Efficacy and safety of rivaroxaban plus aspirin compared with aspirin alone in patients with peripheral arterial disease: a systematic review and meta-analysis

Abstract

Background: Peripheral artery disease (PAD) is a prevalent atherosclerotic disorder associated with significant cardiovascular morbidity. Although aspirin remains the cornerstone of therapy, residual thrombotic risk persists. The addition of rivaroxaban, a factor Xa inhibitor, may enhance protection through dual pathway inhibition. This meta-analysis aimed to evaluate the efficacy and safety of rivaroxaban plus aspirin versus aspirin alone in patients with PAD. Methods: A systematic review and meta-analysis were conducted following PRISMA and AMSTAR guidelines. Randomized controlled trials comparing rivaroxaban plus aspirin with aspirin alone in adults with PAD were included. Data were pooled using a random-effects model in Review Manager 5.4. Risk of bias was assessed with RoB 2 and certainty of evidence was graded using GRADE pro. Results: Six RCTs including 90 325 participants met inclusion criteria. Combination therapy significantly reduced MACE (RR: 0.82, 95% CI: 0.78–0.87), MI (RR: 0.87), ischemic stroke (RR: 0.76), and acute limb ischemia (RR: 0.68), with low heterogeneity (≤35%). No significant reduction was observed in cardiovascular mortality or major amputation. TIMI major bleeding risk increased (RR: 1.41, 95% CI: 1.07–1.84), however intracranial and fatal bleeding rates were similar between groups. Moderate-to-high certainty evidence supports reductions in ischemic and limb events, with increased bleeding risk. Conclusion: Rivaroxaban plus aspirin is associated with improved cardiovascular and limb outcomes compared to aspirin alone in PAD, albeit with a higher risk of major bleeding. Findings should be interpreted in the context of potential publication bias and heterogeneity across trials. Careful patient selection is warranted for optimal risk-benefit balance.