Rivaroxaban With or Without Aspirin Evaluated in Patients With Stable Peripheral or Carotid Artery Disease
December 6, 2017—Findings from the company-sponsored COMPASS trial of rivaroxaban (Xarelto, Bayer AG and Janssen Research & Development, LLC) administered with or without aspirin in patients with stable peripheral or carotid artery disease were recently published by Prof. Sonia S. Anand, MD, et al online ahead of print in The Lancet.
As summarized in The Lancet, COMPASS was a randomized, double-blind, placebo-controlled trial that recruited patients at 602 hospitals, clinics, or community practices from 33 countries on six continents. Eligible patients had a history of peripheral artery disease (PAD) of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, intermittent claudication with objective evidence of PAD), the carotid arteries (previous carotid artery revascularization or asymptomatic carotid artery stenosis of at least 50%), or coronary artery disease with an ankle-brachial index < 0.9.
After a 30-day run-in period, patients were randomly assigned (1:1:1) to receive oral rivaroxaban (2.5 mg twice a day) plus aspirin (100 mg once a day), rivaroxaban twice a day (5 mg with aspirin placebo once a day), or aspirin once a day (100 mg and rivaroxaban placebo twice a day). Randomization was computer generated.
Each treatment group was double dummy, and the patient, investigators, and central study staff were masked to treatment allocation. The primary outcome was cardiovascular death, myocardial infarction, or stroke. The primary PAD outcome was major adverse limb events including major amputation.
The study enrolled 7,470 patients with PAD from 558 centers between March 12, 2013 and May 10, 2016.
The investigators found that the combination of rivaroxaban plus aspirin compared with aspirin alone reduced the composite endpoint of cardiovascular death, myocardial infarction, or stroke (126 [5%] of 2,492 vs 174 [7%] of 2,504; hazard ratio [HR], 0.72; 95% confidence interval [CI], 0.57–0.90; P = .0047), and major adverse limb events including major amputation (32 [1%] vs 60 [2%]; HR, 0.54; 95% CI, 0.35–0.82; P = .0037).
Additionally, they reported that rivaroxaban 5 mg twice a day compared with aspirin alone did not significantly reduce the composite endpoint (149 [6%] of 2,474 vs 174 [7%] of 2,504; HR, 0.86; 95% CI, 0.69–1.08; P = .19), but reduced major adverse limb events including major amputation (40 [2%] vs 60 [2%]; HR, 0.67; 95% CI, 0.45–1.00; P = .05). The median duration of treatment was 21 months.
Finally, the use of the rivaroxaban plus aspirin combination was shown to increase major bleeding compared with the aspirin alone group (77 [3%] of 2,492 vs 48 [2%] of 2,504; HR, 1.61; 95% CI, 1.12–2.31; P = .0089), which was mainly gastrointestinal. Similarly, major bleeding occurred in 79 (3%) of 2,474 patients with rivaroxaban 5 mg and in 48 (2%) of 2,504 in the aspirin alone group (HR, 1.68; 95% CI, 1.17–2.4; P = .0043).
The COMPASS investigators concluded that low-dose rivaroxaban taken twice a day plus aspirin once a day reduced major adverse cardiovascular and limb events when compared with aspirin alone. Although major bleeding was increased, fatal or critical organ bleeding was not.
This combination therapy represents an important advance in the management of patients with PAD. Rivaroxaban alone did not significantly reduce major adverse cardiovascular events compared with aspirin alone, but reduced major adverse limb events and increased major bleeding, advised the investigators in The Lancet.