Are antifibrinolytic drugs equivalent in reducing blood loss and transfusion in cardiac surgery? A meta-analysis of randomized head-to-head trials

Paul A Carless,Annette J Moxey,Barrie J Stokes,David A Henry

doi:10.1186/1471-2261-5-19

Paul A Carless, Annette J Moxey + Show 2 more

Open Access

https://doi.org/10.1186/1471-2261-5-19

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Abstract

BackgroundAprotinin has been shown to be effective in reducing peri-operative blood loss and the need for re-operation due to continued bleeding in cardiac surgery. The lysine analogues tranexamic acid (TXA) and epsilon aminocaproic acid (EACA) are cheaper, but it is not known if they are as effective as aprotinin.MethodsStudies were identified by searching electronic databases and bibliographies of published articles. Data from head-to-head trials were pooled using a conventional (Cochrane) meta-analytic approach and a Bayesian approach which estimated the posterior probability of TXA and EACA being equivalent to aprotinin; we used as a non-inferiority boundary a 20% increase in the rates of transfusion or re-operation because of bleeding.ResultsPeri-operative blood loss was significantly greater with TXA and EACA than with aprotinin: weighted mean differences were 106 mls (95% CI 37 to 227 mls) and 185 mls (95% CI 134 to 235 mls) respectively. The pooled relative risks (RR) of receiving an allogeneic red blood cell (RBC) transfusion with TXA and EACA, compared with aprotinin, were 1.08 (95% CI 0.88 to 1.32) and 1.14 (95% CI 0.84 to 1.55) respectively. The equivalent Bayesian posterior mean relative risks were 1.15 (95% Bayesian Credible Interval [BCI] 0.90 to 1.68) and 1.21 (95% BCI 0.79 to 1.82) respectively. For transfusion, using a 20% non-inferiority boundary, the posterior probabilities of TXA and EACA being non-inferior to aprotinin were 0.82 and 0.76 respectively. For re-operation the Cochrane RR for TXA vs. aprotinin was 0.98 (95% CI 0.51 to 1.88), compared with a posterior mean Bayesian RR of 0.63 (95% BCI 0.16 to 1.46). The posterior probability of TXA being non-inferior to aprotinin was 0.92, but this was sensitive to the inclusion of one small trial.ConclusionThe available data are conflicting regarding the equivalence of lysine analogues and aprotinin in reducing peri-operative bleeding, transfusion and the need for re-operation. Decisions are sensitive to the choice of clinical outcome and non-inferiority boundary. The data are an uncertain basis for replacing aprotinin with the cheaper lysine analogues in clinical practice. Progress has been hampered by small trials and failure to study clinically relevant outcomes.

Highlights

Aprotinin has been shown to be effective in reducing peri-operative blood loss and the need for re-operation due to continued bleeding in cardiac surgery
Studies were eligible for inclusion if they were randomized parallel-group trials, evaluated the drugs as prophylactic interventions in the context of adult elective cardiac surgery, involved the intravenous administration of the trial agents during the pre and/or intra-operative period, and included in their study outcomes the numbers of individuals who received allogeneic red blood cell (RBC) transfusions, or the volume of allogeneic RBCs received by subjects in the intervention groups
Head-to-head trials involving comparisons of aprotinin tranexamic acid (TXA) and epsilon aminocaproic acid (EACA) in elective adult cardiac surgery, which reported information on the main outcomes of interest [6,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38]

Summary

Introduction

Aprotinin has been shown to be effective in reducing peri-operative blood loss and the need for re-operation due to continued bleeding in cardiac surgery. The lysine analogues tranexamic acid (TXA) and epsilon aminocaproic acid (EACA) are cheaper, but it is not known if they are as effective as aprotinin. A popular approach is to minimize perioperative bleeding through the prophylactic use of the antifibrinolytic agents aprotinin, tranexamic acid (TXA), and epsilon aminocaproic acid (EACA) [8]. The benchmark compound, is the most widely used and best established antifibrinolytic medication. It is a non-specific broad-spectrum serine protease inhibitor mainly derived from bovine lungs [9]. TXA and EACA are synthetic lysine analogues, which act principally by blocking lysine binding sites on plasminogen molecules, inhibiting plasmin formation and thereby fibrinolysis [10]

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