Anand SS, et al. - This paper incorporated an analysis of the efficacy of rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease. A reduction was noted in the major adverse cardiovascular and limb events when a low-dose rivaroxaban was taken twice a day plus aspirin once a day when compared to aspirin alone. Despite an increase in the major bleeding, fatal or critical organ bleeding did not increase. This combination therapy reflected a significant advancement in the management of patients with peripheral artery disease. Therapy with rivaroxaban alone did not notably reduce major adverse cardiovascular events compared with aspirin alone. Nonetheless, it reduced major adverse limb events and increased major bleeding.

Methods

• The design of this study was a multicentre, double-blind, randomised placebo-controlled trial.
• The enrollment took place at 602 hospitals, clinics, or community practices, from 33 countries across six continents.
• Enrollees presented with a history of peripheral artery disease of the lower extremities (previous peripheral bypass surgery or angioplasty, limb or foot amputation, intermittent claudication with objective evidence of peripheral artery disease), of the carotid arteries (previous carotid artery revascularisation or asymptomatic carotid artery stenosis of at least 50%), or coronary artery disease with an ankle-brachial index of less than 0.90.
• Following a 30-day run-in period, computer generated randomization was performed of the candidates (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 to aspirin once a day (100 mg and rivaroxaban placebo twice a day).
• The treatment group was double dummy, and the patient, investigators, and central study staff were masked to treatment allocation.
• The primary outcome included cardiovascular death, myocardial infarction or stroke; the primary peripheral artery disease outcome consisted of major adverse limb events including major amputation.

Results

• This study recruited 7,470 patients with peripheral artery disease from 558 centres, between March 12, 2013, and May 10, 2016.
• The rivaroxaban plus aspirin compared with aspirin alone led to a reduction in 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% CI 0.57-0.90, p=0.0047), and major adverse limb events including major amputation (32 [1%] vs 60 [2%]; HR 0.54 95% CI 0.35-0.82, p=0.0037).
• A substantial reduction was not gained by rivaroxaban 5 mg twice a day compared with aspirin alone in the composite endpoint (149 [6%] of 2,474 vs 174 [7%] of 2,504; HR 0.86, 95% CI 0.69-1.08, p=0.19), but reduced major adverse limb events including major amputation (40 [2%] vs 60 [2%]; HR 0.67, 95% CI 0.45-1.00, p=0.05).
• The median duration of treatment was discovered to be 21 months.
• Rivaroxaban plus aspirin combination led to a rise in the 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=0.0089), which appeared to be primarily gastrointestinal.
• Likewise, the occurrence of major bleeding was reported 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 1.17-2.40; p=0.0043).