Sonia S Anand1, Jackie Bosch2, John W Eikelboom3, Stuart J Connolly3, Rafael Diaz4, Peter Widimsky5, Victor Aboyans6, Marco Alings7, Ajay K Kakkar8, Katalin Keltai9, Aldo P Maggioni10, Basil S Lewis11, Stefan Störk12, Jun Zhu13, Patricio Lopez-Jaramillo14, Martin O'Donnell15, Patrick J Commerford16, Dragos Vinereanu17, Nana Pogosova18, Lars Ryden19, Keith A A Fox20, Deepak L Bhatt21, Frank Misselwitz22, John D Varigos23, Thomas Vanassche24, Alvaro A Avezum25, Edmond Chen26, Kelley Branch27, Darryl P Leong3, Shrikant I Bangdiwala28, Robert G Hart3, Salim Yusuf3. 1. Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada; Department of Medicine, McMaster University, Hamilton, ON, Canada. Electronic address: anands@mcmaster.ca. 2. Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada; School of Rehabilitation Sciences, McMaster University, Hamilton, ON, Canada. 3. Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada; Department of Medicine, McMaster University, Hamilton, ON, Canada. 4. Estudios Clínicos Latino America and Instituto Cardiovascular de Rosario, Rosario, Argentina. 5. Cardiocenter, University Hospital Kralovske Vinohrady and Third Faculty of Medicine, Charles University Prague, Prague, Czech Republic. 6. Dupuytren University Hospital, Limoges, France. 7. Amphia Ziekenhuis and Werkgroep Cardiologische centra Nederland, Utrecht, Netherlands. 8. Thrombosis Research Institute and University College London, London, UK. 9. 3rd Department of Internal Medicine. Semmelweis University, Budapest, Hungary. 10. ANMCO Research Center, Florence, Italy. 11. Lady Davis Carmel Medical Centre and the Ruth and Bruce Rappaport School of Medicine, Technion-IIT, Haifa, Israel. 12. Comprehensive Heart Failure Center, University Hospital at University of Würzburg, Würzburg, Germany. 13. FuWai Hospital, Beijing, China. 14. Research Institute, FOSCAL-Bucaramanga, Bucaramanga, Colombia. 15. National University of Ireland, Galway, Ireland. 16. University of Cape Town, Cape Town, South Africa. 17. University of Medicine and Pharmacy Carol Davila, University and Emergency Hospital, Bucharest, Romania. 18. National Research Centre for Preventative Medicine, Moscow, Russia. 19. Department of Medicine K2, Karolinska Institute, Stockholm, Sweden. 20. Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK. 21. Brigham and Women's Hospital Heart and Vascular Center, Harvard Medical School, Boston, MA, USA. 22. Bayer AG, Leverkusen, Germany. 23. Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, Australia. 24. Department of Cardiovascular Sciences, University of Leuven, Leuven, Belgium. 25. Dante Pazzanese Institute of Cardiology & University Santo Amaro, São Paulo, Brazil. 26. Bayer AG, Whippany, NJ, USA. 27. Department of Medicine (Cardiology), University of Washington, Seattle, WA, USA. 28. Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada.
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 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.
RCT Entities:
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.