Patients with peripheral artery disease have an increased risk of cardiovascular morbidity
and mortality. Antiplatelet agents are widely used to reduce these complications.This
was a multicentre, double-blind, randomised placebo-controlled trial for which patients
were recruited at 602 hospitals, clinics, or community practices from 33 countries
across six continents. Eligible patients had 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. 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 to aspirin once a day (100 mg and rivaroxaban placebo twice a day). Randomisation
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 peripheral artery
disease outcome was major adverse limb events including major amputation. This trial
is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.Between
March 12, 2013, and May 10, 2016, we enrolled 7470 patients with peripheral artery
disease from 558 centres. The combination of rivaroxaban plus aspirin compared with
aspirin alone reduced the composite endpoint of cardiovascular death, myocardial infarction,
or stroke (126 [5%] of 2492 vs 174 [7%] of 2504; 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). Rivaroxaban 5 mg twice a day compared with
aspirin alone did not significantly reduce the composite endpoint (149 [6%] of 2474
vs 174 [7%] of 2504; 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 21 months. The use of the rivaroxaban
plus aspirin combination increased major bleeding compared with the aspirin alone
group (77 [3%] of 2492 vs 48 [2%] of 2504; HR 1·61, 95% CI 1·12-2·31, p=0·0089), which
was mainly gastrointestinal. Similarly, major bleeding occurred in 79 (3%) of 2474
patients with rivaroxaban 5 mg, and in 48 (2%) of 2504 in the aspirin alone group
(HR 1·68, 95% CI 1·17-2·40; p=0·0043).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 peripheral artery disease. Rivaroxaban alone did not significantly
reduce major adverse cardiovascular events compared with asprin alone, but reduced
major adverse limb events and increased major bleeding.Bayer AG.
