Transfusion is Associated with Increased 30-Day Mortality and Ischemic Complications in Non-ST Elevation Acute Coronary Syndromes: The ACUITY Trial Steven V. Manoukian1, Michele D. Voeltz1, Frederick Feit2, Roxana Mehran3, George D. Dangas3, Eugenia Nikolsky3, A. Michael Lincoff4, Spencer B. King5, III, E. Magnus Ohman6, Gregg W. Stone3 1Emory University School of Medicine, Atlanta, GA 2New York University School of Medicine, New York, NY 3Columbia University Medical Center, New York, NY 4The Cleveland Clinic, Cleveland, OH 5Fuqua Heart Center, Atlanta, GA 6Duke University Medical Center, Durham, NC

Relevant Conflict of Interest Statement 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 Consultant Speaker sanofi aventis/BMS

Background: Transfusion in ACS and PCI Blood product transfusion is an important complication in acute coronary syndromes (ACS) and percutaneous coronary intervention (PCI) patients treated with potent antithrombotic and antiplatelet agents. Recent data suggest that transfusion is associated with an increase in adverse outcomes in ACS and PCI, including mortality. We assessed the impact of transfusion on mortality and ischemic events in patients with ACS from the ACUITY Trial. Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

806 patients (13.4%) classified as elderly, >75 years of age. Background: The REPLACE-2 Trial Transfusion and Major Bleeding are More Frequent in Elderly Patients Undergoing PCI 806 patients (13.4%) classified as elderly, >75 years of age. p<0.0001 p=0.0001 = Not Elderly, <75 = Elderly, >75 Voeltz MD, Lincoff AM, Feit F, Manoukian SV. Circulation 2005;112(17):II-613.

Background: The REPLACE-2 Trial Transfusion and Mortality in PCI Non-transfused Transfused *p<0.0001 Manoukian SV, Voeltz MD, Attubato MJ, Bittl JA, Feit F, Lincoff AM. CRT 2005.

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

Background: GUSTO IIb, PURSUIT, PARAGON B Transfusion and 30-Day Mortality in ACS Rao SV et al. JAMA 2004;292:1555-1562.

Adjusted for transfusion propensity Background: GUSTO IIb, PURSUIT, PARAGON B Transfusion and 30-Day Mortality in ACS 1.0 10 -4.0 Adjusted for transfusion propensity Adjusted for baseline characteristics Characteristics, bleeding propensity, transfusion Propensity, & nadir HCT 3.77 (3.14, 4.52) 3.54 (2.96, 4.23) 3.94 (3.26, 4.75) (N=24111) *Transfusion as a time-dependent covariate Rao SV et al. JAMA 2004;292:1555-1562.

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. We evaluated outcomes in patients who received transfusion (non-CABG-related) within 30 days of randomization. Manoukian SV, Voeltz MD, Feit F et al. TCT 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 ACUITY Design. 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 Ischemic Endpoints PSup = 0.32 PSup = 0.34 PSup = 0.35 PSup = 0.78 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 ACUITY Trial. Stone GW. ACC 2006.

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.

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 ACUITY Trial. Stone GW. ACC 2006.

319 (2.3%) of 13819 patients had transfusion by 30 days. Results: The ACUITY Trial (N=13819) Transfusion (non-CABG-related) in ACS 319 (2.3%) of 13819 patients had transfusion by 30 days. Patients with transfusion were (p<0.05): older, female, non-smokers, and had lower body weight, diabetes, hypertension, impaired creatinine clearance, elevated biomarkers, and high-risk (ST-changes or elevated biomarkers). more likely to receive pre-treatment with a thienopyridine. more likely to have a >4h randomization to angiography time. Transfusion was less frequent for: Bivalirudin vs. Heparin(s) + GPI (1.6% vs. 2.7%, p<0.0001), Bivalirudin vs. Bivalirudin + GPI (1.6% vs. 2.6%, p<0.0001). Transfusion was associated with higher 30-day mortality and ischemic event rates. Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

Age (median [range], yrs) 72 [38-95] 63 [20-93] <0.0001 Female Results: The ACUITY Trial (N=13819) Transfusion and Baseline Characteristics Transfusion (N=319, 2.3%) No Transfusion (N=13500, 97.7%) P-value Age (median [range], yrs) 72 [38-95] 63 [20-93] <0.0001 Female 56.1% 29.5% Weight (median [IQR], kg) 76 [66-90] 84 [73-95] Diabetes 43.8% 27.7% Hypertension 80.9% 66.7% Current smoker 21.5% 29.3% 0.0027 Prior CABG 22% 17.8% 0.0527 CrCl ≥ 60 ml/min 51% 81.6% Prior thienopyridine 69.3% 63.8% 0.0478 High-risk (ST / biomarkers) 79.5% 72.1% 0.0041 CK-MB / Troponin+ 65.2% 59.3% 0.0382 Random Angiogram >4h 60.8% 53.7% 0.0117 Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

Results: The ACUITY Trial (N=13819) Transfusion by Treatment Strategy P<0.001 P=ns ACUITY Trial. Stone GW. ACC 2006.

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

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

(D/MI/unplanned revasc) 29.2% 7.1% Results: The ACUITY Trial (N=13819) Transfusion, Ischemic Endpoints, and Mortality Transfusion (N=319, 2.3%) No Transfusion (N=13500, 97.7%) P-value Death 11.0% 1.3% <0.0001 Composite ischemia (D/MI/unplanned revasc) 29.2% 7.1% Death/MI 26.0% 5.8% MI 18.8% 4.8% Non-Q wave 13.8% 3.8% Q wave 5.3% 0.9% Unplanned revascularization 9.4% 2.3% Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

Results: The ACUITY Trial Predictors of Transfusion 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 Heparin(s) + GPI (vs. Bivalirudin) 1.420 (1.055-1.910) 0.0060 3.764 (2.919-4.855) <0.0001 2.097 (1.568-2.803) 1.560 (1.209-2.014) 2.233 (1.739-2.867) 1.754 (1.297-2.372) 0.0003 1.457 (1.051-2.020) 0.0241 1.728 (1.256-2.379) 0.0007 Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

Factors associated with an increase in the risk of transfusion: Conclusion: The ACUITY Trial (N=13819) Transfusion in Patients with ACS Transfusion is associated with increased 30-day mortality and ischemic event rates in patients with ACS undergoing an invasive strategy. Bivalirudin results in lower transfusion rates compared to GPI-based strategies. Factors associated with an increase in the risk of transfusion: age, female gender, diabetes, hypertension, chronic kidney disease, anemia; high-risk presentation; treatment with heparin(s) + GPI. Knowledge of these factors is important in the assessment of the transfusion risk of, and decision-making for an individual patient. Minimizing transfusion risk is paramount in order to optimize outcomes in this setting. Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.