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?:abstract
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Background: The VOYAGER PAD trial demonstrated superiority of rivaroxaban plus aspirin versus aspirin to reduce major cardiac and ischemic limb events following lower extremity revascularization (LER). 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. Methods: VOYAGER PAD was a phase 3, international, double-blind, placebo-controlled trial in symptomatic PAD patients undergoing LER 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 endpoint was TIMI major bleeding with ISTH major bleeding a secondary safety outcome. Clopidogrel use was allowed at the discretion of the investigator for up to six months following the qualifying revascularization. Results: 3313 (50.6%) of the randomized patients received clopidogrel, median duration of 29.0 days. Over 3-years the hazard ratio (HR) 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, without statistical heterogeneity (p-interaction =0.92). Rivaroxaban resulted in an early apparent reduction in acute limb ischemia (ALI) within 30 days, HR 0.45 (95%CI 0.14-1.46) with and HR 0.48 (95% CI 0.22-1.01) without clopidogrel (p-interaction = 0.93). Compared with aspirin, rivaroxaban increased TIMI major bleeding similarly regardless of clopidogrel use (p-interaction 0.71). With clopidogrel use >30 days, rivaroxaban was associated with more ISTH major bleeding within 365 days (HR 3.20, 95% CI 1.44-7.13) compared with shorter durations of clopidogrel (p-trend 0.06). Conclusions: In the VOYAGER PAD trial, rivaroxaban plus aspirin reduced the risk of adverse cardiovascular and limb events with an early benefit for ALI regardless of clopidogrel use. The safety of rivaroxaban was consistent regardless of clopidogrel use, but with a trend for more ISTH major bleeding with clopidogrel use > 30 days than a shorter duration. These data support the addition of rivaroxaban to aspirin after LER regardless of concomitant clopidogrel with a short (course ≤ 30 days) associated with less bleeding. Clinical Trial Registration: URL: https://clinicaltrials.gov Unique Identifier: NCT02504216.
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