CPC Clinical Research, Aurora, CO (W.R.H., M.P.B., M.R.N., W.H.C., T.B., N.J., C.N.H.).
University of Colorado School of Medicine, Division of Cardiology, Anschutz Medical Campus, Aurora (W.R.H., M.P.B., C.N.H.).
Circulation. 2020 Dec 8;142(23):2219-2230. doi: 10.1161/CIRCULATIONAHA.120.050465. Epub 2020 Nov 3.
The VOYAGER PAD trial (Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease) demonstrated superiority of rivaroxaban plus aspirin versus aspirin to reduce major cardiac and ischemic limb events after lower extremity revascularization. Clopidogrel is commonly used as a short-term adjunct to aspirin after endovascular revascularization. Whether clopidogrel modifies the efficacy and safety of rivaroxaban has not been described.
VOYAGER PAD was a phase 3, international, double-blind, placebo-controlled trial in patients with symptomatic PAD undergoing lower extremity revascularization randomized to rivaroxaban 2.5 mg twice daily plus 100 mg aspirin daily or rivaroxaban placebo plus aspirin. The primary efficacy outcome was a composite of acute limb ischemia, major amputation of a vascular cause, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety end point was TIMI (Thrombolysis in Myocardial Infarction) major bleeding, with International Society on Thrombosis and Haemostasis major bleeding a secondary safety outcome. Clopidogrel use was allowed at the discretion of the investigator for up to 6 months after the qualifying revascularization.
Of the randomized patients, 3313 (50.6%) received clopidogrel for a median duration of 29.0 days. Over 3 years, the hazard ratio for the primary outcome of rivaroxaban versus placebo was 0.85 (95% CI, 0.71-1.01) with clopidogrel and 0.86 (95% CI, 0.73-1.01) without clopidogrel without statistical heterogeneity ( for interaction=0.92). Rivaroxaban resulted in an early apparent reduction in acute limb ischemia within 30 days (hazard ratio, 0.45 [95% CI, 0.14-1.46] with clopidogrel; hazard ratio, 0.48 [95% CI, 0.22-1.01] without clopidogrel; for interaction=0.93). Compared with aspirin, rivaroxaban increased TIMI major bleeding similarly regardless of clopidogrel use ( for interaction=0.71). With clopidogrel use >30 days, rivaroxaban was associated with more International Society on Thrombosis and Haemostasis major bleeding within 365 days (hazard ratio, 3.20 [95% CI, 1.44-7.13]) compared with shorter durations of clopidogrel ( for trend=0.06).
In the VOYAGER PAD trial, rivaroxaban plus aspirin reduced the risk of adverse cardiovascular and limb events with an early benefit for acute limb ischemia regardless of clopidogrel use. The safety of rivaroxaban was consistent regardless of clopidogrel use but with a trend for more International Society on Thrombosis and Haemostasis major bleeding with clopidogrel use >30 days than with a shorter duration. These data support the addition of rivaroxaban to aspirin after lower extremity revascularization regardless of concomitant clopidogrel, with a short course (≤30 days) associated with less bleeding. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02504216.
VOYAGER PAD 试验（ASA 与利伐沙班在下肢血管重建术治疗外周动脉疾病中的血管结局研究）表明，与阿司匹林相比，利伐沙班加阿司匹林可降低下肢血管重建术后主要心脏和缺血性肢体事件的发生率。氯吡格雷通常作为血管内血管重建术后阿司匹林的短期辅助药物。氯吡格雷是否能改变利伐沙班的疗效和安全性尚未描述。
VOYAGER PAD 是一项国际、双盲、安慰剂对照的 3 期临床试验，研究对象为接受下肢血管重建术的有症状的 PAD 患者，随机分为每日两次口服 2.5mg 利伐沙班加 100mg 阿司匹林或利伐沙班安慰剂加阿司匹林。主要疗效终点是急性肢体缺血、血管原因导致的大截肢、心肌梗死、缺血性卒中和心血管死亡的复合终点。主要安全性终点是血栓溶解治疗心肌梗死（TIMI）大出血，国际血栓与止血学会大出血是次要安全性终点。允许研究者在血管重建后 6 个月内酌情使用氯吡格雷。
在随机分组的患者中，3313 例（50.6%）接受氯吡格雷治疗，中位治疗时间为 29.0 天。在 3 年期间，与安慰剂相比，利伐沙班的主要结局（心血管和肢体事件）的风险比为 0.85（95%CI，0.71-1.01），与氯吡格雷相关，0.86（95%CI，0.73-1.01），无统计学异质性（交互检验=0.92）。利伐沙班在 30 天内早期明显降低急性肢体缺血的发生率（氯吡格雷时，风险比为 0.45[95%CI，0.14-1.46]；无氯吡格雷时，风险比为 0.48[95%CI，0.22-1.01]；交互检验=0.93）。与阿司匹林相比，无论氯吡格雷的使用情况如何，利伐沙班均增加 TIMI 大出血的发生率（交互检验=0.71）。氯吡格雷使用时间>30 天时，利伐沙班在 365 天内的国际血栓与止血学会大出血发生率高于氯吡格雷使用时间较短（风险比为 3.20[95%CI，1.44-7.13]）（趋势检验=0.06）。
在 VOYAGER PAD 试验中，利伐沙班加阿司匹林降低了心血管和肢体不良事件的风险，并在急性肢体缺血方面早期获益，无论氯吡格雷的使用情况如何。利伐沙班的安全性是一致的，无论氯吡格雷的使用情况如何，但氯吡格雷使用时间>30 天时，国际血栓与止血学会大出血的发生率有增加趋势，而氯吡格雷使用时间较短。这些数据支持在下肢血管重建术后加用利伐沙班加阿司匹林，无论是否同时使用氯吡格雷，疗程较短（≤30 天），出血风险较低。
