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

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

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.

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= Major Bleeding 2.2% vs. 4.1%, p= % 2.5% 2.2% 4.1% Voeltz MD, Lincoff AM, Feit F, Manoukian SV. Circulation 2005;112(17):II-737.

Background: The REPLACE-2 Trial Major Bleeding is Associated with Increased Mortality in Elderly Patients Undergoing PCI = Yes = No p< 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.

Background: The REPLACE-2 Trial Predictors of One-Year Mortality in PCI Risk FactorOdds Ratio95% CIp-value Treatment Group (BIV vs. H+GPI) to Age > to Congestive Heart Failure to 5.032< Pre-procedure LV function <35% to Diabetes Mellitus to Prior Angina to Baseline Creatinine Clearance to Major Bleeding to Day Revascularization to Day MI to IABP to 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.

Moscucci M et al. Eur Heart J 2003;24: 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

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

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 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.

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

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

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.

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.

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

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

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.

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]< Female48.3%25.5%< Weight (median [IQR], kg)78.3 [68-93]84 [74-96]< Diabetes35.2%27.1% Hypertension73.8%65.5% Current smoker27.4%31.1% Prior PCI30.3%39.2% CrCl ≥ 60 ml/min62.3%82.8%< High-risk (ST / biomarkers)83.0%75.9% CK-MB / Troponin+70.0%64.7% Any GPI use83.8%68.0%< Sheath removal time >6h24.4%15.7%< PCI duration >1h20%10.5%< Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

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

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

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

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% < Composite ischemia (D/MI/unplanned revasc) 24.2%7.8% < Death/MI20.1%6.1% < MI17.1%5.5% < Non-Q wave12.6%4.8% < Q wave4.8%0.8% < Unplanned revascularization 9.3%3.0% < Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

Results: The ACUITY Trial PCI Population Predictors of Major Bleeding VariableEstimate95% CIP-value Age >75 (vs ) Female gender < Diabetes Hypertension CrCl <60mL/min < Anemia < Prior PCI High-risk (ST / biomarkers) Prior antithrombotic therapy Heparin (s) + GPI ( vs. Bivalirudin) < Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

P-valueRR (95% CI)Risk ratio ± 95% CI Results: The ACUITY Trial PCI Population Predictors of Major Bleeding Age >75 (vs ) Anemia CrCl <60mL/min Diabetes Female gender High-risk (ST / biomarkers) Hypertension Prior PCI Prior antithrombotic therapy Heparin(s) + GPI (vs. Bivalirudin) 1.56 ( ) ( ) < ( ) < ( ) ( ) < ( ) ( ) ( ) ( ) ( ) < Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

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.