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  1. Major Bleeding is Associated with Increased Short-Term Mortality and Ischemic Complications in Non-ST Elevation Acute Coronary Syndromes:The ACUITY TrialSteven 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. Stone41Emory University School of Medicine, Atlanta, GA2New York University School of Medicine, New York, NY3University of California Los Angeles, Los Angeles, CA4Columbia University Medical Center, New York, NY5The Cleveland Clinic, Cleveland, OH6Fuqua Heart Center, Atlanta, GA

  2. 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 Consultant (modest)

  3. 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.

  4. Background: OASIS Registry, OASIS-2, and CUREMajor Bleeding is Associated with Increased Mortality in ACS Eikelboom JW et al. Circulation 2006;114:774-782.

  5. Background: The REPLACE-2 Trial (N=6010)Major Bleeding is Increased with Abciximab and Eptifibatide vs. Bivalirudin in PCI Major Bleeding 2.2% vs. 4.1%, p=0.0021 Major Bleeding 2.5% vs. 4.0%, p=0.0251 4.0% 4.1% 2.5% 2.2% Voeltz MD, Lincoff AM, Feit F, Manoukian SV. Circulation 2005;112(17):II-737.

  6. Background: The REPLACE-2 Trial (N=6010)Predictors of One-Year Mortality in PCI Protocol definition: >3g/dL drop in HgB, intracranial, retroperitoneal, 2U transfusion Voeltz MD, Patel AD, Feit F, et al. Am J Cardiol, in press.

  7. 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.

  8. Medical management UFH or Enoxaparin + GP IIb/IIIa PCI Bivalirudin + GP IIb/IIIa Angiography within 72h R* Bivalirudin Alone CABG Methods: The ACUITY Trial (N=13819) First Randomization Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy 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.

  9. UFH or Enoxaparin Medical management Routine upstream GPI in all pts GPI started in CCL for PCI only PCI Bivalirudin Routine upstream GPI in all pts R R GPI started in CCL for PCI only Bivalirudin Alone CABG Methods: The ACUITY Trial (N=13819) Second Randomization Moderate and high risk unstable angina or NSTEMI undergoing an invasive strategy 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.

  10. P (log rank) Estimate UFH/Enoxaparin + IIb/IIIa (N=4603) 11.7% 0.89 Bivalirudin + IIb/IIIa (N=4604) 11.8% 0.014 Bivalirudin alone (N=4612) 10.1% Methods: The ACUITY Trial (N=13819) Overall Net Clinical OutcomeComposite Endpoint 15 UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone 10 Cumulative Events (%) 5 0 0 5 10 15 20 25 30 35 Days from Randomization ACUITY Trial. Stone GW. ACC 2006.

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

  12. 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.

  13. 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.

  14. Results: The ACUITY Trial (N=13819)Major Bleeding and Baseline Characteristics Manoukian SV, Voeltz MD, Feit F et al. AHA 2006.

  15. Results: The ACUITY Trial (N=13819)Major Bleeding (Non-CABG Related) Stone GW. ACC 2006. Values in yellow = P<0.05

  16. 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.

  17. 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.

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

  19. Results: The ACUITY Trial (N=13819)Predictors of Major Bleeding Risk ratio ± 95% CI RR (95% CI) P-value Manoukian SV, Voeltz MD, Feit F et al. AHA 2006.

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

  21. Results: The ACUITY Trial PCI Population (N=7789)Predictors of Major Bleedingin the PCI Population Risk ratio ± 95% CI RR (95% CI) P-value Manoukian SV, Voeltz MD, Feit F et al. TCT 2006.

  22. Results: The ACUITY Trial (N=13819)Predictors of Mortality at 30 Days Manoukian SV, Feit F, Mehran R, et al. Unpublished.

  23. 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.

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