BACKGROUND Tranexamic acid reduces surgical bleeding and decreases mortality in patients with traumatic extracranial bleeding. Intracranial bleeding is common after traumatic brain injury (TBI) and can cause brain herniation and death. We aimed to assess the effects of tranexamic acid in patients with TBI. METHODS This randomised, placebo-controlled trial was done in 175 hospitals in 29 countries. Adults with TBI who were within 3 h of injury, had a Glasgow Coma Scale (GCS) score of 12 or lower or any intracranial bleeding on CT scan, and no major extracranial bleeding were eligible. The time window for eligibility was originally 8 h but in 2016 the protocol was changed to limit recruitment to patients within 3 h of injury. This change was made blind to the trial data, in response to external evidence suggesting that delayed treatment is unlikely to be effective. We randomly assigned (1:1) patients to receive tranexamic acid (loading dose 1 g over 10 min then infusion of 1 g over 8 h) or matching placebo. Patients were assigned by selecting a numbered treatment pack from a box containing eight packs that were identical apart from the pack number. Patients, caregivers, and those assessing outcomes were masked to allocation. The primary outcome was head injury-related death in hospital within 28 days of injury in patients treated within 3 h of injury. We prespecified a sensitivity analysis that excluded patients with a GCS score of 3 and those with bilateral unreactive pupils at baseline. All analyses were done by intention to treat. This trial was registered with ISRCTN (ISRCTN15088122), ClinicalTrials.gov (NCT01402882), EudraCT (2011-003669-14), and the Pan African Clinical Trial Registry (PACTR20121000441277). RESULTS Between July 20, 2012, and Jan 31, 2019, we randomly allocated 12 737 patients with TBI to receive tranexamic acid (6406 [50·3%] or placebo [6331 [49·7%], of whom 9202 (72·2%) patients were treated within 3 h of injury. Among patients treated within 3 h of injury, the risk of head injury-related death was 18·5% in the tranexamic acid group versus 19·8% in the placebo group (855 vs 892 events; risk ratio [RR] 0·94 [95% CI 0·86-1·02]). In the prespecified sensitivity analysis that excluded patients with a GCS score of 3 or bilateral unreactive pupils at baseline, the risk of head injury-related death was 12·5% in the tranexamic acid group versus 14·0% in the placebo group (485 vs 525 events; RR 0·89 [95% CI 0·80-1·00]). The risk of head injury-related death reduced with tranexamic acid in patients with mild-to-moderate head injury (RR 0·78 [95% CI 0·64-0·95]) but not in patients with severe head injury (0·99 [95% CI 0·91-1·07]; p value for heterogeneity 0·030). Early treatment was more effective than was later treatment in patients with mild and moderate head injury (p=0·005) but time to treatment had no obvious effect in patients with severe head injury (p=0·73). The risk of vascular occlusive events was similar in the tranexamic acid and placebo groups (RR 0·98 (0·74-1·28). The risk of seizures was also similar between groups (1·09 [95% CI 0·90-1·33]). INTERPRETATION Our results show that tranexamic acid is safe in patients with TBI and that treatment within 3 h of injury reduces head injury-related death. Patients should be treated as soon as possible after injury. FUNDING National Institute for Health Research Health Technology Assessment, JP Moulton Charitable Trust, Department of Health and Social Care, Department for International Development, Global Challenges Research Fund, Medical Research Council, and Wellcome Trust (Joint Global Health Trials scheme). TRANSLATIONS For the Arabic, Chinese, French, Hindi, Japanese, Spanish and Urdu translations of the abstract see Supplementary Material.

中文翻译：

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氨甲环酸对急性创伤性脑损伤 (CRASH-3) 患者死亡、残疾、血管闭塞事件和其他发病率的影响：一项随机、安慰剂对照试验。


背景技术氨甲环酸可减少手术出血并降低创伤性颅外出血患者的死亡率。颅内出血在创伤性脑损伤 (TBI) 后很常见，可导致脑疝和死亡。我们的目的是评估氨甲环酸对 TBI 患者的作用。方法 这项随机、安慰剂对照试验在 29 个国家的 175 家医院进行。受伤后 3 小时内患有 TBI 的成年人，格拉斯哥昏迷量表 (GCS) 评分为 12 或更低，或 CT 扫描显示任何颅内出血，且无严重颅外出血，符合资格。符合资格的时间窗口最初为 8 小时，但在 2016 年，方案进行了更改，限制招募受伤后 3 小时内的患者。这一改变是在对试验数据视而不见的情况下进行的，以回应外部证据表明延迟治疗不太可能有效。我们随机分配 (1:1) 患者接受氨甲环酸（10 分钟内负荷剂量 1 g，然后 8 小时内输注 1 g）或匹配的安慰剂。通过从包含八个治疗包的盒子中选择一个编号的治疗包来分配患者，这些治疗包除了包装编号外均相同。患者、护理人员和评估结果的人员都无法了解分配情况。主要结局是在受伤后 3 小时内接受治疗的患者在受伤后 28 天内因头部受伤而在医院死亡。我们预先设定了敏感性分析，排除了 GCS 评分为 3 的患者和基线时双侧瞳孔无反应的患者。所有分析均按意向治疗进行。该试验已在 ISRCTN (ISRCTN15088122)、ClinicalTrials.gov (NCT01402882)、EudraCT (2011-003669-14) 和泛非临床试验注册中心 (PACTR20121000441277) 注册。 结果 2012年7月20日至2019年1月31日期间，我们随机分配12 737名TBI患者接受氨甲环酸（6406 [50·3%]）或安慰剂[6331 [49·7%]，其中9202（72·7%） 2%) 患者在受伤后 3 小时内接受治疗 在受伤后 3 小时内接受治疗的患者中，氨甲环酸组与头部受伤相关的死亡风险为 18·5%，而安慰剂组为 19·8% (855)。 vs 892 次事件；风险比 [RR] 0·94 [95% CI 0·86-1·02]）。氨甲环酸组与头部损伤相关的死亡率为 12·5%，而安慰剂组为 14·0%（485 例与 525 例事件；RR 0·89 [95% CI 0·80-1·00]）。氨甲环酸可以降低轻度至中度头部损伤患者的头部损伤相关死亡比例（RR 0·78 [95% CI 0·64-0·95]），但对于严重头部损伤患者则不然（0·99） [95% CI 0·91-1·07]；异质性 p 值 0·030) 对于轻度和中度头部损伤患者，早期治疗比后期治疗更有效 (p=0·005)，但治疗时间较长。对严重颅脑损伤患者无明显影响(p=0·73)。氨甲环酸组和安慰剂组的血管闭塞事件风险相似 (RR 0·98 (0·74-1·28)。组间癫痫发作风险也相似 (1·09 [95% CI 0·90) -1·33]）。我们的结果表明，氨甲环酸对于 TBI 患者是安全的，并且在受伤后 3 小时内进行治疗可以减少与头部受伤相关的死亡。 资助国家健康研究卫生技术评估研究所、JP 莫尔顿慈善信托基金、健康和社会关怀部、国际发展部、全球挑战研究基金、医学研究理事会和威康信托基金（联合全球健康试验计划）。翻译 对于摘要的阿拉伯语、中文、法语、印地语、日语、西班牙语和乌尔都语翻译，请参阅补充材料。