Randomized controlled trials of aprotinin in cardiac surgery: could clinical equipoise have stopped the bleeding? Clin Trials 2:218-232

Ottawa Health Research Institute, Clinical Epidemiology Program, Ottawa, Ontario, Canada.
Clinical Trials (Impact Factor: 1.93). 02/2005; 2(3):218-29; discussion 229-32. DOI: 10.1191/1740774505cn085oa
Source: PubMed


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.
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.
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 - 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 = 1784), which was 28 times larger than the median trial size.
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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Available from: Brian Hutton, Jan 04, 2014
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    • "Indeed, cases exist in medicine where primary research is shown to be no longer necessary, since combining studies in one synthesis shows significance where individual studies fail to find any. For example, a SR which conducted cumulative meta-analytical techniques on 64 trials investigating the effectiveness of the drug Aprotinin at controlling perioperative bleeding showed that the effectiveness was apparent after only 12 trials (Fergusson et al., 2005). Thus this SR identified 52 unnecessary trials that had a SR been performed after the twelfth study, the treatment effect would have been apparent, duplicate trials would have been avoided, and patients would have experienced the benefit of a useful drug ten years earlier (Freeman et al., 2006). "
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    ABSTRACT: The volume of scientific literature continues to expand and decision-makers are faced with increasingly unmanageable volumes of evidence to assess. Systematic reviews (SRs) are powerful tools that aim to provide comprehensive , transparent, reproducible and updateable summaries of evidence. SR methods were developed, and have been employed, in healthcare for more than two decades, and they are now widely used across a broad range of topics, including environmental management and social interventions in crime and justice, education, international development, and social welfare. Despite these successes and the increasing acceptance of SR methods as a 'gold standard' in evidence-informed policy and practice, misconceptions still remain regarding their applicability. The aim of this article is to separate fact from fiction, addressing twelve common misconceptions that can influence the decision as to whether a SR is the most appropriate method for evidence synthesis for a given topic. Through examples, we illustrate the flexibility of SR methods and demonstrate their suitability for addressing issues on environmental health and chemical risk assessment.
    Environment International 09/2015; DOI:10.1016/j.envint.2015.07.011 · 5.56 Impact Factor
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    • "There were single studies in obstetrics, musculoskeletal disease, kidney disease and gastrointestinal disease. The number of individual research studies in each of the cumulative meta-analyses we identified ranged from 4 trials of continuous versus interrupted techniques for elective midline abdominal fascial closure [12] to more than 60 trials for aprotinin in cardiac surgery [13]. "
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    ABSTRACT: Background “Cumulative meta-analysis” describes a statistical procedure to calculate, retrospectively, summary estimates from the results of similar trials every time the results of a further trial in the series had become available. In the early 1990s, comparisons of cumulative meta-analyses of treatments for myocardial infarction with advice promulgated through medical textbooks showed that research had continued long after robust estimates of treatment effects had accumulated, and that medical textbooks had overlooked strong, existing evidence from trials. Cumulative meta-analyses have subsequently been used to assess what could have been known had new studies been informed by systematic reviews of relevant existing evidence and how waste might have been reduced. Methods and Findings We used a systematic approach to identify and summarise the findings of cumulative meta-analyses of studies of the effects of clinical interventions, published from 1992 to 2012. Searches were done of PubMed, MEDLINE, EMBASE, the Cochrane Methodology Register and Science Citation Index. A total of 50 eligible reports were identified, including more than 1,500 cumulative meta-analyses. A variety of themes are illustrated with specific examples. The studies showed that initially positive results became null or negative in meta-analyses as more trials were done; that early null or negative results were over-turned; that stable results (beneficial, harmful and neutral) would have been seen had a meta-analysis been done before the new trial; and that additional trials had been much too small to resolve the remaining uncertainties. Conclusions This large, unique collection of cumulative meta-analyses highlights how a review of the existing evidence might have helped researchers, practitioners, patients and funders make more informed decisions and choices about new trials over decades of research. This would have led to earlier uptake of effective interventions in practice, less exposure of trial participants to less effective treatments, and reduced waste resulting from unjustified research.
    PLoS ONE 07/2014; 9(7):e102670. DOI:10.1371/journal.pone.0102670 · 3.23 Impact Factor
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    • "The findings about equipoise have clear implications for further research. If there is certainty about the benefits of a clinical intervention, it is regarded as unethical to conduct further evaluation by randomising patients to a usual care control group [21]. Consistent with this principle, there was a high level of agreement that it would be ethically acceptable to conduct further SDD research. "
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    ABSTRACT: Selective decontamination of the digestive tract (SDD) is a prophylactic antibiotic regimen that is not widely used in practice. We aimed to describe the opinions of key 'stakeholders' about the validity of the existing evidence base, likely consequences of implementation, relative importance of their opinions in influencing overall practice, likely barriers to implementation and perceptions of the requirement for further research to inform the decision about whether to embark on a further large randomised controlled trial. This was a Delphi study informed by comprehensive framework of possible determinants of health professionals' behaviour to study Critical Care practice in four countries. There were four key stakeholder participant groups including ICU physicians, pharmacists, clinical leads, and clinical microbiologists/ infectious disease physicians. Round one comprised participant interviews and Rounds two and three were online questionnaires using Delphi method. In this study, 141 participants were recruited of whom 82% were retained. Participants rated themselves as knowledgeable about SDD. Antibiotic resistance was identified as the most important issue. SDD was seen as a low clinical priority but few participants reported strong opposition. There was moderate agreement that research to date has not adequately addressed concerns about antibiotic resistance and lacks generalizability. Participants indicated equipoise with regard to benefits and harms of SDD, and indicated strong support for a further randomised trial. Clinicians have clinical equipoise about the effectiveness of SDD. Future research requires longer follow up to assess antibiotic resistance as well as greater validity/generalizability to provide definitive answers on the effectiveness of decontamination and effects on antibiotic resistance. SDD was regarded as not being a high clinical priority, which may limit future trial participation. These results have identified that a further large randomised controlled trial of SDD in critical care is both warranted and appropriate.
    Critical care (London, England) 11/2013; 17(6):R266. DOI:10.1186/cc13096 · 4.48 Impact Factor
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