The efficacy and safety of direct oral anticoagulants plus aspirin in symptomatic lower extremity peripheral arterial disease: a systematic review and meta-analysis of randomized controlled trials

Patients with lower extremity peripheral artery disease (PAD) are at increased risk of major adverse limb events (MALE). The efficacy and safety of direct oral anticoagulants (DOACs) in this context is evolving. To assess the efficacy and safety of DOAC combined with aspirin compared to the use of antiplatelet agents in patients with symptomatic lower extremity (LE) PAD. We systematically searched PubMed, Embase and Cochrane databases, in September 2020, for randomized controlled trials (RCTs) that were designed to investigate the effect of DOACs in the treatment of PAD. A random-effects meta-analysis was performed targeting ischemic and bleeding events. Three randomized clinical trials were included, providing a total of 9533 patients, and 744 pooled MALE events (316 in DOAC plus aspirin and 428 in control). Only data on rivaroxaban and edoxaban were available. The use of DOAC plus aspirin in PAD patients significantly decreased the rate of MALE (pooled OR 0.70 [0.61–0.83], P < 0.001; I² = 0%). In terms of safety, there was a significantly higher rate of major bleeding events (pooled OR 1.46 [1.16–1.84], P = 0.001; I² = 52%). In rivaroxaban-RCTs, the addition of low-dose rivaroxaban to aspirin was still associated with a lower MALE compared to aspirin alone (pooled OR 0.68 [0.53–0.88], P = 0.003; I² = 28%), but also conferred higher major bleeding rate (pooled OR 1.48 [1.18–1.86], P < 0.001; I² = 0%). In conclusion, our pooled data suggests that for patients with symptomatic LE-PAD, the use of DOAC combined with aspirin reduced the risk of major ischemic limb events at the expense of an increased risk of major bleeding.