Medical School, The University of Edinburgh, Edinburgh, UK.
The George Institute for Global Health, Faculty of Medicine, UNSW, Sydney, Australia.
Cochrane Database Syst Rev. 2023 Jan 26;1(1):CD012144. doi: 10.1002/14651858.CD012144.pub3.
BACKGROUND: This is an update of the Cochrane Review last published in 2017. Survivors of stroke due to intracerebral haemorrhage (ICH) are at risk of major adverse cardiovascular events (MACE). Antithrombotic (antiplatelet or anticoagulant) treatments may lower the risk of ischaemic MACE after ICH, but they may increase the risk of bleeding. OBJECTIVES: To determine the overall effectiveness and safety of antithrombotic drugs on MACE and its components for people with ICH. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (5 October 2021). We also searched the Cochrane Central Register of Controlled Trials (CENTRAL: the Cochrane Library 2021, Issue 10), MEDLINE Ovid (from 1948 to October 2021) and Embase Ovid (from 1980 to October 2021). The online registries of clinical trials searched were the US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (5 October 2021). We screened the reference lists of included randomised controlled trials (RCTs) for additional, potentially relevant RCTs. SELECTION CRITERIA: We selected RCTs in which participants with ICH of any age were allocated to a class of antithrombotic treatment as intervention or comparator. DATA COLLECTION AND ANALYSIS: In accordance with standard methodological procedures recommended by Cochrane, two review authors assessed each selected RCT for its risk of bias and extracted data independently. The primary outcome was a composite of MACE, and secondary outcomes included death, individual components of the MACE composite, ICH growth, functional status and cognitive status. We estimated effects using the frequency of outcomes that occurred during the entire duration of follow-up and calculated a risk ratio (RR) for each RCT. We grouped RCTs separately for analysis according to 1) the class(es) of antithrombotic treatment used for the intervention and comparator, and 2) the duration of antithrombotic treatment use (short term versus long term). We pooled the intention-to-treat populations of RCTs using a fixed-effect model for meta-analysis, but used a random-effects model if RCTs differed substantially in their design or there was considerable heterogeneity (I ≥ 75%) in their results. We applied GRADE to assess the certainty of the evidence. MAIN RESULTS: We identified seven new completed RCTs for this update, resulting in the inclusion of a total of nine RCTs based in secondary care, comprising 1491 participants (average age ranged from 61 to 79 years and the proportion of men ranged from 44% to 67%). The proportion of included RCTs at low risk of bias, by category was: random sequence generation (67%), allocation concealment (67%), performance (22%), detection (78%), attrition (89%), and reporting (78%). For starting versus avoiding short-term prophylactic dose anticoagulation after ICH, no RCT reported MACE. The evidence is very uncertain about the effect of starting short-term prophylactic dose anticoagulation on death (RR 1.00, 95% CI 0.59 to 1.70, P = 1.00; 3 RCTs; very low-certainty evidence), venous thromboembolism (RR 0.84, 95% CI 0.51 to 1.37, P = 0.49; 4 RCTs; very low-certainty evidence), ICH (RR 0.24, 95% CI 0.04 to 1.38, P = 0.11; 2 RCTs; very low-certainty evidence), and independent functional status (RR 2.03, 95% CI 0.78 to 5.25, P = 0.15; 1 RCT; very low-certainty evidence) over 90 days. For starting versus avoiding long-term therapeutic dose oral anticoagulation for atrial fibrillation after ICH, starting long-term therapeutic dose oral anticoagulation probably reduces MACE (RR 0.61, 95% CI 0.40 to 0.94, P = 0.02; 3 RCTs; moderate-certainty evidence) and probably reduces all major occlusive vascular events (RR 0.27, 95% CI 0.14 to 0.53, P = 0.0002; 3 RCTs; moderate-certainty evidence), but probably results in little to no difference in death (RR 1.05, 95% CI 0.62 to 1.78, P = 0.86; 3 RCTs; moderate-certainty evidence), probably increases intracranial haemorrhage (RR 2.43, 95% CI 0.88 to 6.73, P = 0.09; 3 RCTs; moderate-certainty evidence), and may result in little to no difference in independent functional status (RR 0.98, 95% CI 0.78 to 1.24, P = 0.87; 2 RCTs; low-certainty evidence) over one to three years. For starting versus avoiding long-term antiplatelet therapy after ICH, the evidence is uncertain about the effects of starting long-term antiplatelet therapy on MACE (RR 0.89, 95% CI 0.64 to 1.22, P = 0.46; 1 RCT; moderate-certainty evidence), death (RR 1.08, 95% CI 0.76 to 1.53, P = 0.66; 1 RCT; moderate-certainty evidence), all major occlusive vascular events (RR 1.03, 95% CI 0.68 to 1.55, P = 0.90; 1 RCT; moderate-certainty evidence), ICH (RR 0.52, 95% CI 0.27 to 1.03, P = 0.06; 1 RCT; moderate-certainty evidence) and independent functional status (RR 0.95, 95% CI 0.77 to 1.18, P = 0.67; 1 RCT; moderate-certainty evidence) over a median follow-up of two years. For adults within 180 days of non-cardioembolic ischaemic stroke or transient ischaemic attack and a clinical history of prior ICH, there was no evidence of an effect of long-term cilostazol compared to aspirin on MACE (RR 1.33, 95% CI 0.74 to 2.40, P = 0.34; subgroup of 1 RCT; low-certainty evidence), death (RR 1.65, 95% CI 0.55 to 4.91, P = 0.37; subgroup of 1 RCT; low-certainty evidence), or ICH (RR 1.29, 95% CI 0.35 to 4.69, P = 0.70; subgroup of 1 RCT; low-certainty evidence) over a median follow-up of 1.8 years; all major occlusive vascular events and functional status were not reported. AUTHORS' CONCLUSIONS: We did not identify beneficial or hazardous effects of short-term prophylactic dose parenteral anticoagulation and long-term oral antiplatelet therapy after ICH on important outcomes. Although there was a significant reduction in MACE and all major occlusive vascular events after long-term treatment with therapeutic dose oral anticoagulation for atrial fibrillation after ICH, the pooled estimates were imprecise, the certainty of evidence was only moderate, and effects on other important outcomes were uncertain. Large RCTs with a low risk of bias are required to resolve the ongoing dilemmas about antithrombotic treatment after ICH.
背景:这是 Cochrane 综述的更新版本,上次发表于 2017 年。脑出血(ICH)后幸存的中风患者存在发生主要不良心血管事件(MACE)的风险。抗血栓(抗血小板或抗凝)治疗可能降低 ICH 后缺血性 MACE 的风险,但可能增加出血的风险。 目的:确定抗血栓药物对 ICH 患者的 MACE 及其组成部分的总体有效性和安全性。 检索方法:我们检索了 Cochrane 卒中组试验登记处(2021 年 10 月 5 日)。我们还检索了 Cochrane 中央对照试验注册库(CENTRAL:Cochrane 图书馆 2021 年第 10 期)、Medline Ovid(1948 年至 2021 年 10 月)和 Embase Ovid(1980 年至 2021 年 10 月)。检索的临床试验在线注册处包括美国国立卫生研究院正在进行的临床试验注册ClinicalTrials.gov(clinicaltrials.gov)和世界卫生组织(WHO)国际临床试验注册平台(ICTRP)(2021 年 10 月 5 日)。我们筛选了纳入的随机对照试验(RCT)的参考文献,以寻找其他可能相关的 RCT。 选择标准:我们选择了参与者为任何年龄的 ICH 患者的 RCT,将其随机分配到抗血栓治疗的一类作为干预或比较。 数据收集和分析:根据 Cochrane 推荐的标准方法学程序,两名综述作者对每个入选的 RCT 进行了偏倚风险评估,并独立提取数据。主要结局是 MACE 的复合结局,次要结局包括死亡、MACE 复合结局的各个组成部分、ICH 进展、功能状态和认知状态。我们使用整个随访期间发生的结局频率估计效果,并计算每个 RCT 的风险比(RR)。我们根据 1)抗血栓治疗的类别(干预和比较),2)抗血栓治疗的持续时间(短期与长期),将 RCT 分别分组进行分析。对于 RCT 的意向治疗人群,我们使用固定效应模型进行荟萃分析,但如果 RCT 在设计上存在很大差异或结果存在很大异质性(I ≥ 75%),则使用随机效应模型。我们应用 GRADE 评估证据的确定性。 主要结果:我们确定了 7 项新完成的 RCT,因此共纳入了 9 项基于二级护理的 RCT,共纳入 1491 名参与者(平均年龄为 61 至 79 岁,男性比例为 44%至 67%)。按类别划分,纳入 RCT 的偏倚风险比例分别为:随机序列生成(67%)、分配隐藏(67%)、执行(22%)、检测(78%)、失访(89%)和报告(78%)。对于脑出血后开始与避免短期预防性剂量抗凝治疗,没有 RCT 报告 MACE。开始短期预防性剂量抗凝治疗对死亡(RR 1.00,95%CI 0.59 至 1.70,P = 1.00;3 项 RCT;极低确定性证据)、静脉血栓栓塞(RR 0.84,95%CI 0.51 至 1.37,P = 0.49;4 项 RCT;极低确定性证据)、ICH(RR 0.24,95%CI 0.04 至 1.38,P = 0.11;2 项 RCT;极低确定性证据)和独立功能状态(RR 2.03,95%CI 0.78 至 5.25,P = 0.15;1 项 RCT;极低确定性证据)的影响的证据非常不确定,随访时间为 90 天。对于脑出血后开始与避免长期治疗剂量口服抗凝治疗心房颤动,开始长期治疗剂量口服抗凝治疗可能降低 MACE(RR 0.61,95%CI 0.40 至 0.94,P = 0.02;3 项 RCT;中等确定性证据)和所有主要闭塞性血管事件(RR 0.27,95%CI 0.14 至 0.53,P = 0.0002;3 项 RCT;中等确定性证据),但可能导致死亡(RR 1.05,95%CI 0.62 至 1.78,P = 0.86;3 项 RCT;中等确定性证据)、颅内出血(RR 2.43,95%CI 0.88 至 6.73,P = 0.09;3 项 RCT;中等确定性证据)和独立功能状态(RR 0.98,95%CI 0.78 至 1.24,P = 0.87;2 项 RCT;低确定性证据)的差异不大,随访时间为 1 至 3 年。对于脑出血后开始与避免长期抗血小板治疗,开始长期抗血小板治疗对 MACE(RR 0.89,95%CI 0.64 至 1.22,P = 0.46;1 项 RCT;中等确定性证据)、死亡(RR 1.08,95%CI 0.76 至 1.53,P = 0.66;1 项 RCT;中等确定性证据)、所有主要闭塞性血管事件(RR 1.03,95%CI 0.68 至 1.55,P = 0.90;1 项 RCT;中等确定性证据)、ICH(RR 0.52,95%CI 0.27 至 1.03,P = 0.06;1 项 RCT;中等确定性证据)和独立功能状态(RR 0.95,95%CI 0.77 至 1.18,P = 0.67;1 项 RCT;中等确定性证据)的影响的证据不确定,随访时间为两年。对于 180 天内非心源性缺血性中风或短暂性脑缺血发作且有先前 ICH 临床病史的成年人,与阿司匹林相比,长期使用西洛他唑并没有证据表明对 MACE(RR 1.33,95%CI 0.74 至 2.40,P = 0.34;1 项 RCT;低确定性证据)、死亡(RR 1.65,95%CI 0.55 至 4.91,P = 0.37;1 项 RCT;低确定性证据)或 ICH(RR 1.29,95%CI 0.35 至 4.69,P = 0.70;1 项 RCT;低确定性证据)有影响,随访时间为 1.8 年;所有主要闭塞性血管事件和功能状态均未报告。 作者结论:我们没有发现脑出血后短期预防性剂量抗凝和长期抗血小板治疗对重要结局有有益或有害的影响。尽管长期治疗心房颤动时使用治疗剂量的口服抗凝剂显著降低了 MACE 和所有主要闭塞性血管事件,但汇总估计值不精确,证据确定性仅为中等,对其他重要结局的影响也不确定。需要进行低偏倚风险的大型 RCT 来解决脑出血后抗血栓治疗方面的持续争议。
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