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

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Affiliations

  • 1. Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada; Department of Medicine, McMaster University, Hamilton, ON, Canada.
      Authors
    • Anand SS 1
    • Eikelboom JW 1
    • Connolly SJ 1
    • Leong DP 1
    • Hart RG 1
    • Yusuf S 1
    (6 authors)
  • 2. Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, ON, Canada; School of Rehabilitation Sciences, McMaster University, Hamilton, ON, Canada.
      Authors
    • Bosch J 2
    (1 author)
  • 3. Estudios Clínicos Latino America and Instituto Cardiovascular de Rosario, Rosario, Argentina.
      Authors
    • Diaz R 3
    (1 author)
  • 4. Cardiocenter, University Hospital Kralovske Vinohrady and Third Faculty of Medicine, Charles University Prague, Prague, Czech Republic.
      Authors
    • Widimsky P 4
    (1 author)
  • 5. Dupuytren University Hospital, Limoges, France.
      Authors
    • Aboyans V 5
    (1 author)
    • Show all (27)

ORCIDs linked to this article

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Lancet (London, England), 10 Nov 2017, 391(10117):219-229
https://doi.org/10.1016/s0140-6736(17)32409-1 PMID: 29132880 

A comment on this article appears in "Rivaroxaban plus aspirin, compared with aspirin alone, reduced cardiovascular events in patients with stable peripheral or carotid artery disease, but increased the risk of major bleeding." BMJ Evid Based Med. 2018 Oct;23(5):191-192. A comment on this article appears in "Antithrombotic therapy in peripheral artery disease." Lancet. 2018 Jan 20;391(10117):183-184. A comment on this article appears in "Prevention: Rivaroxaban plus aspirin in CAD or PAD." Nat Rev Cardiol. 2018 Jan;15(1):3.

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.

Full text links 

Read article at publisher's site: https://doi.org/10.1016/s0140-6736(17)32409-1

Read article for free, from open access legal sources, via Unpaywall: https://findresearcher.sdu.dk/ws/files/143542325/Rivaroxaban_with_or_without_aspirin_in_patients_with_stable_peripheral_or_carotid_artery_disease.pdfUnpaywall

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