Department of Neurology, Chang Gung University College of Medicine, Chang Gung Memorial Hospital, Keelung Branch, Taiwan.
Division of General Internal Medicine, Massachusetts General Hospital, and Harvard Medical School, Boston.
JAMA Neurol. 2018 Dec 1;75(12):1511-1518. doi: 10.1001/jamaneurol.2018.2215.
Non-vitamin K antagonist oral anticoagulants (NOACs) might be an attractive choice for stroke prevention in people without atrial fibrillation who may harbor a potential source of cardiac emboli, but not if certain individual NOACs carry risks of intracranial hemorrhage that are heightened relative to aspirin.
To conduct a systematic review and meta-analysis of randomized clinical trials to assess the risk of intracranial hemorrhage with individual NOACs vs aspirin across all indications.
We searched PubMed, Embase, CENTRAL, and ClinicalTrials.gov from inception to May 28, 2018, with the terms novel oral anticoagulants, non-vitamin K antagonist oral anticoagulants, direct oral anticoagulants, dabigatran, rivaroxaban, apixaban, edoxaban, warfarin, Coumadin, vitamin K antagonist, aspirin, acetylsalicylic acid, or ASA, and major bleeding, fatal bleeding, or intracranial hemorrhage. We restricted our search to clinical trials on humans. There were no language restrictions.
Randomized clinical trials of 3 months or longer that included a comparison of the outcomes of NOAC use vs use of aspirin.
Two investigators independently abstracted data from eligible studies. We computed a fixed-effect estimate based on the Mantel-Haenszel method.
Odds ratios (ORs) with 95% CI were used as a measure of the association of individual NOAC vs aspirin with the risk of intracranial hemorrhage. The hypothesis that intracranial hemorrhage risk would be higher with NOACs than aspirin was formulated during data collection.
Our principal analysis included 5 randomized clinical trials comparing 1 or more NOACs with aspirin, with 39 398 individuals enrolled. Pooling the results from the fixed-effects model showed that a dose of 15 to 20 mg of rivaroxaban once daily was associated with an increased risk of intracranial hemorrhage (2 trials; OR, 3.31 [95% CI, 1.42 to 7.72]) compared with aspirin, while a 10-mg dose of rivaroxaban once daily or a 5-mg dose twice daily (3 trials; OR, 1.43 [95% CI, 0.93 to 2.21]) and a 5-mg dose of apixaban twice daily (1 trial; OR, 0.84 [95% CI, 0.38 to 1.88]) were not.
A 15-mg to 20-mg dose of rivaroxaban once daily is associated with substantially increased risks of intracranial hemorrhage, while smaller daily doses of rivaroxaban and apixaban were not, implying that risk increase is dose dependent. It may be worthwhile to conduct randomized clinical trials comparing specific NOACs in specific doses (eg, apixaban, 5 mg twice daily) and aspirin in patients without atrial fibrillation, but with potential sources of cardiac emboli that could cause stroke.
对于没有心房颤动但可能存在潜在心源性栓子来源的患者，非维生素 K 拮抗剂口服抗凝剂（NOAC）可能是预防中风的一个有吸引力的选择，但如果某些特定的 NOAC 颅内出血风险相对于阿司匹林增加，则并非如此。
对随机临床试验进行系统评价和荟萃分析，以评估所有适应症下个体 NOAC 与阿司匹林相比颅内出血的风险。
我们从开始到 2018 年 5 月 28 日在 PubMed、Embase、CENTRAL 和 ClinicalTrials.gov 上搜索了新颖口服抗凝剂、非维生素 K 拮抗剂口服抗凝剂、直接口服抗凝剂、达比加群、利伐沙班、阿哌沙班、依度沙班、华法林、Coumadin、维生素 K 拮抗剂、阿司匹林、乙酰水杨酸或 ASA 以及大出血、致命性出血或颅内出血等术语的文章。我们将搜索范围限制在人类临床试验上。没有语言限制。
为期 3 个月或更长时间的随机临床试验，包括比较 NOAC 使用与阿司匹林使用的结果。
两名调查员独立从合格研究中提取数据。我们基于 Mantel-Haenszel 方法计算了固定效应估计值。
比值比（OR）及其 95%CI 用于衡量个体 NOAC 与阿司匹林相比颅内出血风险的关联。在数据收集过程中就提出了这样一种假设，即与阿司匹林相比，NOAC 的颅内出血风险更高。
我们的主要分析纳入了 5 项比较 1 种或多种 NOAC 与阿司匹林的随机临床试验，共有 39398 人参与。来自固定效应模型的汇总结果显示，每日一次 15 至 20 毫克利伐沙班（2 项试验；OR，3.31[95%CI，1.42 至 7.72]）与阿司匹林相比，颅内出血风险增加，而每日一次 10 毫克利伐沙班或每日两次 5 毫克（3 项试验；OR，1.43[95%CI，0.93 至 2.21]）和每日两次 5 毫克阿哌沙班（1 项试验；OR，0.84[95%CI，0.38 至 1.88]）则不然。
每日 15 至 20 毫克利伐沙班与颅内出血风险显著增加相关，而较小的每日剂量利伐沙班和阿哌沙班则不然，这表明风险增加与剂量有关。对于没有心房颤动但有潜在心源性栓子来源的患者，可能值得开展比较特定剂量的特定 NOAC（如阿哌沙班，每日两次 5 毫克）和阿司匹林的随机临床试验。
