1. Major Bleeding is Associated with Increased One-Year Mortality and Ischemic Events in Patients with Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervetnion: The ACUITY Trial Steven V. Manoukian, Frederick Feit, Michele D. Voeltz, George D. Dangas, Ramin Ebrahimi, Martial Hamon, Derek P. Chew, Walter Desmet, Steven R. Steinhubl, A. Michael Lincoff, Spencer B. King III, E. Magnus Ohman, Harvey D. White, Roxana Mehran, Gregg W. Stone, on behalf of the ACUITY Investigators

2. Disclosures Consultant: BMS, Guerbet, Sanofi-Aventis, Schering-Plough, The Medicines Co. Grant Support: Guerbet, The Medicines Co. Lecture honoraria: Guerbet, The Medicines Co. Manoukian SV et al. TCT 2007.

3. Background and Methods: Study Design and Definitions The ACUITY Trial randomized 13,819 patients with moderate and high-risk NSTE-ACS to: –heparin/enoxaparin + GPIIb/IIIa inhibitor, –bivalirudin + GPIIb/IIIa inhibitor, or –bivalirudin alone. 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, –reoperation, –transfusion. Stone GW et al. NEJM 2006;355:2203-16.

4. Moderate- high risk ACS Background and Methods: ACUITY: Study Design 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 Moderate and high-risk NSTE-ACS undergoing an invasive strategy (N = 13,819) Medical management PCI N=7,789 56.4% CABG Stone GW et al. NEJM 2006;355:2203-16.

5. Background: ACUITY Overall: Major Bleeding and Mortality Major Bleeding and Short-Term (30-Day) Mortality 0 1 2 3 4 5 6 7 8 05101520253035 Days from Randomization Percent Mortality Patients at Risk Patients with major bleeding:644633623614609602599589 Patients without major bleeding:1316913009129751295112933129111286412761 Log Rank P–Value: <0.0001 Patients with major bleeding Patients without major bleeding 7.3% 1.2% Manoukian SV et al. J Am Coll Cardiol 2007;49:1362-8.

6. Age ≥75 years 2.55 (1.68-3.87) <0.0001 Left ventricular ejection fraction ≤50% 2.96 (1.99-4.39) <0.0001 Prior stroke 1.94 (1.09-3.44) <0.05 Baseline ST-segment deviation ≥1mm2.32 (1.54-3.50)<0.0001 Baseline cardiac biomarker elevation 1.97 (1.23-3.17) <0.01 Treatment strategy (CABG vs. PCI)3.40 (2.11-5.49)<0.0001 Myocardial infarction within 30 days 3.96 (2.45-6.42) <0.0001 Major bleeding 7.55 (4.68-12.18) <0.0001 Odds ratio ±95% CI P-valueOR (95% CI) Background: ACUITY Overall: Major Bleeding and Mortality Predictors of Short-Term (30-Day) Mortality Manoukian SV et al. J Am Coll Cardiol 2007;49:1362-8.

7. Background: ACUITY PCI: Major Bleeding and Short-Term (30-Day) Events P<0.0001 for all Manoukian SV et al. TCT 2006.

8. Background and Methods: ACUITY PCI: Major Bleeding by Treatment Strategy P<0.0001 Stone GW et al. Lancet 2007;369:907-19. P<0.0001

9. Background: REPLACE-2: Major Bleeding and Mortality Predictors of Long-Term (1-Year) Mortality in PCI Risk FactorHazard Ratio95% CIp-value Age > 752.28(1.51-3.46)0.0001 Pre-procedural anemia2.12(1.43-3.13)0.0002 Body mass index 20-25 vs >251.64(1.08-2.50)0.007 Pre-procedural LV ejection fraction ≤50%2.15(1.44-3.21)0.0002 Congestive heart failure3.58(2.27-5.65)<0.0001 Prior angina2.16(1.25-3.75)0.006 Major Bleeding2.66(1.44-4.92)0.002 30-Day MI2.46(1.44-4.20)0.001 30-Day Revascularization3.30(1.36-8.00)0.008 Feit F et al. Am J Cardiol 2007 in press. (www.ajconline.org/inpress) Protocol definition: >3g/dL drop in Hgb, intracranial, retroperitoneal, 2U transfusion.

10. Background and Methods: Major Bleeding in ACS and PCI Major bleeding is a significant complication of percutaneous coronary intervention (PCI) and acute coronary syndromes (ACS). Major bleeding is associated with increased 30-day mortality and ischemic event rates. Bivalirudin results in lower rates of major bleeding vs. GPI-based strategies. We evaluated the impact of major bleeding on 1-year mortality in patients with ACS undergoing PCI from the ACUITY Trial. Manoukian SV et al. TCT 2007.

11. Results: ACUITY PCI: Major Bleeding Patient Characteristics Major Bleeding (N=462, 5.9%) No Major Bleeding (N=7,327, 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 Prior thienopyridine70.6%68.1% 0.2666 High-risk (ST/biomarkers)83.0%75.9% 0.0007 CK-MB/ Tn+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 et al. TCT 2007.

12. Results: ACUITY PCI: Major Bleeding Long-Term (1-Year) Event Rates P<0.001 for both Manoukian SV et al. TCT 2007.

13. Results: ACUITY PCI: Major Bleeding Long-Term (1-Year) Composite Ischemia Kaplan-Meier Curve 0306090120150180210240270300330360395 0 20 40 10 30 Composite Ischemia (%) Days from Randomization No Major Bleed Major Bleed Observed P (log rank) 17.8% <0.001 34.4% 1 year — Manoukian SV et al. TCT 2007.

14. 0 1 2 3 4 5 6 7 8 9 10 0306090120150180210240270300330360390 Mortality (%) Days from Randomization No major bleed Major bleed Day 30 ± 5 Observed P (log rank) 0.8% <0.001 5.4% — Observed P (log rank) 1.8% <0.0001 7.7% Day 35-395 — Results: ACUITY PCI: Major Bleeding Long-Term (1-Year) Mortality Landmark Analysis Manoukian SV et al. TCT 2007.

15. P-valueRR (95% CI)Risk ratio±95% CI Age >75 (vs. 55-75) Anemia CrCl <60mL/min Diabetes Gender (Female vs. Male) High-risk Hypertension No Prior PCI Prior antithrombotic therapy Treatment (H+GPI vs. BIV) 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) 0.02 2.08 (1.68-2.57) <0.0001 1.42 (1.06-1.90) 0.02 1.33 (1.03-1.70) 0.03 1.47 (1.15-1.88) 0.002 1.23 (0.98-1.55) 0.08 2.08 (1.56-2.76) <0.0001 Results: ACUITY PCI: Predictors of Major Bleeding Manoukian SV et al. TCT 2006.

16. Age≥ 75 years 2.63 (1.92-3.60) <0.0001 Anemia 1.45 (1.07-1.96) 0.016 Baseline CrCl <60mL/min 1.43 (1.03-1.99) 0.033 Diabetes mellitus 1.74 (1.35-2.25) <0.0001 Male 1.46 (1.07-1.98) 0.017 History of CAD 1.97 (1.46-2.65) <0.0001 Baseline ST- deviation ≥1mm1.42 (1.08-1.86)0.011 Baseline cardiac biomarker ↑ 2.05 (1.49-2.81) <0.0001 Revascularization within 30 days 1.70 (1.03-2.81) 0.039 Myocardial infarction within 30 days 2.31 (1.58-3.39) <0.0001 Major bleeding 3.20 (2.28-4.50) <0.0001 Hazard ratio ±95% CI P-valueHR (95% CI) Results: ACUITY PCI: Predictors of Long-Term (1-Year) Mortality Cox model with Major Bleeding, MI and Revasc as time-updated covariates Manoukian SV et al. TCT 2007.

17. Conclusions: ACUITY PCI: Major Bleeding and 1-Year Outcomes 462 patients (5.9%) had major bleeding by 30 days. Patients with major bleeding were (p<0.05): –older, female, lower body weight, diabetes, hypertension, impaired creatinine clearance, ST-changes and/or elevated biomarkers, –less likely to have prior PCI, –more likely to receive GPI, PCI duration >1h, sheath dwell time >6h. 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). Higher 1-year ischemic events (34.4% vs. 17.8%, p<0.001). Predictor of 1-year mortality (HR 3.20, 95% CI 2.28-4.50, p<0.0001). Manoukian SV et al. TCT 2007.