1. Importance and Impact of Bleeding on ACS Clinical Outcomes Sunil V. Rao MD Assistant Professor of Medicine Duke University Medical Center Durham VA Medical Center Duke Clinical Research Institute

2. Disclosures n Consultant and/or Speaker’s Bureau l Sanofi-Aventis l The Medicines Company l Pfizer l Cordis

3. Antithrombotic Pharmacotherapy During PCI: 25 Years of Evolving Therapy 1970sEmpirical treatment with heparin and aspirin 1980sRandomized and observational studies l aspirin: no  restenosis; but  acute complications l heparin: threshold 300 seconds ACT 1990sEra of stents and platelet blockade l stents: “shotgun” approach  ASA + ADP-inhibitors l GP IIb/IIIa blockade: antibody and SMI l heparin:  doses; LMWH 2000sTargeted anticoagulants (DTIs,Anti-Xa) Challenge of optimal combinations 1970sEmpirical treatment with heparin and aspirin 1980sRandomized and observational studies l aspirin: no  restenosis; but  acute complications l heparin: threshold 300 seconds ACT 1990sEra of stents and platelet blockade l stents: “shotgun” approach  ASA + ADP-inhibitors l GP IIb/IIIa blockade: antibody and SMI l heparin:  doses; LMWH 2000sTargeted anticoagulants (DTIs,Anti-Xa) Challenge of optimal combinations

4. Progressively better outcomes with PCI From the NHLBI(I), NHLBI (II), NACI, and NHLBI Dynamic Registries From the NHLBI(I), NHLBI (II), NACI, and NHLBI Dynamic Registries

5. CRUSADE In-Hospital Outcomes Death 4.3% (Re)-Infarction 2.5 % CHF 8.0 % Cardiogenic Shock 2.6% Stroke 0.8 % Non-CABG Transfusion 9.9 % CRUSADE: Quarter 1, 2004-Quarter 4, 2004 (n=39,933)

6. Bleeding and ACS n Older Age n Female Gender n Renal Failure n History of Bleeding n Right Heart Catheterization n GPIIbIIIa antagonists Independent Predictors of Major Bleeding in Marker Positive Acute Coronary Syndromes Moscucci, GRACE Registry, Eur H J 2003

7. Excess dosing of Gp IIb/IIIa and bleeding in women N=32,601 patients from CRUSADE 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

8. Procedural factors Femoral arterial access Sherev DA, CCI 2005

9. “Major” Bleeding – Incidence in ACS Clinical Trials

10. 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 Kaplan Meier Curves for 30-Day Death, Stratified by Bleed Severity

11. Bleeding and Outcomes in NSTE ACS 26,452 patients from PURSUIT, PARAGON A, PARAGON B, GUSTO IIb NST Adjusted Hazard Ratios for Mortality by Bleeding Severity Bleeding severity 30d Death 6 mo Death Mild* 1.61.4 Moderate* 2.72.1 Severe* 10.67.5 *p<0.0001 Bleeding as a time-dependent covariate Rao SV, et.al. AJC 2005

12. Bleeding & Outcomes - Data from CURE Trial Life Threatening MajorMajor MinorMinor No bleeding Mortality (%) 25252020 1515 1010 5 5 00 00303060609090120120150150180180 Eikelboom JW, et. al. Circulation 2006

13. Bleeding Incidence : Impact of definition N=15,858 ACS pts from PURSUIT & PARAGON B Rao SV, et.al. JACC 2006

14. Effect of bleeding definition on 30d death/MI N=15,858 ACS patients from PURSUIT & PARAGON B Rao SV, et.al. JACC 2006 Increased Risk Decreased Risk

15. Mark DB, et al. Circ 1996 Calculating Costs of Ischemia and Bleeding: EPIC EQOL Study (Abciximab in PCI) Abciximab versus Placebo  ischemic costs: $523  major bleed costs: $458 Abciximab versus Placebo  ischemic costs: $523  major bleed costs: $458

16. Risk versus benefit Thrombosis Bleeding

17. Bleeding – Immediate clinical consequences n Cessation of antithrombotic therapy n Hypotension n Reversal of antithrombotic therapy n Blood transfusion

18. 1.0 Less than USMore than US Unadjusted Adjusted for baseline characteristics Adjusted for baseline characteristics and procedures Adjusted for baseline characteristics, procedures, and bleeding 0.24 (0.19 – 0.30) 0.19 (0.15 – 0.25) 0.69 (0.54 – 0.88) 0.76 (0.59 – 1.00) Geographic variation in transfusion relative to U.S. N=24,112 Rao SV, et. al. AHA 2005

19. Variations in Transfusion Rates for NSTE ACS Across Hospitals Percentage of Patients Receiving Blood Transfusions (%) Percentage of Hospitals (%) Yang X, et. al. JACC 2005 Non-CABG Overall

20. Cooperative Cardiovascular Project 30 day death by transfusion and Hct n 78,974 pts > 65 years with confirmed MI n Grouped into categories of admission hematocrit n Excluded pts with bleeding and those with CABG n Primary endpoint: 30-day mortality Wu W, NEJM 2001 Odds ratio for 30 day mortality Odds ratio for 30 day mortality HigherHigher LowerLower HCT< 33 %

21. Transfusion in ACS N=24,111 pts from PURSUIT, PARAGON B, GUSTO IIb Rao SV, et. al., JAMA 2004

22. PRBC Transfusion Among NSTE ACS Patients: Cox model for 30-day Death (N=24,111) *Transfusion as a time-dependent covariate 1.010-4.0 Adjusted for transfusion propensity Adjusted for baseline characteristics Characteristics, bleeding propensity, transfusion Propensity, & nadir HCT 3.77 (3.14, 4.52) 3.54 (2.96, 4.23) 3.94 (3.26, 4.75) Rao SV, et. al., JAMA 2004

23. Adjusted Risk of In-Hospital Outcomes By Transfusion Status* * Non-CABG patients only Yang X, et. al. JACC 2005 * Non-CABG patients only Yang X, et. al. JACC 2005 Death Death or Re-MI Death Death or Re-MI 1 1 2.0 N=74,971 ACS pts. from 478 centers

24. Properties of PRBCs n Low 2,3 DPG* n High O 2 affinity* n Depleted of Nitric Oxide l NO plays a fundamental role in O 2 exchange † n Low 2,3 DPG* n High O 2 affinity* n Depleted of Nitric Oxide l NO plays a fundamental role in O 2 exchange † *Welch HG, et. al. Ann Int Med 1992 †Stamler JS, et. al. Science 1997

25. Effects of Transfusion n Packed red cells l Depleted of NO Function as NO “sinks” Lead to vasoconstriction Platelet aggregation Ineffective O 2 delivery l Associated with increases in CRP and IL6* n Packed red cells l Depleted of NO Function as NO “sinks” Lead to vasoconstriction Platelet aggregation Ineffective O 2 delivery l Associated with increases in CRP and IL6* *Fransen E, et. al. Chest 1999

26. STEEPLE IV enoxaparin STEEPLE OASIS 5 Fondaparinux Fondaparinux REPLACE-2ACUITYBivalirudinREPLACE-2ACUITYBivalirudin STEEPLE Investigators. NEJM 2006 OASIS Investigators. NEJM 2006 Lincoff AM, et. al. JAMA 2003 Stone GW. ACC 2006 STEEPLE Investigators. NEJM 2006 OASIS Investigators. NEJM 2006 Lincoff AM, et. al. JAMA 2003 Stone GW. ACC 2006

27. Addressing the challenge of selecting an anticoagulation strategy Bleeding Risk Ischemic Risk Renal function AgeAge Time to cath CostCost Ease of use PCI vs CABG vs Med Rx

28. Bleeding and ACS outcomes Conclusions n Bleeding is more common than we think n Clinical bleeding and transfusion are associated with worse outcomes and cost n Strategies that maintain an adequate antithrombotic effect to reduce ischemia while minimizing the risk of bleeding may improve survival in patients with acute ischemic heart disease l The traditional efficacy-safety relationship has changed