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.

Original languageEnglish
Pages (from-to)219-229
Number of pages11
JournalThe Lancet
Volume391
Issue number10117
DOIs
StatePublished - 20 Jan 2018

Bibliographical note

Publisher Copyright:
© 2018 Elsevier Ltd

Funding

SSA has received honoraria from Bayer and Novartis. JWE reports grants and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, during this study as well as for projects outside the submitted work; grants and personal fees from Janssen, AstraZeneca, Eli Lilly, GlaxoSmithKline, and Sanofi-Aventis outside the submitted work. SJC reports grants and personal fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, during this study as well as for projects outside the submitted work; grants and personal fees from Janssen, AstraZeneca, Portola and Sanofi-Aventis, outside the submitted work. RD reports grants from Population Health Research Institute during the conduct of this study. PW receives occasional speaker honoraria from Bayer and honoraria for the COMPASS trial National Leader role. VA has received honoraria from Bayer, Bristol-Myers Squibb, Pfizer, Novartis, Merck, Sharp & Dohme, outside the submitted work. MA has received consulting fees from Bayer, Bristol-Myers Squibb, Boehringer Ingelheim, Daiichi Sankyo, Sanofi, and Pfizer. AKK has received personal fees from Bayer AG, Boehringer-Ingelheim, Daiichi Sankyo Europe, Janssen Pharma, Sanofi SA, Armetheon and a grant from Bayer AG. APM reports personal fees from Novartis, Bayer, Cardiorentis, and Fresenius outside the submitted work. BSL reports a grant from Bayer and personal fees from Pfizer/Bristol-Myers Squibb during the conduct of the study. SS reports financial compensation from Bayer AG for work related to the conduct of the study; grants from Servier and Boehringer Ingelheim; grants, personal fees, and non-financial support from Novartis; grants and personal fees from Thermo Fisher; and personal fees from Pfizer outside the submitted work. JZ reports grants from Population Health Research Institute and personal fees from lectures from Bayer and Boehringer Ingelheim outside the submitted work. MO'D received payment from Population Health Research Institute for participant recruitment stipends. PJC was remunerated by Population Health Research Institute for his role as National Leader in South Africa. His department received support from Population Health Research Institute for the conduct of the study. He has also received personal fees from UptoDate outside the submitted work. DV has received grants and honoraria from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi Sankyo, and Johnson & Johnson during the conduct of the study; he also received grants and personal fees from Boehringer Ingelheim, Pfizer, Novartis, and Servier outside the submitted work. LR reports grants from Swedish Heart Lung Foundation, Swedish Diabetes Foundation, Amgen, Bayer AG and grants and personal fees from Boehringer Ingelheim, Merck, Sharp & Dohme, and Novo Nordisk outside the submitted work. KAAF reports grants and personal fees from Bayer/Janssen during the conduct of the study; grants and personal fees from AstraZeneca, personal fees from Sanofi/Regeneron and Eli Lilly outside the submitted work. DLB reports personal fees from Population Health Research Institute during the conduct of the study; grants from Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi-Aventis, The Medicines Company, Roche, Pfizer, Forest Laboratories/AstraZeneca, Ischemix, Amgen, Eli Lilly, Chiesi, and Ironwood; other unfunded research collaborations with FlowCo, PLx Pharma, Takeda, Cardiology, Regado Biosciences, and Boston VA Research Institute, Clinical Cardiology, Veterans Administration, St Jude Medical, Biotronik, Cardax, American College of Cardiology, Boston Scientific, and Merck; personal fees from Duke Clinical Research Institute, Mayo Clinic, Population Health Research Institute, Belvoir Publications, Slack Publications, WebMD, Elsevier, HMP Communications, Harvard Clinical Research Institute, the Journal of the American College of Cardiology, Cleveland Clinic, and Mount Sinai School of Medicine; personal fees and non-financial support from the American College of Cardiology and the Society of Cardiovascular Patient Care; and non-financial support from the American Heart Association outside the submitted work. FM is an employee of Bayer AG, the sponsor of this trial. JDV reports personal fees from Novartis outside the submitted work. TV reports grants and personal fees from Bayer during the conduct of the study; personal fees from Bayer, Pfizer/Bristol-Myers Squibb, Daiichi Sankyo, and Boehringer Ingelheim outside the submitted work. AAA has received honoraria and consulting fees from Boehringer Ingelheim and Pfizer. EC is an employee of Bayer AG, the sponsor of this trial. KB reports grants from Bayer, Astellas, and Janseen outside of the submitted work. RGH has received research support from Bayer AG including personal remuneration for participation in Bayer-sponsored clinical research and on advisory boards. SY has received research grants, honoraria, and travel expenses for lectures from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and AstraZeneca. All other authors declare no competing interests.

FundersFunder number
Armetheon
Forest Laboratories/AstraZeneca
HMP Communications
Harvard Clinical Research Institute
Janssen Pharma
Sanofi SA
Society of Cardiovascular Patient Care
U.S. Department of Veterans Affairs
Mayo Clinic
American Heart Association
Boehringer Ingelheim
Amgen
Eli Lilly and Company
Pfizer
Bayer
Roche
Sanofi
Medtronic
American College of Cardiology Foundation
Icahn School of Medicine at Mount Sinai
Chiesi Farmaceutici
Boehringer Ingelheim
Boston VA Research Institute
Hjärt-Lungfonden
Novo Nordisk
Diabetesförbundet
Servier
Daiichi Sankyo Europe

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