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

Abstract

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Eikelboom reports grants and personal fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, Sanofi Aventis, and Servier during the conduct of the study; grants and personal fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Daiichi Sankyo, Janssen, AstraZeneca, Eli Lilly, GlaxoSmithKline, Pfizer, Janssen, and Sanofi Aventis outside the submitted work; and personal fees from Servier outside the submitted work. Dr Aboyans reports grants and/or honoraria for speaking and consulting from Bayer, Bristol Myers Squibb, Novartis, and Pfizer and personal fees from Boehringer Ingelheim, Amgen, and Bristol Myers Squibb/Pfizer Alliance during the conduct of the study. Dr Abola reported personal fees and nonfinancial support from Bayer during the conduct of the study and personal fees and nonfinancial support from Bayer and AstraZeneca outside the submitted work; Dr Abola has also received speaker fees from Pfizer. Dr Verhamme reported grants from Bayer during the conduct of the study; grants and personal fees from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Pfizer, Portola, and Daiichi Sankyo; and personal fees from AbbVie and Anthos outside the submitted work. Dr Avezum has received honoraria and consulting fees from Boehringer Ingelheim and Pfizer and personal fees from Bayer and Daichii Sankyo outside the submitted work. Dr Fox has received grants and personal fees from AstraZeneca and Bayer/Janssen, as well as personal fees from Lilly and Sanofi/Regeneron. Dr Fox reported grants from Bayer/Janssen during the conduct of the study; grants from AstraZeneca, personal fees from Sanofi/Regeneron, and personal fees from Verseon outside the submitted work. Dr Berkowitz is employed as a clinical research physician by Bayer US LLC. Dr Yusuf reported grants and personal fees from Bayer during the conduct of the study; Dr Yusuf has received research grants and honoraria and travel reimbursement for speaking from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, AstraZeneca, Cadila Pharmaceuticals, and Sanofi Aventis from outside the submitted work. Dr Anand has received speaking honoraria and consulting fees from Bayer and speaking fees from Janssen. No other disclosures were reported.

Figures

Figure 1.. Major Adverse Cardiovascular Event or Major Adverse Limb Event, Including Major Amputation, Stratified by Subtype of Peripheral Artery Disease

Figure 2.. Estimated Number of Ischemic Events Prevented and Bleeding Events Caused per 1000 Patients When Treated With Rivaroxaban and Aspirin in Combination, Compared With Aspirin Alone Over 30 Months

HRCM indicates high-risk comorbidity; HRLP, high-risk limb presentation; MACE, major adverse cardiovascular event; MALE, major adverse limb event.