Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
Lancet. 2014 Mar 15;383(9921):955-62. doi: 10.1016/S0140-6736(13)62343-0. Epub 2013 Dec 4.
Four new oral anticoagulants compare favourably with warfarin for stroke prevention in patients with atrial fibrillation; however, the balance between efficacy and safety in subgroups needs better definition. We aimed to assess the relative benefit of new oral anticoagulants in key subgroups, and the effects on important secondary outcomes.
We searched Medline from Jan 1, 2009, to Nov 19, 2013, limiting searches to phase 3, randomised trials of patients with atrial fibrillation who were randomised to receive new oral anticoagulants or warfarin, and trials in which both efficacy and safety outcomes were reported. We did a prespecified meta-analysis of all 71,683 participants included in the RE-LY, ROCKET AF, ARISTOTLE, and ENGAGE AF-TIMI 48 trials. The main outcomes were stroke and systemic embolic events, ischaemic stroke, haemorrhagic stroke, all-cause mortality, myocardial infarction, major bleeding, intracranial haemorrhage, and gastrointestinal bleeding. We calculated relative risks (RRs) and 95% CIs for each outcome. We did subgroup analyses to assess whether differences in patient and trial characteristics affected outcomes. We used a random-effects model to compare pooled outcomes and tested for heterogeneity.
42,411 participants received a new oral anticoagulant and 29,272 participants received warfarin. New oral anticoagulants significantly reduced stroke or systemic embolic events by 19% compared with warfarin (RR 0·81, 95% CI 0·73-0·91; p<0·0001), mainly driven by a reduction in haemorrhagic stroke (0·49, 0·38-0·64; p<0·0001). New oral anticoagulants also significantly reduced all-cause mortality (0·90, 0·85-0·95; p=0·0003) and intracranial haemorrhage (0·48, 0·39-0·59; p<0·0001), but increased gastrointestinal bleeding (1·25, 1·01-1·55; p=0·04). We noted no heterogeneity for stroke or systemic embolic events in important subgroups, but there was a greater relative reduction in major bleeding with new oral anticoagulants when the centre-based time in therapeutic range was less than 66% than when it was 66% or more (0·69, 0·59-0·81 vs 0·93, 0·76-1·13; p for interaction 0·022). Low-dose new oral anticoagulant regimens showed similar overall reductions in stroke or systemic embolic events to warfarin (1·03, 0·84-1·27; p=0·74), and a more favourable bleeding profile (0·65, 0·43-1·00; p=0·05), but significantly more ischaemic strokes (1·28, 1·02-1·60; p=0·045).
This meta-analysis is the first to include data for all four new oral anticoagulants studied in the pivotal phase 3 clinical trials for stroke prevention or systemic embolic events in patients with atrial fibrillation. New oral anticoagulants had a favourable risk-benefit profile, with significant reductions in stroke, intracranial haemorrhage, and mortality, and with similar major bleeding as for warfarin, but increased gastrointestinal bleeding. The relative efficacy and safety of new oral anticoagulants was consistent across a wide range of patients. Our findings offer clinicians a more comprehensive picture of the new oral anticoagulants as a therapeutic option to reduce the risk of stroke in this patient population.
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在预防房颤患者的卒中方面，四种新型口服抗凝剂与华法林相比具有明显优势；然而，在亚组人群中，需要更好地明确其疗效和安全性之间的平衡。我们旨在评估新型口服抗凝剂在关键亚组人群中的相对获益，以及对重要次要结局的影响。
我们从 2009 年 1 月 1 日至 2013 年 11 月 19 日检索了 Medline 数据库，将搜索范围限定为房颤患者的 3 期、随机试验，这些患者被随机分配接受新型口服抗凝剂或华法林治疗，且试验中同时报告了疗效和安全性结局。我们对来自 RE-LY、ROCKET AF、ARISTOTLE 和 ENGAGE AF-TIMI 48 试验的 71683 名参与者进行了预设的荟萃分析。主要结局为卒中及全身性栓塞事件、缺血性卒中和出血性卒中、全因死亡率、心肌梗死、大出血、颅内出血和胃肠道出血。我们计算了每个结局的相对风险（RR）和 95%置信区间（CI）。我们进行了亚组分析，以评估患者和试验特征的差异是否影响结局。我们使用随机效应模型比较汇总结局，并检测异质性。
42411 名参与者接受了新型口服抗凝剂治疗，29272 名参与者接受了华法林治疗。与华法林相比，新型口服抗凝剂显著降低了 19%的卒中或全身性栓塞事件风险（RR 0.81，95%CI 0.73-0.91；p<0.0001），主要是通过降低出血性卒中（0.49，0.38-0.64；p<0.0001）来实现。新型口服抗凝剂也显著降低了全因死亡率（0.90，0.85-0.95；p=0.0003）和颅内出血（0.48，0.39-0.59；p<0.0001），但增加了胃肠道出血（1.25，1.01-1.55；p=0.04）。我们注意到，在重要的亚组中，卒中或全身性栓塞事件没有异质性，但当中心治疗时间在治疗范围内小于 66%时，新型口服抗凝剂的大出血相对减少更多（0.69，0.59-0.81 比 0.93，0.76-1.13；p 交互作用=0.022）。低剂量新型口服抗凝剂方案与华法林相比，总体上降低了卒中或全身性栓塞事件（1.03，0.84-1.27；p=0.74），且出血风险更小（0.65，0.43-1.00；p=0.05），但显著增加了缺血性卒中（1.28，1.02-1.60；p=0.045）。
本荟萃分析是第一项包括所有四种新型口服抗凝剂在预防房颤患者卒中或全身性栓塞事件的关键性 3 期临床试验数据的分析。新型口服抗凝剂具有有利的风险效益比，可显著降低卒中、颅内出血和死亡率，且大出血与华法林相似，但增加了胃肠道出血。新型口服抗凝剂的相对疗效和安全性在广泛的患者人群中是一致的。我们的研究结果为临床医生提供了一个更全面的新型口服抗凝剂作为降低该患者人群卒中风险的治疗选择。
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