1. Major Bleeding is Associated with Increased 30-Day Mortality and Ischemic Complications in Patients with Non-ST Elevation Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention: The ACUITY Trial Steven V. Manoukian 1, Michele D. Voeltz 1, Frederick Feit 2, Roxana Mehran 3, Eugenia Nikolsky 3, George D. Dangas 3, Ramin Ebrahimi 4, A. Michael Lincoff 5, Spencer B. King, III 6, Gregg W. Stone 3 1 Emory University School of Medicine, Atlanta, GA 2 New York University School of Medicine, New York, NY 3 Columbia University Medical Center, New York, NY 4 University of California Los Angeles, Los Angeles, CA 5 The Cleveland Clinic, Cleveland, OH 6 Fuqua Heart Center, Atlanta, GA

2. Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Steven V. Manoukian, MD, FACCThe Medicines Co. Research Support Consultant Speaker sanofi aventis/BMS Consultant Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Steven V. Manoukian, MD, FACCThe Medicines Co. Research Support Consultant Speaker sanofi aventis/BMS Consultant Relevant Conflict of Interest Statement

3. Background: Major Bleeding in ACS and PCI Major bleeding is a significant complication of acute coronary syndromes (ACS) and percutaneous coronary intervention (PCI). Recent data suggest that major bleeding is associated with an increase in adverse outcomes in ACS and PCI, including mortality. We evaluated the impact of major bleeding on mortality and ischemic events in patients with ACS undergoing PCI from the ACUITY Trial. Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

4. Background: The REPLACE-2 Trial Major Bleeding is Increased with Abciximab and Eptifibatide vs. Bivalirudin in PCI Major Bleeding 2.5% vs. 4.0%, p=0.0251 Major Bleeding 2.2% vs. 4.1%, p=0.0021 4.0% 2.5% 2.2% 4.1% Voeltz MD, Lincoff AM, Feit F, Manoukian SV. Circulation 2005;112(17):II-737.

5. Background: The REPLACE-2 Trial Major Bleeding is Associated with Increased Mortality in Elderly Patients Undergoing PCI = Yes = No p<0.0001 30-Day Mortality 806 patients (13.4%) classified as elderly, >75 years of age. Voeltz MD, Lincoff AM, Feit F, Manoukian SV. Circulation 2005;112(17):II-613.

6. Background: The REPLACE-2 Trial Predictors of One-Year Mortality in PCI Risk FactorOdds Ratio95% CIp-value Treatment Group (BIV vs. H+GPI)0.770.516 to 1.1490.201 Age > 752.0691.273 to 3.3620.0033 Congestive Heart Failure2.9911.777 to 5.032<0.0001 Pre-procedure LV function <35%2.8271.565 to 5.1060.0006 Diabetes Mellitus1.9871.311 to 30.120.0012 Prior Angina1.9481.115 to 3.4030.0191 Baseline Creatinine Clearance1.008 1.000 to 1.0150.0455 Major Bleeding2.7671.444 to 5.3020.0022 30 Day Revascularization3.0751.244 to 7.5970.015 30 Day MI2.5031.428 to 4.3860.0014 IABP3.5981.233 to 10.4990.0191 Feit F, Voeltz MD, Attubato MA, Lincoff AM, Chew D, Bittl JA, Wolski K, Topol EJ, Manoukian SV. Manuscript. Protocol definition: >3g/dL drop in HgB, intracranial, retroperitoneal, 2U transfusion.

7. Moscucci M et al. Eur Heart J 2003;24:1815-23. P<0.001 Overall Unstable NSTEMI STEMI ACS Angina ACS Angina Mortality (%) Background: The GRACE Registry Major Bleeding is Associated with Increased Mortality in ACS

8. Background: OASIS Registry, OASIS-2, and CURE Major Bleeding is Associated with Increased Mortality in ACS Eikelboom JW et al. Circulation 2006;114:774-782.

9. Methods: The ACUITY Trial Study Design and Definitions The ACUITY Trial compared: heparin or enoxaparin + glycoprotein inhibition (H+GPI), bivalirudin + glycoprotein inhibition (BIV+GPI), and bivalirudin monotherapy (BIV) in 13819 patients with moderate and high-risk NSTE- ACS. Major bleeding (non-CABG-related) was defined as: intracranial, intraocular, or retroperitoneal, access site with intervention, hematoma >5cm, Hgb drop >3g/dL with source or >4g/dL without source, transfusion. Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

10. Moderate- high risk ACS Methods: The ACUITY Trial (N=13819) First Randomization Angiography within 72h Aspirin in all Clopidogrel dosing and timing per local practice UFH or Enoxaparin + GP IIb/IIIa Bivalirudin + GP IIb/IIIa Bivalirudin Alone R* *Stratified by pre-angiography thienopyridine use or administration Stone GW et al. AHJ 2004;148:764–75. Medical management PCI CABG Moderate and high-risk unstable angina or NSTEMI undergoing an invasive strategy

11. Methods: The ACUITY Trial (N=13819) Overall Net Clinical Outcome Composite Endpoint 0 5 10 15 05101520253035 Cumulative Events (%) Days from Randomization Estimate P (log rank) 11.7% UFH/Enoxaparin + IIb/IIIa (N=4603) Bivalirudin + IIb/IIIa (N=4604) 0.89 11.8% Bivalirudin alone (N=4612) 0.014 10.1% UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone ACUITY Trial. Stone GW. ACC 2006.

12. P Sup = 0.32P Sup = 0.34P Sup = 0.35P Sup = 0.78 Methods: The ACUITY Trial (N=13819) Overall Ischemic Endpoints Stone GW. ACC 2006.

13. Methods: The ACUITY Trial (N=13819) Overall Bleeding Endpoints P Sup =0.38P Sup <0.0001P Sup =0.31P Sup <.001 Stone GW. ACC 2006.

14. Moderate- high risk ACS Methods: The ACUITY Trial (N=13819) Second Randomization Angiography within 72h Aspirin in all Clopidogrel dosing and timing per local practice Medical management PCI CABG Bivalirudin Alone UFH or Enoxaparin Routine upstream GPI in all pts GPI started in CCL for PCI only R Bivalirudin R Routine upstream GPI in all pts GPI started in CCL for PCI only Stone GW et al. AHJ 2004;148:764–75. Moderate and high-risk unstable angina or NSTEMI undergoing an invasive strategy

15. Methods: The ACUITY Trial (N=13819) Overall Primary Endpoint Measures for Upstream vs. Deferred IIb/IIIa P NI <0.0001 P Sup = 0.93 P NI = 0.044 P Sup = 0.13 P NI < 0.0001 P Sup = 0.009 Stone GW. ACC 2006.

16. Results: The ACUITY Trial PCI Population (N=7789) Major Bleeding (Non-CABG Related) in ACS Patients Undergoing PCI 462 (5.9%) of 7789 patients had major bleeding by 30 days. Patients with major bleeding were (p<0.05): –older, female, and had lower body weight, diabetes, hypertension, impaired creatinine clearance, high-risk (ST-changes or elevated biomarkers), and elevated biomarkers. –less likely to have prior PCI. –more likely to receive a glycoprotein inhibitor, have PCI duration >1h, sheath dwell time >6h. Major bleeding was less frequent for: –Bivalirudin vs. Heparin(s) + GPI (3.5% vs. 6.8%, p<0.0001), –Bivalirudin vs. Bivalirudin + GPI (3.5% vs. 7.5%, p<0.0001). Major bleeding was associated with higher 30-day mortality and ischemic event rates. Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

17. Results: The ACUITY Trial PCI Population (N=7789) Major Bleeding and Baseline Characteristics Major Bleeding (N=462, 5.9%) No Major Bleeding (N=7327, 94.1%) P-value Age (median [range], yrs)69 [37-95]62 [21-92]<0.0001 Female48.3%25.5%<0.0001 Weight (median [IQR], kg)78.3 [68-93]84 [74-96]<0.0001 Diabetes35.2%27.1% 0.0002 Hypertension73.8%65.5% 0.0001 Current smoker27.4%31.1% 0.0929 Prior PCI30.3%39.2% 0.0002 CrCl ≥ 60 ml/min62.3%82.8%<0.0001 High-risk (ST / biomarkers)83.0%75.9% 0.0007 CK-MB / Troponin+70.0%64.7% 0.0271 Any GPI use83.8%68.0%<0.0001 Sheath removal time >6h24.4%15.7%<0.0001 PCI duration >1h20%10.5%<0.0001 Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

18. Results: The ACUITY Trial PCI Population (N=7789) Major Bleeding by Treatment Strategy P<0.0001 Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

19. Results: The ACUITY Trial PCI Population (N=7789) Major Bleeding, Ischemic Endpoints, and Mortality P<0.0001 for all Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

20. Results: The ACUITY Trial PCI Population (N=7789) Major Bleeding and Myocardial Infarction P<0.0001 for all Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

21. Results: The ACUITY Trial PCI Population (N=7789) Major Bleeding, Ischemic Endpoints, and Mortality Major Bleeding (N=462, 5.9%) No Major Bleeding (N=7327, 94.1%) P-value Death5.4%0.8% <0.0001 Composite ischemia (D/MI/unplanned revasc) 24.2%7.8% <0.0001 Death/MI20.1%6.1% <0.0001 MI17.1%5.5% <0.0001 Non-Q wave12.6%4.8% <0.0001 Q wave4.8%0.8% <0.0001 Unplanned revascularization 9.3%3.0% <0.0001 Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

22. Results: The ACUITY Trial PCI Population Predictors of Major Bleeding VariableEstimate95% CIP-value Age >75 (vs. 55-75)1.5601.191-2.0430.0009 Female gender2.0771.676-2.574<0.0001 Diabetes1.2971.034-1.6280.0248 Hypertension1.3251.030-1.7040.0287 CrCl <60mL/min1.6771.293-2.176<0.0001 Anemia1.8891.481-2.409<0.0001 Prior PCI1.4731.154-1.8800.0019 High-risk (ST / biomarkers)1.4211.063-1.9010.0178 Prior antithrombotic therapy1.2320.978-1.5510.0768 Heparin (s) + GPI ( vs. Bivalirudin) 2.0781.562-2.764<0.0001 Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

23. P-valueRR (95% CI)Risk ratio ± 95% CI Results: The ACUITY Trial PCI Population Predictors of Major Bleeding Age >75 (vs. 55-75) Anemia CrCl <60mL/min Diabetes Female gender High-risk (ST / biomarkers) Hypertension 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.

24. Conclusion: The ACUITY Trial PCI Population (N=7789) Major Bleeding in Patients with ACS Undergoing PCI Major bleeding is associated with increased 30-day mortality and ischemic event rates in patients with ACS undergoing PCI. Bivalirudin results in lower rates of major bleeding compared to GPI- based strategies. Factors associated with an increase in the risk of major bleeding: –age, female gender, diabetes, hypertension, chronic kidney disease, prior PCI, anemia; –high-risk presentation; –treatment with heparin(s) + GPI (and trend for prior AT therapy). Knowledge of these factors is important in the assessment of the hemorrhagic risk of, and decision-making for an individual patient. Prevention of major bleeding in this setting is essential to improve outcomes. Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.