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[Lancet在线发表]:CRASH-3: 氨甲环酸对颅脑创伤患者病死率、致残率、血管阻塞事件及其他并发症的影响
2019年11月05日 时讯速递, 进展交流 暂无评论

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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

The CRASH-3 trial collaborators

Lancet Published:October 14, 2019 DOI:https://doi.org/10.1016/S0140-6736(19)32233-0

Background 背景

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.

氨甲环酸减少创伤导致的颅脑以外出血患者的出血及病死率。颅脑创伤(TBI)患者常见颅内出血,可引起脑疝及死亡。我们旨在评价TBI患者使用氨甲环酸的效果。

Methods 方法

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).

这是一项随机安慰剂对照临床试验,在29个国家175所医院进行。入选患者为TBI发生后3小时内,GCS不超过12分或CT扫描提示有颅内出血,且没有颅外大出血。治疗窗最初设置为8小时,但在2016年时,研究方法发生改变,仅纳入创伤后3小时内的患者。这一改变是因有证据显示,延迟治疗可能无效,但在试验数据分析时设盲。我们将患者按照1:1的比例随机分组,分别接受氨甲环酸 (负荷剂量 1 g 10 min内输注,然后输注 1 g,8 h内输注结束) 或安慰剂。对患者进行分组时,从一个装有8个袋子(外形相同,数字不同)的箱子中选择1个带有治疗分组数字的袋子。患者、医务人员及评估预后的人员均对分组隐藏。主要预后指标为颅脑创伤3小时内接受治疗的患者在28天内颅脑创伤相关死亡。我们还预先确定了敏感性分析,分析时排除GCS为3分及基线情况下双侧瞳孔无反应的患者。所有的分析都按照意向治疗原则进行。试验在ISRCTN (ISRCTN15088122), ClinicalTrials.gov (NCT01402882), EudraCT (2011-003669-14) 及泛非洲临床试验注册网站 (PACTR20121000441277) 注册。

Results 结果

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]).

2012年7月20日至2019年1月31日,我们共对12 737 名TBI患者进行随机分组,分别使用氨甲环酸 (6406 [50·3%]) 或安慰剂 ([6331 [49·7%]),其中 9202 (72·2%) 名患者在创伤后3消失内接受治疗。在创伤后3小时内接受治疗的患者中,氨甲环酸组颅脑创伤相关死亡风险为 18·5%,安慰剂组为 19·8% (855 vs 892 个事件; 风险比 [RR] 0·94 [95% CI 0·86–1·02])。在预先确定的敏感性分析 (排除GCS评分3分或基线情况下双侧瞳孔无反应的患者后) 时,氨甲环酸组颅脑创伤相关死亡风险为 12·5%,安慰剂组为 14·0% (485 vs 525 个事件; RR 0·89 [95% CI 0·80–1·00])。氨甲环酸能够降低轻中度颅脑创伤患者颅脑创伤相关死亡风险 (RR 0·78 [95% CI 0·64–0·95]),但对重度颅脑创伤患者无效 (0·99 [95% CI 0·91–1·07]; 异质性p值 0·030)。对于轻中度颅脑创伤患者,早期治疗更有效 (p=0·005),但对重度颅脑创伤患者则无效 (p=0·73)。氨甲环酸组及安慰剂组血管阻塞事件风险相似 (RR 0·98 (0·74–1·28)。两组间癫痫风险相似 (1·09 [95% CI 0·90–1·33])。

Interpretation 结论

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.

我们的结果显示,氨甲环酸对于TBI患者是安全的,在创伤发生3小时内使用能够降低颅脑创伤相关死亡。创伤后应尽快开始治疗。

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).

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