Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial
Effects of tranexamic acid on death, disability, vascular occlusive events and other morbidities in patients with acute traumatic brain injury (CRASH-3): a randomised, placebo-controlled trial
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DOI：
10.1016/s0140-6736(19)32233-0
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发表时间：
2019-11-09
期刊：
影响因子：
168.9
通讯作者：
Mutiso, Vincent
中科院分区：
文献类型：
--
作者：
Roberts, Ian;Shakur-Still, Haleema;Mutiso, Vincent
氨甲环酸可减少创伤性颅外出血患者的手术出血和死亡率。外伤性脑损伤（TBI）后颅内出血很常见，可导致脑疝和死亡。我们的目的是评估氨甲环酸在TBI.Methods患者中的作用，这项随机、安慰剂对照试验在29个国家的175家医院进行。外伤后3小时内，格拉斯哥昏迷量表（GCS）评分为12分或更低，或CT扫描显示有颅内出血，且无严重颅外出血的成人TBI患者符合条件。合格性的时间窗最初为8小时，但在2016年，方案进行了变更，将招募限制在损伤后3小时内。这一变化对试验数据是盲目的，以回应外部证据表明延迟治疗不太可能有效。我们将患者随机分配（1：1）接受氨甲环酸（负荷剂量1g，10分钟后输注1g，8小时）或匹配的安慰剂。通过从包含8个除包装编号外完全相同的包装盒中选择一个编号的治疗包装来分配患者。患者、护理人员和评估结果的人员均对分配情况设盲。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天内在医院发生的头部损伤相关死亡。我们预先设定了敏感性分析，排除了GCS评分为3分的患者和基线时双侧瞳孔无反应的患者。所有分析均通过意向治疗进行。该试验在ISRCTN（ISRCTN15088122），www.example.comClinicalTrials.gov（2011 - 003669 - 14）和泛非临床试验登记处（PACTR20121000441277）。结果2012年7月20日至2019年1月31日，我们将12737例TBI患者随机分为氨甲环酸组（6406例[50.3%]）和安慰剂组（6331例[49.7%]），其中9202例（72.2%）患者在伤后3小时内接受治疗。在受伤后3小时内接受治疗的患者中，氨甲环酸组与安慰剂组相比，头部损伤相关死亡的风险为18.5%，安慰剂组为19.8%（855 vs 892起事件;风险比[RR] 0.94 [95%CI 0.86 - 1.02]）。在预先设定的敏感性分析中，排除了基线时GCS评分为3分或双侧瞳孔无反应的患者，氨甲环酸组与安慰剂组相比，头部损伤相关死亡的风险为12.5%，安慰剂组为14.0%（485 vs 525起事件; RR 0.89 [95%CI 0.80 - 1.00]）。氨甲环酸可降低轻度至中度脑损伤患者的脑损伤相关死亡风险（RR 0。78 [95% CI 0.64 - 0. 95])但在重度脑损伤患者中则无此现象（0.99 [95% CI 0.91 - 1.07];异质性p值0.030）。在轻度和中度脑损伤患者中，早期治疗比晚期治疗更有效（p = 0.005），但在重度脑损伤患者中，治疗时间无明显影响（p = 0.005）。73）。氨甲环酸组和安慰剂组发生血管闭塞事件的风险相似（RR 0.98（0.74 - 1.28））。两组之间癫痫发作的风险也相似（1.09 [95%CI 0.90 - 1.33]）。解释我们的研究结果表明，氨甲环酸在TBI患者中是安全的，并且在损伤后3小时内进行治疗可降低头部损伤相关死亡。患者受伤后应尽快治疗。版权所有（C）2019作者。爱思唯尔有限公司出版
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. Copyright (C) 2019 The Author(s). Published by Elsevier Ltd.