Almutairi Abdulaali R, Zhou Lili, Gellad Walid F, Lee Jeannie K, Slack Marion K, Martin Jennifer R, Lo-Ciganic Wei-Hsuan
Department of Pharmacy Practice and Science, College of Pharmacy, University of Arizona, Tucson, Arizona.
Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; Center for Health Equity Research Promotion, Veterans Affairs Pittsburgh Healthcare System, Pittsburgh, Pennsylvania.
Clin Ther. 2017 Jul;39(7):1456-1478.e36. doi: 10.1016/j.clinthera.2017.05.358. Epub 2017 Jun 28.
The findings from the observational studies comparing the effectiveness and safety of non-vitamin K antagonist oral anticoagulants (NOACs) versus vitamin K antagonists (VKAs) for atrial fibrillation (AF) and venous thromboembolism (VTE) are inconsistent. We conducted separate meta-analyses examining the efficacy/effectiveness and safety of NOACs versus VKAs by disease (AF vs VTE), study design (randomized controlled trials [RCTs] vs observational studies), and NOAC (dabigatran, rivaroxaban, apixaban, and edoxaban).
The main data sources included PubMed/MEDLINE, EMBASE, Web of Science, CINAHL, and Scopus from January 1, 2005, to February 15, 2016. We searched for Phase III RCTs and observational studies comparing NOACs versus VKAs. The primary outcomes were stroke/systemic embolism (SE) for AF; recurrent VTE/fatal pulmonary embolism (PE) for VTE; and major bleeding for both conditions. Secondary outcomes included stroke and myocardial infarction (MI) for AF, recurrent deep vein thrombosis (DVT)/PE for VTE, and mortality, intracranial hemorrhage (ICH), and gastrointestinal bleeding for both conditions. Pooled hazard ratios (HRs) were reported by using inverse variance-weighted random effects models.
A total of 13 RCTs and 27 observational studies (AF, n = 32; VTE, n = 8) were included. For AF, dabigatran and VKAs were comparable for stroke/SE risk in 1 RCT (HR, 0.77 [95% CI, 0.57-1.03]) and 6 observational studies (HR, 1.03 [95% CI, 0.83-1.27]). Rivaroxaban had a 20% decreased risk of stroke/SE in 3 RCTs (HR, 0.80 [95% CI, 0.67-0.95]) compared with VKA, but the effect was nonsignificant in 3 observational studies (HR, 0.78 [95% CI, 0.59-1.04]). Apixaban decreased stroke/systemic embolism risk (HR, 0.79 [95% CI, 0.66-0.95]) compared with VKA in 1 RCT, but edoxaban was comparable to VKA (HR, 0.99 [95% CI, 0.77-1.28]) in 1 RCT (no observational studies available for apixaban/edoxaban). Dabigatran, apixaban, and edoxaban decreased the risk of hemorrhagic stroke, mortality, major bleeding, and ICH by 10% to 71% compared with VKAs but not rivaroxaban. For VTE, NOACs and VKAs were comparable for recurrent VTE/fatal PE/DVT/PE risk in 7 RCTs and 1 observational study. The 7 RCTs demonstrated a 32% to 69% decreased risk of major bleeding for dabigatran, rivaroxaban, and apixaban compared with VKAs. No difference was shown in 1 rivaroxaban observational study (HR, 0.77 [95% CI, 0.40-1.49]) and 1 edoxaban RCT (HR, 0.84 [95% CI, 0.59-1.20]). Except for dabigatran, the NOACs had a 61% to 86% decreased risk of ICH and gastrointestinal bleeding.
Overall, NOACs were comparable or superior to VKAs. Although no observational studies are currently available for apixaban/edoxaban, a few notable inconsistencies exist for dabigatran (ischemic stroke, MI) and rivaroxaban (stroke/SE, major bleeding in VTE) between RCTs and observational studies. Individualizing NOAC/VKA therapy based on benefit/safety profiles and patient characteristics is suggested.
关于非维生素K拮抗剂口服抗凝药（NOACs）与维生素K拮抗剂（VKAs）用于心房颤动（AF）和静脉血栓栓塞（VTE）的有效性和安全性的观察性研究结果并不一致。我们通过疾病（AF与VTE）、研究设计（随机对照试验[RCTs]与观察性研究）以及NOAC（达比加群、利伐沙班、阿哌沙班和依度沙班）分别进行了荟萃分析，以检验NOACs与VKAs的疗效/有效性和安全性。
主要数据来源包括2005年1月1日至2016年2月15日期间的PubMed/MEDLINE、EMBASE、科学网、CINAHL和Scopus。我们检索了比较NOACs与VKAs的III期RCTs和观察性研究。主要结局为AF的卒中/全身性栓塞（SE）；VTE的复发性VTE/致命性肺栓塞（PE）；以及两种情况的大出血。次要结局包括AF的卒中和心肌梗死（MI）、VTE的复发性深静脉血栓形成（DVT）/PE，以及两种情况的死亡率、颅内出血（ICH）和胃肠道出血。采用逆方差加权随机效应模型报告合并风险比（HRs）。
共纳入13项RCTs和27项观察性研究（AF，n = 32；VTE，n = 8）。对于AF，在1项RCT（HR，0.77[95%CI，0.57 - 1.03]）和6项观察性研究（HR，1.03[95%CI，0.83 - 1.27]）中，达比加群和VKAs在卒中/SE风险方面相当。与VKA相比，利伐沙班在3项RCTs中卒中/SE风险降低了20%（HR，0.80[95%CI，0.67 - 0.95]），但在3项观察性研究中效果不显著（HR，0.78[95%CI，0.59 - 1.04]）。在1项RCT中，与VKA相比，阿哌沙班降低了卒中/全身性栓塞风险（HR，0.79[95%CI，0.66 - 0.95]），但在1项RCT中依度沙班与VKA相当（HR，0.99[95%CI，0.77 - 1.28]）（无关于阿哌沙班/依度沙班的观察性研究）。与VKAs相比，达比加群、阿哌沙班和依度沙班使出血性卒中、死亡率、大出血和ICH的风险降低了10%至71%，但利伐沙班未降低。对于VTE，在7项RCTs和1项观察性研究中，NOACs和VKAs在复发性VTE/致命性PE/DVT/PE风险方面相当。7项RCTs表明，与VKAs相比，达比加群、利伐沙班和阿哌沙班大出血风险降低了32%至69%。在1项利伐沙班观察性研究（HR，0.77[95%CI，0.40 - 1.49]）和1项依度沙班RCT（HR，0.84[B%CI，0.59 - 1.20]）中未显示差异。除达比加群外，NOACs使ICH和胃肠道出血风险降低了61%至86%。
总体而言，NOACs与VKAs相当或更优。尽管目前尚无关于阿哌沙班/依度沙班的观察性研究，但在RCTs和观察性研究之间，达比加群（缺血性卒中、MI）和利伐沙班（卒中/SE、VTE中的大出血）存在一些显著的不一致。建议根据获益/安全性概况和患者特征个体化使用NOAC/VKA治疗。
