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 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). 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.

3rd Department of Internal Medicine Semmelweis University Budapest Hungary

Amphia Ziekenhuis and Werkgroep Cardiologische centra Nederland Utrecht Netherlands

ANMCO Research Center Florence Italy

Bayer AG Leverkusen Germany

Bayer AG Whippany NJ USA

Brigham and Women's Hospital Heart and Vascular Center Harvard Medical School Boston MA USA

Cardiocenter University Hospital Kralovske Vinohrady and 3rd Faculty of Medicine Charles University Prague Prague Czech Republic

Centre for Cardiovascular Science University of Edinburgh Edinburgh UK

Comprehensive Heart Failure Center University Hospital at University of Würzburg Würzburg Germany

Dante Pazzanese Institute of Cardiology and University Santo Amaro São Paulo Brazil

Department of Cardiovascular Sciences University of Leuven Leuven Belgium

Department of Epidemiology and Preventive Medicine Monash University Melbourne VIC Australia

Department of Medicine K2 Karolinska Institute Stockholm Sweden

Department of Medicine University of Washington Seattle WA USA

Dupuytren University Hospital Limoges France

Estudios Clínicos Latino America and Instituto Cardiovascular de Rosario Rosario Argentina

FuWai Hospital Beijing China

Lady Davis Carmel Medical Centre and the Ruth and Bruce Rappaport School of Medicine Technion IIT Haifa Israel

National Research Centre for Preventative Medicine Moscow Russia

National University of Ireland Galway Ireland

Population Health Research Institute McMaster University and Hamilton Health Sciences Hamilton ON Canada

Population Health Research Institute McMaster University and Hamilton Health Sciences Hamilton ON Canada; Department of Medicine McMaster University Hamilton ON Canada

Population Health Research Institute McMaster University and Hamilton Health Sciences Hamilton ON Canada; School of Rehabilitation Sciences McMaster University Hamilton ON Canada

Research Institute FOSCAL Bucaramanga Bucaramanga Colombia

Thrombosis Research Institute and University College London London UK

University of Cape Town Cape Town South Africa

University of Medicine and Pharmacy Carol Davila University and Emergency Hospital Bucharest Romania

Comment In

Lancet. 2018 Jan 20;391(10117):183-184. doi: 10.1016/S0140-6736(17)32847-7. PubMed

Comment In

Nat Rev Cardiol. 2018 Jan;15(1):3. doi: 10.1038/nrcardio.2017.192. PubMed

Comment In

BMJ Evid Based Med. 2018 Oct;23(5):191-192. doi: 10.1136/bmjebm-2018-110899. PubMed

References provided by Crossref.org

Comparison of Investigator-Reported vs Centrally Adjudicated Major Adverse Cardiac Events: A Secondary Analysis of the COMPASS Trial

Cardiovascular consequences of discontinuing low-dose rivaroxaban in people with chronic coronary or peripheral artery disease

Role of Combination Antiplatelet and Anticoagulation Therapy in Diabetes Mellitus and Cardiovascular Disease: Insights From the COMPASS Trial

Real-World Dual Antiplatelet Therapy Following Polymer-Free Sirolimus-Eluting Stent Implantations to Treat Coronary Artery Disease

The selective peroxisome proliferator-activated receptor alpha modulator (SPPARMα) paradigm: conceptual framework and therapeutic potential : A consensus statement from the International Atherosclerosis Society (IAS) and the Residual Risk Reduction Initiative (R3i) Foundation

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ClinicalTrials.gov
NCT01776424