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...

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BackgroundPhysical activity at moderate-high intensity is recommended to prevent lifestyle diseases. Patients with atrial fibrillation are at risk of a sedentary lifestyle due to fear of exercise-induced episodes of atrial fibrillation. The burden of arrhythmia can be reduced by physical exercise. The effect of exercise intensity on burden of atrial fibrillation needs to be studied further.Methods and resultsIn a 12-week randomized controlled trial, 76 patients with paroxysmal/persistent atrial fibrillation were allocated to perform exercise at either low intensity or high intensity (50% and 80% of maximal perceived exertion, respectively). Primary outcome was burden of AF measured by daily electrocardiography-reporting during 12 weeks. Secondarily, change in maximal oxygen uptake (peak VO2) and 1-year hospitalization was compared between low and high intensity exercise. Sixty-three patients completed the follow-up. In the intention-to-treat analysis, we found no statistical difference in burden of atrial fibrillation between low and high intensity exercise (incidence rate ratio 0.742, 95% CI 0.29–1.91, P = 0.538). No serious adverse events were reported and there was no difference in hospitalization between the two exercise groups. Both exercise groups improved significantly in peak VO2 (low intensity: 3.62 mL O2/kg/min, SD 3.77; high intensity: 2.87 mL O2/kg/min, SD 4.98), with no statistical difference between-groups (mean difference: 0.76 mL O2/kg/min, 95% CI -3.22–1.7).ConclusionsHigh intensity physical exercise was not superior to low intensity physical exercise in reducing burden of atrial fibrillation. HI exercise was well tolerated; no evidence of an increased risk was found for HI compared to LI exercise. Larger studies are required to further prove our findings.Trial registrationClinicalTrials.gov NCT01817998