Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada; Department of Medicine, McMaster University, Hamilton, ON, Canada.
Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada; School of Rehabilitation Sciences, McMaster University, Hamilton, ON, Canada.
Lancet. 2018 Jan 20;391(10117):219-229. doi: 10.1016/S0140-6736(17)32409-1. Epub 2017 Nov 10.
Patients with peripheral artery disease have an increased risk of cardiovascular morbidity and mortality. Antiplatelet agents are widely used to reduce these complications.
This was a multicentre, double-blind, randomised placebo-controlled trial for which patients were recruited at 602 hospitals, clinics, or community practices from 33 countries across six continents. Eligible patients had a history of peripheral artery disease of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, intermittent claudication with objective evidence of peripheral artery disease), of the carotid arteries (previous carotid artery revascularisation or asymptomatic carotid artery stenosis of at least 50%), or coronary artery disease with an ankle-brachial index of less than 0·90. After a 30-day run-in period, patients were randomly assigned (1:1:1) to receive oral rivaroxaban (2·5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban twice a day (5 mg with aspirin placebo once a day), or to aspirin once a day (100 mg and rivaroxaban placebo twice a day). Randomisation was computer generated. Each treatment group was double dummy, and the patient, investigators, and central study staff were masked to treatment allocation. The primary outcome was cardiovascular death, myocardial infarction or stroke; the primary peripheral artery disease outcome was major adverse limb events including major amputation. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.
Between March 12, 2013, and May 10, 2016, we enrolled 7470 patients with peripheral artery disease from 558 centres. The combination of rivaroxaban plus aspirin compared with aspirin alone reduced the composite endpoint of cardiovascular death, myocardial infarction, or stroke (126 [5%] of 2492 vs 174 [7%] of 2504; hazard ratio [HR] 0·72, 95% CI 0·57-0·90, p=0·0047), and major adverse limb events including major amputation (32 [1%] vs 60 [2%]; HR 0·54 95% CI 0·35-0·82, p=0·0037). Rivaroxaban 5 mg twice a day compared with aspirin alone did not significantly reduce the composite endpoint (149 [6%] of 2474 vs 174 [7%] of 2504; HR 0·86, 95% CI 0·69-1·08, p=0·19), but reduced major adverse limb events including major amputation (40 [2%] vs 60 [2%]; HR 0·67, 95% CI 0·45-1·00, p=0·05). The median duration of treatment was 21 months. The use of the rivaroxaban plus aspirin combination increased major bleeding compared with the aspirin alone group (77 [3%] of 2492 vs 48 [2%] of 2504; HR 1·61, 95% CI 1·12-2·31, p=0·0089), which was mainly gastrointestinal. Similarly, major bleeding occurred in 79 (3%) of 2474 patients with rivaroxaban 5 mg, and in 48 (2%) of 2504 in the aspirin alone group (HR 1·68, 95% CI 1·17-2·40; p=0·0043).
Low-dose rivaroxaban taken twice a day plus aspirin once a day reduced major adverse cardiovascular and limb events when compared with aspirin alone. Although major bleeding was increased, fatal or critical organ bleeding was not. This combination therapy represents an important advance in the management of patients with peripheral artery disease. Rivaroxaban alone did not significantly reduce major adverse cardiovascular events compared with asprin alone, but reduced major adverse limb events and increased major bleeding.
Bayer AG.
外周动脉疾病患者心血管发病率和死亡率增加。抗血小板药物广泛用于降低这些并发症。
这是一项多中心、双盲、随机、安慰剂对照试验，在六大洲 33 个国家的 602 家医院、诊所或社区诊所招募患者。符合条件的患者有下肢外周动脉疾病（下肢旁路手术或血管成形术、肢体或足部截肢、间歇性跛行并有外周动脉疾病的客观证据）、颈动脉（颈动脉再通或无症状颈动脉狭窄至少 50%）或冠状动脉疾病，踝肱指数<0.90。在 30 天的导入期后，患者随机分为（1:1:1）接受口服利伐沙班（每日两次 2.5 毫克）加阿司匹林（每日一次 100 毫克）、每日两次利伐沙班（每日一次 5 毫克加阿司匹林安慰剂）或每日一次阿司匹林（每日一次 100 毫克加利伐沙班安慰剂）。随机化是通过计算机生成的。每组治疗均采用双盲设计，患者、研究者和中央研究人员对治疗分配均不知情。主要终点是心血管死亡、心肌梗死或中风；主要外周动脉疾病结果是主要不良肢体事件，包括主要截肢。这项试验在 ClinicalTrials.gov 上注册，编号为 NCT01776424，目前已对新参与者关闭。
2013 年 3 月 12 日至 2016 年 5 月 10 日期间，我们从 558 个中心招募了 7470 例外周动脉疾病患者。与阿司匹林单药治疗相比，利伐沙班加阿司匹林联合治疗降低了心血管死亡、心肌梗死或中风的复合终点（2492 例患者中 126 例[5%]与 2504 例患者中 174 例[7%]；风险比[HR]0.72，95%CI0.57-0.90，p=0.0047），并降低了主要不良肢体事件，包括主要截肢（32 例[1%]与 60 例[2%]；HR0.54，95%CI0.35-0.82，p=0.0037）。与阿司匹林单药治疗相比，利伐沙班 5mg 每日两次治疗并未显著降低复合终点（2474 例患者中 149 例[6%]与 2504 例患者中 174 例[7%]；HR0.86，95%CI0.69-1.08，p=0.19），但降低了主要不良肢体事件，包括主要截肢（40 例[2%]与 60 例[2%]；HR0.67，95%CI0.45-1.00，p=0.05）。中位治疗时间为 21 个月。与阿司匹林单药治疗相比，利伐沙班加阿司匹林联合治疗增加了大出血（2492 例患者中 77 例[3%]与 2504 例患者中 48 例[2%]；HR1.61，95%CI1.12-2.31，p=0.0089），主要是胃肠道。同样，2474 例利伐沙班 5mg 治疗患者中有 79 例（3%）和 2504 例阿司匹林单药治疗患者中有 48 例（2%）发生大出血（HR1.68，95%CI1.17-2.40；p=0.0043）。
每日两次 5mg 利伐沙班加每日一次阿司匹林治疗与阿司匹林单药治疗相比，降低了主要不良心血管和肢体事件。尽管大出血增加，但致命或关键器官出血并未增加。这种联合治疗代表了外周动脉疾病患者管理的重要进展。与阿司匹林单药治疗相比，每日两次利伐沙班治疗并未显著降低主要不良心血管事件，但降低了主要不良肢体事件，增加了大出血。
拜耳公司。
