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

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.

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:

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, % CABG Stone GW et al. NEJM 2006;355:

Background: ACUITY Overall: Major Bleeding and Mortality Major Bleeding and Short-Term (30-Day) Mortality Days from Randomization Percent Mortality Patients at Risk Patients with major bleeding: Patients without major bleeding: Log Rank P–Value: < Patients with major bleeding Patients without major bleeding 7.3% 1.2% Manoukian SV et al. J Am Coll Cardiol 2007;49:

Age ≥75 years 2.55 ( ) < Left ventricular ejection fraction ≤50% 2.96 ( ) < Prior stroke 1.94 ( ) <0.05 Baseline ST-segment deviation ≥1mm2.32 ( )< Baseline cardiac biomarker elevation 1.97 ( ) <0.01 Treatment strategy (CABG vs. PCI)3.40 ( )< Myocardial infarction within 30 days 3.96 ( ) < Major bleeding 7.55 ( ) < 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:

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

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

Background: REPLACE-2: Major Bleeding and Mortality Predictors of Long-Term (1-Year) Mortality in PCI Risk FactorHazard Ratio95% CIp-value Age > ( ) Pre-procedural anemia2.12( ) Body mass index vs >251.64( )0.007 Pre-procedural LV ejection fraction ≤50%2.15( ) Congestive heart failure3.58( )< Prior angina2.16( )0.006 Major Bleeding2.66( ) Day MI2.46( ) Day Revascularization3.30( )0.008 Feit F et al. Am J Cardiol 2007 in press. ( Protocol definition: >3g/dL drop in Hgb, intracranial, retroperitoneal, 2U transfusion.

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.

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]< 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%< Prior thienopyridine70.6%68.1% High-risk (ST/biomarkers)83.0%75.9% CK-MB/ Tn+70.0%64.7% Any GPI use83.8%68.0%< Sheath removal time >6h24.4%15.7%< PCI duration >1h20%10.5%< Manoukian SV et al. TCT 2007.

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

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

Mortality (%) Days from Randomization No major bleed Major bleed Day 30 ± 5 Observed P (log rank) 0.8% < % — Observed P (log rank) 1.8% < % Day — Results: ACUITY PCI: Major Bleeding Long-Term (1-Year) Mortality Landmark Analysis Manoukian SV et al. TCT 2007.

P-valueRR (95% CI)Risk ratio±95% CI Age >75 (vs ) 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 ( ) ( ) < ( ) < ( ) ( ) < ( ) ( ) ( ) ( ) ( ) < Results: ACUITY PCI: Predictors of Major Bleeding Manoukian SV et al. TCT 2006.

Age≥ 75 years 2.63 ( ) < Anemia 1.45 ( ) Baseline CrCl <60mL/min 1.43 ( ) Diabetes mellitus 1.74 ( ) < Male 1.46 ( ) History of CAD 1.97 ( ) < Baseline ST- deviation ≥1mm1.42 ( )0.011 Baseline cardiac biomarker ↑ 2.05 ( ) < Revascularization within 30 days 1.70 ( ) Myocardial infarction within 30 days 2.31 ( ) < Major bleeding 3.20 ( ) < 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.

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 , p<0.0001). Manoukian SV et al. TCT 2007.