Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial.
Effect of early tranexamic acid administration on mortality, hysterectomy, and other morbidities in women with post-partum haemorrhage (WOMAN): an international, randomised, double-blind, placebo-controlled trial.
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DOI：
10.1016/s0140-6736(17)30638-4
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发表时间：
2017-05-27
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通讯作者：
WOMAN Trial Collaborators
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作者：
WOMAN Trial Collaborators
产后出血是全世界产妇死亡的主要原因。早期给予氨甲环酸可减少创伤患者因出血导致的死亡。我们的目的是评估早期应用氨甲环酸对产后出血妇女的死亡、子宫切除术和其他相关结局的影响。在这项随机、双盲、安慰剂对照试验中，我们从21个国家的193家医院招募了16岁及以上经阴道分娩或剖腹产后临床诊断为产后出血的女性。我们随机分配妇女接受1克静脉氨甲环酸或匹配的安慰剂除了常规护理。如果出血在30分钟后继续，或在首次给药后24小时内停止并重新开始，则可以给予第二剂氨甲环酸或安慰剂1 g。患者通过从包含8个编号包装（除包装编号外均相同）的包装盒中选择一个编号治疗包装进行分配。参与者、护理人员和评估结果的人员对分配情况不知情。我们最初计划入组15000名女性，其复合主要终点为分娩后42天内全因死亡或子宫切除术。 然而，在试验过程中，很明显，进行子宫切除术的决定通常是在随机化的同时做出的。虽然氨甲环酸可以影响这些病例的死亡风险，但不能影响子宫切除术的风险。因此，我们将样本量从15000名妇女增加到20000名妇女，以估计氨甲环酸对产后出血死亡风险的影响。 所有分析都是在意向治疗的基础上进行的。本试验已在ISRCTN 76912190（2008年12月8日）、ClinicalTrials.gov（编号NCT 00872469）和PACTR 201007000192283中注册。在2010年3月至2016年4月期间，20060名女性被招募并随机分配接受氨甲环酸（n= 10051）或安慰剂（n= 10009），其中10036和9985分别被纳入分析。 服用氨甲环酸的女性出血死亡率显著降低[10036例患者中155例[1.5%] vs安慰剂组9985例患者中191例[1.9%]，风险比[RR] 0.81，95%CI 0.65 - 1.00; p= 0.045），尤其是在分娩后3小时内接受治疗的女性中（氨甲环酸组89例[1.2%] vs安慰剂组127例[1.7%]，RR 0.69，95%CI 0.52 - 0.91; p= 0.008）。所有其他死亡原因在各组之间没有显著差异。氨甲环酸并没有减少子宫切除术的发生率（氨甲环酸组358例[3.6%] vs安慰剂组351例[3.5%]，RR 1.02，95%CI 0.88 - 1.07; p= 0.84）。氨甲环酸并没有降低全因死亡或子宫切除术的复合主要终点（氨甲环酸组534例[5.3%]死亡或子宫切除术vs安慰剂组546例[5.5%]，RR 0.97，95%CI 0.87 - 1.09; p= 0.65）。氨甲环酸组与安慰剂组的不良事件（包括血栓栓塞事件）无显著差异。氨甲环酸可减少产后出血妇女的出血死亡，且无不良反应。当用于治疗产后出血时，应在出血发生后尽快给予氨甲环酸。伦敦卫生与热带医学学院、辉瑞公司、英国卫生部、惠康信托基金会和比尔及梅林达盖茨基金会。
Post-partum haemorrhage is the leading cause of maternal death worldwide. Early administration of tranexamic acid reduces deaths due to bleeding in trauma patients. We aimed to assess the effects of early administration of tranexamic acid on death, hysterectomy, and other relevant outcomes in women with post-partum haemorrhage. In this randomised, double-blind, placebo-controlled trial, we recruited women aged 16 years and older with a clinical diagnosis of post-partum haemorrhage after a vaginal birth or caesarean section from 193 hospitals in 21 countries. We randomly assigned women to receive either 1 g intravenous tranexamic acid or matching placebo in addition to usual care. If bleeding continued after 30 min, or stopped and restarted within 24 h of the first dose, a second dose of 1 g of tranexamic acid or placebo could be given. Patients were assigned by selection of a numbered treatment pack from a box containing eight numbered packs that were identical apart from the pack number. Participants, care givers, and those assessing outcomes were masked to allocation. We originally planned to enrol 15 000 women with a composite primary endpoint of death from all-causes or hysterectomy within 42 days of giving birth. However, during the trial it became apparent that the decision to conduct a hysterectomy was often made at the same time as randomisation. Although tranexamic acid could influence the risk of death in these cases, it could not affect the risk of hysterectomy. We therefore increased the sample size from 15 000 to 20 000 women in order to estimate the effect of tranexamic acid on the risk of death from post-partum haemorrhage. All analyses were done on an intention-to-treat basis. This trial is registered with ISRCTN76912190 (Dec 8, 2008); ClinicalTrials.gov, number NCT00872469; and PACTR201007000192283. Between March, 2010, and April, 2016, 20 060 women were enrolled and randomly assigned to receive tranexamic acid (n=10 051) or placebo (n=10 009), of whom 10 036 and 9985, respectively, were included in the analysis. Death due to bleeding was significantly reduced in women given tranexamic acid (155 [1·5%] of 10 036 patients vs 191 [1·9%] of 9985 in the placebo group, risk ratio [RR] 0·81, 95% CI 0·65–1·00; p=0·045), especially in women given treatment within 3 h of giving birth (89 [1·2%] in the tranexamic acid group vs 127 [1·7%] in the placebo group, RR 0·69, 95% CI 0·52–0·91; p=0·008). All other causes of death did not differ significantly by group. Hysterectomy was not reduced with tranexamic acid (358 [3·6%] patients in the tranexamic acid group vs 351 [3·5%] in the placebo group, RR 1·02, 95% CI 0·88–1·07; p=0·84). The composite primary endpoint of death from all causes or hysterectomy was not reduced with tranexamic acid (534 [5·3%] deaths or hysterectomies in the tranexamic acid group vs 546 [5·5%] in the placebo group, RR 0·97, 95% CI 0·87-1·09; p=0·65). Adverse events (including thromboembolic events) did not differ significantly in the tranexamic acid versus placebo group. Tranexamic acid reduces death due to bleeding in women with post-partum haemorrhage with no adverse effects. When used as a treatment for postpartum haemorrhage, tranexamic acid should be given as soon as possible after bleeding onset. London School of Hygiene & Tropical Medicine, Pfizer, UK Department of Health, Wellcome Trust, and Bill & Melinda Gates Foundation.