Rivaroxaban Plus Aspirin Versus Aspirin Alone After Endovascular Revascularization for Symptomatic PAD: Insights From VOYAGER PAD.

Background: 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.
Methods: 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.
Results: 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]; P 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]; P =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]; P =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.
Conclusions: 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.
Competing Interests: Disclosures Dr Anand reports personal fees from Bayer AG and personal fees from Janssen during the conduct of the study, and personal fees from Bayer AG and personal fees from Janssen outside the submitted work. Dr Anand holds an endowed chair in population health from the Heart and Stroke Foundation of Canada, and a Canada research chair in ethnicity and cardiovascular disease. Dr Debus reports grants and personal fees from Bayer AG, institutional grants from Cook LTD, and grants from Terumo Aortic during the conduct of the study. Dr Haskell reports funding support from Janssen pharmaceuticals LLC during the conduct of the study, and funding support from Johnson & Johnson outside the submitted work. Dr Hess reports grants from Bayer during the conduct of the study, and grants from Merck and Amgen outside the submitted work. Dr Muehlhofer is employed by Bayer AG. Dr Berkowitz reports being employed as a clinical research physician at Bayer US, LLC, during the conduct of the study. Dr Bauersachs reports personal fees from Bayer during the conduct of the study, and personal fees from Bristol Myers Squibb, Daiichi-Sankyo, and Pfizer outside the submitted work. Dr Bonaca reports grant support to CPC Clinical Research from Bayer AG and Janssen Pharmaceuticals during the conduct of the study, and grants from Amgen, AstraZeneca, Merck, NovoNordisk, Pfizer, and Sanofi outside the submitted work. Dr Patel reports grants and personal fees from Bayer and grants and personal fees from Janssen during the conduct of the study, and grants and personal fees from AstraZeneca, grants from the National Heart, Lung, and Blood Institute, grants from Medtronic, grants from Phillips Healthcare, and grants and personal fees from Heartflow outside the submitted work. The other authors report no conflicts.