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

Abstract

SummaryBackgroundAntifibrinolytics reduce death from bleeding in trauma and post-partum haemorrhage. We examined the effect of treatment delay on the effectiveness of antifibrinolytics.MethodsWe 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.FindingsWe 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.InterpretationDeath 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.FundingUK 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).

Implementation of tranexamic acid for bleeding trauma patients: a longitudinal and cross-sectional study

“…Across a range of bleeding conditions tranexamic treatment is extremely time dependent, with 10% of the benefit being lost for every 15 min delay 6. ‘High quality’ treatment has been defined within UK trauma systems as starting the TXA infusion within 3 hours of injury, however it is clear that patients in the later stages of this time window get little or no benefit.…”

“…To most effectively decrease overall trauma mortality TXA must be given early6 in all patients suspected of having significant bleeding1 (as per the CRASH-2 inclusion criteria). Early treatment is not currently being achieved, except in those patients treated during the prehospital phase, perhaps suggesting that TXA should be more widely implemented as a prehospital drug.…”

Global Emergency Medicine: A Review of the Literature From 2017

“…Gayet-Ageron et al 19 found in their meta-analysis of 40,183 individual bleeding patients that the timely administration of tranexamic acid was associated with improved survival, with a 10% reduction in survival benefit for every 15 minutes' delay. In the international WOMAN study, researchers similarly found that early administration of tranexamic acid reduced deaths from postpartum hemorrhage when compared to placebo, without any apparent increase in adverse outcomes.…”

Tranexamic acid for significant traumatic brain injury (The CRASH-3 trial): Statistical analysis plan for an international, randomised, double-blind, placebo-controlled trial

“…The results showed that immediate treatment improved survival by more than 70% (OR 1·72, 95% CI 1·42–2·10; p<0·0001) but thereafter, the survival benefit decreased by about 10% for every 15 min of treatment delay until 3 hours, after which there was no benefit 14 . It is reasonable to expect a similar decline in treatment benefit in the context of acute intracranial bleeding.…”

“…In 2017, the WOMAN trial showed that administration of tranexamic acid to women with post-partum haemorrhage within three hours of delivery reduces deaths due to bleeding by about one third 13 . Later in 2017, results from an individual patient-level data meta-analysis of randomised trials of tranexamic acid in acute severe bleeding showed that whilst immediate treatment substantially improves survival, the survival benefit decreases by around 10% for every 15 min of treatment delay until 3 h, after which there was no benefit 14 .…”