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Dennis T. Mangano, PhD, MD; Yinghui Miao, MD, MPH; Alain Vuylsteke, MD; Iulia C. Tudor, PhD; Rajiv Juneja, MD; Daniela Filipescu, MD; Andreas Hoeft, MD; Manuel L. Fontes, MD; Zak Hillel, PhD, MD; Elisabeth Ott, MD; Tatiana Titov, MD, PhD; Cynthia Dietzel, MD; Jack Levin, MD; for the Investigators of The Multicenter Study of Perioperative Ischemia Research Group and the Ischemia Research and Education Foundation

JAMA. 2007;297:471-479.

Context  Acute safety concerns have been raised recently regarding certain hemorrhage-sparing medications commonly used in cardiac surgery. However, no comprehensive data exist regarding their associations with long-term mortality.

Objective  To contrast long-term all-cause mortality in patients undergoing coronary artery bypass graft (CABG) surgery according to use of 2 lysine analog antifibrinolytics (aminocaproic acid and tranexamic acid), the serine protease inhibitor aprotinin, or no antibleeding agent.

Design, Setting, and Participants  Observational study of mortality conducted between November 11, 1996, and December 7, 2006. Following index hospitalization (4374 patients; 69 medical centers), survival was prospectively assessed at 6 weeks, 6 months, and annually for 5 years after CABG surgery among 3876 patients enrolled in a 62-center international cohort study. The associations of survival with hemorrhage-sparing medications were compared using multivariable analyses including propensity adjustments.

Main Outcome Measure  Death (all-cause) over 5 years.

Results  Aprotinin treatment (223 deaths among 1072 patients [20.8% 5-year mortality]) was associated with significantly increased mortality compared with control (128 deaths among 1009 patients [12.7%]; covariate adjusted hazard ratio for death, 1.48; 95% confidence interval, 1.19-1.85), whereas neither aminocaproic acid (132 deaths among 834 patients [15.8%]; adjusted hazard ratio for death, 1.03; 95% confidence interval, 0.80-1.33) nor tranexamic acid (65 deaths among 442 patients [14.7%]; adjusted hazard ratio for death, 1.07; 95% confidence interval, 0.80-1.45) was associated with increased mortality. In multivariable logistic regression, either with propensity adjustment or without, aprotinin was independently predictive of 5-year mortality (adjusted odds ratio with propensity adjustment, 1.48; 95% confidence interval, 1.13-1.93; P = .005) among patients with diverse risk profiles, as well as among those surviving their index hospitalization. Neither aminocaproic nor tranexamic acid was associated with increased risk of death.

Conclusions  These findings indicate that in addition to the previously reported acute renal and vascular safety concerns, aprotinin use is associated with an increased risk of long-term mortality following CABG surgery. Use of aprotinin among patients undergoing CABG surgery does not appear prudent because safer and less expensive alternatives (ie, aminocaproic acid and tranexamic acid) are available.

Author Affiliations: Ischemia Research and Education Foundation, San Bruno, Calif (Drs Mangano, Miao, Titov, and Dietzel); Department of Anesthesia, Papworth Hospital, Cambridge, England (Dr Vuylsteke); Department of Anesthesia, Escorts Heart Institute, New Delhi, India (Dr Juneja); Department of Cardiac Anesthesia and Intensive Care, Institute of Cardiology, Bucharest, Romania (Dr Filipescu); Klinik und Poliklinik für Anaesthesiologie und Spezielle Intensivmedizin, University of Bonn, Bonn, Germany (Dr Hoeft); Department of Anesthesiology, Yale University, New Haven, Conn (Dr Fontes); Department of Cardiac Anesthesia, St Luke's Roosevelt Hospital, New York, NY (Dr Hillel); Institut für Anaesthesiologie, Ludwig-Maximilians Universität, Munich, Germany (Dr Ott); Department of Laboratory Medicine, University of California School of Medicine, San Francisco (Dr Levin). Dr Tudor is now with ALZA Corporation, Mountain View, Calif, and Dr Fontes is now with Weill Medical College of Cornell University, New York, NY.

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ACC/AHA 2007 Guidelines on Perioperative Cardiovascular Evaluation and Care for Noncardiac Surgery: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines on Perioperative Cardiovascular Evaluation for Noncardiac Surgery) Developed in Collaboration With the American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Rhythm Society, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society for Vascular Medicine and Biology, and Society for Vascular Surgery
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