Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
Rivaroxaban or aspirin for patent foramen ovale and embolic stroke of undetermined source: a prespecified subgroup analysis from the NAVIGATE ESUS trial.
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DOI：
10.1016/s1474-4422(18)30319-3
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发表时间：
2018-12
期刊：
影响因子：
--
通讯作者：
NAVIGATE ESUS Investigators
中科院分区：
文献类型：
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作者：
Kasner SE;Swaminathan B;Lavados P;Sharma M;Muir K;Veltkamp R;Ameriso SF;Endres M;Lutsep H;Messé SR;Spence JD;Nedeltechev K;Perera K;Santo G;Olavarria V;Lindgren A;Bangdiwala S;Shoamanesh A;Berkowitz SD;Mundl H;Connolly SJ;Hart RG;NAVIGATE ESUS Investigators
卵圆孔未闭（PFO）是不明原因栓塞性卒中（ESUS）的诱因。既往研究的亚组分析表明，与抗血小板治疗相比，抗凝治疗可减少卒中复发。我们假设，在入组NAVIGATE ESUS试验的PFO患者中，与阿司匹林相比，利伐沙班（一种口服Xa因子抑制剂）抗凝治疗可降低复发性缺血性卒中的风险。NAVIGATE ESUS是一项在31个国家的459个中心进行的双盲、随机、III期试验，旨在评估利伐沙班与阿司匹林相比用于ESUS患者二级卒中预防的疗效和安全性。对于这一预先规定的亚组分析，根据经胸超声心动图（TTE）和经食管超声心动图（TOE）定义有和无PFO的队列。主要疗效结局为治疗组间至缺血性卒中复发的时间。根据国际血栓和止血学会的标准，主要安全性结局是大出血。主要分析基于意向治疗人群。此外，我们对隐源性卒中和PFO患者随机接受抗凝或抗血小板治疗的研究进行了系统回顾和随机效应荟萃分析。在2014年12月23日至2017年9月20日期间，7213名参与者入组并分配接受利伐沙班（n=3609）或阿司匹林（n=3604）。由于试验提前终止，患者平均随访11个月。根据TTE或TOE，534例（7.4%）患者报告存在PFO。接受阿司匹林治疗的PFO患者的缺血性卒中复发率为4.8例/100人年，而接受利伐沙班治疗的患者为2.6例/100人年。在已知有PFO的患者中，没有足够的证据支持利伐沙班和阿司匹林之间缺血性卒中复发风险的差异（风险比[HR] 0.54; 95%CI 0.22 - 1.36），而在无已知PFO的患者中，风险相似（1.06; 0.84 - 1.33; pinteraction= 0.18）。在检测到PFO的患者（HR 2.05; 95% CI 0.51 - 8.18）和未检测到PFO的患者（HR 2.82; 95% CI 1.69 - 4.70; pinteraction= 0.68）中，利伐沙班与阿司匹林的大出血风险相似。随机效应荟萃分析将来自NAVIGATE ESUS的数据与来自先前两项试验（PICSS和CLOSE）的数据相结合，得出缺血性卒中的总体比值比为0·48（95% CI 0·24-0·96; p=0·04），有利于抗凝治疗，无异质性证据。在合并PFO的ESUS患者中，抗凝治疗可能将复发性卒中的风险降低约一半，尽管仍存在很大的不精确性。抗凝治疗与抗血小板治疗或PFO封堵术或两者的专门试验是必要的。拜耳和杨森。
Patent foramen ovale (PFO) is a contributor to embolic stroke of undetermined source (ESUS). Subgroup analyses from previous studies suggest that anticoagulation could reduce recurrent stroke compared with antiplatelet therapy. We hypothesised that anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, would reduce the risk of recurrent ischaemic stroke compared with aspirin among patients with PFO enrolled in the NAVIGATE ESUS trial. NAVIGATE ESUS was a double-blinded, randomised, phase 3 trial done at 459 centres in 31 countries that assessed the efficacy and safety of rivaroxaban versus aspirin for secondary stroke prevention in patients with ESUS. For this prespecified subgroup analysis, cohorts with and without PFO were defined on the basis of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE). The primary efficacy outcome was time to recurrent ischaemic stroke between treatment groups. The primary safety outcome was major bleeding, according to the criteria of the International Society of Thrombosis and Haemostasis. The primary analyses were based on the intention-to-treat population. Additionally, we did a systematic review and random-effects meta-analysis of studies in which patients with cryptogenic stroke and PFO were randomly assigned to receive anticoagulant or antiplatelet therapy. Between Dec 23, 2014, and Sept 20, 2017, 7213 participants were enrolled and assigned to receive rivaroxaban (n=3609) or aspirin (n=3604). Patients were followed up for a mean of 11 months because of early trial termination. PFO was reported as present in 534 (7·4%) patients on the basis of either TTE or TOE. Patients with PFO assigned to receive aspirin had a recurrent ischaemic stroke rate of 4·8 events per 100 person-years compared with 2 ·6 events per 100 person-years in those treated with rivaroxaban. Among patients with known PFO, there was insufficient evidence to support a difference in risk of recurrent ischaemic stroke between rivaroxaban and aspirin (hazard ratio [HR] 0·54; 95% CI 0·22–1·36), and the risk was similar for those without known PFO (1·06; 0·84–1·33; pinteraction=0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51–8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69–4·70; pinteraction=0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24–0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity. Among patients with ESUS who have PFO, anticoagulation might reduce the risk of recurrent stroke by about half, although substantial imprecision remains. Dedicated trials of anticoagulation versus antiplatelet therapy or PFO closure, or both, are warranted. Bayer and Janssen.