Antifibrinolytics,Aspirin and Cardiac Surgery: Evidence,Guidelines and Implications for Current Research

Eikelboom J.W. , Mehta S.R. , Anand S.S. , Xie C. , Fox K.A. , Yusuf S. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006; 114: 774–782.

Ranucci M. , Bozzetti G. , Ditta A. , Cotza M. , Carboni G. , Ballotta A. Surgical reexploration after cardiac operations: why a worse outcome? Ann Thorac Surg 2008; 86: 1557–1562.

Mehta R.H. , Sheng S. , O'Brien S.M. , Grover F.L. , Gammie J.S. , Ferguson T.B. Reoperation for bleeding in patients undergoing coronary artery bypass surgery: incidence, risk factors, time trends, and outcomes. Circ Cardiovasc Qual Outcomes 2009; 2: 583–590.

Myles P.S. , Smith J. , Knight J. , Cooper D.J. , Silbert B. , McNeil J. Aspirin and tranexamic acid for coronary artery surgery (ATACAS) trial: rationale and design. Am Heart J 2008; 155: 224–230.

Mangano D.T. , Tudor I.C. , Dietzel C. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006; 354: 353–365.

Karkouti K. , Beattie W.S. , Dattilo K.M. , McCluskey S.A. , Ghannam M. , Hamdy A. A propensity score case-control comparison of aprotinin and tranexamic acid in high-transfusion-risk cardiac surgery. Transfusion 2006; 46: 327–338.

Royston D. , van Haaften N. , De Vooght P. Aprotinin; friend or foe? A review of recent medical literature. Eur J Anaesthesiol 2007; 24: 6–14.

Myles P.S. Antifibrinolytic therapy: evidence, bias, confounding (and politics!). J Extra Corpor Technol 2007; 39: 308–310.

Fergusson D.A. , Hebert P.C. , Mazer C.D. , Fremes S. , MacAdams C. , Murkin J.M. A comparison of aprotinin and lysine analogues in high-risk cardiac surgery. N Engl J Med 2008; 358: 2319–2331.

Sniecinski R.M. , Chen E.P. , Makadia S.S. , Kikura M. , Bolliger D. , Tanaka K.A. Changing from aprotinin to tranexamic acid results in increased use of blood products and recombinant factor VIIa for aortic surgery requiring hypothermic arrest. J Cardiothorac Vasc Anesth 2010; 24: 959–963.

Ngaage D.L. , Bland J.M. Lessons from aprotinin: is the routine use and inconsistent dosing of tranexamic acid prudent? Meta-analysis of randomised and large matched observational studies. Eur J Cardiothorac Surg 2010; 37: 1375–1383.

Ioannidis J.P.A. Why most published research findings are false. PLoS Med 2005; 2: e124.

Fleming T.R. , Sharples K. , McCall J. , Moore A. , Rodgers A. , Stewart R. Maintaining confidentiality of interim data to enhance trial integrity and credibility. Clin Trials 2008; 5: 157–167.

Fleming T.R. Identifying and addressing safety signals in clinical trials. N Engl J Med 2008; 359: 1400–1402.

Levi M. , Cromheecke M.E. , de Jonge E. , Prins M.H. , de Mol B.J. , Briet E. Pharmacological strategies to decrease excessive blood loss in cardiac surgery: a meta-analysis of clinically relevant endpoints. Lancet 1999; 354: 1940–1947.

Sedrakyan A. , Treasure T. , Elefteriades J.A. Effect of aprotinin on clinical outcomes in coronary artery bypass graft surgery: a systematic review and meta-analysis of randomized clinical trials. J Thorac Cardiovasc Surg 2004; 128: 442–448.

Pocock S.J. When to stop a clinical trial. BMJ 1992; 305: 235–240.

DeMets D.L. , Pocock S.J. , Julian D.G. The agonising negative trend in monitoring of clinical trials. Lancet 1999; 354: 1983–1988.

Henry D. , Carless P. , Fergusson D. , Laupacis A. The safety of aprotinin and lysine-derived antifibrinolytic drugs in cardiac surgery: a meta-analysis. CMAJ 2009; 180: 183–193.

Ferraris V.A. , Brown J.R. , Despotis G.J. , Hammon J.W. , Reece T.B. , Saha S.P. 2011 update to the Society of Thoracic Surgeons and the Society of Cardiovascular Anesthesiologists blood conservation clinical practice guidelines. Ann Thorac Surg 2011; 91: 944–982.

Health Canada. Health Canada decision on Trasylol (apro-tinin). From http://www.hc-sc.gc.ca/dhp-mps/medeff/res/eap-gce_trasylol-eng.php. Accessed July 2012.

European Medicines Agency. Questions and answers on the review of antifibrinolytic medicines (aprotinin, amino-caproic acid and tranexamic acid). From http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_docu-ment/Antifibrinolytic_medicines/WC500122924.pdf. Accessed July 2012.

Martin K. , Wiesner G. , Breuer T. , Lange R. , Tassani P. The risks of aprotinin and tranexamic acid in cardiac surgery: a one-year follow-up of 1188 consecutive patients. Anesth Analg 2008; 107: 1783–1790.

Hunter G.R. , Young G.B. Seizures after cardiac surgery. J Cardiothorac Vasc Anesth 2011; 25: 299–305.

Martin K. , Knorr J. , Breuer T. , Gertler R. , Macguill M. , Lange R. Seizures after open heart surgery: comparison of epsilon-aminocaproic acid and tranexamic acid. J Cardiothorac Vasc Anesth 2011; 25: 20–25.

Manji R.A. , Grocott H.P. , Leake J. , Ariano R.E. , Manji J.S. , Menkis A.H. Seizures following cardiac surgery: the impact of tranexamic acid and other risk factors. Can J Anesth 2012; 59: 6–13.

Goldstone A.B. , Bronster D.J. , Anyanwu A.C. , Goldstein M.A. , Filsoufi F. , Adams D.H. Predictors and outcomes of seizures after cardiac surgery: a multivariable analysis of 2,578 patients. Ann Thorac Surg 2011; 91: 514–518.

Dentz M.E. , Slaughter T.F. , Mark J.B. Early thrombus formation on heparin-bonded pulmonary artery catheters in patients receiving epsilon aminocaproic acid. Anesthesiology 1995; 82: 583–586.

Kluger R. , Olive D.J. , Stewart A.B. , Blyth C.M. Epsilon-aminocaproic acid in coronary artery bypass graft surgery: pre-incision or postheparin? Anesthesiology 2003; 99: 1263–1269.

Lison S. , Dietrich W. , Braun S. , Boehm J. , Schuster T. , Englhard A. Enhanced thrombin generation after cardiopulmonary bypass surgery. Anesth Analg 2011; 112: 37–45.

Ponschab M. , Landoni G. , Biondi-Zoccai G. , Bignami E. , Frati E. , Nicolotti D. Recombinant activated factor VII increases stroke in cardiac surgery: a meta-analysis. J Cardiothorac Vasc Anesth 2011; 25: 804–810.

Kalavrouziotis D. , Voisine P. , Mohammadi S. , Dionne S. , Dagenais F. High-dose tranexamic acid is an independent predictor of early seizure after cardiopulmonary bypass. Ann Thorac Surg 2012; 93: 148–154.

Lecker I. , Orser B.A. , Mazer C.D. “Seizing” the opportunity to understand antifibrinolytic drugs. Can J Anesth 2012; 59: 1–5.

Iplikcioglu A.C. , Berkman M.Z. The effect of short-term anti-fibrinolytic therapy on experimental vasospasm. Surg Neurol 2003; 59: 10–6; discussion 16–7.

Schlag M.G. , Hopf R. , Redl H. Convulsive seizures following subdural application of fibrin sealant containing tranexamic acid in a rat model. Neurosurgery 2000; 47: 1463–1467.

Yeh H.M. , Lau H.P. , Lin P.L. , Sun W.Z. , Mok M.S. Convulsions and refractory ventricular fibrillation after intrathecal injection of a massive dose of tranexamic acid. Anesthesiology 2003; 98: 270–272.

Furtmuller R. , Schlag M.G. , Berger M. , Hopf R. , Huck S. , Sieghart W. Tranexamic acid, a widely used antifibrinolytic agent, causes convulsions by a gamma-aminobutyric acid(A) receptor antagonistic effect. J Pharmacol Exp Ther 2002; 301: 168–173.

Dowd N.P. , Karski J.M. , Cheng D.C. , Carroll J.A. , Lin Y. , James R.L. Pharmacokinetics of tranexamic acid during cardiopul-monary bypass. Anesthesiology 2002; 97: 390–399.

Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy–I: Prevention of death, myocardial infarction, and stroke by prolonged anti-platelet therapy in various categories of patients. BMJ 1994; 308: 81–106.

Alghamdi A.A. , Moussa F. , Fremes S.E. Does the use of preoper-ative aspirin increase the risk of bleeding in patients undergoing coronary artery bypass grafting surgery? Systematic review and meta-analysis. J Card Surg 2007; 22: 247–256.

Sun J.C. , Whitlock R. , Cheng J. , Eikelboom J.W. , Thabane L. , Crowther M.A. The effect of pre-operative aspirin on bleeding, transfusion, myocardial infarction, and mortality in coronary artery bypass surgery: a systematic review of randomized and observational studies. Eur Heart J 2008; 29: 1057–1071.

Sung J.J. , Lau J.Y. , Ching J.Y. , Wu J.C. , Lee Y.T. , Chiu P.W. Continuation of low-dose aspirin therapy in peptic ulcer bleeding: a randomized trial. Ann Intern Med 2010; 152: 1–9.

Cao L. , Young N. , Liu H. , Silvestry S. , Sun W. , Zhao N. Preoperative aspirin use and outcomes in cardiac surgery patients. Ann Surg 2012; 255: 399–404.

Ferraris V.A. , Ferraris S.P. , Moliterno D.J. , Camp P. , Walenga J.M. , Messmore H.L. The Society of Thoracic Surgeons practice guideline series: aspirin and other antiplatelet agents during operative coronary revascularization (executive summary). Ann Thorac Surg 2005; 79: 1454–1461.

Bell A.D. , Roussin A. , Cartier R. , Chan W.S. , Douketis J.D. , Gupta A. The use of antiplatelet therapy in the outpatient setting: Canadian Cardiovascular Society Guidelines Executive Summary. Can J Cardiol 2011; 27: 208–221.

Douketis J.D. , Spyropoulos A.C. , Spencer F.A. , Mayr M. , Jaffer A.K. , Eckman M.H. Perioperative management of antithrom-botic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e326S–50S.

Deja M.A. , Kargul T. , Domaradzki W. , Stacel T. , Mazur W. , Wojakowski W. Effects of preoperative aspirin in coronary artery bypass grafting: a double-blind, placebo-controlled, randomized trial. J Thorac Cardiovasc Surg 2012; 144: 204–209.

Collins R. , MacMahon S. Reliable assessment of the effects of treatment on mortality and major morbidity, I: clinical trials. Lancet 2001; 357: 373–380.

Tunis S.R. , Stryer D.B. , Clancy C.M. Practical clinical trials: increasing the value of clinical research for decision making in clinical and health policy. JAMA 2003; 290: 1624–1632.

Hennekens C.H. , Demets D. The need for large-scale randomized evidence without undue emphasis on small trials, meta-analyses, or subgroup analyses. JAMA 2009; 302: 2361–2362.