1. 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 A. Michael Lincoff, MD, FACC Vice Chairman for Research Department of Cardiovascular Medicine Director, Cleveland Clinic Cardiovascular Coordinating Center Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University The Cleveland Clinic Foundation A. Michael Lincoff, MD, FACC Vice Chairman for Research Department of Cardiovascular Medicine Director, Cleveland Clinic Cardiovascular Coordinating Center Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University The Cleveland Clinic Foundation EDICT for ACS SlideCAST

2. 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

3. 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

4. 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

5. Program Faculty A. Michael Lincoff, MD, FACC Vice Chairman for Research Department of Cardiovascular Medicine Medicine Director, Cleveland Clinic Cardiovascular Coordinating Center Center Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Western Reserve University The Cleveland Clinic Foundation Cleveland, OH A. Michael Lincoff, MD, FACC Vice Chairman for Research Department of Cardiovascular Medicine Medicine Director, Cleveland Clinic Cardiovascular Coordinating Center Center Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University Western Reserve University The Cleveland Clinic Foundation Cleveland, OH Sunil V. Rao, MD, FACC Assistant Professor of Medicine Duke University Medical Center Director, Cardiac Catheterization Laboratories Laboratories Durham VA Medical Center Durham, NC Charles V. Pollack, MD, FACEP, FAAEM FAAEM Chairman, Department of Emergency Medicine Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine University of Pennsylvania School of Medicine of Medicine Philadelphia, PA Sunil V. Rao, MD, FACC Assistant Professor of Medicine Duke University Medical Center Director, Cardiac Catheterization Laboratories Laboratories Durham VA Medical Center Durham, NC Charles V. Pollack, MD, FACEP, FAAEM FAAEM Chairman, Department of Emergency Medicine Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine University of Pennsylvania School of Medicine of Medicine Philadelphia, PA

6. Financial Disclosures Sunil V. Rao, MD, FACC Grant/Research Support: Cordis Consultant: sanofi-aventis, The Medicines Co. Speakers Bureau: sanofi-aventis, Cordis, The Medicines Co. Charles V. Pollack, MD, FACEP, FAAEM Grant/Research Support: GlaxoSmithKline Consultant: The Medicines Co., Schering-Plough, sanofi-aventis, BMS, Genentech Speakers Bureau: Schering-Plough, sanofi-aventis, BMS, Genentech Sunil V. Rao, MD, FACC Grant/Research Support: Cordis Consultant: sanofi-aventis, The Medicines Co. Speakers Bureau: sanofi-aventis, Cordis, The Medicines Co. Charles V. Pollack, MD, FACEP, FAAEM Grant/Research Support: GlaxoSmithKline Consultant: The Medicines Co., Schering-Plough, sanofi-aventis, BMS, Genentech Speakers Bureau: Schering-Plough, sanofi-aventis, BMS, Genentech

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

8. 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

9. Advancing Management of Acute Coronary Syndromes Linking Science and Landmark Studies to the Front Lines of Cardiology Practice Introduction to EDICT for ACS Forum Critical Challenges in Cardiovascular DiseaseIntroduction A. Michael Lincoff, MD, FACC Vice Chairman for Research Department of Cardiovascular Medicine Director, Cleveland Clinic Cardiovascular Coordinating Center Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University The Cleveland Clinic Foundation A. Michael Lincoff, MD, FACC Vice Chairman for Research Department of Cardiovascular Medicine Director, Cleveland Clinic Cardiovascular Coordinating Center Professor of Medicine Cleveland Clinic Lerner College of Medicine of Case Western Reserve University The Cleveland Clinic Foundation

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

11. 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

12. 199219951998200120042007 19971999 UFH LMWH TIMI 11B 2004 SYNERGY Bivalirudin 2003 REPLACE 2 ASA IIb/IIIa antagonists 1995 2001 1998 EPISTENT PURSUIT 2001 ESPRIT GUSTO 4 2004 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

13. 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, FACC Assistant Professor of Medicine Duke University Medical Center Director, Cardiac Catheterization Laboratories Durham VA Medical Center Durham, NC Sunil V. Rao, MD, FACC Assistant Professor of Medicine Duke University Medical Center Director, Cardiac Catheterization Laboratories Durham VA Medical Center Durham, NC

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

15. 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

16. 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

17. Death4.3% (Re)-Infarction2.5% CHF8.0% Cardiogenic Shock2.6% Stroke0.8% Non-CABG Transfusion9.9% Bhatt DL, et al. JAMA. 2004 Nov 3;292(17):2096-104. CRUSADE In-Hospital Outcomes

18. 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

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

20. Independent Predictors of Major Bleeding in Marker Positive Acute Coronary Syndromes Moscucci, GRACE Registry, Eur Heart J. 2003 Oct;24(20):1815-23. Predictors of Major Bleeding in ACS Older Age Older Age Female Gender Female Gender Renal Failure Renal Failure History of Bleeding History of Bleeding Right Heart Catheterization Right Heart Catheterization GPIIb-IIIa antagonists GPIIb-IIIa antagonists

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

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

23. REPLACE-2 Multivariate Predictors of Major Bleeding RISK FACTORS Odds Ratio 95% CI p-value Baseline risk factors Age > 75 1.482 1.009 to 2.176 0.045 Gender (M vs. F) 0.652 0.477 to 0.890 0.0072 Prior Angina 1.589 1.077 to 2.345 0.0197 Creatinine clearance* 0.993 0.987 to 0.998 0.0061 Anemia1.403 1.015 to 1.939 0.0401 Peri-procedural risk factors Treatment Group (BIV vs. H+GPI) 0.508 0.352 to 0.733 0.0003 Provisional GPI received 2.679 1.591 to 4.512 0.0002 Procedure Duration >1h 2.049 1.217 to 3.449 0.0069 Time to Sheath Removal >6h 1.614 1.064 to 2.448 0.0244 ICU stay (days) 1.25 1.183 to 1.321 <0.0001 IABP8.705 3.433 to 22.072 <0.0001 Feit F et al. Unpublished (in manuscript)

24. 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

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

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

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

28. 26,452 patients from PURSUIT, PARAGON A, PARAGON B, GUSTO IIb NST Bleeding severity and adjusted hazard of death *p<0.0001 Bleeding and Outcomes in NSTE ACS Bleeding Severity30d Death30d Death/MI6 mo. Death Mild* 1.61.31.4 Moderate* 2.73.32.1 Severe*10.65.67.5 *Bleeding as a time-dependent covariate Rao SV, et al. Am J Cardiol. 2005 Nov 1;96(9):1200-6. Epub 2005 Sep 12

29. Major Bleeding, Ischemic Endpoints, and Mortality P<0.0001 for all Manoukian SV, Voeltz MD, Feit F et al. TCT 2006. Results: The ACUITY Trial PCI Population (N=7,789)

30. Major Bleeding and Myocardial Infarction P<0.0001 for all Manoukian SV, Voeltz MD, Feit F et al. TCT 2006. Results: The ACUITY Trial PCI Population (N=7,789)

31. Major and Minor Bleeding in PCI Bleeding Increases Mortality and Events Kinnaird TD et al. AM J Cardiol 2003;92:930-5. 10,974 patients undergoing PCI, Washington Hospital Center, 1991-2000. 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

32. 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

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

34. Bleeding Incidence in ACS Clinical Trials Rao SV, et al. J Am Coll Cardiol. 2006 Feb 21;47(4):809-16. Epub 2006 Jan 26

35. 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 1987. Jul;76(1):142-54.

36. N Engl J Med. 1993 Nov 25;329(22):1615-22. 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

37. Bleeding Incidence Among 15,858 NSTE ACS Patients: Impact of Definition Rao SV, et al. J Am Coll Cardiol. 2006 Feb 21;47(4):809-16. Epub 2006 Jan 26

38. Bleeding Scales Among NSTE ACS Patients Bleeding Scales Among NSTE ACS Patients Rao SV, et al. J Am Coll Cardiol. 2006 Feb 21;47(4):809-16. Epub 2006 Jan 26 TIMI and GUSTO – Adjusted Hazard of 30 d Death/MI N=15,858

39. 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

40. 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:

41. 30-Day Survival By Transfusion Group Rao SV, et. al., JAMA 2004;292:1555–1562 Transfusion in ACS N=24,111N=24,111

42. *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

43. 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

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

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

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

47. 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

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

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

50. 6,002 patients in REPLACE-2 806 patients (13.4%) classified as elderly, >75 years of age p<0.0001p=0.0001 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.

51. p<0.0001 p=0.0001 6,002 patients in REPLACE-2. 806 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.

52. Excessive Dosing of Anticoagulants by Age Alexander KA, JAMA 2005;294:3108–16. 12.5 28.7 8.5 33.1 37 12.5 64.5 38.5 16.5 0 10 20 30 40 50 60 70 LMW HeparinUF HeparinGP Iib/IIIa % RBC Transfusion <65 yrs65Š75 yrs>75 yrs

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

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

55. 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) 0.50.5 1.01.01.51.52.02.02.52.5 Excess Dosing More Likely to Bleed Alexander KP, et. al. Circulation 2006 N=32,601 patients from CRUSADE

56. Bleeding is Increased in Patients With Impaired Renal Function Undergoing PCI 60 ml/min N=4824 60 ml/min N=4824 < 60 ml/min N=886 p value 30-d Death 5 (0.1%) 14 (1.6%) < 0.001 < 0.001 30-d Myocardial infarction 305 (6.3%) 75 (8.5%) 0.018 0.018 30-d urgent revascularization 61 (1.3%) 10 (1.1%) 0.738 0.738 Triple ischemic endpoint 338 (7.0%) 84 (9.5%) 0.010 0.010 In-hospital protocol major bleeding 123 (2.5%) 54 (6.1%) < 0.001 < 0.001 TIMI major + minor bleeding 114 (2.4%) 46 (5.2%) < 0.001 < 0.001 Creatinine Clearance Chew DP et al. Am J Cardiol 2005;95:581–585.

57. 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. 14.3 g/dL) Lower Hemoglobin (11.7 vs. 14.3 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]:1037-13- 31A. Abstract.

58. 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=0.0001 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]:1037- 13-31A. Abstract.

59. NSTE-ACS Mortality Stratified by Hemoglobin Sabatine MS. Circulation 2005 Unadjusted Hb (g/dL)nOR(95% Cl)OR(95% Cl)P value >17 2161.47(1.03–2.10)1.45(0.94–2.23)0.093 16–17 8121.21(0.97–1.51)1.27(0.98–1.65)0.066 15–1621301.0 reference1.0 reference 14–1533901.06(0.89–1.22)1.11(0.93–1.33)0.251 13–1435201.02(0.88–1.19)1.04(0.86–1.24)0.709 12–1323311.09(0.92–1.28)1.07(0.88–1.30)0.514 11–12 9761.20(0.97–1.47)1.04(0.81–1.34)0.755 10–11 3431.41(1.05–1.89)1.29(0.92–1.82)0.145 9–10 3422.44(1.88–3.18)2.69(2.01–3.60)<0.001 9–10 3422.44(1.88–3.18)2.69(2.01–3.60)<0.001 8–9 3062.24(1.69–2.96)2.45(1.80–3.33)<0.001 <8 1373.97(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

60. 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

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

62. 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. 2000 Feb 1;101(4):366-71 Calculating Costs of Ischemia and Bleeding: EPIC EQOL Study (Abciximab in PCI) Calculating Costs of Ischemia and Bleeding: EPIC EQOL Study (Abciximab in PCI)

63. 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

64. 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

65. 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

66. 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

67. Non-ST-Segment Elevation Acute Coronary Syndrome: Initial Presentation and Implications for Selecting Treatment Strategies Does One Size Fit All? The Emergency Medicine Perspective Charles V. Pollack, MD, FACEP, FAAEM Chairman, Department of Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine University of Pennsylvania School of Medicine Philadelphia, PA Charles V. Pollack, MD, FACEP, FAAEM Chairman, Department of Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine University of Pennsylvania School of Medicine Philadelphia, PA

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

69. 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

70. 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

71. 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

72. 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

73. 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

74. 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

75. 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

76. 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

77. 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

78. 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

79. 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

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

81. 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

82. 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

83. 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

84. 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 (0.77-0.97) <0.0010.015 7.3%7.8% 1.08 (0.93-1.24) 0.020.32 5.7%3.0% 0.53 (0.43-0.65) <0.001<0.001 p value (non inferior) (superior) UFH/Enoxaparin + GPI vs. Bivalirudin Alone Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16.

85. 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 (0.71-1.03) 0.88 (0.75-1.02) 0.90 (0.77-1.05) 0.82 (0.68-0.98) 0.86 (0.74-0.99) 0.96 (0.77-1.19) 0.79 (0.64-0.97) 0.90 (0.78-1.04) 0.87 (0.75-1.00) 0.86 (0.70-1.04) 0.09 0.16 0.03 0.71 0.02 0.16 0.05 0.12 0.89 0.47 0.43 0.28 0.91 RR (95% CI) Bivalirudin alone better UFH/Enox + IIb/IIIa better Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16.

86. 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 (0.65-0.89) 1.02 (0.86-1.21) 12.2% 7.1% 13.3% 9.4% 0.92 (0.80-1.06) 0.75 (0.61-0.93) 0.23 0.01 <0.001 0.83 0.35 0.02 0.18 13.0% 8.6% 13.7% 10.6% 0.96 (0.80-1.14) 0.81 (0.69-0.95) 0.61 0.01 0.42 Biomarkers (CK/Trop) ST Deviation TIMI Risk Score Pre Thienopyridine 6.4%10.2%0.63 (0.43-0.91)0.01 9.4%10.2%0.92 (0.77-1.10) 0.34 13.9%15.2%0.92 (0.76-1.11)0.36 Yes (n=5192) No (n=4023) RR (95% CI) Bivalirudin alone better UFH/Enox + IIb/IIIa better Stone GW, McLaurin BT. NEJM. 2006 Nov 23;355(21):2203-16. ACUITYNet Clinical Outcome Composite

87. 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

88. CURE: Ischemic Endpoints Were Reduced within 24h of Randomization Adapted from Yusuf S, et al. Circulation. 2003;107:966-972. Hours After Randomization Cumulative Hazard Rates 0.0 0.005 0.010 0.015 0.020 0.025 024681012141618202224 RR = 0.67 P = 0.003 Placebo + ASA Clopidogrel 33%RRR

89. Bleeding Among CABG Patients Receiving Clopidogrel Excludes transfers out within 48 hours and contraindications 95% CI Odds Ratio 1.01.02.02.0 0.50.5 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, www.crusadeqi.com

90. 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

91. 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

92. 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

93. 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

94. 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

95. 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

96. 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. 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

97. 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

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

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

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

101. Based on your clinical assessment, this patients risk of short-term (30-Day) ischemic events is: A.Low B.Moderate C.High D.Very high Case #1

102. Which of this patients baseline factors do you consider most important for determining this patients ischemic risk? A. Advanced age B. Anginal pattern C. ECG findings D. Biomarkers * Case #1

103. Based on your clinical assessment, this patients risk of incurring a short-term (30-Day) hemorrhagic event related to PCI is: A.Low B.Moderate C.High D.Very high Case #1

104. Which of this patients baseline factors do you consider most important for determining hemorrhagic risk? A. Advanced age B. Hypertension C. Impaired creatinine clearance D. Anemia * Case #1

105. In ACS patients, do you alter your choice of anticoagulant/ antithrombotic therapy based upon an assessment of the individual patients risk of hemorrhagic complications? A. Yes B. No * Case #1

106. Among those of you who would alter or customize antithrombotic therapy based on an ACS patients risk for hemorrhage in the setting of PCI, which of the following baseline characteristics would you consider most important in supporting the use of a hemorrhage- minimizing anithrombotic regimen: A. Elderly and female B. Renal insufficiency and positive biomarkers C. Anemia and high risk ischemic features * Case #1

107. What would you likely use for anticoagulation in this patient, prior to catheterization, if you anticipated catheterization would occur in 4 hours or less? A. Unfractionated heparin alone B. Enoxaparin alone C. Bivalirudin alone D. A heparin with a GP IIb/IIIa inhibitor E. Fondaparinux * Case #1

108. What would your choice of upstream anticoagulation therapy be, if you anticipated cardiac catheterization the same day (within 12 hours)? A. Unfractionated heparin alone B. Enoxaparin alone C. Bivalirudin alone D. A heparin with a GP IIb/IIIa inhibitor E. Fondaparinux * Case #1

109. What would your choice of upstream anticoagulation therapy be, if you anticipated cardiac catheterization the next day (within 24 hours)? A. Unfractionated heparin alone B. Enoxaparin alone C. Bivalirudin alone D. A heparin with a GP IIb/IIIa inhibitor E. Fondaparinux * Case #1

110. 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

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

112. Case #2: ECG New inferior changesNew lateral changes

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

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

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

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

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

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

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

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

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

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

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

124. 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

125. 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

126. 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 12-24 hours? Agreement? Disagreement? EDICT for ACS INTERACTIVE FORUM Faculty, Expert Panel, and Participants

127. 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

128. 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

129. 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

130. 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

131. 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

132. 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

133. 7. Practical and process-oriented recommendations 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