Welcome to the EDICT for ACS Cardiovascular Forum

Critical Challenges in Cardiovascular Medicine Advancing Management of Acute Coronary Syndromes(ACS)Establishing Interventional Cardiology & Emergency Medicine Therapeutic Teams Linking Science and Landmark Studies to the Front Lines of Cardiology Practice Steven V. Manoukian, MD, FACC Director, Interventional Cardiology Emory-Crawford Long Hospital Emory University School of Medicine President, American Heart Association, Atlanta Div. Atlanta, GA

EDICT for ACS Mission Statement: Bringing together interventional cardiologists and emergency medicine specialists to manage patients collaboratively and seamlessly in order to improve clinical outcomes in ACS

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

Educational Objectives As a result of this session, cardiologists and emergency physicians will be able to assess and implement optimal antithrombotic strategies for patients with acute coronary syndromes (ACS).As a result of this session, cardiologists and emergency physicians will be able to assess and implement optimal antithrombotic strategies for patients with acute coronary syndromes (ACS). As a result of this session, attendees will understand impact of specific pharmacologic agents on outcomes, including ischemic endpoints, bleeding, and mortality for patients with ACS.As a result of this session, attendees will understand impact of specific pharmacologic agents on outcomes, including ischemic endpoints, bleeding, and mortality for patients with ACS. As a result of this session, attendees are able to discuss the impact that new trials are likely to have on future management of patients with ACS.As a result of this session, attendees are able to discuss the impact that new trials are likely to have on future management of patients with ACS. As a result of this session, ED physicians and cardiologists will learn to apply AHA/ACC, ACCP, and other national guidelines in order to optimize therapy ACSAs a result of this session, ED physicians and cardiologists will learn to apply AHA/ACC, ACCP, and other national guidelines in order to optimize therapy ACS As a result of this session, cardiologists and emergency physicians will be able to assess and implement optimal antithrombotic strategies for patients with acute coronary syndromes (ACS).As a result of this session, cardiologists and emergency physicians will be able to assess and implement optimal antithrombotic strategies for patients with acute coronary syndromes (ACS). As a result of this session, attendees will understand impact of specific pharmacologic agents on outcomes, including ischemic endpoints, bleeding, and mortality for patients with ACS.As a result of this session, attendees will understand impact of specific pharmacologic agents on outcomes, including ischemic endpoints, bleeding, and mortality for patients with ACS. As a result of this session, attendees are able to discuss the impact that new trials are likely to have on future management of patients with ACS.As a result of this session, attendees are able to discuss the impact that new trials are likely to have on future management of patients with ACS. As a result of this session, ED physicians and cardiologists will learn to apply AHA/ACC, ACCP, and other national guidelines in order to optimize therapy ACSAs a result of this session, ED physicians and cardiologists will learn to apply AHA/ACC, ACCP, and other national guidelines in order to optimize therapy ACS

Program Faculty Steven V. Manoukian, MD, FACC Director, Interventional Cardiology Emory-Crawford Long Hospital Emory University School of Medicine President, American Heart Association, Atlanta Div. Atlanta, GA Sunil V. Rao MD Assistant Professor of Medicine Duke University Medical Center Durham VA Medical Center Duke Clinical Research Institute James Hoekstra, MD Professor and Chairman Department of Emergency Medicine Wake Forest University Health Center Winston-Salem, NC Steven V. Manoukian, MD, FACC Director, Interventional Cardiology Emory-Crawford Long Hospital Emory University School of Medicine President, American Heart Association, Atlanta Div. Atlanta, GA Sunil V. Rao MD Assistant Professor of Medicine Duke University Medical Center Durham VA Medical Center Duke Clinical Research Institute James Hoekstra, MD Professor and Chairman Department of Emergency Medicine Wake Forest University Health Center Winston-Salem, NC

Financial Disclosures Steven V. Manoukian, MD, FACC Grant/Research Support: The Medicines Company Speakers Bureau: The Medicines Company Sunil V. Rao, MD Consultant: sanofi-aventis, The Medicines Company, Pfizer, Cordis Research funding: Agency for Healthcare Research & Quality, National Institute for Aging, American College of Cardiology James Hoekstra, MD Grant/Research Support: Schering-Plough, Biosite Consultant: Schering-Plough, The Medicines Co., sanofi-aventis Speakers Bureau: Schering-Plough, BMS, sanofi-aventis Steven V. Manoukian, MD, FACC Grant/Research Support: The Medicines Company Speakers Bureau: The Medicines Company Sunil V. Rao, MD Consultant: sanofi-aventis, The Medicines Company, Pfizer, Cordis Research funding: Agency for Healthcare Research & Quality, National Institute for Aging, American College of Cardiology James Hoekstra, MD Grant/Research Support: Schering-Plough, Biosite Consultant: Schering-Plough, The Medicines Co., sanofi-aventis Speakers Bureau: Schering-Plough, BMS, sanofi-aventis

NOTE There will be off-label discussionsindications and dosingduring this CME symposium, and speakers will note such off-label information. This information does not imply or constitute endorsement of such strategies, which must be evaluated on the basis of evidence and expert analysis. Off-Label Discussion and Information

EDICT for ACS CD-ROM Comprehensive Cardiovascular CD-ROM Resource includes: CME-certified National Experts SlideCASTs on ACS Clinical Trials and Bleeding EDICT for ACS CME Program SlideCAST Direct links to CME-certified WebCASTs in cardiovascular medicine Direct links to CME-certified ACS- WRAP and PCI-WRAP Landmark trials and guidelines in ACS

EDICT for ACS on the Web Updated Information about ACS Management, Guidelines, and Trials will be available on: EDICTforACS.comClinicalWebcasts.comMedicineCAST.netCardioCAST.net EDICTforACS.comClinicalWebcasts.comMedicineCAST.netCardioCAST.net

We Request That You… Please fill out your question and answer cards as program proceeds so we can collect them and discuss during the Q&A session Please fill out the Course Survey and Evaluation forms to obtain CME credit, and hand the form to the staff at the desk outside Please fill out your question and answer cards as program proceeds so we can collect them and discuss during the Q&A session Please fill out the Course Survey and Evaluation forms to obtain CME credit, and hand the form to the staff at the desk outside

Advancing Management of Acute Coronary Syndromes Linking Science and Landmark Studies to the Front Lines of Cardiology Practice Introduction to EDICT for ACS Forum Steven V. Manoukian, MD, FACC Director, Interventional Cardiology Emory-Crawford Long Hospital Emory University School of Medicine President, American Heart Association, Atlanta Div. Atlanta, GA Critical Challenges in Cardiovascular DiseaseIntroduction

Fuster V et al. J Am Coll Cardiol 2005;46: Co-Existent Stable and Acute Lesions Chronic Atherosclerosis Acute Thrombosis

SYNERGYLMWHESSENCE 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.

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

Sites of Antithrombotic Drug Action Tissue factor Plasma clotting cascade Plasma clotting cascade Prothrombin Thrombin Fibrinogen Fibrin Thrombus Platelet aggregation Platelet activation Collagen Thromboxane A 2 ADP AT Aspirin Clopidogrel Prasugrel Cangrelor Eptifibatide Abciximab Tirofiban (GPI) Bivalirudin Hirudin Argatroban Factor Xa Factor Xa Heparin LMWHs Fibrinolytics Fondaparinux AT

UFH LMWH TIMI 11B 2004 SYNERGY Bivalirudin 2003 REPLACE 2 ASA IIb/IIIa antagonists EPISTENT PURSUIT 2001 ESPRIT GUSTO ISAR REACT Clopidogrel CURE 2000 Anti-thrombotic agents Anti-platelet agents Evolving ACS Therapies and Patterns of Antithrombotic Use* ACUITY 2006 ISAR-REACT 2 * Width of bar represents approximate degree of use of antiplatelet or anticoagulants at a particular time

Thank You

A Science-to-Strategy Analysis of Bleeding Issues in Acute Coronary Syndromes A Science-to-Strategy Analysis of Bleeding Issues in Acute Coronary Syndromes BLEEDING IN THE SETTING OF ACUTE CORONARY SYNDROMES (ACS) Clinical Implications and Effects on Mortality and Resource Utilization BLEEDING IN THE SETTING OF ACUTE CORONARY SYNDROMES (ACS) Clinical Implications and Effects on Mortality and Resource Utilization Sunil V. Rao MD Assistant Professor of Medicine Duke University Medical Center Durham VA Medical Center Duke Clinical Research Institute Sunil V. Rao MD Assistant Professor of Medicine Duke University Medical Center Durham VA Medical Center Duke Clinical Research Institute

Ischemic Complications Death MI Urgent TVR Death MI Urgent TVR Evolving Paradigm for Evaluating ACS Management Strategies Composite Adverse Event Endpoints

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 Paradigm for Evaluating ACS Management Strategies

Periprocedural Complications Clinical Benefit Death Major Disability Death Major Disability Cost Ease of Use Duration of Therapy Accounting for Bleeding and Ischemic Endpoints Cost Ease of Use Duration of Therapy Accounting for Bleeding and Ischemic Endpoints Composite Adverse Event Endpoints Evolving Paradigm for Evaluating ACS Management Strategies

Death4.3% (Re)-Infarction2.5% CHF8.0% Cardiogenic Shock2.6% Stroke0.8% Non-CABG Transfusion9.9% Bhatt DL, et al. JAMA Nov 3;292(17): CRUSADE In-Hospital Outcomes

Bleeding in ACS - Agenda Predictors of bleeding in ACS Predictors of bleeding in ACS Outcomes associated with bleeding Outcomes associated with bleeding l Impact of definition on outcomes Outcomes associated with blood transfusion Outcomes associated with blood transfusion Special populations at risk Special populations at risk l Elderly l Chronic kidney disease l Anemia Cost implications of bleeding Cost implications of bleeding

What predicts bleeding among patients with ACS ? Bleeding in ACS Question to be answered:

Independent Predictors of Major Bleeding in Marker Positive Acute Coronary Syndromes Moscucci, GRACE Registry, Eur Heart J Oct;24(20): 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-value RR (95% CI) Risk ratio ± 95% CI Predictors of Major Bleeding Age >75 (vs ) 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 ( ) ( ) < ( ) < ( ) ( ) < ( ) ( ) ( ) ( ) ( ) < Manoukian SV, Voeltz MD, Feit F et al. TCT Results: The ACUITY Trial PCI Population

P-value RR (95% CI) Age >75 (vs ) Anemia CrCl <60mL/min Diabetes Female gender High-risk (ST / biomarkers) Hypertension Heparin (s) + GPI (vs. Bivalirudin) ( ) ( ) < ( ) < ( ) ( ) < ( ) ( ) ( ) Predictors of Transfusion Risk ratio ± 95% CI Manoukian SV, Voeltz MD, Feit F et al. TCT Results: The ACUITY Trial

REPLACE-2 Multivariate Predictors of Major Bleeding RISK FACTORS Odds Ratio 95% CI p-value Baseline risk factors Age > to Gender (M vs. F) to Prior Angina to Creatinine clearance* to Anemia to Peri-procedural risk factors Treatment Group (BIV vs. H+GPI) to Provisional GPI received to Procedure Duration >1h to Time to Sheath Removal >6h to ICU stay (days) to < IABP to < Feit F et al. Unpublished (in manuscript)

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 Procedural characteristics such as procedure duration and sheath dwell time also predict bleeding complications 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 Procedural characteristics such as procedure duration and sheath dwell time also predict bleeding complications Bleeding PredictorsConclusions

Does bleeding influence the prognosis of ACS patients ? Bleeding in ACS Question to be answered:

Moscucci M et al. Eur Heart J 2003;24: 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 < log-rank p-value for no bleeding vs. mild bleeding = 0.02 log-rank p-value for mild vs. moderate bleeding < log-rank p-value for moderate vs. severe <0.001 Bleeding & Outcomes Rao SV, et al. Am J Cardiol Nov 1;96(9): 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< Bleeding and Outcomes in NSTE ACS Bleeding Severity30d Death30d Death/MI6 mo. Death Mild* Moderate* Severe* *Bleeding as a time-dependent covariate Rao SV, et al. Am J Cardiol Nov 1;96(9): Epub 2005 Sep 12

Major Bleeding, Ischemic Endpoints, and Mortality P< for all Manoukian SV, Voeltz MD, Feit F et al. TCT Results: The ACUITY Trial PCI Population (N=7,789)

Major Bleeding and Myocardial Infarction P< for all Manoukian SV, Voeltz MD, Feit F et al. TCT Results: The ACUITY Trial PCI Population (N=7,789)

Major and Minor Bleeding in PCI Bleeding Increases Mortality and Events Kinnaird TD et al. AM J Cardiol 2003;92: ,974 patients undergoing PCI, Washington Hospital Center, In-Hospital Clinical Events Major(n=588)Minor(n=1,394)None(n=8,992) Death 7.5%* 7.5%* 1.8%*0.6% Q-wave myocardial infarction 1.2%* 0.7% 0.7% 0.2% Non-Q-wave myocardial infarction 30.7%* 30.7%* 16.8%*11.8% Repeat lesion angioplasty 1.9%* § 0.8% 0.8% 0.3% Major adverse cardiac event 6.6%* 6.6%* 2.2%*0.6% Bleeding Complication * p<0.001 versus none p<0.001 versus minor p<0.01 versus none § p<0.05 versus minor

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 loss-dependent with worse bleeding associated with worse outcomes This relationship is persistent after robust statistical adjustment for confounders Bleeding is associated with adverse short- and long-term outcomes among patients with ACS and those undergoing PCI l Mortality rates are higher among those who bleed l MI rates are higher among those who bleed The risk is loss-dependent with worse bleeding associated with worse outcomes This relationship is persistent after robust statistical adjustment for confounders Bleeding and OutcomesConclusions

How does one assess bleeding severity? Bleeding in ACS Question to be answered:

Bleeding Incidence in ACS Clinical Trials Rao SV, et al. J Am Coll Cardiol Feb 21;47(4): Epub 2006 Jan 26

Bleeding Definitions TIMI Definition TIMI Definition l Major ICH ICH Associated with Hgb decrease 5 g/dl or HCT decrease 15% Associated with Hgb decrease 5 g/dl or HCT decrease 15% l Minor Observed blood loss associated with Hgb decrease 3 g/dl or HCT decrease 10% Observed blood loss associated with Hgb decrease 3 g/dl or HCT decrease 10% No identifiable source but Hgb decrease 4 g/dl or HCT decrease 12% No identifiable source but Hgb decrease 4 g/dl or HCT decrease 12% l Minimal Overt hemorrhage with Hgb drop < 3 g/dl or HCT drop < 9% Overt hemorrhage with Hgb drop < 3 g/dl or HCT drop < 9% Chesebro JH. Circulation Jul;76(1):

N Engl J Med Nov 25;329(22): Erratum in: N Engl J Med 1994 Feb 17;330(7):516 Bleeding Definitions GUSTO Definition GUSTO Definition l Severe or life threatening ICH or hemodynamic compromise requiring treatment ICH or hemodynamic compromise requiring treatment l Moderate Requiring transfusion Requiring transfusion l Mild Not meeting criteria for Severe or Moderate Not meeting criteria for Severe or Moderate

Bleeding Incidence Among 15,858 NSTE ACS Patients: Impact of Definition Rao SV, et al. J Am Coll Cardiol Feb 21;47(4): Epub 2006 Jan 26

Bleeding Scales Among NSTE ACS Patients Bleeding Scales Among NSTE ACS Patients Rao SV, et al. J Am Coll Cardiol Feb 21;47(4): Epub 2006 Jan 26 TIMI and GUSTO – Adjusted Hazard of 30 d Death/MI N=15,858

Clearly defining bleeding severity can be difficult, but there are definitions that have been used in clinical trials and registries Not all of these definitions have been validated in terms of prognosis TIMI and GUSTO are 2 of the most commonly used definitions Bleeding definitions that include clinical events (e.g. GUSTO) are better at predicting outcomes Clearly defining bleeding severity can be difficult, but there are definitions that have been used in clinical trials and registries Not all of these definitions have been validated in terms of prognosis TIMI and GUSTO are 2 of the most commonly used definitions Bleeding definitions that include clinical events (e.g. GUSTO) are better at predicting outcomes Bleeding DefinitionsConclusions

Do blood transfusions have predictive value? Do blood transfusions correct negative impact of bleeding? Do blood transfusions have predictive value? Do blood transfusions correct negative impact of bleeding? Bleeding in ACS Questions to be answered:

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

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 P< for all Manoukian SV, Voeltz MD, Feit F et al. TCT Results: The ACUITY Trial (N=13,819)

Transfusion and Myocardial Infarction P< for all Manoukian SV, Voeltz MD, Feit F et al. TCT 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< Manoukian SV, Voeltz MD, Attubato MJ, Bittl JA, Feit F, Lincoff AM. CRT Abstract.

Although there has never been a randomized trial of blood transfusion in patients with ACS, the available observational data consistently supports a relationship between blood transfusion and increased adverse outcomes, including death, MI, and unplanned revascularization Blood transfusion is best avoided in ACS patients whenever possible Although there has never been a randomized trial of blood transfusion in patients with ACS, the available observational data consistently supports a relationship between blood transfusion and increased adverse outcomes, including death, MI, and unplanned revascularization Blood transfusion is best avoided in ACS patients whenever possible Blood TransfusionConclusions

Are there certain ACS subpopulations at especially high risk for bleeding, transfusion, and morbidity/mortality? Bleeding in ACS Question to be answered:

Bleeding RisksTransfusions by Age Alexander KA, JAMA 2005;294:3108–16.

6,002 patients in REPLACE patients (13.4%) classified as elderly, >75 years of age p<0.0001p= REPLACE-2: Elderly Patients Have Increased Major Bleeding and Transfusions = Not Elderly, <75 = Elderly, >75 Voeltz MD, Lincoff AM, Feit F, Manoukian SV. Circulation 2005;112(17):II-613. Abstract.

p< p= ,002 patients in REPLACE patients (13.4%) classified as elderly, >75 years of age. 806 patients (13.4%) classified as elderly, >75 years of age. Elderly Patients in REPLACE-2: Increased 30-Day Mortality With Major Bleeding and Transfusions Voeltz MD, Lincoff AM, Feit F, Manoukian SV. Circulation 2005;112(17):II-613. Abstract.

Excessive Dosing of Anticoagulants by Age Alexander KA, JAMA 2005;294:3108– LMW HeparinUF HeparinGP Iib/IIIa % RBC Transfusion <65 yrs65Š75 yrs>75 yrs

RBC Transfusions by Excess Dosing Alexander KA, JAMA 2005;294:3108–16.

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

Excess Dosing of Gp IIb/IIIa and Bleeding in Women OverallOverall WomenWomen MenMen 1.46 (1.22, 1.73) 1.72 (1.30, 2.28) 1.27 (0.97, 1.66) Excess Dosing More Likely to Bleed Alexander KP, et. al. Circulation 2006 N=32,601 patients from CRUSADE

Bleeding is Increased in Patients With Impaired Renal Function Undergoing PCI 60 ml/min N= ml/min N=4824 < 60 ml/min N=886 p value 30-d Death 5 (0.1%) 14 (1.6%) < < d Myocardial infarction 305 (6.3%) 75 (8.5%) d urgent revascularization 61 (1.3%) 10 (1.1%) Triple ischemic endpoint 338 (7.0%) 84 (9.5%) In-hospital protocol major bleeding 123 (2.5%) 54 (6.1%) < < TIMI major + minor bleeding 114 (2.4%) 46 (5.2%) < < Creatinine Clearance Chew DP et al. Am J Cardiol 2005;95:581–585.

Anemia Identifies High-Risk The Unrecognized Risk Factor Older Older Female Female Lower BMI Lower BMI Fewer Caucasians Fewer Caucasians Lower Hemoglobin (11.7 vs g/dL) Lower Hemoglobin (11.7 vs g/dL) Lower Hematocrit (34.6 vs. 41.8%) Lower Hematocrit (34.6 vs. 41.8%) Less Tobacco use Less Tobacco use More Diabetes Mellitus More Diabetes Mellitus More history of CHF, MI, PCI, CABG More history of CHF, MI, PCI, CABG REPLACE-2 Anemic Patient Baseline Characteristics: (Anemia in 22.7%) Voeltz MD, Attubato MJ, Feit F, Lincoff AM, Manoukian SV. J Am Coll Cardiol 2005;45(3)[Suppl A]: A. Abstract.

Major Bleeding is Increased in Anemic Patients Undergoing PCI 6,010 patients in REPLACE-2. 1,362 patients (22.7%) classified as anemic based upon WHO definition. Major bleeding = 3.2% Major Bleeding 2.8% 4.9% P= Protocol definition: >3g/dL drop in HgB, intracranial, retroperitoneal, 2U transfusion Voeltz MD, Attubato MJ, Feit F, Lincoff AM, Manoukian SV. J Am Coll Cardiol 2005;45(3)[Suppl A]: A. Abstract.

NSTE-ACS Mortality Stratified by Hemoglobin Sabatine MS. Circulation 2005 Unadjusted Hb (g/dL)nOR(95% Cl)OR(95% Cl)P value > (1.03–2.10)1.45(0.94–2.23) – (0.97–1.51)1.27(0.98–1.65) – reference1.0 reference 14– (0.89–1.22)1.11(0.93–1.33) – (0.88–1.19)1.04(0.86–1.24) – (0.92–1.28)1.07(0.88–1.30) – (0.97–1.47)1.04(0.81–1.34) – (1.05–1.89)1.29(0.92–1.82) – (1.88–3.18)2.69(2.01–3.60)< – (1.88–3.18)2.69(2.01–3.60)< – (1.69–2.96)2.45(1.80–3.33)<0.001 < (2.76–5.70)3.49(2.35–5.20)<0.001 Abbreviations: CI, confidence interval; Hb, hemoglobin; OR, odds ration. Adapted with permission. Abbreviations: CI, confidence interval; Hb, hemoglobin; OR, odds ration. Adapted with permission. Unadjusted and adjusted odds ratios for cardiovascular mortality in patients with non-ST elevation acute coronary syndromes at 30 days stratefied by hemoglobin Adjusted for baseline characteristics

Certain ACS patient populations are at especially high risk for bleeding and mortality l Elderly, females, CKD, anemia Improper dosing of anticoagulants is a common error and is associated with bleeding risk in the elderly, females, and those with CKD Anemia places patients at risk for both bleeding and mortality Certain ACS patient populations are at especially high risk for bleeding and mortality l Elderly, females, CKD, anemia Improper dosing of anticoagulants is a common error and is associated with bleeding risk in the elderly, females, and those with CKD Anemia places patients at risk for both bleeding and mortality High-Risk PopulationsConclusions

Does bleeding influence the cost of care for patients with ischemic heart disease? Bleeding in ACS Question to be answered:

Abciximab versus Placebo ischemic costs:$523 major bleed costs:$458 Abciximab versus Placebo ischemic costs:$523 major bleed costs:$458 Mark DB, et al. Circulation Feb 1;101(4): Calculating Costs of Ischemia and Bleeding: EPIC EQOL Study (Abciximab in PCI) Calculating Costs of Ischemia and Bleeding: EPIC EQOL Study (Abciximab in PCI)

The available costs data confirms that a balance must be struck between ischemia reduction and bleeding. Both ischemic complications and bleeding are associated with increased costs. The available costs data confirms that a balance must be struck between ischemia reduction and bleeding. Both ischemic complications and bleeding are associated with increased costs. Bleeding and CostsConclusions

Bleeding Among Patients with ACS Conclusions Antithrombotic therapies are cornerstone Rx Antithrombotic therapies are cornerstone Rx l Must balance thrombosis and hemostasis Certain patient and PCI procedure characteristics predict bleeding Certain patient and PCI procedure characteristics predict bleeding l Age, female gender, CKD, procedure time, sheath dwell time Diabetes and anemia are newly identified risk factors for bleeding among ACS patients Diabetes and anemia are newly identified risk factors for bleeding among ACS patients

ConclusionsBleeding 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 Assessing bleeding severity is important Assessing bleeding severity is important Many definitions have been used Many definitions have been used Definitions that include clinical events appear to be more useful than those that include only laboratory parameters Definitions that include clinical events appear to be more useful than those that include only laboratory parameters Blood transfusion is associated with increased mortality in ACS patients Blood transfusion is associated with increased mortality in 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 Assessing bleeding severity is important Assessing bleeding severity is important Many definitions have been used Many definitions have been used Definitions that include clinical events appear to be more useful than those that include only laboratory parameters Definitions that include clinical events appear to be more useful than those that include only laboratory parameters Blood transfusion is associated with increased mortality in ACS patients Blood transfusion is associated with increased mortality in ACS patients

ConclusionsBleeding 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 Bleeding costs can offset the savings realized by reduced ischemic complications Bleeding costs can offset the savings realized by reduced ischemic complications Given the body of evidence related to bleeding and transfusion, therapies that can reduce ischemia while minimizing the risk for bleeding have the potential to further improve outcomes among patients with ACS Given the body of evidence related to bleeding and transfusion, therapies that can reduce ischemia while minimizing the risk for bleeding have the potential to further improve outcomes among patients with ACS 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 Bleeding costs can offset the savings realized by reduced ischemic complications Bleeding costs can offset the savings realized by reduced ischemic complications Given the body of evidence related to bleeding and transfusion, therapies that can reduce ischemia while minimizing the risk for bleeding have the potential to further improve outcomes among patients with ACS Given the body of evidence related to bleeding and transfusion, therapies that can reduce ischemia while minimizing the risk for bleeding have the potential to further improve outcomes among patients with ACS

A Science-to-Strategy Analysis of Landmark Trials in Acute Coronary Syndromes (ACS) Applying New Data and Established Guidelines to the Practice of Interventional Cardiology and Emergency Medicine A Science-to-Strategy Analysis of Landmark Trials in Acute Coronary Syndromes (ACS) Applying New Data and Established Guidelines to the Practice of Interventional Cardiology and Emergency Medicine Critical Challenges in Cardiovascular Medicine Steven V. Manoukian, MD, FACC Director, Interventional Cardiology Emory-Crawford Long Hospital Emory University School of Medicine President, American Heart Association, Atlanta Div. Atlanta, GA

ACS Program Agenda Recent landmark clinical trials n ICTUS n ISAR-REACT 2 n SYNERGY n OASIS 5 n ACUITY –Antithrombotic strategy –Timing –PCI n Conclusions Conclusions about ACS management Frequent Questions Recent landmark clinical trials n ICTUS n ISAR-REACT 2 n SYNERGY n OASIS 5 n ACUITY –Antithrombotic strategy –Timing –PCI n Conclusions Conclusions about ACS management Frequent Questions

Actions of Thrombin on Blood Cells and Blood Vessels Endothelium Neutrophil Platelet Monocyte Lymphocyte Smooth Muscle cell Thrombin Cytokines Growth factors Autocoids Proteases Cytokines Growth factors Autocoids Proteases Shape and permeability changes Shape and permeability changes Coughlin SR, Nature 2000; 407: Serine protease generated at sites of vascular injury. Potent platelet activator (PAR-protease activated receptor). Elicits host of responses in vascular endothelium: - Shape & permeability changes - Mobilization of adhesive molecules to endothelial surface - Stimulation of autocoid and cytokine production. Chemotactic for monocytes. Mitogenic for lymphocytes & mesenchymal cells.

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

ECG and Outcome in TACTICS/TIMI 18 ST-segment s ( n = 852 ) ST-segment s ( n = 852 ) Death / MI / Rehospitalization at 6 Months Cannon et al. N Engl J Med 2001; 344: No ST-segment s ( n = 1368 ) No ST-segment s ( n = 1368 ) Conservative Invasive Risk Stratification

Death/MI/hosp Tn T > 0.01 ng/ml Death/MI/hosp Death/MI Death/MI/hosp Death/MI Death/MI/hosp Death/MI Tn T > 0.01 ng/ml Tn T < 0.01 ng/ml 6 Months30 Days Cannon et al. N Engl J Med 2001; 344: Conservative Invasive Troponin and Outcome in TACTICS/TIMI 18 Risk Stratification < <

CRUSADE: In-Hospital Outcomes Peterson, E.D. et al. JAMA 2006;295: No. of Events (%) by Hospital Adherence Quartile Population1 (Lowest)244 (Highest)P value Overall (N = 64775)(n = 12329)(n = 15255)(n = 18364)(n = 18827) Death 784 (6.36) 772 (5.06) 850 (4.63) 786 (4.17) <.001 Death/MI*1119 (9.08)1280 (8.39)1223 (6.66)1201 (6.38) <.001 Stroke 96 (0.78) 146 (0.96) 171 (0.93) 134 (0.71).31 CHF 908 (7.36) 1747 (11.45)1727 (9.40)1541 (8.19).24 NSTEMI (N = 57260)(n = 9892)(n = 12597)(n = 18149)(n = 16622) Death 760 (7.68) 701 (5.56) 843 (4.64) 718 (4.32)<.001 Death/MI*1055 (10.67)1128 (8.95)1206 (6.64)1105 (6.65) <.001 Stroke 96 (0.80) 146 (0.98) 171 (0.94) 134 (0.72).25 CHF862 (8.71) 1368 (10.68) 1851 (10.20)1424 (8.57).13 *Indicates in-hospital death or recurrent MI. Population1 (Lowest)244 (Highest)P value Overall (N = 64775)(n = 12329)(n = 15255)(n = 18364)(n = 18827) Death 784 (6.36) 772 (5.06) 850 (4.63) 786 (4.17) <.001 Death/MI*1119 (9.08)1280 (8.39)1223 (6.66)1201 (6.38) <.001 Stroke 96 (0.78) 146 (0.96) 171 (0.93) 134 (0.71).31 CHF 908 (7.36) 1747 (11.45)1727 (9.40)1541 (8.19).24 NSTEMI (N = 57260)(n = 9892)(n = 12597)(n = 18149)(n = 16622) Death 760 (7.68) 701 (5.56) 843 (4.64) 718 (4.32)<.001 Death/MI*1055 (10.67)1128 (8.95)1206 (6.64)1105 (6.65) <.001 Stroke 96 (0.80) 146 (0.98) 171 (0.94) 134 (0.72).25 CHF862 (8.71) 1368 (10.68) 1851 (10.20)1424 (8.57).13 *Indicates in-hospital death or recurrent MI.

The Evolving World of ACS Recent Landmark Trials Science Recent Trials Clinical Strategies Science Recent Trials Clinical Strategies

Case for Invasive Management FRISC II TACTICS FRISC II TACTICS

Probability of death Non-invasive (n=1235) Invasive (n=1222) InvasiveNoninvasive RR (95 % CI) p 2.2 %4.0 % 0.56 ( ) FRISC II Mortality at One-Year Invasive versus Non-invasive Management Strategies Lancet. 1999; 354:701-7

Time (months) % Patients CONS INV O.R % CI (0.62, 0.97) p=0.025 O.R % CI (0.62, 0.97) p= % 15.9% TACTICS Primary Endpoint: Death, MI, Rehosp for ACS at 6 Months Cannon CP, Weintraub WS. N Engl J Med Jun 21;344(25):

Recent Clinical Trials ISAR REACT-2 SYNERGY OASIS-5 ACUITY ISAR REACT-2 SYNERGY OASIS-5 ACUITY

Is a GP IIb/IIIa receptor antagonist required in patients with ACS going to PCI, or is high dose clopidogrel sufficient? ISAR-REACT 2 Question to be answered:

ISAR-REACT 2 Trial: Study Design Primary Endpoint: Composite of death, MI, and urgent target vessel revascularization (TVR) due to myocardial ischemia within 30 days Secondary Endpoint: In-hospital major and minor bleeding Primary Endpoint: Composite of death, MI, and urgent target vessel revascularization (TVR) due to myocardial ischemia within 30 days Secondary Endpoint: In-hospital major and minor bleeding 2022 patients with an episode of angina within the preceding 48 hours Elevated troponin T or new ST-segment changes or presumed new BBB Significant lesions in a native vessel or bypass graft undergoing PCI 2022 patients with an episode of angina within the preceding 48 hours Elevated troponin T or new ST-segment changes or presumed new BBB Significant lesions in a native vessel or bypass graft undergoing PCI Abciximab n=1012 Abciximab n=1012 Placebo n=1010 Placebo n=1010 Pre-treatment with high dose (600mg) clopidogrel at least 2 hours pre-procedure Pre-treatment with high dose (600mg) clopidogrel at least 2 hours pre-procedure Kastrati A, Mehilli J, et al. JAMA Apr 5;295(13):1531-8

Composite of death, MI, or urgent TVR due to Myocardial Ischemia within 30 days (%) Kastrati A, Mehilli J, et al. JAMA Apr 5;295(13): ISAR-REACT 2: Primary Endpoint p=0.03 ( n = 2022 )

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

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

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

Even with clopidogrel pretreatment, heparin therapy alone is inadequate to prevent ischemic events in high risk ACS patients undergoing PCI This effect was primarily present in troponin-positive patients Even with clopidogrel pretreatment, heparin therapy alone is inadequate to prevent ischemic events in high risk ACS patients undergoing PCI This effect was primarily present in troponin-positive patients ISAR-REACT 2 Trial: Conclusions/Caveats

What is the role of enoxaparin in patients with non–ST segment elevation ACS at high risk for ischemic cardiac complications managed with an early invasive approach ? SYNERGY Question to be answered:

Study Design At least 2 of 3 required: Age 60 ST (transient) or (+) CK-MB or troponin 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) 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

SYNERGY: Primary Results (30 Days) EnoxaparinUFH Unadjusted (n = 4,993)(n = 4,985)P value Death and MI14.0%14.5%0.40 Death3.2%3.1%0.71 MI11.7%12.7%0.14 EnoxaparinUFH Unadjusted (n = 4,993)(n = 4,985)P value Death and MI14.0%14.5%0.40 Death3.2%3.1%0.71 MI11.7%12.7%0.14 SYNERGY Trial Investigators. JAMA 2004;292:45-54

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

SYNERGY Bleeding Events GUSTO severe2.7%2.2%0.08 TIMI major (clinical): 9.1%7.6%0.008 CABG-related6.8%5.9%0.08 Non-CABG-related2.4%1.8%0.03 Hb/HCT drop (algorithm)15.2%12.5%< Any RBC transfusion17.0%16.0%0.16 ICH< 0.1%< 0.1%NS GUSTO severe2.7%2.2%0.08 TIMI major (clinical): 9.1%7.6%0.008 CABG-related6.8%5.9%0.08 Non-CABG-related2.4%1.8%0.03 Hb/HCT drop (algorithm)15.2%12.5%< Any RBC transfusion17.0%16.0%0.16 ICH< 0.1%< 0.1%NS 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. 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 not superior to unfractionated heparin but was noninferior for non–ST-segment elevation ACS. 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 SYNERGY: Conclusions/Caveats

Is fondaparinux an alternative to enoxaparin in higher-risk ACS patients? OASIS-5 Question to be answered:

OASIS-5 Study Design Yusuf S, et al. N Engl J Med. 2006;354(14): 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 practice200 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 and Safety at Day 9 Yusuf S, et al. N Engl J Med. 2006;354(14): Hazard ratio 1.01 (95% CI, ) Cumulative Hazard Days Cumulative Hazard Days Hazard ratio 0.52 (95% CI, ) Bleeding Death, MI, RI Fondaparinux Enoxaparin

Efficacy End Points at 6 Months End pointEnoxaparinFondaparinuxP value Death/MI/ refractory ischemia13.2%12.3%0.06 Death/MI11.4%10.5%0.05 Death6.5%5.8%0.05 MI6.6%6.3% 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):

PCIProcedural Complications Events (30 Days) Enoxaparin n=3089 Fondaparinux n=3118 P value Any UFH during PCI53.8%18.8% Any procedural complication 8.6%9.6%0.18 Abrupt closure1.1%1.5%0.20 Catheter thrombus0.5%1.3%0.001 Vascular access8.1%3.3%< Pseudo-aneurysm1.6%1.0%0.39 Large hematoma4.4%1.6%< Yusuf S, et al. N Engl J Med. 2006;354(14):

Among patients with NSTE-ACS, fondaparinux was non-inferior for primary composite endpoint of death, MI or refractory ischemia at day 9 compared with enoxaparin. There was a significant reduction in the safety endpoint of major bleeding at 9 days and the secondary endpoint of mortality at 30 days and 6 months. In the OASIS-5 trial, the relationship between bleeding and mortality requires further investigation The optimal approach to using fondaparinux in the catheterization lab has yet to be defined, and therefore, its use in this setting is currently not recommended Among patients with NSTE-ACS, fondaparinux was non-inferior for primary composite endpoint of death, MI or refractory ischemia at day 9 compared with enoxaparin. There was a significant reduction in the safety endpoint of major bleeding at 9 days and the secondary endpoint of mortality at 30 days and 6 months. In the OASIS-5 trial, the relationship between bleeding and mortality requires further investigation The optimal approach to using fondaparinux in the catheterization lab has yet to be defined, and therefore, its use in this setting is currently not recommended OASIS-5: Conclusions/Caveats

Sites of Antithrombotic Drug Action Tissue factor Plasma clotting cascade Plasma clotting cascade Prothrombin Thrombin Fibrinogen Fibrin Thrombus Platelet aggregation Platelet activation Collagen Thromboxane A 2 ADP AT Aspirin Clopidogrel Prasugrel Cangrelor Eptifibatide Abciximab Tirofiban (GPI) Bivalirudin Hirudin Argatroban Factor Xa Factor Xa Heparin LMWHs Fibrinolytics Fondaparinux AT

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

REPLACE-2 ACS Subgroup n = 1330 n = 4495 Rajagopal V, Lincoff AM et al. AHJ ACS No ACS Death, MI, UR - 30 Days (%) Heparin + GP IIb/IIIa Bivalirudin ACS No ACS Death - 1 Year (%) Heparin + GP IIb/IIIa Bivalirudin

When given by itself (with provisional GP IIb/IIa usage) is a strategy of bivalirudin alone comparable to the use of UFH/enoxaparin plus a GP IIb/IIIa antagonist in moderate and high risk ACS patients managed invasively? ACUITY Questions to be answered: When given with a GP IIb/IIIa antagonist, does bivalirudin provide benefit over UFH/enoxaparin in moderate and high risk ACS patients managed invasively ?

Bivalirudin in ACS: Hypotheses In moderate- and high-risk patients patients with ACS undergoing an invasive strategy, compared to UFH or LMWH + GP IIb/IIIa inhibitors: n Bivalirudin + GP IIb/IIIa inhibitors will result in less adverse ischemic events and less bleeding n Bivalirudin alone will result in similar rates of ischemic events and markedly reduced bleeding In moderate- and high-risk patients patients with ACS undergoing an invasive strategy, compared to UFH or LMWH + GP IIb/IIIa inhibitors: n Bivalirudin + GP IIb/IIIa inhibitors will result in less adverse ischemic events and less bleeding n Bivalirudin alone will result in similar rates of ischemic events and markedly reduced bleeding

Inclusion/Exclusion Criteria Age 18 years Chest pain 10 within 24h At least one of: New ST depression or transient ST elevation 1 mm Troponin I, T, or CKMB Documented CAD All other 4 TIMI risk criteria - Age 65 years - Aspirin within 7 days - 2 angina episodes w/i 24h - 3 cardiac risk factors Written informed consent Age 18 years Chest pain 10 within 24h At least one of: New ST depression or transient ST elevation 1 mm Troponin I, T, or CKMB Documented CAD All other 4 TIMI risk criteria - Age 65 years - Aspirin within 7 days - 2 angina episodes w/i 24h - 3 cardiac risk factors Written informed consent Inclusion CriteriaExclusion Criteria No angiography within 72h Acute STEMI or shock Bleeding diathesis or major bleed within 2 weeks Platelet count 100,000/mm 3 INR >1.5 control CrCl 30 ml/min Abcx or 2 prior LMWH doses Prior UFH, LMWH (1 dose), eptifibatide and tirofiban were allowed Allergy to drugs, contrast No angiography within 72h Acute STEMI or shock Bleeding diathesis or major bleed within 2 weeks Platelet count 100,000/mm 3 INR >1.5 control CrCl 30 ml/min Abcx or 2 prior LMWH doses Prior UFH, LMWH (1 dose), eptifibatide and tirofiban were allowed Allergy to drugs, contrast Moderate-high risk unstable angina or NSTEMI ACUITY Design. Stone GW et al. AHJ 2004;148:764–75

Moderate- high risk ACS 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* *Stratified by pre-angiography thienopyridine use or administration ACUITY Design. Stone GW et al. AHJ 2004;148:764–75 Medical management PCI CABG

Moderate- high risk ACS 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

UF HeparinEnoxaparinBivalirudin U/Kgmg/Kgmg/kg* Bolus601.0 sc bid0.1 iv Infusion/h iv PCI ACT s 0.30 iv bolus iv bolus bolus iv 1.75/h infusion iv 4 CABGPer institution Per institution 5 Medical mgt None 6 ACUITY: Study Medications Anti-thrombin agents (started pre angiography) 1 Target aPTT seconds 2 If last enoxaparin dose 8h - <16h before PCI; 3 If maintenance dose discontinued or 16h from last dose 4 Discontinued at end of PCI with option to continue at 0.25mg/kg for 4-12h if GPIIb/IIIa inhibitor not used 5 Bivalirudin option for off-pump same as PCI dose. For on-pump bivalirudin discontinued 2 hours before 6 Option to continue with pre-PCI anti-thrombotic regimen at physician discretion Stone GW, McLaurin BT. NEJM Nov 23;355(21): * This is an off-label dose used in the ACUITY Trial

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 Nov 23;355(21):

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 Nov 23;355(21):

Primary Results by Treatment UFH/Enox + GP IIb/IIIa Bivalirudin + GP IIb/IIIa Bivalirudin alone Endpoint Rate P ValueRateP Value Net clinical outcome 11.7%11.8% <0.001 NI 10.1% Sup Ischemic events 7.3%7.7%0.007 NI7.8%0.011 NI Major bleeding 5.7%5.3%0.001 NI3.0% <0.001 Sup NI = non-inferiority; Sup = superiority Gregg Stone, ACC 2006 Presentation Stone GW, McLaurin BT. NEJM Nov 23;355(21):

Components of the Ischemic Composite P Sup = 0.32P Sup = 0.34P Sup = 0.35P Sup = 0.78 Stone GW, McLaurin BT. NEJM Nov 23;355(21): UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin alone

Ischemic Composite Endpoint Cumulative Events (%) Days from Randomization Estimate P (log rank) 7.3% UFH/Enoxaparin + IIb/IIIa (N=4603) Bivalirudin + IIb/IIIa (N=4604) % Bivalirudin alone (N=4612) % UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone Stone GW, McLaurin BT. NEJM Nov 23;355(21):

Major Bleeding Endpoint Cumulative Events (%) Days from Randomization Estimate P (log rank) 5.7% UFH/Enoxaparin + IIb/IIIa (N=4603) Bivalirudin + IIb/IIIa (N=4604) % Bivalirudin alone (N=4612) < % UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone Stone GW, McLaurin BT. NEJM Nov 23;355(21):

Net Clinical Outcome Composite Endpoint Cumulative Events (%) Days from Randomization Estimate P (log rank) 11.7% UFH/Enoxaparin + IIb/IIIa (N=4603) Bivalirudin + IIb/IIIa (N=4604) % Bivalirudin alone (N=4612) % UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone Stone GW, McLaurin BT. NEJM Nov 23;355(21):

Major Bleeding Endpoints P Sup =0.38P Sup <0.0001P Sup =0.31P Sup <.001 UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin alone Stone GW, McLaurin BT. NEJM Nov 23;355(21): % 5.7% 11.1% 5.3% 3.0% 9.1% All major bleedingNon CABG major bleeding (primary endpoint) 30 day events (%) Heparin+GPI(N=4603)Bivalirudin+GPI(N=4604)Bivalirudin alone(N=4612)

Net Clinical Outcome Composite UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone Men (n=6444) Women (n=2771) Diabetes (n=2585) No diabetes (n=6630) CrCl 60 (n=6993) CrCl <60 (n=1644) Age <65 (n=5051) Age 65 (n=4164) Risk ratio ±95% CI Risk ratio ±95% CI Bival Alone UFH/Enox + IIb/IIIa 7.8% 12.9% US (n=5224) OUS (n=3991) 10.6% 9.5% 8.9% 16.1% 10.8% 9.8% 9.5% 11.6% 9.2% 14.7% 11.8% 11.5% 10.4% 16.8% 13.7% 10.9% 13.5% PP int 0.86 ( ) 0.88 ( ) 0.90 ( ) 0.82 ( ) 0.86 ( ) 0.96 ( ) 0.79 ( ) 0.90 ( ) 0.87 ( ) 0.86 ( ) RR (95% CI) Bivalirudin alone betterUFH/Enox + IIb/IIIa better Stone GW, McLaurin BT. NEJM Nov 23;355(21):

ACUITY compares two new strategies against the currently defined standard of care in ACS patients managed with an early invasive strategy 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 Whether or not reductions in bleeding will translate into longer-term reductions in mortality is yet to be determined ACUITY compares two new strategies against the currently defined standard of care in ACS patients managed with an early invasive strategy 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 Whether or not reductions in bleeding will translate into longer-term reductions in mortality is yet to be determined ACUITY: Conclusions/Caveats

Question to be answered: Is there an advantage to using a GP IIb/IIIa antagonist routinely upstream in rapidly, invasively managed ACS patients, versus selective use in the cath lab for PCI? ACUITY Timing Trial

Moderate- high risk ACS Study Design – Second Randomization Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,800) Angiography within 72h 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 Stone GW, et al. JAMA 2007; 297:

Upstream llb/llla vs. Selective llb/lll vs. Bivalirudin Alone Timing TrialNet Clinical Outcome Composite Endpoint Stone GW, et al. JAMA 2007; 297:

The ACUITY Timing trial compared the outcomes with upstream GPI use with the outcomes for selective, in-lab use for PCI in rapidly invasively managed ACS patients; additional comparisons were made to the bivalirudin-alone arm Upstream IIb/IIIa use was associated with slightly fewer ischemic events, slightly more bleeding, and identical net clinical benefit to a selective in-lab IIb/IIIa strategy In comparison to the IIb/IIIa arms, bivalirudin alone had comparable ischemic outcomes, less bleeding, and superior net clinical benefit. Future analyses will need to focus on the duration of therapy, and look more closely at comparisons with the bivalirudin-alone strategy The ACUITY Timing trial compared the outcomes with upstream GPI use with the outcomes for selective, in-lab use for PCI in rapidly invasively managed ACS patients; additional comparisons were made to the bivalirudin-alone arm Upstream IIb/IIIa use was associated with slightly fewer ischemic events, slightly more bleeding, and identical net clinical benefit to a selective in-lab IIb/IIIa strategy In comparison to the IIb/IIIa arms, bivalirudin alone had comparable ischemic outcomes, less bleeding, and superior net clinical benefit. Future analyses will need to focus on the duration of therapy, and look more closely at comparisons with the bivalirudin-alone strategy ACUITY Timing Trial: Conclusions/Caveats

Question to be answered: What were the outcomes in the ACUITY patients who underwent PCI? ACUITYPCI Subset

Management Strategy (N=13,819) 56.4% 11.4% 32.2% CABG (n=1,539) Medical Rx (n=4,491) PCI (n=7,789) Heparin + IIb/IIIa N = 2,561 Heparin + IIb/IIIa N = 2,561 Bivalirudin + IIb/IIIa N = 2,609 Bivalirudin + IIb/IIIa N = 2,609 Bivalirudin alone N = 2,619 Bivalirudin alone N = 2,619 Stone GW, McLaurin BT. NEJM Nov 23;355(21):

ACUITYPCI Major Bleeding UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone P Sup =0.32 P Sup < % 7.5% 3.5% Non CABG major bleeding (primary endpoint) 30 day events (%) Heparin+GPI (N=2561) Bivalirudin+GPI (N=2609) Bivalirudin alone (N=2619) Stone GW, McLaurin BT. NEJM Nov 23;355(21):

Components of Ischemia–PCI pts Heparin* + IIb/IIIa vs. Bivalirudin + IIb/IIIa vs. Bivalirudin Alone *Heparin=unfractionated or enoxaparin p=0.16p=0.45 p=0.37p=0.53 p=0.16p=0.19 p=0.31P= % 0.9% 5.6% 3.2% 3.7% 3.2% 6.6% 9.3% 1.1% 8.8% 6.5% Composite ischemia DeathMyocardial infarction Unplanned revasc for ischemia 30 day events (%) Stone GW, McLaurin BT. NEJM Nov 23;355(21): Heparin+GPI (N=2561) Bivalirudin+GPI (N=2609) Bivalirudin alone (N=2619)

Troponin (+) PatientsPCI RR [95%CI] 0.93 [ ] RR [95%CI] 1.12 [ ] RR [95%CI] 0.59 [ ] UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone Interaction P values = 0.46, 0.86 and 0.28 respectively Stone GW, McLaurin BT. NEJM Nov 23;355(21):

Thienopyridine Exposed Not Thienopyridine Exposed Thienopyridine Exposure RR [95%CI] 0.81 ( ) RR [95%CI] 0.96 ( ) RR [95%CI] 0.50 ( ) RR [95%CI] 1.07 ( ) RR [95%CI] 1.37 ( ) RR [95%CI] 0.61 ( ) Interaction P values = 0.17, 0.19 and 0.65 respectively Stone GW, McLaurin BT. NEJM Nov 23;355(21):

PCI patients in ACUITY demonstrated outcomes similar to those of the overall triali. e., comparable ischemic outcomes, less bleeding, and superior net clinical outcomes This was true even in troponin (+) patients, although in this case net clinical outcomes were noninferior with bivalirudin monotherapy A controversial subgroup are patients with or without clopidogrel exposure prior to intervention: In patients not exposed to clopidogrel, bivalirudin monotherapy was associated with a slightly higher rate of ischemic events. The significance of this is uncertain at present. PCI patients in ACUITY demonstrated outcomes similar to those of the overall triali. e., comparable ischemic outcomes, less bleeding, and superior net clinical outcomes This was true even in troponin (+) patients, although in this case net clinical outcomes were noninferior with bivalirudin monotherapy A controversial subgroup are patients with or without clopidogrel exposure prior to intervention: In patients not exposed to clopidogrel, bivalirudin monotherapy was associated with a slightly higher rate of ischemic events. The significance of this is uncertain at present. ACUITYPCI: Conclusions/Caveats

ConclusionsRecent ACS Trials ISAR REACT 2Clopidogrel loading alone is not sufficient in ACS patients; Troponin (+) patients derive significant benefit with GP IIb/IIIa antagonists SYNERGYEnoxaparin is an alternative in invasively managed patients, but may have slightly higher bleeding, especially when UFH is indiscriminately added in the cath lab ISAR REACT 2Clopidogrel loading alone is not sufficient in ACS patients; Troponin (+) patients derive significant benefit with GP IIb/IIIa antagonists SYNERGYEnoxaparin is an alternative in invasively managed patients, but may have slightly higher bleeding, especially when UFH is indiscriminately added in the cath lab

OASIS 5Fondaparinux has less bleeding than enoxaparin, non-inferior clinical outcomes at 9 days, and less death and death/MI at 6 months; UFH is probably required in the cath labdose unknown. ACUITYBivalirudin with provisional GPI has less bleeding than UFH/LMWH + GPI, comparable ischemic outcomes, and superior net clinical benefit. Bivalirudin + GPI is comparable to UFH/LMWH + GPI OASIS 5Fondaparinux has less bleeding than enoxaparin, non-inferior clinical outcomes at 9 days, and less death and death/MI at 6 months; UFH is probably required in the cath labdose unknown. ACUITYBivalirudin with provisional GPI has less bleeding than UFH/LMWH + GPI, comparable ischemic outcomes, and superior net clinical benefit. Bivalirudin + GPI is comparable to UFH/LMWH + GPI ConclusionsRecent ACS Trials

NSTE-ACS is common and associated with high morbidity and mortality Early invasive strategy is preferred in higher-risk individuals Early initiation of appropriate antiplatelet and antithrombin therapy is important for reduction of ischemic events Balancing the risk of ischemic and bleeding complications is essential to maximize clinical benefit in individual patients The evidence base and strategies for optimal management of NSTE-ACS continue to evolve NSTE-ACS is common and associated with high morbidity and mortality Early invasive strategy is preferred in higher-risk individuals Early initiation of appropriate antiplatelet and antithrombin therapy is important for reduction of ischemic events Balancing the risk of ischemic and bleeding complications is essential to maximize clinical benefit in individual patients The evidence base and strategies for optimal management of NSTE-ACS continue to evolve ConclusionsACS Management

Non-ST-Segment Elevation Acute Coronary Syndrome: Initial Presentation and Implications for Selecting Treatment Strategies Does One Size Fit All? James Hoekstra, MD Professor and Chairman Department of Emergency Medicine Wake Forest University Health Center Winston-Salem, NC The Emergency Medicine Perspective

Changing the Calculations for Assessing Guidelines Adherence Anderson HV, Bach RG, J Am Coll Cardiol 2005;46: 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.

The Challenge: Balancing Efficacy and Safety Current guidelines (2002) emphasize reduction of ischemic risk in NSTE ACSespecially for upstream therapy initiated in the ED Current guidelines (2002) emphasize reduction of ischemic risk in NSTE ACSespecially for upstream therapy initiated in the ED Updated guidelines (2007) are expected to include data on the harm that bleeding events cause, diminishing ischemic efficacy in some patients Updated guidelines (2007) are expected to include data on the harm that bleeding events cause, diminishing ischemic efficacy in some patients Emergency physicians are comfortable with the goal of reducing ischemic risk... and traditionally have left concern over bleeding to downstream providers Emergency physicians are comfortable with the goal of reducing ischemic risk... and traditionally have left concern over bleeding to downstream providers

The Challenge: Balancing Efficacy and Safety Emergency physicians are accustomed to assessing ischemic risk... but have little data to guide them in assessing bleeding riska task not previously considered to be in their domain Emergency physicians are accustomed to assessing ischemic risk... but have little data to guide them in assessing bleeding riska task not previously considered to be in their domain More than ever, balanced pharmacotherapy will require multidisciplinary collaboration, pathways, anticipation of consistent care (especially time from ED to cath), and individualized patient assessment More than ever, balanced pharmacotherapy will require multidisciplinary collaboration, pathways, anticipation of consistent care (especially time from ED to cath), and individualized patient assessment

Ischemic Risk Stratification Three levels of risk strat are pertinent to the ED: Three levels of risk strat are pertinent to the ED: low, intermediate, or high risk that ischemic symptoms are a result of CAD low, intermediate, or high risk of short-term death or nonfatal MI from ACS dynamic, ongoing risk-oriented evaluation of low- or intermediate-risk patients for conversion to high-risk status that is linked to intensity of treatment

Ischemic 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 Markers Markers CPK-MB, Troponins I and T, Myoglobin CPK-MB, Troponins I and T, Myoglobin Markers of ischemia and inflammation? Markers of ischemia and inflammation? 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 decisionmaking better as research tools than for real-time clinical decisionmaking

Guidelines Call for Therapeutic Response to Identification of Ischemic Risk Anti-ischemic therapy Anti-ischemic therapy Oxygen, nitroglycerin, beta-blockers, morphine Oxygen, nitroglycerin, beta-blockers, morphine Anti-thrombotic therapy Anti-thrombotic therapy ASA, anticoagulant ASA, anticoagulant Anti-platelet therapy Anti-platelet therapy Anti-activation therapy with clopidogrel, anti- aggregation therapy with a GP IIb/IIIa receptor antagonist Anti-activation therapy with clopidogrel, anti- aggregation therapy with a GP IIb/IIIa receptor antagonist low risk low risk mod risk mod risk high risk high risk

Selection of Therapy in the ED is Traditionally Based on Reducing Ischemic Risk Escalation of therapy for ischemia in this setting is associated with increased risk of bleeding Escalation of therapy for ischemia in this setting is associated with increased risk of bleeding This price to be paid has generally been accepted and tolerated, especially in patients at high ischemic risk, who benefit disproportionately from advanced therapy This price to be paid has generally been accepted and tolerated, especially in patients at high ischemic risk, who benefit disproportionately from advanced therapy l Enox superior to UFH in patients with higher TIMI Risk Scores l Clopidogrel + ASA superior to ASA alone in patients with higher TIMI Risk Scores l GP IIb/IIIa receptor antagonists benefit troponin positive patients more than troponin negative patients

Selection of Therapy in the ED Should Include Consideration of Bleeding Risk Just as in the Cath Lab and the CCU, we must also be attentive to the impact of bleeding risk Just as in the Cath Lab and the CCU, we must also be attentive to the impact of bleeding risk In the ED, bleeding risk is impacted by In the ED, bleeding risk is impacted by l Choice of therapy l Dosing l Duration and reversibility of therapy and impact on selection of downstream therapy

Selection of Therapy in the ED Must Include Consideration of Bleeding Risk Age Age Gender Gender Renal insufficiency Renal insufficiency Baseline anemia Baseline anemia Expectation of prolonged medical therapy Expectation of prolonged medical therapy

How Do We Balance? One Guys Opinion of Choices for Upstream Therapy Pertinent data since 2002 ACC/AHA Guidelines: Pertinent data since 2002 ACC/AHA Guidelines: l INTERACT l SYNERGY l OASIS-5 l ISAR-REACT-2 l REPLACE-2 l ACUITY l CRUSADE and NRMI data

How Do We Balance? One Guys Opinion of Choices for Upstream Therapy: Antithrombotics OptionPatient Ease of Use Ischemic Efficacy Reduction of Bleeding Risk UFH Low risk not indicated Mod risk BBB High risk BBB Enox Low risk not indicated Mod risk AB*C High risk AB*C Bival (not yet approved in ED) Low risk not indicated upstream Mod risk B-BA High risk B-** B to C+ A * If medical management only, enox is ++++ ** ease of use higher if no IIb/IIIa is used * If medical management only, enox is ++++ ** ease of use higher if no IIb/IIIa is used

How Do We Balance? One Guys Opinion of Choices for Upstream Therapy: Antiplatelets OptionPatient Ease of Use Ischemic Efficacy Reduction of Bleeding Risk ASA Low risk AAB Mod risk AAB High risk AAB clopidogrel Low risk not indicated Mod risk ABB High risk AAB-C* GP IIb/IIIa Low risk not indicated Mod risk not indicated High risk BAB- * CABG concern

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: (2002 update at summary in Circulation 2002;106: ) 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: ACC/AHA Guidelines for Therapy

Hospital Care Anti-Thrombotic 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

Hospital Care 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

Hospital Care Platelet GP IIb/IIIa Inhibitors 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

ACUITYPrimary Endpoint Measures (ITT) Bivalirudin alone better UFH/Enox + IIb/IIIa better Risk ratio ±95% CI Risk ratio ±95% CI PrimaryendpointBivalalone UFH/Enox + IIb/IIIa RR (95% CI) Net clinical outcome Ischemic composite Major bleeding Upper boundary non-inferiority 11.7%10.1% 0.86 ( ) < %7.8% 1.08 ( ) %3.0% 0.53 ( ) <0.001<0.001 p value (non inferior) (superior) UFH/Enoxaparin + GPI vs. Bivalirudin Alone Stone GW, McLaurin BT. NEJM Nov 23;355(21):

ACUITYNet Clinical Outcome Composite UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone Men (n=6444) Women (n=2771) Diabetes (n=2585) No diabetes (n=6630) CrCl 60 (n=6993) CrCl <60 (n=1644) Age <65 (n=5051) Age 65 (n=4164) Risk ratio ±95% CI Risk ratio ±95% CI Bival Alone UFH/Enox + IIb/IIIa 7.8% 12.9% US (n=5224) OUS (n=3991) 10.6% 9.5% 8.9% 16.1% 10.8% 9.8% 9.5% 11.6% 9.2% 14.7% 11.8% 11.5% 10.4% 16.8% 13.7% 10.9% 13.5% PP int 0.86 ( ) 0.88 ( ) 0.90 ( ) 0.82 ( ) 0.86 ( ) 0.96 ( ) 0.79 ( ) 0.90 ( ) 0.87 ( ) 0.86 ( ) RR (95% CI) Bivalirudin alone better UFH/Enox + IIb/IIIa better Stone GW, McLaurin BT. NEJM Nov 23;355(21):

UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone Yes (n=3197) No (n=6008) Low (0-2) (n=1291) Intermed (3-4) (n=4407) High (5-7) (n=2449) Elevated (n=5368) Normal (n=3841) Risk ratio ±95% CI Risk ratio ±95% CI Bival Alone UFH/Enox + IIb/IIIa 9.2% 11.3% 12.2% 11.1% PP int 0.76 ( ) 1.02 ( ) 12.2% 7.1% 13.3% 9.4% 0.92 ( ) 0.75 ( ) < % 8.6% 13.7% 10.6% 0.96 ( ) 0.81 ( ) Biomarkers (CK/Trop) ST Deviation TIMI Risk Score Pre Thienopyridine 6.4%10.2%0.63 ( ) %10.2%0.92 ( ) %15.2%0.92 ( )0.36 Yes (n=5192) No (n=4023) RR (95% CI) Bivalirudin alone better UFH/Enox + IIb/IIIa better Stone GW, McLaurin BT. NEJM Nov 23;355(21): ACUITYNet Clinical Outcome Composite

Hospital Care Clopidogrel Therapy 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

CURE: Ischemic Endpoints Were Reduced within 24h of Randomization Adapted from Yusuf S, et al. Circulation. 2003;107: Hours After Randomization Cumulative Hazard Rates RR = 0.67 P = Placebo + ASA Clopidogrel 33%RRR

Bleeding Among CABG Patients Receiving Clopidogrel Excludes transfers out within 48 hours and contraindications 95% CI Odds Ratio Clopidogrel WorseClopidogrel Better Clopidogrel >5 days 1.30 (0.95, 1.78) Risk-adjusted Analyses Clopidogrel Within 5 days 1.33 (1.12, 1.58) unpublished CRUSADE data,

Factors that Should Influence Choice of Upstream Therapy for NSTE ACS Age Age l Older patients more likely to have ischemic events l Older patients more likely to have bleeding events Gender Gender l Women more likely to present late and atypically l Women more likely to have bleeding events Diabetes Diabetes l Diabetics more likely to present atypically and have ischemic events

Factors that Should Influence Choice of Upstream Therapy for NSTE ACS Renal status Renal status l Without appropriate adjustment for CrCl, may increase bleeding events associated with UFH, enox, and GP IIb/IIIa agents Anticipated downstream management Anticipated downstream management l PCI, CABG capability and time to cath Troponin Troponin l Troponin + shown to respond better to early (vs later) cath early (vs later) cath enox (vs UFH) enox (vs UFH) clopidogrel + ASA (vs ASA monotherapy) clopidogrel + ASA (vs ASA monotherapy) GP IIb/IIIa therapy GP IIb/IIIa therapy

Factors that Should Influence Choice of Upstream Therapy for NSTE ACS H / H H / H l Anemic patients more likely to have bleeding events Weight Weight l Smaller patients more likely to be overdosed l Larger patients more likely to be underdosed and may have renal issues Perceived CABG risk (short-term) Perceived CABG risk (short-term) l Impacts timing of clopidogrel dosing l Among GP IIb/IIIa agents, mitigates against abciximab

Example of Multidisciplinary, Collaborative Management: Scenario 1 64 y/o male with NSTEMI 64 y/o male with NSTEMI Hemodynamically stable, now pain-free Hemodynamically stable, now pain-free CRF: smoking, diabetic CRF: smoking, diabetic No cath lab at facility, patient refuses transfer No cath lab at facility, patient refuses transfer Optimal management: Optimal management: l ASA, enox, clopidogrel l consider GP IIb/IIIa if develops pain or becomes unstable

Example of Multidisciplinary, Collaborative Management: Scenario 2 64 y/o male with NSTEMI 64 y/o male with NSTEMI Hemodynamically stable, now pain-free Hemodynamically stable, now pain-free CRF: smoking, diabetic, renal insufficiency CRF: smoking, diabetic, renal insufficiency No cath lab at facility, patient refuses transfer No cath lab at facility, patient refuses transfer Optimal management: Optimal management: l ASA, enox (adjusted for CrCl), clopidogrel l consider GP IIb/IIIa (adjusted for CrCl) if develops pain or becomes unstable

Example of Multidisciplinary, Collaborative Management: Scenario 3 64 y/o male with NSTEMI 64 y/o male with NSTEMI Hemodynamically stable, now pain-free Hemodynamically stable, now pain-free CRF: smoking, diabetic CRF: smoking, diabetic Will go to cath tomorrow morning Will go to cath tomorrow morning Optimal management: Optimal management: l ASA, heparin, consider clopidogrel (or give if PCI) l consider GP IIb/IIIa if develops pain or becomes unstable

Example of Multidisciplinary, Collaborative Management: Scenario 4 84 y/o male with NSTEMI 84 y/o male with NSTEMI Hemodynamically stable, now pain-free Hemodynamically stable, now pain-free CRF: smoking, diabetic CRF: smoking, diabetic Will go to cath tomorrow morning Will go to cath tomorrow morning Optimal management: Optimal management: l ASA, consider bival*, calculate CrCl l consider GP IIb/IIIa if develops pain or becomes unstable l Clopidogrel if PCI * Not yet FDA approved

Example of Multidisciplinary, Collaborative Management: Scenario 5 84 y/o male with NSTEMI 84 y/o male with NSTEMI Hemodynamically stable, now pain-free Hemodynamically stable, now pain-free CRF: smoking, diabetic CRF: smoking, diabetic Going to cath in next 2-4 hours Going to cath in next 2-4 hours Optimal management: Optimal management: l ASA, bival*, calculate CrCl l consider GP IIb/IIIa if develops pain or becomes unstable l Clopidogrel if PCI * Not yet FDA approved

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

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

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

We in the ED should be using optimal medical therapy for NSTE ACS, just as in the CCU or the cath lab. We in the ED must work with our colleagues in Cardiology to develop pathways for proper 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. A seamless transition of care is most likely to result in good outcomes. Optimal Management of NSTE ACS: ED to Cardiology

Case Studies in Acute Coronary Syndromes Moderated by: Interventional Cardiology Co-Chairman Emergency Medicine Co-Chairman Regional Expert Panel Members Moderated by: Interventional Cardiology Co-Chairman Emergency Medicine Co-Chairman Regional Expert Panel Members

Case #1: History 76 year old WM with h/o stent to LAD 1 year ago. 76 year old WM 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. PMH: IDDM, HTN, CHOL. 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. ECG.

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

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 is most important in determining their ischemic risk? A. Advanced age B. Anginal pattern C. ECG findings D. Biomarkers * Case #1

This patients risk of short-term (30-Day) hemorrhagic events is: A.Low B.Moderate C.High D.Very high Case #1

Which of this patients baseline factors is most important in determining their hemorrhagic risk? A. Advanced age B. Hypertension C. Impaired creatinine clearance D. Anemia * Case #1

P-value RR (95% CI) Risk ratio ± 95% CI Results: The ACUITY Trial (N=13819) Predictors of Major Bleeding Age >75 (vs ) Anemia CrCl <60mL/min Diabetes Female gender High-risk (ST / biomarkers) Hypertension No prior PCI Heparin(s) + GPI (vs. Bivalirudin) 1.51 ( ) < ( ) < ( ) < ( ) ( ) < ( ) < ( ) ( ) ( ) < Manoukian SV, Voeltz MD, Feit F et al. AHA 2006.

Based upon this patients overall profile, I am more concerned about: A. Ischemic risk B. Hemorrhagic risk Case #1

In ACS, do you alter your choice of anticoagulant therapy due to an individual patients risk of hemorrhagic complications? A. Yes B. No * Case #1

In this patient, would you select anticoagulant therapy primarily based upon the risk of hemorrhagic complications? A. Yes B. No * Case #1

What would you use for anticoagulation in this patient, prior to catheterization? A. Unfractionated heparin alone B. Enoxaparin alone C. Bivalirudin alone D. A heparin with a GP IIb/IIIa inhibitor * Case #1

What would your choice of upstream anticoagulation therapy be, if you anticipated cardiac catheterization immediately (within 4 hours)? A. Unfractionated heparin alone B. Enoxaparin alone C. Bivalirudin alone D. A heparin with a GP IIb/IIIa inhibitor * 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 * 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 * Case #1

Case #1: Pre-angiography Heparin initiated, catheterization 18 h later ACT 173 seconds. *

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 #1: Post-Angiography *

Do you believe that major hemorrhagic complications independently increase mortality in ACS? A. Yes B. No Case #1

Results: The ACUITY Trial (N=13819) Major Bleeding, Ischemic Endpoints, and Mortality P< for all Manoukian SV, Voeltz MD, Feit F et al. AHA 2006.

Do you believe that major hemorrhagic complications are more important than MI in influencing mortality in ACS? A. Less important B. Same importance C. More important * Case #1

Results from The ACUITY Trial (N=13819) Predictors of Mortality at 30 Days Predictors of Mortality at 30 Days in The ACUITY Trial VariableOR 95% CI p-value Major Bleeding < MI (within 30 days) < LVEF < 50% < Age > 75 years < ECG Changes < Elevated Cardiac Markers Prior CVA PCI (vs. CABG) < Manoukian SV, Feit F, Mehran R, et al. Unpublished.

Case #2: History 67 year old WF without prior cardiac history. 67 year old WF without prior cardiac history. Multiple short episodes of chest pain today. Multiple short episodes of chest pain today. Unrelieved with NTG sl, IV; metoprolol IV. Unrelieved with NTG sl, 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.

Case #2: ECG New inferior changesNew lateral changes

This patients risk of short-term (30-Day) ischemic events is: A.Low B.Moderate C.High D.Very high * Case #2

This patients risk of short-term (30-Day) hemorrhagic events is: A.Low B.Moderate C.High D.Very high * Case #2

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

Which of these factors is most important in considering the need for immediate catheterization in this patient? A. Advanced age B. Positive biomarkers C. ECG findings D. Refractory discomfort * Case #2

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

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

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

Case #2: Pre-Angiography Bivalirudin started, immediate catheterization

Case #2: Angiography

Case #2: Post-Angiography

Case #3: History 82 year old WF with h/o MI, PTCA/LAD year old WF with h/o MI, PTCA/LAD Exertional and rest chest pressure x 72 hours, now pain-free in ED. Exertional and rest chest pressure x 72 hours, 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.

This patients risk of short-term (30-Day) ischemic events is: A.Low B.Moderate C.High D.Very high * Case #3

This patients risk of short-term (30-Day) hemorrhagic events is: A.Low B.Moderate C.High D.Very high * Case #3

Based upon this patients overall profile, I am more concerned about: A. Ischemic risk B. Hemorrhagic risk * Case #3

What would you use for upstream anticoagulation in this patient whose catheterization is planned for 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 * Case #3

Case #3: Pre-Angiography Heparin initiated, catheterization the next day ACT 187 seconds.

Case #3: Angiography

Case #3: Post-Angiography

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 cath lab, prior to catheterization. C. In the cath lab, after catheterization and decision to proceed with PCI, but prior to PCI. D. In the cath 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 reduction of ischemic and bleeding endpoints) * Concluding Questions

INTERACTIVE FORUM Applying Evidence, Trials, and Clinical Realities to Multidisciplinary ACS Care EDICT for ACS INTERACTIVE FORUM Faculty, Expert Panel, and Participants

1.How should interventional cardiologists and emergency physicians collaborate to deliver optimal care for ACS? Can and should EDICT therapeutic teams be organized, and if so, what form should they take? Who should be on these teams? What are the responsibilities and mandates of such a team? Policies? Pathways? Therapeutic consistency? How should protocols for EDICT for ACS be generated? EDICT for ACS INTERACTIVE FORUM Faculty, Expert Panel, and Participants

2.Understanding the mind sets and action drivers of EDICT for ACS team members, i.e., interventional cardiologists (ICs) versus emergency physicians (EPs): Are emergency physicians guideline-driven? Are they more likely to adhere strictly to AHA/ACC guidelines than ICs? Why do they adopt strategies? Are IC decisions, practices, and protocols driven more by clinical experience, and trial-based data? Does this lead to a divergence of treatment approaches for ACS? How can and should these differences be reconciled? 2.Understanding the mind sets and action drivers of EDICT for ACS team members, i.e., interventional cardiologists (ICs) versus emergency physicians (EPs): Are emergency physicians guideline-driven? Are they more likely to adhere strictly to AHA/ACC guidelines than ICs? Why do they adopt strategies? Are IC decisions, practices, and protocols driven more by clinical experience, and trial-based data? Does this lead to a divergence of treatment approaches for ACS? How can and should these differences be reconciled? EDICT for ACS INTERACTIVE FORUM Faculty, Expert Panel, and Participants

3. In which patient types are IC and EP care strategies for ACS patients most closely aligned currently? Medical therapy for low risk groups? Where is there agreement? Disagreement? Moderate or high risk patients going to catheterization/PCI within 4 hours (relatively immediately)? Agreement? Disagreement? Moderate or high risk groups with anticipated catheterization within hours? Agreement? Disagreement? EDICT for ACS INTERACTIVE FORUM Faculty, Expert Panel, and Participants

4. What clinical outcome measures would an EDICT for ACS team or review panel follow to evaluate success or failure of their NSTE- ACS protocols, processes, and therapies? Door to catheterization/PCI time? Measure against CRUSADE findings and benchmarks? Other benchmarks? Time to onset of antithrombotic therapy? Length of hospitalization? Cost of hospitalization? Bleeding complications? Ischemic complications? EDICT for ACS INTERACTIVE FORUM Faculty, Expert Panel, and Participants

5.Can EDICT for ACS teams develop a quick checklist or risk stratification tool to determine importance of bleeding risk? What risk factors should suggest bleeding-sparing strategies as dominant antithrombotic strategy? What are bleeding reduction strategies? When should they take precedence? How should this be incorporated into protocol? EDICT for ACS INTERACTIVE FORUM Faculty, Expert Panel, and Participants

6. What specific ACS strategies can this group agree upon as it relates to NSTE-ACS, and therefore, recommend for adoption by an EDICT for ACS team? Timing of invasive strategy? ASAP? Depending on risk group? Clopidogrel use: When? In Whom? How much? Caveats? GPIIb/IIIa receptor antagonist: When? Upstream? At catheterization? Routine? Provisional? EDICT for ACS INTERACTIVE FORUM Faculty, Expert Panel, and Participants

6. Recommendations for EDICT for ACS strategies (continued)? Direct thrombin inhibitor (bivalirudin)? In which patient populations? Monotherapy? When to initiate? Crossovers? When not to initiate? How should new ACC/AHA guidelines impact decisions about bivalirudin? Where would EPs and ICs introduce bivalirudin into process-of-care pathway for ACS? EDICT for ACS INTERACTIVE FORUM Faculty, Expert Panel, and Participants

6. Recommendations for ACS strategies (continued)? Enoxaparin? When to use? When not to use? What if consistency cannot be maintained? Crossovers? Heparin? When to use? When not to use? What if consistency cannot be maintained? Crossovers? Fondaparinux? EDICT for ACS INTERACTIVE FORUM Faculty, Expert Panel, and Participants

6.Recommendations for EDICT for ACS clinical strategies (continued)? Statins: Should they be initiated in ED as part of EDICT strategy? If so, at what point? What agent? At what dose? Beta-blockers? ACEIs or ARBs? In certain subsets? Diabetics? Heart failure? * EDICT for ACS INTERACTIVE FORUM Faculty, Expert Panel, and Participants

7. Practical and process-oriented recommenda- tions for and EDICT for ACS program: How often should EDICT for ACS leadership committee meet within an institution? What should its goals be? Protocols? Compliance? Measuring outcomes? How should findings and recommendations be disseminated? Education? EdictforACS.com? How should it be used? * EDICT for ACS INTERACTIVE FORUM Faculty, Expert Panel, and Participants

Thank You