Major Bleeding is Associated with Increased Short-Term Mortality and Ischemic Complications in Non-ST Elevation Acute Coronary Syndromes: The ACUITY Trial Steven V. Manoukian1, Michele D. Voeltz1, Frederick Feit2, Ramin Ebrahimi3,Roxana Mehran4, Eugenia Nikolsky4, Jeffrey W. Moses4, A. Michael Lincoff5, Spencer B. King, III6, Gregg W. Stone4 1Emory University School of Medicine, Atlanta, GA 2New York University School of Medicine, New York, NY 3University of California Los Angeles, Los Angeles, CA 4Columbia University Medical Center, New York, NY 5The Cleveland Clinic, Cleveland, OH 6Fuqua Heart Center, Atlanta, GA

Presenter Disclosure Information 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, FACC The Medicines Co. Research Support (modest) Consultant (modest) Speaker (modest) sanofi aventis/BMS

Background: The ACUITY Trial (N=13819) Major Bleeding in ACS and PCI Major bleeding is a significant complication of non-ST elevation acute coronary syndromes (NSTE-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 short-term mortality and ischemic events in patients with moderate and high-risk NSTE-ACS undergoing an invasive strategy. Manoukian SV, Voeltz MD, Feit F et al. AHA 2006.

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.

Background: The REPLACE-2 Trial (N=6010) 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% 4.1% 2.5% 2.2% Voeltz MD, Lincoff AM, Feit F, Manoukian SV. Circulation 2005;112(17):II-737.

Pre-procedural Anemia 30-Day Revascularization Background: The REPLACE-2 Trial (N=6010) Predictors of One-Year Mortality in PCI Variable OR (95%CI) p-value Age ≥ 75 2.28 (1.51, 3.46) 0.0001 Pre-procedural Anemia 2.12 (1.49, 3.13) 0.0002 BMI > 25 (vs. 20-25) 0.61 (0.40, 0.99) 0.007 Pre-procedure LVEF ≤ 50% 2.15 (1.44, 3.21) CHF 3.58 (2.27, 5.65) <.0001 Prior Angina 2.16 (1.25, 3.75) 0.006 Major Bleeding 2.66 (1.44, 4.92) 0.002 30-Day MI 2.46 (1.44, 4.20) 0.001 30-Day Revascularization 3.30 (1.36, 8.00) 0.008 Protocol definition: >3g/dL drop in HgB, intracranial, retroperitoneal, 2U transfusion Voeltz MD, Patel AD, Feit F, et al. Am J Cardiol, in press.

Methods: The ACUITY Trial (N=13819) Study Design and Definitions The ACUITY Trial was a randomized comparison of: (1) bivalirudin alone (BIV), (2) heparin or enoxaparin + glycoprotein inhibition (H+GPI), (3) BIV + glycoprotein inhibition (BIV+GPI), in moderate and high-risk NSTE-ACS. Major bleeding (non-CABG-related) was defined as: intracranial, intraocular, or retroperitoneal; access site bleed with intervention; hematoma >5cm; Hgb drop >3g/dL with source or >4g/dL without source; or transfusion. Manoukian SV, Voeltz MD, Feit F et al. AHA 2006.

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

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

Days from Randomization Methods: The ACUITY Trial (N=13819) Overall Net Clinical Outcome Composite Endpoint 15 UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone 10 Cumulative Events (%) 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% 5 5 10 15 20 25 30 35 Days from Randomization ACUITY Trial. Stone GW. ACC 2006.

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

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

644 (4.7%) of 13819 patients had major bleeding. Results: The ACUITY Trial (N=13819) Major Bleeding (Non-CABG Related) in ACS 644 (4.7%) of 13819 patients had major bleeding. Patients with major bleeding were (p<0.05): older, more likely to be female, of lower body weight, and have diabetes, hypertension, and impaired creatinine clearance, more likely to present with elevated cardiac biomarkers or as high-risk (ST-changes or elevated biomarkers), less likely to use tobacco and have prior PCI. Major bleeding was less frequent in patients treated with: Bivalirudin vs. Heparin(s) + GPI (3.0% vs. 5.7%, p<0.0001), Bivalirudin vs. Bivalirudin + GPI (3.0% vs. 5.3%, p<0.0001). Major bleeding was associated with higher 30-day mortality and ischemic event rates. Manoukian SV, Voeltz MD, Feit F et al. AHA 2006.

Major Bleeding (N=644, 4.7%) No Major Bleeding (N=13,175, 95.3%) Results: The ACUITY Trial (N=13819) Major Bleeding and Baseline Characteristics Major Bleeding (N=644, 4.7%) No Major Bleeding (N=13,175, 95.3%) P-value Age (median [range], yrs) 69 [37-95] 62 [20-93] <0.0001 Female 49.4% 29.1% Weight (median [IQR], kg) 79.5 [68-92] 84 [73-95] Diabetes 34.5% 27.8% 0.0002 Hypertension 73.3% 66.7% 0.0005 CrCl ≥ 60 ml/min 62.7% 81.8% Current smoker 24.7% 29.3% 0.0126 Prior PCI 29.0% 37.8% High risk (ST / biomarkers) 82.0% 71.8% CK-MB / Troponin + 68.1% 59% Manoukian SV, Voeltz MD, Feit F et al. AHA 2006.

Results: The ACUITY Trial (N=13819) Major Bleeding (Non-CABG Related) UFH/Enoxaparin + GP IIb/IIIa (N=4,603) Bivalirudin + GP IIb/IIIa (N=4,604) Bivalirudin alone (N=4,612) Any major bleeding 5.7% 5.3% 3.0% Intracranial 0.07% 0.04% Retroperitoneal 0.5% 0.6% 0.2% Access site 2.5% 0.8% - req interv/surgery 0.3% - hematoma ≥5 cm 2.2% 0.7% Hgb  ≥3 g/dL with overt source 1.8% 1.0% Hgb  ≥4 g/dL with no overt source Blood transfusion 2.7% 2.6% 1.6% Reoperation for bleed 0.1% Stone GW. ACC 2006. Values in yellow = P<0.05

Results: The ACUITY Trial (N=13819) Major Bleeding, Ischemic Endpoints, and Mortality P<0.0001 for all Manoukian SV, Voeltz MD, Feit F et al. AHA 2006.

Results: The ACUITY Trial (N=13819) Major Bleeding and Myocardial Infarction P<0.0001 for all Manoukian SV, Voeltz MD, Feit F et al. AHA 2006.

(D/MI/unplanned revasc) 23.1% 6.8% Results: The ACUITY Trial (N=13819) Major Bleeding, Ischemic Endpoints, and Mortality Major Bleeding (N=644, 4.7%) No Major Bleeding (N=13175, 95.3%) P-value Death 7.3% 1.2% <0.0001 Composite ischemia (D/MI/unplanned revasc) 23.1% 6.8% Death/MI 19.4% 5.6% MI 14.6% 4.6% Non-Q wave 10.6% 3.8% Q wave 4.2% 0.9% Unplanned revascularization 7.6% 2.2% Manoukian SV, Voeltz MD, Feit F et al. AHA 2006.

Results: The ACUITY Trial (N=13819) Predictors of Major Bleeding Risk ratio ± 95% CI RR (95% CI) P-value Age >75 (vs. 55-75) Anemia CrCl <60mL/min Diabetes Female gender High-risk (ST / biomarkers) Hypertension No prior PCI Heparin(s) + GPI (vs. Bivalirudin) 1.51 (1.21-1.89) <0.0001 1.88 (1.54-2.29) 1.54 (1.24-1.90) 1.21 (1.00-1.46) 0.052 1.90 (1.59-2.26) 1.67 (1.32-2.11) 1.23 (1.00-1.52) 0.0476 1.36 (1.11-1.67) 0.0028 2.04 (1.62-2.56) Manoukian SV, Voeltz MD, Feit F et al. AHA 2006.

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

High-risk (ST / biomarkers) Hypertension No prior PCI Results: The ACUITY Trial PCI Population (N=7789) Predictors of Major Bleeding in the PCI Population Risk ratio ± 95% CI RR (95% CI) P-value Age >75 (vs. 55-75) Anemia CrCl <60mL/min Diabetes Female gender High-risk (ST / biomarkers) Hypertension No 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) 1.30 (1.03-1.63) 0.0248 2.08 (1.68-2.57) 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) Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

Results: The ACUITY Trial (N=13819) Predictors of Mortality at 30 Days Predictors of Mortality at 30 Days in The ACUITY Trial Variable OR 95% CI p-value Age > 75 years 2.55 1.68-3.87 <0.0001 LVEF < 50% 2.96 1.99-4.39 Prior CVA 1.94 1.09-3.44 0.024 ECG Changes 2.32 1.54-3.50 Elevated Cardiac Markers 1.97 1.23-3.17 0.005 MI (within 30 days) 3.96 2.45-6.42 Major Bleeding 7.55 4.68-12.18 PCI (vs. CABG) 0.29 0.18-0.47 Manoukian SV, Feit F, Mehran R, et al. Unpublished.

An increased risk of major bleeding is associated with: Conclusion: The ACUITY Trial (N=13819) Major Bleeding in Patients with ACS Major bleeding is associated with increased short-term mortality and ischemic event rates. Bivalirudin results in lower rates of major bleeding compared to GPI-based strategies. An increased risk of major bleeding is associated with: baseline factors: age, female gender, chronic kidney disease, anemia, hypertension, no prior PCI; presentation factors: high-risk presentation; treatment factors: treatment with heparin(s) + GPI. Knowledge of these findings is important in the assessment of the hemorrhagic risk of, and decision-making for each patient. Prevention of major bleeding is essential in order to minimize rates of short-term mortality and ischemic events in NSTE-ACS. Manoukian SV, Voeltz MD, Feit F et al. AHA 2006.