Rymer Jennifer, Anand Sonia S, Sebastian Debus E, Haskell Lloyd P, Hess Connie N, Jones W Schuyler, Muehlhofer Eva, Berkowitz Scott D, Bauersachs Rupert M, Bonaca Marc P, Patel Manesh R
Duke Clinical Research Institute, Division of Cardiology, Duke University, Durham, NC (J.R., W.S.J., M.R.P.).
Population Health Research Institute, Hamilton Health Sciences and McMaster University, Canada (S.S.A.).
Circulation. 2023 Dec 12;148(24):1919-1928. doi: 10.1161/CIRCULATIONAHA.122.063806. Epub 2023 Oct 18.
Rivaroxaban plus aspirin compared with aspirin alone reduced major cardiac and ischemic limb events after lower extremity revascularization (LER) in the VOYAGER PAD (Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for Peripheral Artery Disease) trial. The effect has not been described in patients undergoing endovascular LER.
The VOYAGER PAD trial randomized 6564 patients with symptomatic peripheral artery disease to a double-blinded treatment with 2.5 mg of rivaroxaban BID or matching placebo and 100 mg of aspirin daily. The primary efficacy outcome was a composite of acute limb ischemia, major amputation of a vascular pathogenesis, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety end point was Thrombolysis in Myocardial Infarction major bleeding. A prespecified subgroup of patients who underwent endovascular revascularization was included.
Endovascular LER occurred in 4379 (66.7%) patients and surgical LER in 2185 (33.3%). Over a 3-year follow-up, rivaroxaban reduced the risk of the primary outcome by 15% (hazard ratio [HR], 0.85 [95% CI, 0.76-0.96]) with an absolute risk reduction of 0.92% at 6 months and 1.04% at 3 years and a consistent benefit in those receiving endovascular (HR, 0.89 [95% CI, 0.76-1.03]) or surgical LER (HR, 0.81 [95% CI, 0.67-0.98]; interaction=0.43). For endovascular-treated patients, rivaroxaban reduced the risk of acute limb ischemia or major amputation of a vascular pathogenesis by 30% (HR, 0.70 [95% CI, 0.54-0.90]; =0.005) with an absolute risk reduction of 1.0% at 6 months and 2.0% at 3 years compared with aspirin alone. Among endovascular-treated patients, the median duration of concomitant dual antiplatelet therapy with clopidogrel treatment was 31 days (interquartile range, 30-58). There was a consistent benefit for rivaroxaban regardless of background clopidogrel. Thrombolysis in Myocardial Infarction major bleeding was significantly higher for the rivaroxaban and aspirin group for the endovascular cohort (HR, 1.66 [95% CI, 1.06-2.59]) with an absolute risk increase of 0.9% at 3 years with no increase in intracranial or fatal bleeding observed (HR, 0.86 [95% CI, 0.40-1.87]; =0.71). Mortality with rivaroxaban was higher in the endovascular-treated patients (HR, 1.24 [95% CI, 1.02-1.52]), although this finding was isolated to specific regions.
Rivaroxaban added to aspirin or dual antiplatelet therapy after LER for peripheral artery disease reduces ischemic risk and increases major bleeding without an increased risk of intracranial or fatal bleeding. These benefits are consistent in those treated with endovascular and surgical approaches with significant benefits for major adverse limb events. These data support the use of rivaroxaban in addition to aspirin or dual antiplatelet therapy after endovascular intervention for symptomatic peripheral artery disease.
在VOYAGER PAD（阿司匹林联合利伐沙班用于外周动脉疾病血管内或外科肢体血运重建的血管结局研究）试验中，与单独使用阿司匹林相比，利伐沙班联合阿司匹林可降低下肢血运重建（LER）后主要心脏和缺血性肢体事件的发生率。尚未有研究描述其在接受血管内LER患者中的疗效。
VOYAGER PAD试验将6564例有症状外周动脉疾病患者随机分为两组，分别接受每日两次2.5mg利伐沙班或匹配安慰剂及100mg阿司匹林的双盲治疗。主要疗效结局为急性肢体缺血、血管源性大截肢、心肌梗死、缺血性卒中或心血管死亡的复合终点。主要安全终点为心肌梗死溶栓大出血。纳入了一个预先设定的接受血管内血运重建的患者亚组。
4379例（66.7%）患者接受了血管内LER，2185例（33.3%）患者接受了外科LER。在3年的随访中，利伐沙班使主要结局风险降低了15%（风险比[HR]，0.85[95%CI，0.76 - 0.96]），6个月时绝对风险降低0.92%，3年时为1.04%，且在接受血管内（HR，0.89[95%CI，0.76 - 1.03]）或外科LER的患者中均有一致的获益（HR，0.81[95%CI，0.67 - 0.98]；交互作用 = 0.43）。对于接受血管内治疗的患者，与单独使用阿司匹林相比，利伐沙班使急性肢体缺血或血管源性大截肢的风险降低了30%（HR，0.70[95%CI，0.54 - 0.90]；P = 0.005），6个月时绝对风险降低1.0%，3年时为2.0%。在接受血管内治疗的患者中，与氯吡格雷联合使用的双重抗血小板治疗的中位持续时间为31天（四分位间距，30 - 58）。无论氯吡格雷的使用情况如何，利伐沙班均有一致的获益。血管内队列中，利伐沙班和阿司匹林组的心肌梗死溶栓大出血显著更高（HR，1.66[95%CI，1.06 - 2.59]），3年时绝对风险增加0.9%，未观察到颅内或致命性出血增加（HR，0.86[95%CI，0.40 - 1.87]；P = 0.71）。在接受血管内治疗的患者中，使用利伐沙班的死亡率更高（HR，1.24[95%CI，1.02 - 1.52]），尽管这一发现仅限于特定地区。
在外周动脉疾病LER后，利伐沙班联合阿司匹林或双重抗血小板治疗可降低缺血风险并增加大出血风险，但颅内或致命性出血风险未增加。这些获益在接受血管内和外科治疗的患者中均一致，对主要不良肢体事件有显著益处。这些数据支持在有症状外周动脉疾病血管内干预后，除阿司匹林或双重抗血小板治疗外，加用利伐沙班。
