2. Jointly Sponsored by the University of Massachusetts Medical School Office of Continuing Education and CMEducation Resources, LLC. Funded by an Independent Educational Grant from The Medicines Company Accreditation Information

3. Instructions for Receiving Category 1 AMA Credit Participants: This SlideCAST is a CME-certified program that must be viewed in its entirety to receive CME credit. You should view the slides in their original order, and then access the online CME test as directed at the end of the program. If program content or total number of slides are expanded, reduced, or modified in any way, the program no longer qualifies for CME. Presenters: This SlideCAST is a CME-certified program that must be presented in its entirety for your audience to receive CME credit. You should present the slides in their original order, either as a PowerPoint presentation or in print form, and then instruct your audience how to access the test online. If program content or total number of slides are expanded, reduced, or modified in any way, the program no longer qualifies for CME and must be reviewed and certified by your own institution. Program Requirements

4. Intended Audience: This SlideCAST is designed for interventional cardiologists, cardiologists, and emergency medicine physicians, and other healthcare providers caring for patients with acute cardiovascular disease. Registration: Enrollment for this SlideCAST is complimentary, and clinicians are invited to participate in this CME-certified program and/or share this invitation with other colleagues, departmental staff members, and healthcare professionals. Grantor Support: Supported by an independent educational grant from The Medicines Company, Inc. Accreditation Information

5. Accreditation Statement for Jointly-Sponsored Programs This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of The University of Massachusetts Medical School and CMEducation Resources, LLC. The University of Massachusetts Medical School is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation Statement The University of Massachusetts Medical School designates this educational activity for a maximum of 1.5 AMA PRA Category 1 Credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity. Accreditation Information

6. Policy on Faculty And Provider Disclosure It is the policy of the University of Massachusetts Medical School to ensure fair balance, independence, objectivity and scientific rigor in all activities. All faculty participating in CME activities sponsored by the University of Massachusetts Medical School are required to present evidence-based data, identify and reference off-label product use and disclose all relevant financial relationships with those supporting the activity or others whose products or services are discussed. Faculty disclosure will be provided in the activity materials. For additional CME-certified programs in cardiovascular health: Please visit us at www.EDICTforACS.com (click anywhere on banner below) Accreditation Information

7. Deepak L. Bhatt, MD, FACC, FSCAI, FESC, FACP Associate Director, Cleveland Clinic Cardiovascular Coordinating Center Staff, Cardiac, Peripheral, and Carotid Intervention Associate Professor of Medicine Department of Cardiovascular Medicine Cleveland Clinic Foundation Frederick Feit, MD, FACC Director Cardiac Catheterization and Interventional Cardiology Bellevue Hospital Center Associate Professor of Medicine New York University School of Medicine New York, NY Deborah Diercks, MD Assistant Professor of Medicine Department of Emergency Medicine University of California Davis, California James Ferguson III, MD Associate Director, Cardiology Research Texas Heart Institute at St. Luke's Episcopal Hospital Associate Professor Baylor College of Medicine Clinical Assistant Professor University of Texas Health Science Center at Houston Christopher Granger, MD Associate Professor of Medicine Director of Cardiac Care Unit Division of Cardiovascular Medicine Duke University Medical Center ACS Forum Leadership Panel

8. Judd E. Hollander, MD Professor Clinical Research Director Department of Emergency Medicine University of Pennsylvania Philadelphia, PA David M. Lang, DO, FACOEP, FACEP Chief Emergency Medicine Mount Sinai Medical Center Miami Beach, FL Steven V. Manoukian, MD, FACC Director, Interventional Cardiology Emory-Crawford Long Hospital Emory University School of Medicine President American Heart Association, Atlanta Division Atlanta, GA Ralph G. Nader, MD, FACC, FACP, FSCAI Co-Medical Director Cardiovascular Labs at Mount-Sinai/Miami Heart Miami, FL E. Magnus Ohman, MD, FRCPI, FACC Professor of Medicine Director, Program for Advanced Coronary Disease Division of Cardiology Duke University Medical Center Durham, NC ACS Forum Leadership Panel

9. Charles Pollack, MD, FACEP Chairman, Department of Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine University of Pennsylvania School of Medicine Philadelphia, PA Sunil V. Rao MD Assistant Professor of Medicine Duke University Medical Center Director, Cardiac Catheterization Laboratories Durham VA Medical Center Durham, NC ACS Forum Leadership Panel

10. Deepak L. Bhatt, MD: Consultant/Honoraria or Grant/Research Support: Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, Eisai, Glaxo Smith Kline, Millennium, Paringenix, PDL, Schering Plough, sanofi-aventis, The Medicines Company. Deborah Diercks, MD: Grants/Research Support: Invoice Technology, The Medicines Company. Consultant: Invoice Technology, sanofi-aventis U.S., Astellas. Speakers Bureau: Bristol-Myers Squibb, Schering-Plough, sanofi-aventis U.S Frederick Feit, MD: Consultant: The Medicines Company James Ferguson III, MD: Grant/Research Support: Eisai Pharmaceuticals, The Medicines Company. Vitatron/Medtronic. Consulting/Honoraria: Bristol Myers-Squibb, Eisai Pharmaceuticals, GlaxoSmithKline, Prism Pharmaceuticals, sanofi-aventis, Schering- Plough, Takeda, The Medicines Company, Therox. Speakers Bureau: Bristol Myers- Squibb, sanofi-aventis, Schering-Plough Ralph G. Nader, MD: Nothing to disclose. E. Magnus Ohman, MD: Research Grants: Berlex, sanofi-aventis, Schering-Plough Corporation, Bristol Meyer Squibb, Millennium. Stockholder: Medtronic. Consultant: Response Biomedical, Liposcience, Inovise Medical ACS Leadership Panel Financial Disclosures

11. Christopher Granger, MD: Educational Grants and/or Research Support: Alexion, Astra Zeneca, Procter and Gamble, sanofi-aventis, Novartis, Boehringer Ingelheim, Genentech, and Berlex Judd E. Hollander, MD: Grant/Research Support: sanofi-aventis, Biosite, Scios, The Medicines Company. Consultant: sanofi-aventis, Biosite, Scios, The Medicines Company. Speakers Bureau: sanofi-aventis, Biosite, Scios, The Medicines Company David Lang, DO: Honoraria: Roche and Pfizer. Consultant: Aventis Steven V. Manoukian, MD: Grant/ Research Support: The Medicines Company Speakers Bureau: The Medicines Company Charles Pollack, MD: Grant/Research Support: GlaxoSmithKline. Consultant: The Medicines Company, Schering-Plough, sanofi-aventis, BMS, Genentech. Speakers Bureau: Schering-Plough, sanofi-aventis, BMS, Genentech 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 ACS Leadership Panel Financial Disclosures

12. Thomas Amidon, MD The Hope Heart Institute Atul Aggarwal, MD Nebraska Heart Institute Himanshu Aggarwal, MD Nebraska Heart Institute Keith Benzuly, MD, FACC Northwestern University Joseph J. Brennan Jr., MD Yale University School of Medicine Carl Chudnofsky, MD Albert Einstein Medical Center Michael J. Cowley, MD Medical College of Virginia Harold Dauerman, MD University of Vermont William J. French, MD UCLA Medical Center Satyendra Giri, MD Baystate Health Systems Paul A. Gurbel, MD Johns Hopkins University ACS Faculty Review Committee * Complete affiliations and financial disclosures for Review Committee members are listed at end of slide deck.

13. Tim Henry, MD Minneapolis Heart Institute Kurt Kleinschmidt, MD UT Southwestern Medical Center James Leggett, MD Hope Heart Institute Glenn Levine, MD Baylor College of Medicine John J. Lopez, MD University of Chicago Reginald Low, MD University of California, Davis Roberto Medina, MD Florida Medical Clinic Barry L. Molk, MD, FACC University of Colorado Reynaldo Mulingtapang, MD University of South Florida Robert A. Mulliken, MD University of Chicago Hospitals Sandeep Nathan, MD, FACC Rush Medical College Paul E. Pepe, MD, MPH UT Southwestern Medical Center ACS Faculty Review Committee * Complete affiliations and financial disclosures for Review Committee members are listed at end of slide deck.

14. Robert N. Piana, MD Vanderbilt University Vincent J. Pompili, MD, FACC Case School of Medicine Matthew J. Price, MD Scripps Clinic Douglas J. Spriggs, MD, FACC University of South Florida Lowell H. Steen, Jr., MD Loyoyla University Chicago David J. Robinson, MD, MS, FACEP UT Health Sciences Center Joseph F. Stella, DO, FACC Heart Care Centers of Illinois Rex J. Winters, MD Long Beach Memorial Heart Institute ACS Faculty Review Committee * Complete affiliations and financial disclosures for Review Committee members are listed at end of slide deck.

15. Physicians will learn about the impact that bleeding has on outcomes in patients with acute coronary ischemic syndromes (ACS) Physicians will learn what factors predict bleeding in patients with ACS Physicians will learn what predictive value different bleeding scales have on outcomes in patients with ACS Physicians will learn how to implement strategies that balance risk of bleeding and ischemia. Physicians will learn how to apply landmark trials and analyses of bleeding and ACS to clinical situations. Educational Objectives

16. 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 A CME-Certified Activity Developed by the National Experts' Educational Forum in Cardiovascular Disease BLEEDING IN THE SETTING OF ACUTE CORONARY SYNDROMES (ACS) Clinical Implications and Effects on Mortality and Resource Utilization A CME-Certified Activity Developed by the National Experts' Educational Forum in Cardiovascular Disease

17. 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

18. 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.

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

20. 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

21. 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

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

23. 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

24. 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

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

26. 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

27. 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

28. 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

29. 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)

30. 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

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

32. 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

33. 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

34. 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

35. 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)

36. 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)

37. 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

38. 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

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

40. 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

41. 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.

42. 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

43. 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

44. 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

45. 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

46. 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:

47. 30-Day Survival By Transfusion Group Rao SV, et. al., JAMA 2004;292:1555–1562 Transfusion in ACS N=24,111N=24,111

48. *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

49. 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

50. 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)

51. 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)

52. 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.

53. 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

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

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

56. 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.

57. 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.

58. 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

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

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

61. 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

62. 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.

63. 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.

64. 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.

65. 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

66. 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

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

68. 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)

69. 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

70. 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

71. 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

72. 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

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74. Thomas Amidon, MD Medical Director The Hope Heart Institute Overlake Internal Medicine Associates Seattle, WA Atul Aggarwal, MD Nebraska Heart Institute Lincoln, NE Himanshu Aggarwal, MD Nebraska Heart Institute St. Frances Med Center Grand Island, NE Keith Benzuly, MD, FACC Assistant Professor of Medicine Bluhm Cardiovascular Institute Northwestern University Feinberg School of Medicine Chicago, IL ACS Faculty Review Committee Joseph J. Brennan Jr., MD Associate Professor of Medicine, Cardiology Director, Interventional Fellowship Program Yale University School of Medicine New Haven, CT Carl Chudnofsky, MD Chairman Department of Emergency Medicine Albert Einstein Medical Center Philadelphia, PA Michael J. Cowley, MD Professor Department of Internal Medicine Division of Cardiology Medical College of Virginia Virginia Commonwealth University Richmond, VA

75. Harold Dauerman, MD Director, Cardiovascular Catheterization Laboratory Professor of Medicine Fletcher Allen Health Care University of Vermont College of Medicine Burlington, VT William J. French, MD Medical Director Catheterization Laboratory UCLA Medical Center Los Angeles, CA Satyendra Giri, MD Section Chief Vascular Medicine Program Baystate Health Systems Springfield, MA ACS Faculty Review Committee Paul A. Gurbel, MD Helen Dalsheimer Director of the Division of Cardiology at Sinai Hospital of Baltimore Associate Professor of Medicine Division of Cardiology Johns Hopkins University School of Medicine Baltimore, MD Tim Henry, MD Minneapolis Heart Institute Foundation Associate Professor University of Minnesota School of Medicine Minneapolis, MD Kurt Kleinschmidt, MD Associate Professor Director of Toxicology Fellowship Program UT Southwestern Medical Center Dallas, TX

76. James Leggett, MD Associate Medical Director Hope Heart Institute Seattle, WA Glen Levine, MD Director, Cardiac Catheterization Lab Associate Professor of Medicine Baylor College of Medicine Chief, Critical Cardiac Care Houston VA Medical Center Houston, TX John J. Lopez, MD Associate Professor of Medicine Director Cardiac Catheterization and Interventional Cardiology University of Chicago Chicago, IL Reginald Low, MD Chief, Division of Cardiovascular Medicine University of California, Davis Davis, CA ACS Faculty Review Committee Barry L. Molk, MD, FACC Associate Clinical Professor University of Colorado Health Science Center Aurora Denver Cardiology Associates Denver, CO Reynaldo Mulingtapang, MD Assistant Professor of Medicine Director, University of South Florida Interventional Cardiology Program Tampa, FL Robert A. Mulliken, MD Medical Director, Emergency Department University of Chicago Hospitals Associate Professor University of Chicago School of Medicine Chicago, IL Sandeep Nathan, MD, FACC Assistant Professor of Medicine Rush Medical College, Section of Cardiology Rush University Medical Center Director, Cardiovascular Intervention Chicago, IL

77. Robert N. Piana, MD Associate Professor of Medicine Vanderbilt University School of Medicine Director, Cardiac Catheterization Laboratories Nashville, TN Vincent J. Pompili, MD, FACC Director of Interventional Cardiology University Hospitals Associate Professor of Medicine Case School of Medicine Cleveland, OH Matthew J. Price, MD Director Cardiac Catheterization Laboratory Scripps Clinic Division of Cardiovascular Diseases La Jolla, CA David J. Robinson, MD, MS, FACEP Associate Professor, Research Director and Vice-Chair Dept. of Emergency Medicine University of Texas Health Sciences Center Houston, TX ACS Faculty Review Committee Joseph F. Stella, DO, FACC Heart Care Centers of Illinois Clinical Assistant Professor Loyola University Medical Center Chicago, IL Paul E. Pepe, MD, MPH Riggs Family Chair in Emergency Medicine Professor and Division Chairman Emergency Medicine University of Texas Southwestern Medical Center Dallas, TX Douglas J. Spriggs, MD, FACC Clinical Assistant Professor Depts. of Internal Medicine and Family Practice University of South Florida College of Medicine Clearwater Cardiovascular and Interventional Consultants Clearwater, FL

78. ACS Faculty Review Committee Lowell H. Steen, Jr., MD Associate Professor of Medicine, Cardiology Loyoyla University Chicago Stritch School of Medicine Rex J. Winters, MD Director of Invasive Cardiology Long Beach Memorial Heart Institute

79. Thomas Amidon, MD: Nothing to disclose. Atul Aggarwal, MD: Grant/Research Support: Aventis, Schering-Plough Himanshu Aggarwal, MD: Nothing to disclose. Keith Benzuly, MD, FACC: Speakers Bureau: The Medicines Company Joseph J. Brennan Jr., MD: Nothing to disclose. Carl Chudnofsky, MD: Nothing to disclose. Michael J. Cowley, MD: Nothing to disclose. Harold Dauerman, MD: Grant/Research Support: Boston Scientific, Guidant. Consultant: The Medicines Company, Arginox. William J. French, MD: Nothing to disclose. Satyendra Giri, MD: Nothing to disclose. Paul A. Gurbel, MD: Grant/Research Support: Schering-Plough, Millennium, AstraZeneca, Bayer, Haemoscope, NIH, Medtronic, Boston Scientific Thomas Amidon, MD: Nothing to disclose. Atul Aggarwal, MD: Grant/Research Support: Aventis, Schering-Plough Himanshu Aggarwal, MD: Nothing to disclose. Keith Benzuly, MD, FACC: Speakers Bureau: The Medicines Company Joseph J. Brennan Jr., MD: Nothing to disclose. Carl Chudnofsky, MD: Nothing to disclose. Michael J. Cowley, MD: Nothing to disclose. Harold Dauerman, MD: Grant/Research Support: Boston Scientific, Guidant. Consultant: The Medicines Company, Arginox. William J. French, MD: Nothing to disclose. Satyendra Giri, MD: Nothing to disclose. Paul A. Gurbel, MD: Grant/Research Support: Schering-Plough, Millennium, AstraZeneca, Bayer, Haemoscope, NIH, Medtronic, Boston Scientific ACS Review Committee Financial Disclosures

80. Tim Henry, MD: Nothing to disclose. Kurt Kleinschmidt, MD: Consultant: The Medicines Company. Speakers Bureau: sanofi-aventis. James Leggett, MD: Grant/Research Support: The Medicines Company, sanofi-aventis Glenn Levine, MD: Speakers Bureau: sanofi-aventis John J. Lopez, MD: Nothing to disclose. Reginald Low, MD: Nothing to disclose. Roberto Medina, MD: Speakers Bureau: The Medicines Company Barry L. Molk, MD, FACC: Nothing to disclose. Reynaldo Mulingtapang, MD: Grant/Research Support: GlaxoSmithKline. Consultant: Medtronic AAA, Abbott. Speakers Bureau: Pfizer. Major Shareholder: Vascular Architects. Abbott. Speakers Bureau: Pfizer. Major Shareholder: Vascular Architects. Robert A. Mulliken, MD: Nothing to disclose. Sandeep Nathan, MD, FACC: Research Support: Guilford. Speakers Bureau: The Medicines Company, sanofi-aventis. sanofi-aventis. ACS Review Committee Financial Disclosures

81. Paul E. Pepe, MD, MPH: Nothing to disclose. Robert N. Piana, MD: Speakers Bureau: sanofi-aventis Vincent J. Pompili, MD, FACC: Major Shareholder: Arteriocyte, Inc. Matthew J. Price, MD: Nothing to disclose. Douglas J. Spriggs, MD, FACC: Nothing to disclose. Lowell H. Steen, Jr., MD: Nothing to disclose. David J. Robinson, MD, MS, FACEP: Nothing to disclose. Joseph F. Stella, DO, FACC: Nothing to disclose. Rex J. Winters, MD: Consultant: Cordis, Johnson & Johnson, Guidant. Speakers Bureau: The Medicines Company. Paul E. Pepe, MD, MPH: Nothing to disclose. Robert N. Piana, MD: Speakers Bureau: sanofi-aventis Vincent J. Pompili, MD, FACC: Major Shareholder: Arteriocyte, Inc. Matthew J. Price, MD: Nothing to disclose. Douglas J. Spriggs, MD, FACC: Nothing to disclose. Lowell H. Steen, Jr., MD: Nothing to disclose. David J. Robinson, MD, MS, FACEP: Nothing to disclose. Joseph F. Stella, DO, FACC: Nothing to disclose. Rex J. Winters, MD: Consultant: Cordis, Johnson & Johnson, Guidant. Speakers Bureau: The Medicines Company. ACS Review Committee Financial Disclosures

82. CME Test Complimentary CME Test: To access the complimentary CME test, program participants must have internet access. Participants can access the on-line evaluation form and receive instant online notification of credit by clicking on the program icon below. Click Here for CME Click Here for CME Click Here for CME Click Here for CME