Rivaroxaban and Aspirin in Patients With Symptomatic Lower Extremity Peripheral Artery Disease A Subanalysis of the COMPASS Randomized Clinical Trial

Importance Patients with symptomatic lower extremity peripheral artery disease (LE-PAD) experience an increased risk of major vascular events. There is limited information on what clinical features of symptomatic LE-PAD prognosticate major vascular events and whether patients at high risk have a greater absolute benefit from low-dose rivaroxaban and aspirin. Objective To quantify the risk of major vascular events and investigate the response to treatment with low-dose rivaroxaban and aspirin among patients with symptomatic LE-PAD based on clinical presentation and comorbidities. Design, Setting, and Participants This is a subanalysis of a previously reported subgroup of patients with symptomatic LE-PAD who were enrolled in a large, double-blind, placebo-controlled randomized clinical trial (Cardiovascular Outcomes for People Using Anticoagulation Strategies [COMPASS]) in 602 centers in 33 countries from March 2013 to January 2020. Data analysis was completed from May 2016 to June 2020. Interventions A combination of low-dose rivaroxaban and aspirin compared with aspirin alone. Main Outcomes and Measures Thirty-month incidence risk of myocardial infarction, stroke and cardiovascular death (MACE), major adverse limb events (MALE) including major vascular amputation, and bleeding. Results The COMPASS trial enrolled 4129 patients with symptomatic LE-PAD (mean [SD] age, 66.8 [8.8] years; 2932 men [71.0%]). The 30-month Kaplan-Meier incidence risk of MACE or MALE, including major amputation, was 22.6% in those with prior amputation (this outcome was observed in 54 patients), 17.6% (n = 15) in those with Fontaine III or IV symptoms, and 11.8% (n = 142) in those with previous peripheral artery revascularization, classifying these features as high-risk limb presentations. The 30-month incidence risk of MACE or MALE, including major amputation, was 14.1% (n = 118) in those with kidney dysfunction, 13.5% (n = 67) in those with heart failure, 13.4% (n = 199) in those with diabetes, and 12.8% (n = 222) in those with polyvascular disease, classifying these features as high-risk comorbidities. Among patients with either high-risk limb presentations or high-risk comorbidities, treatment with rivaroxaban and aspirin compared with aspirin alone was associated with an estimated 4.2% (95% CI, 1.9%-6.2%) absolute risk reduction for MACE or MALE, including major amputation, at 30 months. Although the estimated absolute risk increase of major bleeding was higher with rivaroxaban and aspirin in combination than aspirin alone (2.0% [95% CI, 0.5%-3.9%]) for patients with either high-risk limb presentation or high-risk comorbidity, the estimated absolute risk increase of fatal or critical organ bleeding was low in this high-risk group (0.4% [95% CI, 0.2%-1.8%]), such that the net clinical benefit was estimated to be 3.2% (95% CI, 0.6%-5.3%). Conclusions and Relevance Patients with LE-PAD with high-risk limb presentations or high-risk comorbidities had a high incidence of major vascular events. For these patients, treatment with rivaroxaban and aspirin in combination compared with aspirin alone led to a large absolute reduction in vascular risk. This secondary analysis of a randomized clinical trial assesses the clinical features of symptomatic lower extremity peripheral artery disease that may prognosticate major vascular events and whether affected patients may benefit from low-dose rivaroxaban and aspirin. Question What features prognosticate vascular risk and response to low-dose rivaroxaban and aspirin treatment among patients with symptomatic lower extremity peripheral artery disease? Findings In this secondary analysis of a randomized clinical trial, the risk of major vascular events was greater than 10% over 30 months for patients with previous peripheral revascularization, previous amputation, or Fontaine III or IV symptoms and patients with comorbidities of kidney dysfunction, heart failure, diabetes, or polyvascular disease. These patients at high risk had an estimated 4.2% absolute risk reduction for major vascular events when treated with combination rivaroxaban and aspirin vs aspirin alone. Meaning Per this analysis, patients with high-risk lower extremity peripheral artery disease limb presentations or comorbidities, who are not at high bleeding risk, should be considered for treatment with combination rivaroxaban and aspirin.