1.
The efficacy and safety of topical tranexamic acid: A systematic review and meta-analysis
Montroy J, Hutton B, Moodley P, Fergusson N A, Cheng W, Tinmouth A, Lavallee L T, Fergusson D A, Breau R H
Transfusion Medicine Reviews. 2018
Abstract
Tranexamic acid (TXA) is an effective hemostatic agent used for the reduction of blood loss and transfusion. However, the safety profile of TXA remains in question due to a potential increased risk of venous thromboembolism. By applying TXA topically as opposed to intravenously, systemic absorption may be reduced and unwanted side-effects mitigated. The objective of our review is to investigate the efficacy and safety of topically applied tranexamic acid compared to both placebo, and the intravenous administration. Cochrane Central Register of Controlled Trials, MEDLINE, Embase, ISI Web of Science, PubMed, and Clinicaltrials.gov were searched from inception to November, 2016. We included randomized controlled trials that compared topical tranexamic acid to either placebo (or standard care) or intravenous administration, in adult patients. Surgical and non-surgical trials were included. Abstract, full-text selection, data extraction and risk of bias assessment were all performed in duplicate. In total, 67 studies involving 6,034 patients met inclusion criteria. The majority of trials evaluated orthopedic procedures. Compared to placebo, the administration of topical TXA significantly reduced the odds of receiving a blood transfusion (pooled OR 0.28, 95% CI 0.20 to 0.38; P < 0.001) and significantly reduced mean blood loss (WMD -276.6, 95% CI -327.8 to -225.4; P < 0.0001). When compared to the intravenous administration, there was no difference between the two groups in terms of transfusion requirements (pooled OR 1.03, 95% CI 0.72 to 1.46; P=0.88) or blood loss (WMD -21.95, 95% CI -66.61 to 27.71; P=0.34). There was no difference in the odds of developing a venous thromboembolic complication between the topical TXA and control groups (pooled OR=0.78, 95% CI 0.47 to 1.29; P=0.33) or the topical and intravenous groups (pooled OR=0.75, 95% CI 0.39 to 1.46; P=0.40). The topical application of TXA effectively reduces both transfusion risk and blood loss compared to placebo, without increasing thromboembolic risks. There were no major differences between topical and intravenous tranexamic acid with respect to safety and efficacy, and both were superior to placebo with regards to blood loss and transfusion requirements. Further study of the topical application is required outside of the field of orthopedics.
2.
The safety and efficacy of lysine analogues in cancer patients: a systematic review and meta-analysis
Montroy J, Fergusson NA, Hutton B, Lavalle LT, Morash C, Cagiannos I, Cnossen S, Fergusson DA, Breau RH
Canadian Society of Transfusion Medicine. 2017;:39.. 89.
3.
Risks of harms using antifibrinolytics in cardiac surgery: systematic review and network meta-analysis of randomised and observational studies
Hutton B, Joseph L, Fergusson D, Mazer CD, Shapiro S, Tinmouth A
Bmj.. 2012;345:e5798.
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Abstract
OBJECTIVE To estimate the relative risks of death, myocardial infarction, stroke, and renal failure or dysfunction between antifibrinolytics and no treatment following the suspension of aprotinin from the market in 2008 for safety reasons and its recent reintroduction in Europe and Canada. DESIGN Systematic review and network meta-analysis. DATA SOURCES A Cochrane review of antifibrinolytic treatments was chosen as the starting point for this systematic review. Medline, Embase, and the Cochrane register of trials were searched with no date restrictions for observational evidence. STUDY SELECTION Propensity matched or adjusted observational studies with two or more of the interventions of interest (aprotinin, tranexamic acid, epsilon-aminocaproic acid, and no treatment) that were carried out in patients undergoing cardiac surgery. DATA ANALYSIS Network meta-analysis was used to compare treatments, and odds ratios with 95% credible intervals were estimated. Meta-analyses were carried out for randomised controlled trials alone and for randomised controlled trials with observational studies. RESULTS 106 randomised controlled trials and 11 observational studies (43 270 patients) were included. Based on the results from analysis of randomised controlled trials, tranexamic acid was associated on average with a reduced risk of death compared with aprotinin (odds ratio 0.64, 95% credible interval 0.41 to 0.99). When observational data were incorporated, comparisons showed an increased risk of mortality with aprotinin on average relative to tranexamic acid (odds ratio 0.71, 95% credible interval 0.50 to 0.98) and epsilon-aminocaproic acid (0.60, 0.43 to 0.87), and an increased risk of renal failure or dysfunction on average relative to all comparators: odds ratio 0.66 (95% credible interval 0.45 to 0.88) compared with no treatment, 0.66 (0.48 to 0.91) versus tranexamic acid, and 0.65 (0.45 to 0.88) versus epsilon-aminocaproic acid. CONCLUSION Although meta-analyses of randomised controlled trials were largely inconclusive, inclusion of observational data suggest concerns remain about the safety of aprotinin. Tranexamic and epsilon-aminocaproic acid are effective alternatives that may be safer for patients.
4.
Randomized controlled trials of aprotinin in cardiac surgery: could clinical equipoise have stopped the bleeding?
Fergusson D, Glass KC, Hutton B, Shapiro S
Clinical Trials. 2005;2((3):):218-29; Discussion 229-32.
Abstract
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 - 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. 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.