Lancet. 2019 Jun 29;393(10191):2613-2623. doi: 10.1016/S0140-6736(19)30840-2. Epub 2019 May 22.
BACKGROUND: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. METHODS: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). FINDINGS: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29-146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0- 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25-1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39-1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65-1·60]; p=0·92). INTERPRETATION: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention. FUNDING: British Heart Foundation.
背景:抗血小板治疗可降低闭塞性血管疾病患者发生主要血管事件的风险,但可能增加颅内出血的风险。存活最常见的颅内出血(脑出血)亚型的患者存在出血和闭塞性血管事件的双重风险,但抗血小板治疗是否可以安全使用尚不清楚。本研究旨在评估抗血小板治疗对复发性脑出血的相对和绝对影响,以及这种风险是否可能超过任何减少闭塞性血管事件的效果。
方法:REstart 或 STop 抗血栓随机试验(RESTART)是一项在英国 122 家医院进行的前瞻性、随机、开放标签、盲终点、平行组试验。我们招募了正在服用抗血栓(抗血小板或抗凝)药物预防闭塞性血管疾病的成年人(≥18 岁),当他们发生脑出血时停止抗血栓治疗并存活 24 小时。采用包含最小化的计算机随机化,将参与者(1:1)随机分配至开始或避免抗血小板治疗。我们对参与者进行了长达 5 年的主要结局(复发性症状性脑出血)随访。我们使用 Cox 比例风险回归分析了所有随机参与者的数据,调整了最小化协变量。本试验在 ISRCTN 注册(注册号 ISRCTN71907627)。
结果:2013 年 5 月 22 日至 2018 年 5 月 31 日期间,共有 537 名参与者入组,脑出血发病后中位数 76 天(IQR 29-146):268 名参与者被分配至开始治疗组,269 名(1 名退出)被分配至避免抗血小板治疗组。参与者中位随访时间为 2.0 年(IQR [1.0-3.0];完整性 99.3%)。268 名接受抗血小板治疗的参与者中有 12 名(4%)发生脑出血复发,而 268 名避免抗血小板治疗的参与者中有 23 名(9%)(调整后的危险比 0.51 [95%CI 0.25-1.03];p=0.060)。268 名接受抗血小板治疗的参与者中有 18 名(7%)发生大出血事件,而 268 名避免抗血小板治疗的参与者中有 25 名(9%)(0.71 [0.39-1.30];p=0.27),268 名接受抗血小板治疗的参与者中有 39 名(15%)发生主要闭塞性血管事件,而 268 名避免抗血小板治疗的参与者中有 38 名(14%)(1.02 [0.65-1.60];p=0.92)。
结论:这些结果排除了抗血小板治疗对复发性脑出血风险的增加,除了非常微小的增加,对于正在服用抗血栓药物预防闭塞性血管疾病的患者,当他们发生脑出血时,抗血小板治疗可能会增加脑出血的风险。复发性脑出血的风险可能太小,无法超过抗血小板治疗对二级预防的既定益处。
资金:英国心脏基金会。
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