Elsevier

The Lancet

Volume 391, Issue 10117, 20–26 January 2018, Pages 219-229
The Lancet

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

https://doi.org/10.1016/S0140-6736(17)32409-1Get rights and content

Summary

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.

Introduction

Patients with carotid artery disease or with peripheral artery disease of the lower extremities are at high risk for major adverse cardiovascular events,1, 2, 3 and patients with peripheral artery disease of the lower extremities are also at high risk for major adverse limb events such as severe limb ischaemia and amputation.4 In addition to smoking cessation and exercise, statins, angiotensin converting enzyme (ACE) inhibitors, and antiplatelet agents (aspirin or a P2Y12 inhibitor) are used to reduce vascular complications.4, 5, 6 Anticoagulant therapies have not been shown to be superior to antiplatelet therapy in peripheral artery disease and have unacceptably high rates of major bleeding.7 Specifically, high intensity (international normalised ratio [INR] of 3–4·5) and moderate intensity warfarin (INR 2–3) used with aspirin does not reduce major adverse cardiovascular events but does increase the risk of life-threatening bleeding, including intracranial haemorrhage.7, 8 Furthermore, ticagrelor was not superior to clopidogrel in reducing major adverse cardiovascular events or major adverse limb events in patients with peripheral artery disease.9 Dual antiplatelet therapy is not consistently superior to single antiplatelet therapy in reducing major adverse cardiovascular events or major adverse limb events in patients with peripheral artery disease.10, 11 Vorapaxar, a platelet receptor modulator, did not reduce major adverse cardiovascular events in patients with peripheral artery disease but acute limb ischaemia was significantly reduced, and there was an increase in moderate and severe bleeding.12

Research in context

Evidence before this study

Patients with peripheral artery disease are at high risk for major cardiovascular and limb events. The mainstay of treatment for patients with peripheral artery disease includes use of a single antiplatelet agent daily to prevent major adverse cardiovascular events. Other antithrombotic regimens have been tested in patients with peripheral artery disease including vitamin K antagonists and newer antiplatelet agents including P2Y12 antagonists used alone or in combination with aspirin, but none have been shown to be superior to antiplatelet therapy alone.

Added value of this study

The peripheral artery disease analysis of the COMPASS trial shows that use of low-dose rivaroxaban twice a day, together with aspirin 100 mg once a day, reduces cardiovascular death, myocardial infarction, stroke, and acute limb ischaemia and amputation, compared with aspirin alone. Although there is an increase in bleeding leading to more hospital admissions, there is no excess of fatal bleeding, intracranial bleeding, or bleeding into critical organs. Thus, the net clinical benefit favours the use of low-dose rivaroxaban plus aspirin.

Implications of all the available evidence

The combination of low dose rivaroxaban twice a day with aspirin could replace aspirin alone as standard of care in patients with stable peripheral artery disease who are not at high risk for bleeding.

Rivaroxaban, an oral factor Xa inhibitor, is effective in treating venous thromboembolism,13 and has been shown to prevent thromboembolic events in atrial fibrillation.14 Low dose rivaroxaban prevents venous thromboembolism after orthopaedic surgery,15 and the Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 51 (ATLAS-2) trial16 showed that low-dose rivaroxaban (2·5 mg twice a day) used in addition to dual antiplatelet therapy reduced major adverse cardiovascular events in patients with acute coronary syndromes, although rivaroxaban alone (5 mg twice a day) increased major, intracranial, and fatal bleeds. In the COMPASS trial,17 we sought to identify whether a low dose of rivaroxaban given twice a day when used with aspirin or without aspirin, was more effective than aspirin alone in reducing major adverse cardiovascular events and major adverse limb events in patients with peripheral artery disease.

Section snippets

Study design and participants

The design of COMPASS has been previously published.17 COMPASS was a multicentre, double-blind, randomised, placebo-controlled trial comparing low-dose rivaroxaban with aspirin or rivaroxaban alone (with aspirin placebo) versus aspirin alone (with rivaroxaban placebo) for prevention of cardiovascular death, myocardial infarction, and stroke in patients with coronary artery disease or peripheral artery disease who were receiving other proven therapies. Patients with a need for dual antiplatelet

Results

Between March 12, 2013, and May 10, 2016, 27 395 patients were enrolled into the overall COMPASS trial. The planned original sample size for COMPASS was 19 500 patients of which we planned to enrol at least 5000 patients with peripheral artery disease (25% of the total). However the sample size was increased due to slower than expected recruitment and a lower than expected aggregate event rate of the primary outcome, 6048 participants with symptomatic peripheral artery disease were enrolled and

Discussion

Patients with peripheral artery disease who were enrolled into the COMPASS trial and received the combination of rivaroxaban 2·5 mg twice a day plus aspirin 100 mg a day had fewer major adverse cardiovascular events by 28%, major adverse limb events by 46%, and the composite of major adverse cardiovascular or limb events by 31% compared with the aspirin alone group. Although this combination was associated with an increase in risk of major bleeding, there was no excess in fatal or critical

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