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
Angèle Gayet-Ageron, David Prieto-Merino, Katharine Ker, et al
Lancet Published Online November 7, 2017
http://dx.doi.org/10.1016/S0140-6736(17)32455-8
Summary
Background 背景
Antifibrinolytics reduce death from bleeding in trauma and post-partum haemorrhage. We examined the effect of treatment delay on the effectiveness of antifibrinolytics.
抗纤溶药物能够减少创伤出血及产后出血。我们研究了治疗延迟对于抗纤溶药物疗效的影响。
Methods 方法
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.
我们对样本量超过1000例患者的评估抗纤溶药物治疗急性严重出血的随机试验进行了一项患者水平meta分析。我们通过检索MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, PubMed, Popline, 以及 WHO International Clinical Trials Registry Platform找到1946年1月1日至2017年4月7日间进行的临床试验。主要疗效指标为避免出血导致的死亡。我们采用logistic模型检验了治疗厌恶对疗效的影响。我们还通过敏感性分析研究了测量误差（错误分类）的影响。研究在PROSPERO注册，注册号为42016052155。
Findings 结果
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.
我们获得了有关氨甲环酸治疗急性严重出血（创伤或产后出血）的2项随机试验共40138名患者的数据。共有3558例死亡，其中1408例(40%)死于出血。多数(884/1408 [63%])出血导致的死亡发生于起病12小时内。产后出血导致的死亡高峰在生产后2-3小时。氨甲环酸显著增加出血后存活率（比数比 [OR] 1·20, 95% CI 1·08–1·33; p=0·001），且出血部位未见异质性（交互作用 p=0·7243）。治疗延迟显著降低疗效(p<0·0001)。出血后立即治疗改善存活率超过70% (OR 1·72, 95% CI 1·42–2·10; p<0·0001)。此后，治疗每延迟15分钟，生存获益降低10%，至3小时后治疗既无获益。氨甲环酸治疗并不增加血管阻塞事件，出血部位之间无异质性(p=0·5956)。治疗延迟不影响氨甲环酸对血管阻塞事件的影响。
Interpretation 结论
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.
出血导致的死亡在发病后很快出现，即使很短时间的治疗延迟也会显著降低氨甲环酸的疗效。必须立即对患者进行治疗。需要进一步研究加深我们对于氨甲环酸作用机制的认识。
Funding 基金
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).
