Rivaroxaban with or without aspirin in patients with stable peripheral or carotid artery disease: an international, randomised, double-blind, placebo-controlled trial

Abstract

BACKGROUND Patients with peripheral artery disease have an increased risk of cardiovascular morbidity and mortality. Antiplatelet agents are widely used to reduce these complications. METHODS 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. FINDINGS Between March 12, 2013, and May 10, 2016, we ; 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). INTERPRETATION 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. FUNDING Bayer AG. Methods 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, i...

The coagulation system in atherothrombosis: Implications for new therapeutic strategies

“…Treatment with a combination of very‐low dose rivaroxaban and aspirin provided a clear net clinical benefit, both in patients with CAD and PAD. For the latter, a group of patients with either peripheral artery disease or carotid artery disease, not only major adverse cardiovascular events (MACE) were significantly reduced, but there was also a significant reduction in major adverse limb events (MALE) and amputations for patients treated with the combination of rivaroxaban and aspirin . As described above, no other pharmaceutical therapy in PAD patients had shown such a clear reduction in both cardiovascular and limb events thus far (Table ).…”

“…As described above, no other pharmaceutical therapy in PAD patients had shown such a clear reduction in both cardiovascular and limb events thus far (Table ). The relative risk reduction with combination therapy compared to aspirin alone was demonstrated in all patient groups, including patients with carotid artery disease, PAD, or CAD …”

Peripheral vascular disease risk in diabetic individuals without coronary heart disease

“…We found high rates of peripheral vascular disease among participants with diabetes and multiple cardiovascular disease risk factors but without prevalent CHD, revealing a potentially underdiagnosed and undertreated group of patients. It may be especially important to identify these high-risk patients given recent evidence that anti-platelet and anticoagulation therapy may provide significant reductions in rates of cardiac, cerebral and lower extremity vascular disease events [21]. …”

Guidelines on diagnosis, prognosis, and management of peripheral artery disease in patients with foot ulcers and diabetes (IWGDF 2019 update)

“…There is no specific evidence supporting the most appropriate antiplatelet agent in patients with diabetes, PAD, and ulceration; however, a number of recent guidelines have favoured clopidogrel over aspirin in the management of patients with PAD . A subanalysis of a recent trial of antiplatelets and anticoagulation suggested that the combination of aspirin and the direct oral anticoagulant rivaroxaban was more effective at reducing major limb events when compared with aspirin alone in patients with PAD; however, this strategy was at the expense of an increase in (nonfatal) bleeding events . Although 45% had diabetes, no information was provided about the presence of a foot ulcer, and the outcomes of these patients were not reported separately.…”