Tranexamic acid for the prevention of postpartum bleeding: Protocol for a systematic review and individual patient data meta-analysis.

BACKGROUND: Tranexamic acid (TXA) reduces the risk of death and is recommended as a treatment for women with severe postpartum bleeding. There is hope that giving TXA shortly before or immediately after birth could prevent postpartum bleeding. Extending the use of TXA to prevent harmful postpartum bleeding could improve outcomes for millions of women; however we must carefully consider the balance of benefits and potential harms. This article describes the protocol for a systematic review and individual patient data (IPD) meta-analysis to assess the effectiveness and safety of TXA for preventing postpartum bleeding in all women giving birth, and to explore how the effects vary by underlying risk and other patient characteristics.   Methods: We will search for prospectively registered, randomised controlled trials involving 500 patients or more assessing the effects of TXA in women giving birth. Two authors will extract data and assess risk of bias. IPD data will be sought from eligible trials. Primary outcomes will be life-threatening bleeding and thromboembolic events. We will use a one-stage model to analyse the data. Subgroup analyses will be conducted to explore whether the effectiveness and safety of TXA varies by underlying risk, type birth, maternal haemoglobin (Hb), and timing of TXA. This protocol is registered on PROSPERO (CRD42022345775).  Conclusions: This systematic review and IPD meta-analysis will address important clinical questions about the effectiveness and safety of the use of TXA for the prevention of postpartum bleeding that cannot be answered reliably using aggregate data and will inform the decision of who to treat.   PROSPERO registration: CRD42022345775  Keywords   Anti-fibrinolytics; Tranexamic acid; childbirth; postpartum haemorrhage; meta-analysis.

Tranexamic acid for gastrointestinal bleeding: can a reduction in the risk of death be discounted? A systematic review and meta-analysis of individual patient data from 64 724 bleeding patients.

OBJECTIVES: HALT-IT was an international, randomised trial which assessed the effects of tranexamic acid (TXA) in 12 009 patients with gastrointestinal (GI) bleeding. The results found no evidence that TXA reduces death. It is widely accepted that results of trials should be interpreted in the context of other relevant evidence. We conducted a systematic review and individual patient data (IPD) meta-analysis to assess if the results of HALT-IT are compatible with evidence for TXA in other bleeding conditions. DESIGN: Systematic review and IPD meta-analysis of randomised trials involving ≥5000 patients assessing TXA for bleeding. We searched our Antifibrinolytics Trials Register on 1 November 2022. Two authors extracted data and assessed risk of bias. DATA SYNTHESIS: We used a one-stage model to analyse IPD in a regression model stratified by trial. We assessed heterogeneity of the effect of TXA on death within 24 hours and vascular occlusive events (VOEs). RESULTS: We included IPD for 64 724 patients from four trials involving patients with traumatic, obstetric and GI bleeding. Risk of bias was low. There was no evidence for heterogeneity between trials for the effect of TXA on death or for the effect of TXA on VOEs. TXA reduced the odds of death by 16% (OR=0.84, 95% CI: 0.78 to 0.91, p<0.0001; p-heterogeneity=0.40). In patients treated within 3 hours of bleeding onset, TXA reduced the odds of death by 20% (0.80, 0.73 to 0.88, p<0.0001; p-heterogeneity=0.16). TXA did not increase the odds of VOEs (0.94, 0.81 to 1.08, p for effect=0.36; p-heterogeneity=0.27). CONCLUSIONS: There is no evidence for statistical heterogeneity between trials assessing the effect of TXA on death or VOEs in different bleeding conditions. When the HALT-IT results are considered in the context of other evidence, a reduction in the risk of death cannot be discounted. TRIAL REGISTRATION NUMBER: PROSPERO CRD42019128260.Cite Now.

A cost-effectiveness and value of information analysis to inform future research of tranexamic acid for older adults experiencing mild traumatic brain injury.

BACKGROUND: Tranexamic acid reduces head injury deaths in patients with CT scan evidence of intracranial bleeding after mild traumatic brain injury (TBI). However, the cost-effectiveness of tranexamic acid for people with mild TBI in the pre-hospital setting, prior to CT scanning, is uncertain. A large randomised controlled trial (CRASH-4) is planned to address this issue, but the economic justification for it has not been established. The aim of the analysis was to estimate the likelihood of tranexamic acid being cost-effective given current evidence, the treatment effects required for cost-effectiveness, and the expected value of performing further research. METHODS: An early economic decision model compared usual care for mild TBI with and without tranexamic acid, for adults aged 70 and above. The evaluation was performed from a UK healthcare perspective over a lifetime time horizon, with costs reported in 2020 pounds (GBP) and outcomes reported as quality-adjusted life years (QALYs). All analyses used a £20,000 per QALY cost-effectiveness threshold. RESULTS: In the base case analysis, tranexamic acid was associated with an incremental cost-effectiveness ratio of £4885 per QALY gained, but the likelihood of it being cost-effective was highly dependent on the all-cause mortality treatment effect. The value of perfect information was £22.4 million, and the value of perfect information for parameters that could be collected in a trial was £21.9 million. The all-cause mortality risk ratio for tranexamic acid and the functional outcomes following TBI had the most impact on cost-effectiveness. CONCLUSIONS: There is a high degree of uncertainty in the cost-effectiveness of tranexamic acid for older adults experiencing mild TBI, meaning there is a high value of performing future research in the UK. The value in a global context is likely to be far higher.

Fármacos antifibrinolíticos para tratar la hemorragia posparto primaria / Antifibrinolytic drugs for treating primary postpartum hemorrhage

No disponible

Effect of tranexamic acid by baseline risk of death in acute bleeding patients: a meta-analysis of individual patient-level data from 28 333 patients.

BACKGROUND: Early administration of the antifibrinolytic drug tranexamic acid reduces death from bleeding in trauma and postpartum haemorrhage. We examined how the effectiveness and safety of antifibrinolytic drugs varies by the baseline risk of death as a result of bleeding. METHODS: We performed an individual patient-level data meta-analysis of randomised trials including more than 1000 patients that assessed antifibrinolytics in acute severe bleeding. We identified trials performed between January 1, 1946 and July 5, 2018 (PROSPERO, number 42016052155). RESULTS: Two randomised trials were selected where 28 333 patients received tranexamic acid treatment within 3 h after the onset of acute bleeding. Baseline characteristics to estimate the risk of death as a result of bleeding were divided into four categories: Low (0-5%), intermediate (6-10%), high (11-20%), and very high (>20%). Most patients had a low baseline risk of death as a result of bleeding (23 008 [81%]). Deaths as a result of bleeding occurred in all baseline risk categories with 240 (1%), 202 (8%), 232 (14%), and 357 (30%) deaths in the low-, intermediate-, high-, and very high-risk categories, respectively. The effectiveness of tranexamic acid did not vary by baseline risk when given within 3 h after bleeding onset (P=0.51 for interaction term). There was no increased risk of vascular occlusive events with tranexamic acid and it did not vary by baseline risk categories (P=0.25). CONCLUSIONS: Tranexamic acid appears to be safe and effective regardless of baseline risk of death. Because many deaths are in patients at low and intermediate risk, tranexamic acid use should not be restricted to the most severely injured or bleeding patients.

Tranexamic acid for post-partum haemorrhage: What, who and when.

Tranexamic acid reduces bleeding by inhibiting the breakdown of blood clots. It is cost-effective and heat-stable with a long shelf life. In the WOMAN trial, tranexamic acid reduced deaths due to bleeding with no increase in thromboembolic events. The effect was greatest when women received tranexamic acid within 3 h of childbirth (RR = 0.69, 95% CI 0.52-0.91). The WHO recommends that women with post-partum haemorrhage receive 1 g tranexamic acid intravenously as soon as possible after giving birth, followed by a second dose if bleeding continues after 30 min or restarts within 24 h since the first dose. Urgent treatment is critical because women with post-partum haemorrhage bleed to death quickly, and tranexamic acid is most effective when given early. Evidence suggests there is no benefit when the drug is given more than 3 h after bleeding onset. Alternative routes of administration and use of tranexamic acid in the prevention of post-partum haemorrhage are research priorities.

Tranexamic acid for the prevention of postpartum bleeding in women with anaemia: study protocol for an international, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Postpartum haemorrhage (PPH) is responsible for about 100,000 maternal deaths every year, most of which occur in low- and middle-income countries. Tranexamic acid (TXA) reduces bleeding by inhibiting the enzymatic breakdown of fibrin blood clots. TXA decreases blood loss in surgery and reduces death due to bleeding after trauma. When given within 3 h of birth, TXA reduces deaths due to bleeding in women with PPH. However, for many women, treatment of PPH is too late to prevent death. Over one third of pregnant women in the world are anaemic and many are severely anaemic. These women have an increased risk of PPH and suffer more severe outcomes if PPH occurs. There is an urgent need to identify a safe and effective way to reduce postpartum bleeding in anaemic women. METHODS/DESIGN: The WOMAN-2 trial is an international, multicentre, randomised, double-blind, placebo-controlled trial to quantify the effects of TXA on postpartum bleeding in women with moderate or severe anaemia. Ten thousand women with moderate or severe anaemia who have given birth vaginally will be randomised to receive 1 g of TXA or matching placebo by intravenous injection immediately (within 15 min) after the umbilical cord is cut or clamped. The primary outcome is the proportion of women with a clinical diagnosis of primary PPH. The cause of PPH will be described. Data on maternal health and wellbeing, maternal blood loss and its consequences, and other health outcomes will be collected as secondary outcomes. The main analyses will be on an 'intention-to-treat' basis, irrespective of whether the allocated treatment was received. Results will be presented as appropriate effect estimates with a measure of precision (95% confidence intervals). Subgroup analyses will be based on the severity of anaemia (moderate versus severe) and type of labour (induced or augmented versus spontaneous). A study with 10,000 patients will have over 90% power to detect a 25% relative reduction from 10 to 7.5% in PPH. The trial will be conducted in hospitals in Africa and Asia. DISCUSSION: The WOMAN-2 trial should provide reliable evidence for the effects of TXA for preventing postpartum bleeding in women with anaemia. TRIAL REGISTRATION: ISRCTN, ISRCTN62396133 . Registered on 7 December 2017; ClincalTrials.gov, ID: NCT03475342 . Registered on 23 March 2018.

Outcome measures in clinical trials of treatments for acute severe haemorrhage.

BACKGROUND: Acute severe haemorrhage is a common complication of injury, childbirth, surgery, gastrointestinal pathologies and other medical conditions. Bleeding is a major cause of death, but patients also die from non-bleeding causes, the frequency of which varies by the site of haemorrhage and between populations. Because patients can bleed to death within hours, established interventions inevitably take priority over randomisation into a trial. These circumstances raise challenges in selecting appropriate outcome measures for clinical trials of haemostatic interventions. MAIN BODY: We use data from three large randomised controlled trials in acute severe haemorrhage (CRASH-2, WOMAN and HALT-IT) to explore the strengths and limitations of outcome measures commonly used in trials of haemostatic treatments, including all-cause and cause-specific mortality, blood transfusion and surgical interventions. Many deaths following acute severe haemorrhage are due to patient comorbidities or complications rather than bleeding. If non-bleeding deaths are unaffected by a haemostatic intervention, even large trials will have low power to detect an effect on all-cause mortality. Due to the dilution from deaths unaffected or reduced by the trial treatment, all-cause mortality can also obscure important harmful effects. Additionally, because the relative contributions of different causes of death vary within and between patient populations, all-cause mortality is not generalisable. Different causes of death occur at different time intervals from bleeding onset, with bleeding deaths generally occurring early. Time-specific mortality can therefore be used as a proxy for cause in un-blinded trials where bias is a concern or in situations where cause of death cannot be assessed. Urgent treatment is critical, and so post-randomisation blood transfusion and surgery are often planned before or at the time of randomisation and therefore cannot be influenced by the trial treatment. CONCLUSIONS: All-cause mortality has low power, lacks generalisability and can obscure harmful effects. Cause-specific mortality, such as death due to bleeding or thrombosis, avoids these drawbacks. In certain scenarios, time-specific mortality can be used as a proxy for cause-specific mortality. Blood transfusion and surgical procedures have limited utility as outcome measures in trials of haemostatic treatments.

Antifibrinolytic drugs for treating primary postpartum haemorrhage.

BACKGROUND: Postpartum haemorrhage (PPH) - heaving bleeding within the first 24 hours after giving birth - is one of the main causes of death of women after childbirth. Antifibrinolytics, primarily tranexamic acid (TXA), have been shown to reduce bleeding in surgery and safely reduces mortality in trauma patients with bleeding without increasing the risk of adverse events.An earlier Cochrane review on treatments for primary PPH covered all the various available treatments - that review has now been split by types of treatment. This new review concentrates only on the use of antifibrinolytic drugs for treating primary PPH. OBJECTIVES: To determine the effectiveness and safety of antifibrinolytic drugs for treating primary PPH. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (28 May 2017) and reference lists of retrieved studies. SELECTION CRITERIA: Randomised controlled trials (RCTs), including cluster-randomised trials of antifibrinolytic drugs (aprotinin, TXA, epsilon-aminocaproic acid (EACA) and aminomethylbenzoic acid, administered by whatever route) for primary PPH in women.Participants in the trials were women after birth following a pregnancy of at least 24 weeks' gestation with a diagnosis of PPH, regardless of mode of birth (vaginal or caesarean section) or other aspects of third stage management.We have not included quasi-randomised trials, or cross-over studies. Studies reported as abstracts have not been included if there was insufficient information to allow assessment of risk of bias.In this review we only identified studies looking at TXA. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data from each study using an agreed form. We entered data into Review Manager software and checked for accuracy.For key review outcomes, we rated the quality of the evidence as 'high', 'moderate', 'low' or 'very low' according to the GRADE approach. MAIN RESULTS: Three trials (20,412 women) met our inclusion criteria. Two trials (20,212 women) compared intravenous (IV) TXA with placebo or standard care and were conducted in acute hospital settings (labour ward, emergency department) (in high-, middle- and low-income countries).One other trial (involving 200 women) was conducted in Iran and compared IV TXA with rectal misoprostol, but did not report on any of this review's primary or GRADE outcomes. There were no trials that assessed EACA, aprotinin or aminomethylbenzoic acid.Standard care plus IV TXA for the treatment of primary PPH compared with placebo or standard care aloneTwo trials (20,212 women) assessed the effect of TXA for the treatment of primary PPH compared with placebo or standard care alone. The larger of these (The WOMAN trial) contributed over 99% of the data and was assessed as being at low risk of bias. The quality of the evidence varied for different outcomes, Overall, evidence was mainly graded as moderate to high quality.The data show that IV TXA reduces the risk of maternal death due to bleeding (risk ratio (RR) 0.81, 95% confidence interval (CI) 0.65 to 1.00; two trials, 20,172 women; quality of evidence: moderate). The quality of evidence was rated as moderate due to imprecision of effect estimate. The effect was more evident in women given treatment between one and three hours after giving birth with no apparent reduction when given after three hours (< one hour = RR 0.80, 95% CI 0.55 to 1.16; one to three hours = RR 0.60, 95% CI 0.41 to 0.88; > three hours = RR 1.07, 95% 0.76 to 1.51; test for subgroup differences: Chi² = 4.90, df = 2 (P = 0.09), I² = 59.2%). There was no heterogeneity in the effect by mode of birth (test for subgroup differences: Chi² = 0.01, df = 1 (P = 0.91), I² = 0%). There were fewer deaths from all causes in women receiving TXA, although the 95% CI for the effect estimate crosses the line of no effect (RR 0.88, 95% CI 0.74 to 1.05; two trials, 20,172 women, quality of evidence: moderate). Results from one trial with 151 women suggest that blood loss of ≥ 500 mL after randomisation may be reduced (RR 0.50, 95% CI 0.27 to 0.93; one trial, 151 women; quality of evidence: low). TXA did not reduce the risk of serious maternal morbidity (RR 0.99, 95% CI 0.83 to 1.19; one trial, 20,015 women; quality of evidence: high), hysterectomy to control bleeding (RR 0.95, 95% CI 0.81 to 1.12; one trial, 20,017 women; quality of evidence: high) receipt of blood transfusion (any) (RR 1.00, 95% CI 0.97 to 1.03; two trials, 20,167 women; quality of evidence: moderate) or maternal vascular occlusive events (any), although results were imprecise for this latter outcome (RR 0.88, 95% CI 0.54 to 1.43; one trial, 20,018 women; quality of evidence: moderate). There was an increase in the use of brace sutures in the TXA group (RR 1.19, 95% CI 1.01, 1.41) and a reduction in the need for laparotomy for bleeding (RR 0.64, 95% CI 0.49, 0.85). AUTHORS' CONCLUSIONS: TXA when administered intravenously reduces mortality due to bleeding in women with primary PPH, irrespective of mode of birth, and without increasing the risk of thromboembolic events. Taken together with the reliable evidence of the effect of TXA in trauma patients, the evidence suggests that TXA is effective if given as early as possible.Facilities for IV administration may not be available in non-hospital settings therefore, alternative routes to IV administration need to be investigated.

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.

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).

Tranexamic acid in bleeding trauma patients: an exploration of benefits and harms.

BACKGROUND: The CRASH-2 trial showed that tranexamic acid (TXA) administration reduces mortality in bleeding trauma patients. However, the effect appeared to depend on how soon after injury TXA treatment was started. Treatment within 3 h reduced bleeding deaths whereas treatment after 3 h increased the risk. We examine how patient characteristics vary by time to treatment and explore whether any such variations explain the time-dependent treatment effect. METHODS: Exploratory analysis were carried out, including per-protocol analyses, of data from the CRASH-2 trial, a randomised placebo-controlled trial of the effect of TXA on mortality in 20,211 trauma patients with, or at risk of, significant bleeding. We examine how patient characteristics (age, type of injury, presence or absence of head injury, Glasgow coma scale (GCS), systolic blood pressure and capillary refill time) vary with time to treatment and use univariable (restriction) and multivariable methods to examine whether any such variations explain the time-dependent effect of TXA. If not explained by differences in patient characteristics, we planned to conduct separate prespecified subgroup analyses for the early benefit and late harm. RESULTS: There was no substantial variation in age or capillary refill by time to treatment. However, the proportion of patients with blunt trauma, the proportion with head injury and mean systolic blood pressure increased as time to treatment increased. Mean GCS decreased as time to treatment increased. Analyses restricted to patients with blunt trauma, those without head injury and those with a systolic blood pressure <100 mmHg showed that these characteristics did not explain the time-dependent treatment effect. In a multivariable analysis the interaction with time to treatment remained highly significant (p < 0.0001). Separate subgroup analyses that examine how the benefits of early TXA treatment and the harms of late TXA treatment vary by systolic blood pressure (≤75, 76-89, >89 mmHg); GCS (severe 3-8, moderate 9-12, mild 13-15); and type of injury (penetrating versus blunt) showed no significant heterogeneity. CONCLUSIONS: The time-dependent effect of TXA in bleeding trauma patients is not explained by the type of injury, the presence or absence of head injury or systolic blood pressure. When given within 3 h of injury, TXA reduces death due to bleeding regardless of type of injury, GCS or blood pressure. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00375258 . Registered on 11 September 2006.

The effectiveness and safety of anti-fibrinolytics in patients with acute intracranial haemorrhage: statistical analysis plan for an individual patient data meta-analysis.

INTRODUCTION: The Anti-fibrinolytics Trialists Collaboration aims to increase knowledge about the effectiveness and safety of anti-fibrinolytic treatment by conducting individual patient data (IPD) meta-analyses of randomised trials. This article presents the statistical analysis plan for an IPD meta-analysis of the effects of anti-fibrinolytics for acute intracranial haemorrhage. METHODS: The protocol for the IPD meta-analysis has been registered with PROSPERO (CRD42019128260). We will conduct an individual patient data meta-analysis of randomised controlled trials with 500 patients or more assessing the effects of anti-fibrinolytics in acute intracranial haemorrhage. The primary outcomes will be 1) death from stroke or head injury within 30 days of randomisation, and 2) death from stroke or head injury, or dependency within 90 days of randomisation. The primary outcomes will be limited to patients treated within three hours of injury or stroke onset. We will report treatment effects using odds ratios and 95% confidence intervals. We use logistic regression models to examine how the effect of anti-fibrinolytics vary by time to treatment, severity of intracranial bleeding, and age. We will also examine the effect of anti-fibrinolytics on secondary outcomes including death, dependency, vascular occlusive events, seizures, and neurological outcomes. Secondary outcomes will be assessed in all patients irrespective of time of treatment. All analyses will be conducted on an intention-to-treat basis. CONCLUSIONS: This IPD meta-analysis will examine important clinical questions about the effects of anti-fibrinolytic treatment in patients with intracranial haemorrhage that cannot be answered using aggregate data. With IPD we can examine how effects vary by time to treatment, bleeding severity, and age, to gain better understanding of the balance of benefit and harms on which to base recommendations for practice.

Cochrane: the unfinished symphony of research synthesis.

The NHS needs valid information on the safety and effectiveness of healthcare interventions. Cochrane systematic reviews are an important source of this information. Traditionally, Cochrane has attempted to identify and include all relevant trials in systematic reviews on the basis that if all trials are identified and included, there should be no selection bias. However, a predictable consequence of the drive to include all trials is that some studies are included that are not trials (false positives). Including such studies in reviews might increase bias. More effort is needed to authenticate trials to be included in reviews, but this task is bedevilled by the enormous increase in the number of 'trials' conducted each year. We argue that excluding small trials from reviews would release resources for more detailed appraisal of larger trials. Conducting fewer but broader reviews that contain fewer but properly validated trials might better serve patients' interests.

Exploring redundant research into the effect of tranexamic acid on surgical bleeding: further analysis of a systematic review of randomised controlled trials.

OBJECTIVES: We examined whether apparent redundancy in a cumulative meta-analysis of trials is justified by concern about bias, random error or generalisability of the results. DESIGN: Cumulative meta-analysis, risk of bias assessment, trial sequential analysis, description of study participants over time and a review of rationales for conducting trials. DATA SOURCE: 126 randomised trials included in a systematic review assessing of tranexamic acid on blood transfusion in surgery. RESULTS: The cumulative meta-analysis including all trials shows that the pooled estimate first reached statistical significance after the second trial in 1993. When the analysis was limited to the 38 high-quality trials and adjusted to account for potential systematic and random errors, the uncertainty was resolved after the 22nd trial in 2008. When the analysis was restricted to the two high-quality, prospectively registered trials, the cumulative z-curve crossed p=0.05 but not the monitoring boundary, suggesting an early potentially spurious statistically significant result. As precision of the pooled estimate increased, the number of trials initiated increased, although trial activity appeared to move to other surgery types. Most (62%) reports cited at least one systematic review. Of 118 reports examined, concern about generalisability was the reason for initiating the trial in 60%. Other reasons were to address a question other than the effect on bleeding (26%) and to confirm previously observed results (4%). Unawareness of previous research was apparent in 4% trials, while the rationale was unclear in 3%. CONCLUSIONS: Our results indicate that poor quality is a more important cause of redundant research than the failure to review existing evidence. Concerns about generalisability of results is the main motivation for new trials. Contrary to previous claims, our results suggest that systematic reviews showing treatment effects can stimulate an increase in trial activity rather than reduce it.

Antifibrinolytic drugs for acute traumatic injury.

BACKGROUND: Uncontrolled bleeding is an important cause of death in trauma victims. Antifibrinolytic treatment has been shown to reduce blood loss following surgery and may also be effective in reducing blood loss following trauma. OBJECTIVES: To assess the effect of antifibrinolytic drugs in patients with acute traumatic injury. SEARCH METHODS: We ran the most recent search in January 2015. We searched the Cochrane Injuries Group's Specialised Register, The Cochrane Library, Ovid MEDLINE(R), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid OLDMEDLINE(R), Embase Classic+Embase (OvidSP), PubMed and clinical trials registries. SELECTION CRITERIA: Randomised controlled trials of antifibrinolytic agents (aprotinin, tranexamic acid [TXA], epsilon-aminocaproic acid and aminomethylbenzoic acid) following acute traumatic injury. DATA COLLECTION AND ANALYSIS: From the results of the screened electronic searches, bibliographic searches, and contacts with experts, two authors independently selected trials meeting the inclusion criteria, and extracted data. One review author assessed the risk of bias for key domains.Outcome measures included: mortality at end of follow-up (all-cause); adverse events (specifically vascular occlusive events [myocardial infarction, stroke, deep vein thrombosis or pulmonary embolism] and renal failure); number of patients undergoing surgical intervention or receiving blood transfusion; volume of blood transfused; volume of intracranial bleeding; brain ischaemic lesions; death or disability.We rated the quality of the evidence as 'high', 'moderate', 'low' or 'very low' according to the GRADE approach. MAIN RESULTS: Three trials met the inclusion criteria.Two trials (n = 20,451) assessed the effect of TXA. The larger of these (CRASH-2, n = 20,211) was conducted in 40 countries and included patients with a variety of types of trauma; the other (n = 240) restricted itself to those with traumatic brain injury (TBI) only.One trial (n = 77) assessed aprotinin in participants with major bony trauma and shock.The pooled data show that antifibrinolytic drugs reduce the risk of death from any cause by 10% (RR 0.90, 95% CI 0.85 to 0.96; P = 0.002) (quality of evidence: high). This estimate is based primarily on data from the CRASH-2 trial of TXA, which contributed 99% of the data.There is no evidence that antifibrinolytics have an effect on the risk of vascular occlusive events (quality of evidence: moderate), need for surgical intervention or receipt of blood transfusion (quality of evidence: high). There is no evidence for a difference in the effect by type of antifibrinolytic (TXA versus aprotinin) however, as the pooled analyses were based predominantly on trial data concerning the effects of TXA, the results can only be confidently applied to the effects of TXA. The effects of aprotinin in this patient group remain uncertain.There is some evidence from pooling data from one study (n = 240) and a subset of data from CRASH-2 (n = 270) in patients with TBI which suggest that TXA may reduce mortality although the estimates are imprecise, the quality of evidence is low, and uncertainty remains. Stronger evidence exists for the possibility of TXA reducing intracranial bleeding in this population. AUTHORS' CONCLUSIONS: TXA safely reduces mortality in trauma patients with bleeding without increasing the risk of adverse events.  TXA should be given as early as possible and within three hours of injury, as further analysis of the CRASH-2 trial showed that treatment later than this is unlikely to be effective and may be harmful. Although there is some promising evidence for the effect of TXA in patients with TBI, substantial uncertainty remains.Two ongoing trials being conducted in patients with isolated TBI should resolve these remaining uncertainties.

Comparison of routes for achieving parenteral access with a focus on the management of patients with Ebola virus disease.

BACKGROUND: Dehydration is an important cause of death in patients with Ebola virus disease (EVD). Parenteral fluids are often required in patients with fluid requirements in excess of their oral intake. The peripheral intravenous route is the most commonly used method of parenteral access, but inserting and maintaining an intravenous line can be challenging in the context of EVD. Therefore it is important to consider the advantages and disadvantages of different routes for achieving parenteral access (e.g. intravenous, intraosseous, subcutaneous and intraperitoneal). OBJECTIVES: To compare the reliability, ease of use and speed of insertion of different parenteral access methods. SEARCH METHODS: We ran the search on 17 November 2014. We searched the Cochrane Injuries Group's Specialised Register, Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily, Ovid MEDLINE(R) and Ovid OLDMEDLINE(R), Embase Classic + Embase (OvidSP), CINAHL (EBSCOhost), clinicaltrials.gov and screened reference lists. SELECTION CRITERIA: Randomised controlled trials comparing different parenteral routes for the infusion of fluids or medication. DATA COLLECTION AND ANALYSIS: Two review authors examined the titles and abstracts of records obtained by searching the electronic databases to determine eligibility. Two review authors extracted data from the included trials and assessed the risk of bias. Outcome measures of interest were success of insertion; time required for insertion; number of insertion attempts; number of dislodgements; time period with functional access; local site reactions; clinicians' perception of ease of administration; needlestick injury to healthcare workers; patients' discomfort; and mortality. For trials involving the administration of fluids we also collected data on the volume of fluid infused, changes in serum electrolytes and markers of renal function. We rated the quality of the evidence as 'high', 'moderate', 'low' or 'very low' according to the GRADE approach for the following outcomes: success of insertion, time required for insertion, number of dislodgements, volume of fluid infused and needlestick injuries. MAIN RESULTS: We included 17 trials involving 885 participants. Parenteral access was used to infuse fluids in 11 trials and medications in six trials. None of the trials involved patients with EVD. Intravenous and intraosseous access was compared in four trials; intravenous and subcutaneous access in 11; peripheral intravenous and intraperitoneal access in one; saphenous vein cutdown and intraosseous access in one; and intraperitoneal with subcutaneous access in one. All of the trials assessing the intravenous method involved peripheral intravenous access.We judged few trials to be at low risk of bias for any of the assessed domains.Compared to the intraosseous group, patients in the intravenous group were more likely to experience an insertion failure (risk ratio (RR) 3.89, 95% confidence interval (CI) 2.39 to 6.33; n = 242; GRADE rating: low). We did not pool data for time to insertion but estimates from the trials suggest that inserting intravenous access takes longer (GRADE rating: moderate). Clinicians judged the intravenous route to be easier to insert (RR 0.15, 95% CI 0.04 to 0.61; n = 182). A larger volume of fluids was infused via the intravenous route (GRADE rating: moderate). There was no evidence of a difference between the two routes for any other outcomes, including adverse events.Compared to the subcutaneous group, patients in the intravenous group were more likely to experience an insertion failure (RR 14.79, 95% CI 2.87 to 76.08; n = 238; GRADE rating: moderate) and dislodgement of the device (RR 3.78, 95% CI 1.16 to 12.34; n = 67; GRADE rating: low). Clinicians also judged the intravenous route as being more difficult to insert and patients were more likely to be agitated in the intravenous group. Patients in the intravenous group were more likely to develop a local infection and phlebitis, but were less likely to develop erythema, oedema or swelling than those in the subcutaneous group. A larger volume of fluids was infused into patients via the intravenous route. There was no evidence of a difference between the two routes for any other outcome.There were insufficient data to reliably determine if the risk of insertion failure differed between the saphenous vein cutdown (SVC) and intraosseous method (RR 4.00, 95% CI 0.51 to 31.13; GRADE rating: low). Insertion using SVC took longer than the intraosseous method (MD 219.60 seconds, 95% CI 135.44 to 303.76; GRADE rating: moderate). There were no data and therefore there was no evidence of a difference between the two routes for any other outcome.There were insufficient data to reliably determine the relative effects of intraperitoneal or central intravenous access relative to any other parenteral access method. AUTHORS' CONCLUSIONS: There are several different ways of achieving parenteral access in patients who are unable meet their fluid requirements with oral intake alone. The quality of the evidence, as assessed using the GRADE criteria, is somewhat limited because of the lack of adequately powered trials at low risk of bias. However, we believe that there is sufficient evidence to draw the following conclusions: if peripheral intravenous access can be achieved easily, this allows infusion of larger volumes of fluid than other routes; but if this is not possible, the intraosseous and subcutaneous routes are viable alternatives. The subcutaneous route may be suitable for patients who are not severely dehydrated but in whom ongoing fluid losses cannot be met by oral intake.A film to accompany this review can be viewed here (http://youtu.be/ArVPzkf93ng).