The safety of aprotinin and lysine-derived antifibrinolytic drugs in cardiac surgery: a meta-analysis

Abstract

CMAJ ResearchBackground: Because of recent concerns about the safety of aprotinin, we updated our 2007 Cochrane review that compared the relative benefits and risks of aprotinin and the lysine analogues tranexamic acid and epsilon aminocaproic acid. Methods:We searched electronic databases, including CEN-TRAL, MEDLINE, EMBASE, Google and Google Scholar for trials of antifibrinolytic drugs used in adults scheduled for cardiac surgery. Searches were updated to January 2008. By comparing aprotinin and the 2 lysine analogues to control, we derived indirect head-to-head comparisons of aprotinin to the other drugs. We derived direct estimates of risks and benefits by pooling estimates from head-to-head trials of aprotinin and tranexamic acid or epsilon aminocaproic acid. Results:For indirect estimates, we identified 49 trials involving 182 deaths among 7439 participants. The summary relative risk (RR) for death with aprotinin versus placebo was 0.93 (95% confidence interval [CI] 0.69-1.25). In the 19 trials that included tranexamic acid, there were 24 deaths among 1802 participants. The summary RR was 0.55 (95% CI 0.24-1.25). From the risk estimates derived for individual drugs, we calculated an indirect summary RR of death with use of aprotinin versus tranexamic acid of 1.69 (95% CI 0.70-4.10). To calculate direct estimates of death for aprotinin versus tranexamic acid, we identified 13 trials with 107 deaths among 3537 participants. The summary RR was 1.43 (95% CI 0.98-2.08). Among the 1840 participants, the calculated estimates of death for aprotinin compared directly to epsilon aminocaproic acid was 1.49 (95% CI 0.98-2.28). We found no evidence of an increased risk of myocardial infarction with use of aprotinin compared with the lysine analogues in either direct or indirect analyses. Compared with placebo or no treatment, all 3 drugs were effective in reducing the need for red blood cell transfusion. The RR of transfusion with use of aprotinin was 0.66 (95% CI 0.61-0.72). The RR of transfusion was 0.70 (95% CI 0.61-0.80) for tranexamic acid, and it was 0.75 (95% CI 0.58-0.96) for use of epsilon aminocaproic acid. Aprotinin was also effective in reducing the need for reoperation because of bleeding (RR 0.48,. Interpretation:The risk of death tended to be consistently higher with use of aprotinin than with use of lysine analogues. Aprotinin had no clear advantages to offset these harms. Either tranexamic acid or epsilon aminocaproic acid should be recommended to prevent bleeding after cardiac surgery. Une version française de ce résumé est disponible à l'adresse www.cmaj.ca/cgi/content/full/180/2/183/DC1 New information has been provided by the Blood Conservation Using Antifibrinolytics in a Randomized Trial (BART) study, 13 which compared the efficacy and safety of aprotinin and lysine analogues in cardiac surgery patients at high risk of perioperative mortality. This large trial was designed to compare the impact of these drugs with respect to clinically important bleeding outcomes. The trial was stopped premature...

Influência do ácido épsilon aminocapróico no sangramento e na hemotransfusão pós-operatória em cirurgia valvar mitral

“…With the decrease of blood products it can be reduced the risk of infection and transfusion reactions, further supporting the need for the use of EACA. Efficacy of epsilon-aminocaproic acid, among the current options for use of antifibrinolytic agents in relation to the reduction of postoperative bleeding and the need for blood transfusions is questioned and conflicting in many studies literature [19][20][21].…”

Evidence-based practice and health technology assessment: a call for anesthesiologists to engage in knowledge translation

“…Parmi les exemples convaincants d'études randomisées d'apparence contradictoire, citons la question des bêtabloquants administrés en période périopératoire aux patients subissant une chirurgie non cardiaque 7 et l'utilisation de l'aprotinine en chirurgie cardiaque. [8][9][10] L'interprétation de n'importe quelle étude de façon isolée entraînera une simplification excessive et potentiellement dangereuse des avantages et des risques d'une intervention thérapeutique donnée.…”

“…Lorsqu'une comparaison directe des interventions a finalement été rapportée dans l'étude BART, 9 une image plus complète de la base changeante de données probantes est apparue, et l'équilibre global s'est déplacé de « incertain » (intervalles de confiance vastes) à défavorable à l'aprotinine (intervalles de confiance serrés, révélant une importante nocivité); il a été observé que ce médicament augmentait de façon significative le risque de décès, même s'il réduisait le besoin de transfusion sanguine. 9,10 É valuation des technologies de la santé: un complément à la médecine fondée sur des données probantes Pour se concentrer sur l'application de données probantes au patient individuel, il devrait également y avoir un cadre guidant la prise de décision pour des groupes de patients et qui reconnaisse les contraintes du « monde réel » de la prestation de soins de santé. Nous vivons à une époque de décisions qui sont de plus en plus motivées par les politiques en matière de santé: la prise de décision pour garantir que les devenirs de santé sont optimisés pour toutes les populations de patients avec un ensemble donné de ressources (ressources humaines, infrastructure, temps, argent).…”

“…Compelling examples of apparently contradictory randomized trials include the issue of beta-blockers given perioperatively for patients undergoing noncardiac surgery 7 and the use of aprotinin for cardiac surgery. [8][9][10] Interpretation of any trial in isolation will lead to a potentially risky oversimplification of the risks and benefits of a given therapeutic intervention.…”

“…Even though aprotinin reduced the need for blood transfusion, this drug significantly increased the risk of death. 9,10 Health technology assessment: complementary to EBM Since EBM is focused on applying evidence to the individual patient, there should also be a framework to guide decision-making for groups of patients while also recognizing the ''real world'' constraints of healthcare delivery. This is an era of decisions that are driven increasingly by health policy, i.e., decision-making to ensure that health outcomes are maximized across patient populations within a given set of resources (human resources, infrastructure, time, money).…”