-1.30) 0.95 (0.80-1.14) 0.11 Biomarkers (CK/Trop) Elevated (n=5072) Normal (n=3402) 16.2% 16.4% 17.2% 14.3% 0.97 (0.86-1.11) 1.20 (1.01-1.44) 0.07 Pre Thienopyridine Yes (n=5751) No (n=3305) 1 yr KM estimate ACUITY 1-Year Data as presented at ACC 2007. P value interaction only between subgroups

Death at One Year Interaction Analysis UFH/Enoxaparin + GPIIb/IIIa vs. Bivalirudin alone Hazard ratio ±95% CI Hazard ratio ±95% CI Bivalalone UFH/Enox + IIb/IIIa HR (95% CI) P int 0.96 Bivalirudin alone better UFH/Enox + IIb/IIIa better 3.2%4.0% 0.95 (0.70-1.29) 6.8%6.7% 1.03 (0.64-1.66) 4.0%4.3% 0.95 (0.66-1.37) Actual Treatment PCI (n=5179) CABG (n=1040) Medical (n=2994) 4.8%2.4%5.0%3.6% 1.04 (0.80-1.34) 0.84 (0.55-1.28) 0.40 Biomarkers (CK/Trop) Elevated (n=5072) Normal (n=3402) 3.5%4.0%4.2%4.4% 0.90 (0.68-1.18) 1.05 (0.74-1.48) 0.52 Pre Thienopyridine Yes (n=5751) No (n=3305) 1 yr KM estimate

Antiplatelet Therapy: 2007 Platelet GP IIb/IIIa Inhibitors I I IIa IIb III ICS with recurrent ischemia on ASA, clopidogrel, and anticoag: add IIb/IIIa upstream EIS: it is reasonable to give both clopidogrel and IIb/IIIa upstream EIS: Can omit IIb/IIIa if bivalirudin is anticoagulant and at least 300mg clopidogrel given > 6h prior to cath ICS with recurrent ischemia on ASA, clopidogrel, and anticoag: add IIb/IIIa upstream EIS: it is reasonable to give both clopidogrel and IIb/IIIa upstream EIS: Can omit IIb/IIIa if bivalirudin is anticoagulant and at least 300mg clopidogrel given > 6h prior to cath

CREDO: 15 hrs (not 6 hrs) Until Clinical Benefit Seen with 300 mg Load Steinhubl S et al, J Am Coll Cardiol 2006;47:939-943. Death, MI, UTVR (%) Placebo Pretreatment (N_915) Clopidogrel Pretreatment < 15 hours (N=645) Clopidogrel Pretreatment > 15 hours (N=202) 8.3%8.3% 7.8%7.8% 3.5%3.5% 0 5 10 15 20 25 DaysDays 10864201086420

Quadruple Composite Ischemic Composite ACUITY Major Bleeding 1.00 (0.89-1.11) 1.12 (0.97-1.29) 0.80 (0.67-0.95) 012 Deferred GP IIb-IIIa better (n=4,602) Upstream GP IIb-IIIa better (n=4,605) RR (95% CI) Risk ratio ±95% CI ACUITY Timing Analysis (N=9,207) ACUITY as presented at ACC 2006.

Excessive Dosing of Acute Medications by Age Alexander KA, JAMA 2005;294:3108-16.

RBC Transfusions by Excess Dosing RBC Transfusion (%) Alexander KA, JAMA 2005;294:3108-16.

Death Death or Re-MI Death 1 1 2.0 Adjusted Risk of In-Hospital Outcomes By Transfusion Status* * Non-CABG patients only Yang X, J Am Coll Cardiol 2005;46:1490-5.

Cumulative Effects of Dosing Errors Combined Use of Heparin and GP IIb-IIIa Alexander KA, JAMA 2005;294:3108-16.

Hospital Link Between Overall Guidelines Adherence and Mortality Peterson et al, JAMA 2006;295:1863-1912. Every 10% in guidelines adherence Every 10% in guidelines adherence 10% in mortality (OR=0.90, 95% CI: 0.84-0.97)

We should be using optimal medical therapy for NSTE ACS in the ED, just as in the CCU or the cath lab. We should be using optimal medical therapy for NSTE ACS in the ED, just as in the CCU or the cath lab. There are new agents that will change the ED and the cath lab approach to ACS management, both in terms of pharmacologic stabilization (antithrombotic and antiplatelet therapy) and invasive management (namely, the speed with which the patient goes to the cath lab). There are new agents that will change the ED and the cath lab approach to ACS management, both in terms of pharmacologic stabilization (antithrombotic and antiplatelet therapy) and invasive management (namely, the speed with which the patient goes to the cath lab). Conclusions: NSTE ACS - 2007

We must work with our colleagues in cardiology to develop pathways for optimal use of antithrombotic and antiplatelet therapy at all levels, to facilitate early invasive management whenever feasible, and to address issues related to bleeding risk as well as ischemic risk. We must work with our colleagues in cardiology to develop pathways for optimal use of antithrombotic and antiplatelet therapy at all levels, to facilitate early invasive management whenever feasible, and to address issues related to bleeding risk as well as ischemic risk. New (up)streams of care have been introduced and require consideration in ED New (up)streams of care have been introduced and require consideration in ED In ACS management, one size clearly does NOT fit all! In ACS management, one size clearly does NOT fit all! Conclusions: NSTE ACS

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

Anticoagulation Anticoagulation l EIS: Enoxaparin (I-A), UFH (I-A), or bivalirudin (I-B) Strong support for bivalirudin when time to lab is quick and/or when bleeding risk is higher (screen for patients at hgher risk for bleeding)Strong support for bivalirudin when time to lab is quick and/or when bleeding risk is higher (screen for patients at hgher risk for bleeding) l ECS: Enoxaparin (I-A), UFH (I-A), or fondaparinux (I-B) (I-B) Strong support for fondaparinux when bleeding risk is higher, but more problematic if catheterization later requiredStrong support for fondaparinux when bleeding risk is higher, but more problematic if catheterization later required l Individual patient characteristics (ischemic risk, bleeding risk, time to cath) should drive choices, which should be made collaboratively by EM and cardiology Summary 2007 Guidelines: Upstream Medical Stabilization

Anticoagulation Anticoagulation l The Writing Committee believes that inadequate unconfounded, comparative information is available to recommend a preferred [anticoagulation] regimen when an early, invasive strategy is used for UA/NSTEMI, and physician and health care system preference, together with individualized patient application, is advised. Summary 2007 Guidelines Upstream Medical Stabilization

Antiplatelet therapy Antiplatelet therapy l Everybody gets ASA l Clopidogrel use much more strongly supported in 2007 Guidelines than in 2002, but CABG caveat still operative! l Clopidogrel OR a GPI upstream (I-A) for high risk patients, and consider BOTH (IIa-B) l Collaboration again critical, as choice of anticoagulant may impact choice of antiplatelet therapy, and institutional posture re: pretreatment with clopidogrel may override other concerns Antiplatelet therapy Antiplatelet therapy l Everybody gets ASA l Clopidogrel use much more strongly supported in 2007 Guidelines than in 2002, but CABG caveat still operative! l Clopidogrel OR a GPI upstream (I-A) for high risk patients, and consider BOTH (IIa-B) l Collaboration again critical, as choice of anticoagulant may impact choice of antiplatelet therapy, and institutional posture re: pretreatment with clopidogrel may override other concerns Summary 2007 Guidelines Upstream Medical Stabilization

Earlier use of clopidogrelEarlier use of clopidogrel New antithromboticsbivalirudin (for invasive) and fondaparinux for conservative and new antithrombotic/antiplatelet combinationsNew antithromboticsbivalirudin (for invasive) and fondaparinux for conservative and new antithrombotic/antiplatelet combinations Faster time to cath for NSTE ACS patientsFaster time to cath for NSTE ACS patients More emphasis by cardiologists on bleeding risk... sometimes prompting different considerations in the EDMore emphasis by cardiologists on bleeding risk... sometimes prompting different considerations in the ED Earlier use of clopidogrelEarlier use of clopidogrel New antithromboticsbivalirudin (for invasive) and fondaparinux for conservative and new antithrombotic/antiplatelet combinationsNew antithromboticsbivalirudin (for invasive) and fondaparinux for conservative and new antithrombotic/antiplatelet combinations Faster time to cath for NSTE ACS patientsFaster time to cath for NSTE ACS patients More emphasis by cardiologists on bleeding risk... sometimes prompting different considerations in the EDMore emphasis by cardiologists on bleeding risk... sometimes prompting different considerations in the ED Summary 2007 Guidelines Changes Likely to Impact the ED

Why Bleeding Matters: A Cautionary Note For The Emergency Medicine Specialist Importance of Multi-specialty ED and IC Therapeutic (EDICT) Alignment of Upstream Care for ACS Sunil Rao, MD, FACC Director of Interventional Cardiology Veterans Administration Medical Center Assistant Professor Division of Cardiovascular Medicine Duke University Medical Center Why Bleeding Matters: A Cautionary Note For The Emergency Medicine Specialist Importance of Multi-specialty ED and IC Therapeutic (EDICT) Alignment of Upstream Care for ACS Sunil Rao, MD, FACC Director of Interventional Cardiology Veterans Administration Medical Center Assistant Professor Division of Cardiovascular Medicine Duke University Medical Center Getting in the (Up)Stream of Things

ACS Case Presentation 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?

Medical Rx (cath) Time AdmissionCathDischarge No Cath Cath PCI Surgery Medical Rx (no cath) Medical Rx No disease (82 % of total) (18 % of total) (52% of total, 63% of those undergoing cath) 40 % < 48 hrs 12 % > 48 hrs (12% of total, 15% of those undergoing cath) 63 % < 48 hrs 19 % > 48 hrs CRUSADE Registry 10/04-9/05 n=35,897 Patient X ACS Management Pathways Cath Medical Rx

Ischemic Complications Hemorrhage HIT Death MI Urgent TVR Death MI Urgent TVR Major Bleeding Minor Bleeding Thrombocytopenia Major Bleeding Minor Bleeding Thrombocytopenia Composite Adverse Event Endpoints Evolving ED Paradigm for Evaluating ACS Management Strategies Although these complications usually are not seen in the ED, choices made in the ED influence the likelihood of these adverse events! Although these complications usually are not seen in the ED, choices made in the ED influence the likelihood of these adverse events!

Options for NSTE-ACS Therapy in 2007 Antiplatelet therapies Antiplatelet therapies l ASA, Clopidogrel l Glycoprotein IIb/IIIa inhibitors Antithrombin therapy Antithrombin therapy l UFH l Enoxaparin l Fondaparinux l Bivalirudin Risk stratification Risk stratification l Conservative l Invasive Antiplatelet therapies Antiplatelet therapies l ASA, Clopidogrel l Glycoprotein IIb/IIIa inhibitors Antithrombin therapy Antithrombin therapy l UFH l Enoxaparin l Fondaparinux l Bivalirudin Risk stratification Risk stratification l Conservative l Invasive

Risk of events Risk of bleeding Thrombosis Hemostasis Two sides of the same coin Degree of Anticoagulation Risk Balancing Ischemic Events and Bleeding Risk

CRUSADE In-Hospital Outcomes: 2006 Death 3.6% (Re)-Infarction 1.8% CHF 6.6% Cardiogenic Shock 2.2% Stroke 0.7% RBC Transfusion* 9.1% * Excluding CABG-related transfusions CRUSADE DATA: January 1, 2006 – December 31, 2006 (n= 29,825)

ACS-related Bleeding Relevant Questions for the Emergency Medicine Specialist Who bleeds? Can we risk stratify? Who bleeds? Can we risk stratify? Should bleeding risk affect upstream antithrombotic care? If so, how? Should bleeding risk affect upstream antithrombotic care? If so, how? Is bleeding bad or a necessary evil? Is bleeding bad or a necessary evil? Can blood transfusion correct risks associated with bleeding? Can blood transfusion correct risks associated with bleeding? Does bleeding affect resource use? Does bleeding affect resource use? What options do we have to balance efficacy (reduced risk for ischemic outcomes) and safety (reduced bleeding)? What options do we have to balance efficacy (reduced risk for ischemic outcomes) and safety (reduced bleeding)?

Bleeding in ACS Identification Questions to be answered 1] Who bleeds? 1] Who bleeds? 2] What risk factors are predictive of 2] What risk factors are predictive of bleeding? bleeding? 3] How should initial choices for 3] How should initial choices for upstream care be influenced by upstream care be influenced by bleeding risk? bleeding risk? Questions to be answered 1] Who bleeds? 1] Who bleeds? 2] What risk factors are predictive of 2] What risk factors are predictive of bleeding? bleeding? 3] How should initial choices for 3] How should initial choices for upstream care be influenced by upstream care be influenced by bleeding risk? bleeding risk?

Independent predictors of major bleeding in marker- positive acute coronary syndromes Moscucci, GRACE Registry, Eur Heart J. 2003 Oct;24(20):1815-23. Predictors of Major Bleeding in ACS Older Age Older Age Female Gender Female Gender Renal Failure Renal Failure History of Bleeding History of Bleeding Right Heart Catheterization Right Heart Catheterization GPIIb-IIIa Antagonists GPIIb-IIIa Antagonists

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

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

Older age, chronic kidney disease, female gender are consistently associated with bleeding and blood transfusion Older age, chronic kidney disease, female gender are consistently associated with bleeding and blood transfusion Analysis of large randomized trials have also identified novel risk factors for bleeding such as diabetes and anemia Analysis of large randomized trials have also identified novel risk factors for bleeding such as diabetes and anemia These risk factors can readily be identified during the ED evaluation of a patient with ACS These risk factors can readily be identified during the ED evaluation of a patient with ACS Bleeding Predictors Conclusions

Questions to be answered Questions to be answered 1] Is bleeding bad or a necessary evil? 2] What is the relationship between bleeding and patient outcomes in ACS? bleeding and patient outcomes in ACS? 3] What initial choices can the ED physician make that are compatible with physician make that are compatible with guidelines and that will reduce bleeding? guidelines and that will reduce bleeding? Questions to be answered Questions to be answered 1] Is bleeding bad or a necessary evil? 2] What is the relationship between bleeding and patient outcomes in ACS? bleeding and patient outcomes in ACS? 3] What initial choices can the ED physician make that are compatible with physician make that are compatible with guidelines and that will reduce bleeding? guidelines and that will reduce bleeding? Bleeding in ACS Consequences

Moscucci M et al. Eur Heart J 2003;24:1815-23. P<0.001 Overall Unstable NSTEMI STEMI ACS Angina ACS Angina Patients (%) Major Bleeding Predicts Mortality in ACS 24,045 ACS patients in the GRACE registry, in-hospital death

log rank p-value for all four categories <0.0001 log-rank p-value for no bleeding vs. mild bleeding = 0.02 log-rank p-value for mild vs. moderate bleeding <0.0001 log-rank p-value for moderate vs. severe <0.001 Bleeding and Outcomes in ACS Rao SV, et al. Am J Cardiol. 2005 Nov 1;96(9):1200-6. Epub 2005 Sep 12. Kaplan Meier Curves for 30-Day Death, Stratified by Bleed Severity N=26,452 ACS patients from GUSTO IIb, PARAGON A, PARAGON B, & PURSUIT

26,452 patients from PURSUIT, PARAGON A, PARAGON B, GUSTO IIb NST Bleeding severity and adjusted hazard of death *p<0.0001 Bleeding and Outcomes in NSTE-ACS Bleeding Severity30d Death30d Death/MI6 mo. Death Mild* 1.61.31.4 Moderate* 2.73.32.1 Severe*10.65.67.5 *Bleeding as a time-dependent covariate Rao SV, et al. Am J Cardiol. 2005 Nov 1;96(9):1200-6. Epub 2005 Sep 12.

Bleeding is associated with adverse short- and long-term outcomes among patients with ACS and those undergoing PCI Bleeding is associated with adverse short- and long-term outcomes among patients with ACS and those undergoing PCI l Mortality rates are higher among those who bleed l MI rates are higher among those who bleed The risk is dose-dependent with worse bleeding associated with worse outcomes The risk is dose-dependent with worse bleeding associated with worse outcomes This relationship is persistent after robust statistical adjustment for confounders This relationship is persistent after robust statistical adjustment for confounders Decisions made in the ED may affect subsequent bleeding risk, and in turn, clinical outcomes Decisions made in the ED may affect subsequent bleeding risk, and in turn, clinical outcomes Bleeding and Outcomes Conclusions

Bleeding in ACS Question To Be Answered Can blood transfusion correct adverse outcomes associate with bleeding? Can blood transfusion correct adverse outcomes associate with bleeding? Question To Be Answered Can blood transfusion correct adverse outcomes associate with bleeding? Can blood transfusion correct adverse outcomes associate with bleeding?

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

*Transfusion as a time-dependent covariate Cox Model for 30-day Death N=24,111N=24,111 Rao SV, et. al., JAMA 2004;292:1555–1562. PRBC Transfusion Among NSTE ACS Patients PRBC Transfusion Among NSTE ACS Patients

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

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

Increased 1-year mortality in transfused patients Adjusted Odds Ratio 4.26 (2.25–8.08) Transfusion Post PCI REPLACE 2 One Year Mortality P<0.0001 Manoukian SV, Voeltz MD, Attubato MJ, Bittl JA, Feit F, Lincoff AM. CRT 2005. Abstract.

Blood transfusion is independently associated with death and re-MI Blood transfusion is independently associated with death and re-MI Transfusion does not correct the adverse impact bleeding and is not an insurance policy for choices made in the ED Transfusion does not correct the adverse impact bleeding and is not an insurance policy for choices made in the ED Blood transfusion is best avoided in ACS patients whenever possible Blood transfusion is best avoided in ACS patients whenever possible Decisions regarding bleeding risk should be part of ED decision-making process Decisions regarding bleeding risk should be part of ED decision-making process Blood Transfusion Conclusions

Bleeding in ACS Question To Be Answered Does bleeding impact resource use? Does bleeding impact resource use? Question To Be Answered Does bleeding impact resource use? Does bleeding impact resource use?

Bleeding and Resource Use: Predictors of Total Costs Mod/sev bleed Per patient cost - $530 Transfusion - $2080, P < 0.01 Per patient cost - $287 Mod/sev bleed Per patient cost - $530 Transfusion - $2080, P < 0.01 Per patient cost - $287 Model C-index=0.87 Adjusted for patient characteristics Model C-index=0.87 Adjusted for patient characteristics Rao SV, et. al. ACC 2007. N=1235 pts from GUSTO IIb

The available costs data clearly show that a balance must be struck between ischemia reduction and bleeding The available costs data clearly show that a balance must be struck between ischemia reduction and bleeding l Both ischemic complications and bleeding are associated with increased costs such that any cost savings realized by reducing one is offset by cost increases associated with the other Although these costs are not realized in the ED, the choices made there impact costs downstream Although these costs are not realized in the ED, the choices made there impact costs downstream Bleeding and Costs Conclusions

What therapeutic options do ED physicans and cardiologists have to balance efficacy (reduced risk for ischemic outcomes) and safety (bleeding)? Bleeding in ACS Question To Be Answered

X Xa II IIa (Thrombin) (Prothrombin) TFVIIa IX IXa Xa Inhibitors - Fondaparinux Direct Thrombin Inhibitors - Bivalirudin Va Targets for Intervention

New Strategies: 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. New Strategies: 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. UA/NSTEMI Strategy Overview ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.

OASIS 5 Study Design NSTE ACS patients 2 of 3: Age > 60, ECG, Markers N=20,000 NSTE ACS patients 2 of 3: Age > 60, ECG, Markers N=20,000 Fondaparinux 2.5 mg SC QD Enoxaparin 1 mg/kg SC BID Death-MI-ischemia at 9d Major bleeding* at 9d Death-MI-ischemia at 9d Major bleeding* at 9d *ICH, RP, IO, Transfusion, Hgb 3 gm/dl

OASIS 5

Patients Undergoing PCI OASIS 5 and 6 OASIS 5 Investigators NEJM 2006 OASIS 6 Investigators JAMA 2006 OASIS 5 Investigators NEJM 2006 OASIS 6 Investigators JAMA 2006Rx None (n=2867) Lysis (n=5436) 1° PCI (n=3789) 1.02.00.5 Favors Fondaparinux Favors UFH or Placebo Catheter Thrombus

Moderate- high risk ACS ACUITY Study Design – First Randomization Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819) Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819) Angiography within 72h Aspirin in all Clopidogrel dosing and timing per local practice UFH or Enoxaparin + GP IIb/IIIa Bivalirudin + GP IIb/IIIa Bivalirudin Alone R* ACUITY Design. Stone GW et al. AHJ 2004;148:764–75 Medical management PCI CABG Primary endpoint: Net Clinical Composite Death, MI, TVR, Bleeding Primary endpoint: Net Clinical Composite Death, MI, TVR, Bleeding

ACUITY: Primary results – 30 days UFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone P NI <0.001 P Sup = 0.015 P NI = 0.011 P Sup = 0.32 P NI <0.001 P Sup <0.001 Stone GW et al. NEJM 2006;355:2203-16

0306090120150180210240270300330360390 0 4 5 Mortality (%) Days from Randomization 2 1 Mortality: 524 Total Deaths at 1-year UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone 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, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16.

ACUITY PCI: High Risk* Patients Risk Ratio ±95% CI RR (95% CI) Hazard Ratio ±95% CI HR (95% CI) UFH/Enox+ IIb/IIIa better * High risk = Tn, CKMB or ECG Δs Bivalirudin better 30 day Results 1 year Results Composite ischemia 1.08 (0.88- 1.32) Major bleeding 0.55 (0.42- 0.72) Mortality 0.94 (0.67-1.31) UFH/Enox+ IIb/IIIa better

Mortality (%) Days from Randomization 0306090120150180210240270300330360390 0 5 15 30 10 25 20 1 year Estimate Major Bleed only (without MI) (N=551)12.5% 28.9%Both MI and Major Bleed (N=94) 3.4%No MI or Major Bleed (N=12,557) MI only (without Major Bleed) (N=611)8.6% Impact of MI and Major Bleeding (non-CABG) in the First 30 Days on Risk of Death Over 1 Year 28.9% 12.5% 8.6% 3.4%

Day 0 – 2 after MI12.6 (7.8-20.4) 29 (37.6) <0.0001 Day 3 – 7 after MI5.3 (2.7-10.4) 11 (14.3) <0.0001 Day 8 – 35 after MI1.6 (0.8-3.1)12 (15.6)0.18 Day > 35 after MI1.2 (0.8-1.9)25 (32.5)0.34 Day 0 – 2 after Major Bleed3.0 (1.6-5.6)12 (12.9)0.0009 Day 3 – 7 after Major Bleed4.0 (2.1-7.5) 15 (16.1) <0.0001 Day 8 – 35 after Major Bleed4.5 (2.8-7.4)25 (26.9)<0.0001 Day > 35 after Major Bleed2.2 (1.5-3.2) 41 (44.1) <0.0001 P-value Deaths (n/%) HR ± 95% CI 0.5 1 2 4 8 16 HR (CI) Impact of MI and Major Bleeding (non-CABG) in the First 30 Days on Risk of Death Over 1 Year

ACS Case Presentation 77 year-old female presented to ED with 2 weeks of progressive angina, one episode lasting 90 minutes 77 year-old female presented 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, POC TnI 0.79 (ULN 0.5), nl CKMB, CrCL 40 ml/min, Hgb 9.7 g/dl ECG non-specific, POC 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 Anticoagulant choices in ED? l Risk stratification strategy?

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 gtt initiated Angiography Angiography Case Presentation

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

Bleeding Among Patients with ACS Conclusions There are several therapeutic pathways for NSTE ACS care There are several therapeutic pathways for NSTE ACS care The (up)stream of care begins in the emergency department The (up)stream of care begins in the emergency department Choices made in the ED impact downstream events Choices made in the ED impact downstream events l Ischemic complications l Bleeding complications

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

Conclusions Bleeding in ACS Coordination of care through cooperation between ED and IC Treatment (EDICT for ACS) is essential to navigate the new landscape Coordination of care through cooperation between ED and IC Treatment (EDICT for ACS) is essential to navigate the new landscape ACC/AHA guidelines now recognize the value of bleeding reduction in ACS care ACC/AHA guidelines now recognize the value of bleeding reduction in ACS care Bivalirudin is a Class I (Level of evidence: B) recommended antithrombin agent for NSTE ACS patients undergoing an invasive strategy Bivalirudin is a Class I (Level of evidence: B) recommended antithrombin agent for NSTE ACS patients undergoing an invasive strategy ACUITY demonstrates that bivalirudin provides protection from ischemic events while reducing bleeding risk ACUITY demonstrates that bivalirudin provides protection from ischemic events while reducing bleeding risk Coordination of care through cooperation between ED and IC Treatment (EDICT for ACS) is essential to navigate the new landscape Coordination of care through cooperation between ED and IC Treatment (EDICT for ACS) is essential to navigate the new landscape ACC/AHA guidelines now recognize the value of bleeding reduction in ACS care ACC/AHA guidelines now recognize the value of bleeding reduction in ACS care Bivalirudin is a Class I (Level of evidence: B) recommended antithrombin agent for NSTE ACS patients undergoing an invasive strategy Bivalirudin is a Class I (Level of evidence: B) recommended antithrombin agent for NSTE ACS patients undergoing an invasive strategy ACUITY demonstrates that bivalirudin provides protection from ischemic events while reducing bleeding risk ACUITY demonstrates that bivalirudin provides protection from ischemic events while reducing bleeding risk

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

PCI 7 7 Fondaparinux 6 6 Bivalirudin 5 5 Enoxaparin + GPI Enoxaparin + GPI 4 4 UFH + GPI 3 3 Clopidogrel 2 2 ASA 1 1 ASA PCI Bleeding risk factors CABG likely or planned Bleeding risk factors Renal dysfunction PCI Year 2007 ACC-AHA NSTEMI Guidelines Seven Streams of Success Early Invasive Therapy Year 2007 ACC-AHA NSTEMI Guidelines Seven Streams of Success Early Invasive Therapy + Clopidogrel No clopidogrel pretreatment Aspirin allergy

Bivalirudin PCI Clopidogrel+ ASA+ UFH/Enoxaparin Bivalirudin + Clopidogrel/ASA Switching

ACS (Acute Controversy Syndrome): Cardiovascular Emergency Case Studies Emergency Medicine and Cardiovascular Specialists Engage in the Acute Collaboration Syndrome From ACS Risk Profiles to Patient Care: Case Studies in ACSDoing the Right Thing in the Right Patient ACS (Acute Controversy Syndrome): Cardiovascular Emergency Case Studies Emergency Medicine and Cardiovascular Specialists Engage in the Acute Collaboration Syndrome From ACS Risk Profiles to Patient Care: Case Studies in ACSDoing the Right Thing in the Right Patient Getting in the Stream of Things

Case Studies in Acute Coronary Syndromes Acknowledgement is made to Dr. Steven Manoukian, MD and CMEducation Resources, LLC for patient cases studies, cineangiograms, and/or assistance in preparation of case studies for this segment of the program

Case #1: History and Findings 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)

New anterior and lateral ST / T changes. Case #1: 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 Case #1

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 * Case #1

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 Case #1

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 * Case #1

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 * Case #1

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 * Case #1

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 * Case #1

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 * Case #1

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 * Case #1

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 * Case #1

Case #2: History 77 year-old white female without prior cardiac history 77 year-old white female without prior cardiac history Multiple short episodes of chest pain today Multiple short episodes of chest pain today Unrelieved with NTG sl and IV; metoprolol IV Unrelieved with NTG sl and IV; metoprolol IV PMH: DM, HTN, CHOL PMH: DM, HTN, CHOL PE: benign (weight 65 kg). PE: benign (weight 65 kg). Labs: Hgb 11.7, Cr 1.1, CK 285/9, Tr 2.7 Labs: Hgb 11.7, Cr 1.1, CK 285/9, Tr 2.7 ECG ECG

New inferior changesNew lateral changes Case #2: ECG

Based upon this patients overall profile, when selecting an antithrombotic regimen, you are more likely be concerned about: A. Ischemic risk B. Hemorrhagic risk * Case #2

Which of the following factors would you consider most important when evaluating the need for immediate catheterization in this patient? A. Advanced age B. Positive biomarkers C. ECG findings D. Refractory discomfort * Case #2

Would a plan of immediate versus delayed catheterization influence your choice of anticoagulation therapy? A.Yes B.No * Case #2

If this patient was going for immediate catheterization (now), which of the following regimens would you start? A. Unfractionated heparin alone B. Enoxaparin alone C. Bivalirudin alone D. A heparin with a GP IIb/IIIa inhibitor E. Fondaparinux * Case #2

If catheterization had to be delayed 2-4 hours (availability of lab, transfer, etc.), which of the following regimens would you start? A. Unfractionated heparin alone B. Enoxaparin alone C. Bivalirudin alone D. A heparin with a GP IIb/IIIa inhibitor E. Fondaparinux * Case #2

Case #3: History 82 year old white-female with history of MI, PTCA/LAD in 1997 82 year old white-female with history of MI, PTCA/LAD in 1997 Presents with exertional chest pain as well as chest pressure at rest x 72 hours, but is now pain-free in ED Presents with exertional chest pain as well as chest pressure at rest x 72 hours, but is now pain-free in ED PMH: IRDM, HTN, CHOL PMH: IRDM, HTN, CHOL PE: 2/6 murmur at apex (weight 58 kg) PE: 2/6 murmur at apex (weight 58 kg) Labs: Hgb 11.1, Cr 1.6, CK 37/1, Tr <0.03 Labs: Hgb 11.1, Cr 1.6, CK 37/1, Tr <0.03 ECG. ECG.

Case #3: ECG No notable findings compared to old ECG.

What would you use for upstream anticoagulation in this patient whose catheterization is planned for the next day: i.e., within 24 hours? A. Unfractionated heparin alone B. Enoxaparin alone C. Bivalirudin alone D. A heparin with a GP IIb/IIIa inhibitor E. Fondaparinux * Case #3

In general, in an ACS patient with moderate or high risk ischemic features, at what point in the patients course would you administer clopidogrel? A. In the ED, immediately. B. In the catheterization lab, prior to catheterization. C. In the catheterization lab, after catheterization and decision to proceed with PCI, but prior to PCI. D. In the catheterization lab, post-PCI. * Concluding Questions

In general, based on my interpretation of the current evidence for selecting anticoagulation therapy in ACS patients, therapy is best guided by: A. Ischemic risk (reduction of ischemic endpoints) B. Bleeding risk (reduction of bleeding endpoints) C. Balance of ischemic and bleeding risk, and selection of a strategy that optimizes net clinical benefit (optimizes aggregate reduction of both ischemic and bleeding endpoints) * Concluding Questions

1) How do ED specialists incorporate new streams of care for NSTEMI introduced by Year 2007 ACC/AHA Guidelines for NSTEMI - Bivaliridion for initial invasive strategy? Fondaprinux for initial conservative therapy? 2) How do new guidelines affect clopidogrel treatment at front lines of ED care? 3) How do ED specialists and cardiologists synchronize on new GLs and newly introduced options? 4) Questions * Discussion Points

Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Program Chairman Chairman, Department of Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine.

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Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Program Chairman Chairman, Department of Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine.

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Presentation on theme: "Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Program Chairman Chairman, Department of Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine."— Presentation transcript:

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