Stroke Trials Unit, Division of Clinical Neuroscience, University of Nottingham, Nottingham, UK.
Stroke, Nottingham University Hospitals NHS Trust, Nottingham, UK.
Health Technol Assess. 2019 Jul;23(35):1-48. doi: 10.3310/hta23350.
Tranexamic acid reduces death due to bleeding after trauma and postpartum haemorrhage.
The aim of the study was to assess if tranexamic acid is safe, reduces haematoma expansion and improves outcomes in adults with spontaneous intracerebral haemorrhage (ICH).
The TICH-2 (Tranexamic acid for hyperacute primary IntraCerebral Haemorrhage) study was a pragmatic, Phase III, prospective, double-blind, randomised placebo-controlled trial.
Acute stroke services at 124 hospitals in 12 countries (Denmark, Georgia, Hungary, Ireland, Italy, Malaysia, Poland, Spain, Sweden, Switzerland, Turkey and the UK).
Adult patients (aged ≥ 18 years) with ICH within 8 hours of onset.
Exclusion criteria were ICH secondary to anticoagulation, thrombolysis, trauma or a known underlying structural abnormality; patients for whom tranexamic acid was thought to be contraindicated; prestroke dependence (i.e. patients with a modified Rankin Scale [mRS] score > 4); life expectancy < 3 months; and a Glasgow Coma Scale score of < 5.
Participants, allocated by randomisation, received 1 g of an intravenous tranexamic acid bolus followed by an 8-hour 1-g infusion or matching placebo (i.e. 0.9% saline).
The primary outcome was functional status (death or dependency) at day 90, which was measured by the shift in the mRS score, using ordinal logistic regression, with adjustment for stratification and minimisation criteria.
A total of 2325 participants (tranexamic acid, = 1161; placebo, = 1164) were recruited from 124 hospitals in 12 countries between 2013 and 2017. Treatment groups were well balanced at baseline. The primary outcome was determined for 2307 participants (tranexamic acid, = 1152; placebo, = 1155). There was no statistically significant difference between the treatment groups for the primary outcome of functional status at day 90 [adjusted odds ratio (aOR) 0.88, 95% confidence interval (CI) 0.76 to 1.03; = 0.11]. Although there were fewer deaths by day 7 in the tranexamic acid group (aOR 0.73, 95% CI 0.53 to 0.99; = 0.041), there was no difference in case fatality at 90 days (adjusted hazard ratio 0.92, 95% CI 0.77 to 1.10; = 0.37). Fewer patients experienced serious adverse events (SAEs) after treatment with tranexamic acid than with placebo by days 2 ( = 0.027), 7 ( = 0.020) and 90 ( = 0.039). There was no increase in thromboembolic events or seizures.
Despite attempts to enrol patients rapidly, the majority of participants were enrolled and treated > 4.5 hours after stroke onset. Pragmatic inclusion criteria led to a heterogeneous population of participants, some of whom had very large strokes. Although 12 countries enrolled participants, the majority (82.1%) were from the UK.
Tranexamic acid did not affect a patient's functional status at 90 days after ICH, despite there being significant modest reductions in early death (by 7 days), haematoma expansion and SAEs, which is consistent with an antifibrinolytic effect. Tranexamic acid was safe, with no increase in thromboembolic events.
Future work should focus on enrolling and treating patients early after stroke and identify which participants are most likely to benefit from haemostatic therapy. Large randomised trials are needed.
Current Controlled Trials ISRCTN93732214.
This project was funded by the National Institute for Health Research Health Technology Assessment programme and will be published in full in ; Vol. 23, No. 35. See the NIHR Journals Library website for further project information. The project was also funded by the Pragmatic Trials, UK, funding call and the Swiss Heart Foundation in Switzerland.
氨甲环酸可减少创伤和产后出血后的出血性死亡。
本研究旨在评估氨甲环酸是否安全，是否可减少血肿扩大并改善自发性脑出血（ICH）成人的预后。
TICH-2（氨甲环酸治疗超急性原发性脑出血）研究是一项实用的、III 期、前瞻性、双盲、随机、安慰剂对照试验。
12 个国家（丹麦、格鲁吉亚、匈牙利、爱尔兰、意大利、马来西亚、波兰、西班牙、瑞典、瑞士、土耳其和英国）的 124 家医院的急性卒中服务。
ICH 发病后 8 小时内的成年患者（年龄≥18 岁）。
ICH 继发于抗凝、溶栓、创伤或已知的结构性异常；认为氨甲环酸禁忌的患者；发病前依赖（即改良 Rankin 量表[mRS]评分＞4）；预期寿命＜3 个月；格拉斯哥昏迷量表评分＜5。
参与者通过随机分配接受 1g 静脉氨甲环酸推注，随后进行 8 小时 1g 输注或匹配的安慰剂（即 0.9%生理盐水）。
主要结局是第 90 天的功能状态（死亡或依赖），通过 mRS 评分的变化，使用有序逻辑回归进行测量，并进行分层和最小化标准的调整。
共从 12 个国家的 124 家医院招募了 2325 名参与者（氨甲环酸组，n=1161；安慰剂组，n=1164），招募时间为 2013 年至 2017 年。治疗组在基线时平衡良好。2307 名参与者确定了主要结局（氨甲环酸组，n=1152；安慰剂组，n=1155）。治疗组在第 90 天的功能状态主要结局方面无统计学差异[调整后的优势比（aOR）0.88，95%置信区间（CI）0.76 至 1.03；=0.11]。虽然氨甲环酸组第 7 天的死亡率较低（aOR 0.73，95%CI 0.53 至 0.99；=0.041），但 90 天的病死率无差异（调整后的危险比 0.92，95%CI 0.77 至 1.10；=0.37）。氨甲环酸治疗的患者在第 2（=0.027）、7（=0.020）和 90 天（=0.039）时发生严重不良事件（SAE）的人数少于安慰剂。血栓栓塞事件或癫痫发作无增加。
尽管尝试快速招募患者，但大多数患者是在卒中发病后＞4.5 小时入组和治疗的。实用的纳入标准导致患者人群存在异质性，其中一些患者的脑出血非常大。尽管有 12 个国家招募了参与者，但大多数（82.1%）来自英国。
尽管氨甲环酸可显著降低早期死亡率（7 天）、血肿扩大和 SAE，但并未影响 ICH 后 90 天患者的功能状态，这与抗纤维蛋白溶解作用一致。氨甲环酸是安全的，没有增加血栓栓塞事件。
未来的工作应集中在卒中后早期招募和治疗患者，并确定哪些患者最有可能从止血治疗中获益。需要进行大型随机试验。
当前对照试验 ISRCTN93732214。
本项目由英国国家卫生研究院卫生技术评估计划资助，全文将在；第 23 卷，第 35 期。请访问 NIHR 期刊库网站以获取项目的进一步信息。该项目还得到了英国实用试验和瑞士心脏基金会的资助。
