Katharine Ker

Effect of tranexamic acid on surgical bleeding: systematic review and cumulative meta-analysis

Objective To assess the effect of tranexamic acid on blood transfusion, thromboembolic events, and mortality in surgical patients. Design Systematic review and meta-analysis. Data sources Cochrane central register of controlled trials, Medline, and Embase, from inception to September 2011, the World Health Organization International Clinical Trials Registry Platform, and the reference lists of relevant articles. Study selection Randomised controlled trials comparing tranexamic acid with no tranexamic acid or placebo in surgical patients. Outcome measures of interest were the number of patients receiving a blood transfusion; the number of patients with a thromboembolic event (myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism); and the number of deaths. Trials were included irrespective of language or publication status. Results 129 trials, totalling 10 488 patients, carried out between 1972 and 2011 were included. Tranexamic acid reduced the probability of receiving a blood transfusion by a third (risk ratio 0.62, 95% confidence interval 0.58 to 0.65; P<0.001). This effect remained when the analysis was restricted to trials using adequate allocation concealment (0.68, 0.62 to 0.74; P<0.001). The effect of tranexamic acid on myocardial infarction (0.68, 0.43 to 1.09; P=0.11), stroke (1.14, 0.65 to 2.00; P=0.65), deep vein thrombosis (0.86, 0.53 to 1.39; P=0.54), and pulmonary embolism (0.61, 0.25 to 1.47; P=0.27) was uncertain. Fewer deaths occurred in the tranexamic acid group (0.61, 0.38 to 0.98; P=0.04), although when the analysis was restricted to trials using adequate concealment there was considerable uncertainty (0.67, 0.33 to 1.34; P=0.25). Cumulative meta-analysis showed that reliable evidence that tranexamic acid reduces the need for transfusion has been available for over 10 years. Conclusions Strong evidence that tranexamic acid reduces blood transfusion in surgery has been available for many years. Further trials on the effect of tranexamic acid on blood transfusion are unlikely to add useful new information. However, the effect of tranexamic acid on thromboembolic events and mortality remains uncertain. Surgical patients should be made aware of this evidence so that they can make an informed choice.

Traffic calming for the prevention of road traffic injuries: systematic review and meta-analysis

Objective: To assess whether area-wide traffic calming schemes can reduce road crash related deaths and injuries. Design: Systematic review and meta-analysis. Data sources: Cochrane Injuries Group Specialised Register, Cochrane Central Register of Controlled Trials, Medline, EMBASE, Sociological Abstracts Science (and social science) citation index, National Technical Information service, Psychlit, Transport Research Information Service, International Road Research Documentation, and Transdoc, and web sites of road safety organisation were searched; experts were contacted, conference proceedings were handsearched, and relevant reference lists were checked. Inclusion criteria: Randomised controlled trials, and controlled before/after studies of area-wide traffic calming schemes designed to discourage and slow down through traffic on residential roads. Methods: Data were collected on road user deaths, injuries, and traffic crashes. For each study rate ratios were calculated, the ratio of event rates before and after intervention in the traffic calmed area divided by the corresponding ratio of event rates in the control area, which were pooled to give an overall estimate using a random effects model. Findings: Sixteen controlled before/after studies met our inclusion criteria. Eight studies reported the number of road user deaths: pooled rate ratio 0.63 (95% confidence interval (CI) 0.14 to 2.59). Sixteen studies reported the number of injuries (fatal and non-fatal): pooled rate ratio 0.89 (95% CI 0.80 to 1.00). All studies were in high income countries. Conclusion: Area-wide traffic calming in towns and cities has the potential to reduce road traffic injuries. However, further rigorous evaluations of this intervention are needed, especially in low and middle income countries.

Avoidable mortality from giving tranexamic acid to bleeding trauma patients: an estimation based on WHO mortality data, a systematic literature review and data from the CRASH-2 trial

BackgroundThe CRASH-2 trial showed that early administration of tranexamic acid (TXA) safely reduces mortality in bleeding in trauma patients. Based on data from the CRASH-2 trial, global mortality data and a systematic literature review, we estimated the number of premature deaths that might be averted every year worldwide through the use of TXA.MethodsWe used CRASH-2 trial data to examine the effect of TXA on death due to bleeding by geographical region. We used WHO mortality data (2008) and data from a systematic review of the literature to estimate the annual number of in-hospital trauma deaths due to bleeding. We then used the relative risk estimates from the CRASH-2 trial to estimate the number of premature deaths that could be averted if all hospitalised bleeding trauma patients received TXA within one hour of injury, and within three hours of injury. Sensitivity analyses were used to explore the effect of uncertainty in the parameter estimates and the assumptions made in the model.ResultsThere is no evidence that the effect of TXA on death due to bleeding varies by geographical region (heterogeneity p = 0.70). Based on WHO data and our systematic literature review, we estimate that each year worldwide there are approximately 400,000 in-hospital trauma deaths due to bleeding. If patients received TXA within one hour of injury then approximately 128,000 (uncertainty range [UR] ≈ 72,000 to 172,000) deaths might be averted. If patients received TXA within three hours of injury then approximately 112,000 (UR ≈ 68,000 to 148,000) deaths might be averted. Country specific estimates show that the largest numbers of deaths averted would be in India and China.ConclusionsThe use of TXA in the treatment of traumatic bleeding has the potential to prevent many premature deaths every year. A large proportion of the potential health gains are in low and middle income countries.

The knowledge system underpinning healthcare is not fit for purpose and must change

The medical literature is biased and inundated with poor quality trials. Ian Roberts and colleagues explain how these problems affect systematic reviews and how they might be overcome

How systematic reviews cause research waste.

In the Lancet Series on Research, Iain Chalmers and colleagues argue that waste could be avoided if all research was preceded by a systematic assessment of the existing evidence. We agree in principle, but contend that many systematic reviews, by including small unreliable trials, increase waste by promoting underpowered trials. Eff orts by Cochrane and others to locate all trials have meant that many low-quality, single-centre trials, often with inaccuracies, are easily accessible. Most meta-analyses are dominated by such trials. The median number of trials in Cochrane reviews is six to 16, and the median number of patients per trial is about 80. Inclusion of such trials in meta-analyses results in infl ated treatment eff ects. Small trials are prone to publication and other selection biases, are often low quality, and, because single-centre trials have less oversight than multicentre trials, they are more susceptible to misconduct. Systematic reviews of small trials increase waste by advertising to the scientifi c community infl ated, often significant treatment effects that become smaller or absent when large, high-quality trials are done. Effect estimates from systematic reviews often inform sample size calculations. However, because most reviews provide exaggerated estimates of treatment effects due to inclusion of small, poor-quality trials, new trials will be underpowered to detect modest but potentially important effects. Because small trials that show no evidence of benefi t are less likely to be published, a cycle of large eff ects and small trials is established. To ignore results from small trials and postulate plausible treatment eff ects that would be clinically worthwhile would be preferable. Failure of systematic reviews to acknowledge the unreliability of small, single-centre trials should raise concerns about the value for money provided by reviews. More than 10 years ago, UK National Institute for Health Research-funded research questioned the value of time-consuming and costly searches to identify trials in the grey literature and foreign language databases in view of the low quality of the identified trials. Even for trials in established databases, the poor quality of small trials and the unreliability of their reporting does not warrant the rigour with which their results are extracted, synthesised, rated, and graded. However, despite evidence showing that meta-analyses of small trials are unreliable, the systematic review community, including Cochrane, does reviews much as it did 20 years ago. Quality is assessed, but everything that purports to be a randomised trial is included. Chalmers and Glasziou estimate that around 85% of investment in health research is wasted. However, the negative emotions provoked by such losses can lead to an escalation of commitment that only worsens the loss—known as the sunk cost fallacy. Attempts by the systematic review community to extract valid information from small, poor-quality trials is an example of this fallacy. Small trials that are poorly undertaken and reported are an indefensible waste of resources and an abuse of the altruism of trial participants, but the damage has been done. Employing legions of reviewers to pick through the detritus in the hope of extracting morsels of useful information might not be the best use of resources.

Effect of treatment delay on the effectiveness and safety of antifibrinolytics in acute severe haemorrhage: a meta-analysis of individual patient-level data from 40 138 bleeding patients

Summary Background Antifibrinolytics reduce death from bleeding in trauma and post-partum haemorrhage. We examined the effect of treatment delay on the effectiveness of antifibrinolytics. Methods We did an individual patient-level data meta-analysis of randomised trials done with more than 1000 patients that assessed antifibrinolytics in acute severe bleeding. We identified trials done between Jan 1, 1946, and April 7, 2017, from MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, PubMed, Popline, and the WHO International Clinical Trials Registry Platform. The primary measure of treatment benefit was absence of death from bleeding. We examined the effect of treatment delay on treatment effectiveness using logistic regression models. We investigated the effect of measurement error (misclassification) in sensitivity analyses. This study is registered with PROSPERO, number 42016052155. Findings We obtained data for 40 138 patients from two randomised trials of tranexamic acid in acute severe bleeding (traumatic and post-partum haemorrhage). Overall, there were 3558 deaths, of which 1408 (40%) were from bleeding. Most (884 [63%] of 1408) bleeding deaths occurred within 12 h of onset. Deaths from post-partum haemorrhage peaked 2–3 h after childbirth. Tranexamic acid significantly increased overall survival from bleeding (odds ratio [OR] 1·20, 95% CI 1·08–1·33; p=0·001), with no heterogeneity by site of bleeding (interaction p=0·7243). Treatment delay reduced the treatment benefit (p<0·0001). Immediate treatment improved survival by more than 70% (OR 1·72, 95% CI 1·42–2·10; p<0·0001). Thereafter, the survival benefit decreased by 10% for every 15 min of treatment delay until 3 h, after which there was no benefit. There was no increase in vascular occlusive events with tranexamic acid, with no heterogeneity by site of bleeding (p=0·5956). Treatment delay did not modify the effect of tranexamic acid on vascular occlusive events. Interpretation Death from bleeding occurs soon after onset and even a short delay in treatment reduces the benefit of tranexamic acid administration. Patients must be treated immediately. Further research is needed to deepen our understanding of the mechanism of action of tranexamic acid. Funding UK NIHR Health Technology Assessment programme, Pfizer, BUPA Foundation, and J P Moulton Charitable Foundation (CRASH-2 trial). London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation (WOMAN trial).

Beta‐2 Receptor Antagonists for Traumatic Brain Injury: A Systematic Review of Controlled Trials in Animal Models

A systematic review and meta‐analysis of controlled trials was undertaken to assess the effects of beta‐2 receptor antagonists in animal models of traumatic brain injury (TBI). Database and reference list searches were performed to identify eligible studies. Outcome data were extracted on functional status, as measured by the grip test or neurological severity score (NSS), and cerebral edema, as measured by brain water content (BWC). Data were pooled using the random‐effects model. Seventeen controlled trials involving 817 animals were identified. Overall methodological quality was poor. Results from the grip test suggest that the treatment group maintained grip for a longer period than the control group; pooled weighted mean difference (WMD) = 8.28 (95% CI 5.78–10.78). The treatment group was found to have a lower NSS (i.e., better neurological function); pooled WMD =−3.28 (95% CI −4.72 to −1.85). Analysis of the cerebral edema data showed that the treatment group had a lower BWC than the control; pooled WMD =−0.42 (95% CI −0.59 to −0.26). There was evidence of statistical heterogeneity between comparisons for all outcomes. Evidence for small study effects was found for the grip test and BWC outcomes. The evidence from animal models of TBI suggests that beta‐2 receptor antagonists can improve functional outcome and lessen cerebral edema. However, the poor methodological quality of the included studies and presence of small study effects may have influenced these findings.

Road safety in low- and middle-income countries: a neglected research area

It is estimated that each year between 20 and 50 million people are disabled and 1.2 million people die as a result of road traffic crashes, with 90% of the deaths occurring in low- and middle-income countries (LMICs).1 Furthermore, whereas a decrease in deaths has been observed in high-income countries, this is not the case in LMICs, where deaths are projected to increase by 80% over the next 20 years to become the second leading cause in the global burden of disease ranking.1 The identification and implementation of effective preventive interventions are essential for tackling this growing epidemic. Systematic reviews of the evidence are vital for identifying and quantifying the effects of interventions, and their findings should have a …

How effective are some common treatments for traumatic brain injury

Surveys show that mannitol, hyperventilation, cerebrospinal fluid drainage, and barbiturates are commonly used in the United Kingdom, Europe, and the United States to treat traumatic brain injury.1 2 3 Yet the effects of such treatments are uncertain. Traumatic brain injury is a major cause of death and disability worldwide. Every year at least 10 million people sustain a traumatic brain injury serious enough to result in death or admission to hospital.4 Bearing in mind that almost half of all patients with traumatic brain injury experience long term disability5 6 and that most injury occurs in young adults, the medical, social, and financial burden is clear. The Cochrane Injuries Group maintains a specialised register of randomised controlled trials of interventions for traumatic brain injury and has searched extensively for trials evaluating the effects of mannitol, hyperventilation, cerebrospinal fluid drainage, and barbiturates. The group has also prepared, and regularly updates, systematic reviews to assess the effects of barbiturates,7 hyperventilation,8 and mannitol.9 In 1998 the Cochrane Injuries Group highlighted the absence of reliable evidence for the effectiveness of these four treatments10 when searches identified only three small trials of barbiturates,11 12 …

How effective is tranexamic acid for acute gastrointestinal bleeding

Acute gastrointestinal bleeding is a common emergency. It encompasses upper gastrointestinal bleeding (such as from peptic ulcers and oesophageal varices)1 and lower gastrointestinal bleeding (commonly from diverticular disease, colitis, and cancer).2 The risk is greater in older adults, and many cases are associated with the use of non-steroidal anti-inflammatory drugs.3 In the UK acute gastrointestinal bleeding accounts for about 75 000 hospital admissions each year and has a case fatality of about 10%.3 4 Case fatality may be higher in patients already hospitalised for another condition.1 More effective treatments for acute gastrointestinal bleeding are needed. Tranexamic acid (TXA) reduces clot breakdown by inhibiting the action of plasmin, which is involved in fibrinolysis. A systematic review of randomised controlled trials in surgical patients shows that TXA, given before or during surgery, reduces the probability of receiving a blood transfusion by about a third (relative risk 0.62, 95% confidence interval 0.58 to 0.65).5 The effect of tranexamic acid on thromboembolic events such as myocardial infarction, stroke, deep vein thrombosis, and pulmonary embolism, however, was uncertain.5 The CRASH-2 trial showed that administration of TXA to bleeding trauma patients reduced death due to bleeding (relative risk 0.85, 0.76 to 0.96) and all cause mortality (relative risk 0.91, 0.85 to 0.97) with no apparent increase in thromboembolic events.6 Among patients treated soon after injury, the reduction in mortality with TXA was even greater.7 The knowledge that TXA reduces bleeding in surgery and reduces mortality in trauma …