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Randomized controlled trials of aprotinin in cardiac surgery: could clinical equipoise have stopped the bleeding?

Ottawa Health Research Institute, Clinical Epidemiology Program, Ottawa, Ontario, Canada; Clinical Trials Research Group, McGill University, Montreal, Quebec, Canada dafergusson{at}ohri.ca

Kathleen Cranley Glass

Clinical Trials Research Group, McGill University, Montreal, Quebec, Canada; Departments of Human Genetics and Pediatrics and Biomedical Ethics Unit, McGill University, Montreal, Quebec, Canada

Brian Hutton

Ottawa Health Research Institute, Clinical Epidemiology Program, Ottawa, Ontario, Canada

Stan Shapiro

Clinical Trials Research Group, McGill University, Montreal, Quebec, Canada; Departments of Human Genetics and Pediatrics and Biomedical Ethics Unit, McGill University, Montreal, Quebec, Canada; Department of Epidemiology and Biostatistics, McGill University, Montreal, Quebec, Canada

Background Aprotinin is a serine protease inhibitor used to limit perioperative bleeding and reduce the need for donated blood transfusions during cardiac surgery. Randomized controlled trials of aprotinin evaluating its effect on the outcome of perioperative transfusion have been published since 1987, and systematic reviews were conducted in 1992 and 1997.

Methods A systematic search was conducted for all RCTs of aprotinin that used placebo controls or were open-label with no active control treatment. Data collected included the primary outcome, objective of each study, whether a systematic review was cited or conducted as part of the background and/or rationale for the study and the number of previously published RCTs cited. Cumulative meta-analyses were performed.

Results Sixty-four randomized, controlled trials of aprotinin were found, conducted between 1987 and 2002, reporting an endpoint of perioperative transfusion. Median trial size was 64 subjects, with a range of 20 to 1784. A cumulative meta-analysis indicated that aprotinin greatly decreased the need for perioperative transfusion, stabilizing at an odds ratio of 0.25 (p, 10 2 6) by the 12th study, published in June of 1992. The upper limit of the confidence interval never exceeded 0.65 and results were similar in all subgroups. Citation of previous RCTs was extremely low, with a median of 20% of prior trials cited. Only 7 of 44 (15%) of subsequent reports referenced the largest trial (N ¹/4 1784), which was 28 times larger than the median trial size.

Conclusions This study demonstrates that investigators evaluating aprotinin were not adequately citing previous research, resulting in a large number of RCTs being conducted to address efficacy questions that prior trials had already definitively answered. Institutional review boards and journals could reduce the number of redundant trials by requiring investigators to conduct adequate searches for prior evidence and conducting systematic reviews.

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