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

Summary

Background

Coronary artery disease is a major cause of morbidity and mortality worldwide, and is a consequence of acute thrombotic events involving activation of platelets and coagulation proteins. Factor Xa inhibitors and aspirin each reduce thrombotic events but have not yet been tested in combination or against each other in patients with stable coronary artery disease.

Methods

In this multicentre, double-blind, randomised, placebo-controlled, outpatient trial, patients with stable coronary artery disease or peripheral artery disease were recruited at 602 hospitals, clinics, or community centres in 33 countries. This paper reports on patients with coronary artery disease. Eligible patients with coronary artery disease had to have had a myocardial infarction in the past 20 years, multi-vessel coronary artery disease, history of stable or unstable angina, previous multi-vessel percutaneous coronary intervention, or previous multi-vessel coronary artery bypass graft surgery. After a 30-day run in period, patients were randomly assigned (1:1:1) to receive rivaroxaban (2·5 mg orally twice a day) plus aspirin (100 mg once a day), rivaroxaban alone (5 mg orally twice a day), or aspirin alone (100 mg orally once a day). Randomisation was computer generated. Each treatment group was double dummy, and the patients, investigators, and central study staff were masked to treatment allocation. The primary outcome of the COMPASS trial was the occurrence of myocardial infarction, stroke, or cardiovascular death. This trial is registered with ClinicalTrials.gov, number NCT01776424, and is closed to new participants.

Findings

Between March 12, 2013, and May 10, 2016, 27 395 patients were enrolled to the COMPASS trial, of whom 24 824 patients had stable coronary artery disease from 558 centres. The combination of rivaroxaban plus aspirin reduced the primary outcome more than aspirin alone (347 [4%] of 8313 vs 460 [6%] of 8261; hazard ratio [HR] 0·74, 95% CI 0·65–0·86, p<0·0001). By comparison, treatment with rivaroxaban alone did not significantly improve the primary outcome when compared with treatment with aspirin alone (411 [5%] of 8250 vs 460 [6%] of 8261; HR 0·89, 95% CI 0·78–1·02, p=0·094). Combined rivaroxaban plus aspirin treatment resulted in more major bleeds than treatment with aspirin alone (263 [3%] of 8313 vs 158 [2%] of 8261; HR 1·66, 95% CI 1·37–2·03, p<0·0001), and similarly, more bleeds were seen in the rivaroxaban alone group than in the aspirin alone group (236 [3%] of 8250 vs 158 [2%] of 8261; HR 1·51, 95% CI 1·23–1·84, p<0·0001). The most common site of major bleeding was gastrointestinal, occurring in 130 [2%] patients who received combined rivaroxaban plus aspirin, in 84 [1%] patients who received rivaroxaban alone, and in 61 [1%] patients who received aspirin alone. Rivaroxaban plus aspirin reduced mortality when compared with aspirin alone (262 [3%] of 8313 vs 339 [4%] of 8261; HR 0·77, 95% CI 0·65–0·90, p=0·0012).

Interpretation

In patients with stable coronary artery disease, addition of rivaroxaban to aspirin lowered major vascular events, but increased major bleeding. There was no significant increase in intracranial bleeding or other critical organ bleeding. There was also a significant net benefit in favour of rivaroxaban plus aspirin and deaths were reduced by 23%. Thus, addition of rivaroxaban to aspirin has the potential to substantially reduce morbidity and mortality from coronary artery disease worldwide.

Funding

Bayer AG.

Introduction

Coronary artery disease is a global medical problem and a leading cause of morbidity and mortality.¹ Patients with coronary artery disease are at risk for myocardial infarction, ischaemic stroke, and cardiovascular death. The underlying pathophysiology of these events in patients with atherosclerosis is rupture or erosion of an atherosclerotic plaque which exposes the sub-endothelial matrix to circulating blood.² This activates both platelet aggregation and the coagulation cascade, which leads to an occlusive thrombus in the artery.³ Aspirin irreversibly blocks the formation of thromboxane A2, which reduces platelet aggregation, and is widely used for the prevention of ischaemic events in patients with coronary artery disease, because randomised trials have shown a reduction in the risk of vascular events by about 20%.³

Research in context

Evidence before this study

Stable coronary artery disease is a serious health problem globally. The effects of Factor Xa inhibitor drugs in patients with coronary artery disease have been studied with both apixaban and rivaroxaban. Higher dose anticoagulation with apixaban was not effective after acute coronary syndrome and caused too much bleeding. Lower doses of rivaroxaban, 2·5 mg and 5 mg twice a day, reduced vascular events in the ATLAS 2 study, when given as an additional treatment to mostly dual antiplatelet therapy in patients after acute coronary syndrome. The 2·5 mg dose reduced vascular events and mortality and had less bleeding than the 5 mg dose. This led to approval in many countries and provided the impetus to study rivaroxaban in patients with stable coronary artery disease.

Added value of this study

The COMPASS trial has now shown that in patients with stable coronary artery disease, most of whom are many years from either myocardial infarction or a revascularisation procedure, rivaroxaban 2·5 mg given twice a day in combination with aspirin 100 mg once a day reduces major vascular events by 26% and reduces death by 24%. Rivaroxaban increased major bleeding by 69%, but there was no significant increase in either intracranial or fatal bleeding. Results were consistent across a variety of patient subgroups. Thus, COMPASS has extended the positive results of ATLAS 2, showing that addition of rivaroxaban to aspirin is effective with an acceptable bleeding risk that mostly involves the gastrointestinal tract. However, COMPASS enrolled a large population of stable patients with coronary artery disease, almost all of whom were remote from recent events such as surgery or stent procedures, which provides more generalisable evidence than ATLAS 2.

Implications of all the available evidence

Addition of rivaroxaban to aspirin treatment in patients with stable coronary artery disease at almost any stage of their disease has the potential to substantially reduce morbidity and mortality of a high-risk population.

Vitamin K antagonists such as warfarin inhibit (or prevent) the function of the vitamin K-dependent coagulation proteins and the formation of thrombin. Vitamin K antagonists also lower cardiovascular events after myocardial infarction, although their use is limited by the potential for excessive bleeding.⁴ Combined therapy with vitamin K antagonists and aspirin has also been assessed, and has shown additional benefit against recurrent myocardial infarction and death compared with aspirin alone; however, clinical uptake has been restricted by increased serious bleeding, including intracranial haemorrhage.⁴ Factor Xa inhibitors provide more specific competitive inhibition of coagulation proteins with improved or similar efficacy to warfarin, and lower rates of intracranial bleeding.5, 6, 7, 8 Although conceptually attractive, experience with combined use of a factor Xa inhibitor and an antiplatelet agent has had mixed results.9, 10 In patients with acute coronary syndrome, a dose of 5 mg twice a day of the factor Xa inhibitor apixaban showed no reduction in thrombotic events when combined with antiplatelet therapy; and increased fatal and intracranial bleeding compared with placebo.⁹ On the other hand, in the ATLAS 2 trial,¹⁰ lower doses of rivaroxaban were tested in patients on antiplatelet therapy (mostly dual antiplatelet therapy in the first year of follow-up and mostly aspirin thereafter). Rivaroxaban reduced the risk of major ischaemic events, and particularly the lowest dose of rivaroxaban (2·5 mg twice a day) when added to antiplatelet therapy, reduced the composite outcome of stroke, myocardial infarction, and cardiovascular death and also reduced overall mortality, with a moderately increased risk of haemorrhage. The higher dose of rivaroxaban tested (5 mg twice a day) when added to antiplatelet therapy increased bleeding, with higher risk of fatal bleeding than the lower dose.

In stable coronary artery disease, trials of dual antiplatelet therapy have provided inconsistent results. Addition of clopidogrel to aspirin in stable coronary artery disease did not substantially reduce major vascular events.¹¹ By contrast, the addition of ticagrelor to aspirin in chronic stable coronary artery disease, 1–3 years after acute coronary syndrome reduced major vascular events, but increased bleeding and did not significantly reduce mortality.¹² Thus, there is a need to improve current approaches to antithrombotic therapy for stable coronary artery disease.

There have been no studies of a factor Xa inhibitor in patients with stable coronary artery disease, most of whom receive single antiplatelet therapy. The addition of a low dose of a factor Xa inhibitor to single antiplatelet therapy in these patients has the potential to substantially reduce vascular events, especially if this can be achieved with an acceptable increase of bleeding. It is also possible that a strategy of using a moderate dose of factor Xa inhibitor alone could be superior to antiplatelet therapy. In the cardiovascular outcomes for people using anticoagulation strategies (COMPASS) trial, we hypothesised that low-dose rivaroxaban and aspirin together, or a higher dose of rivaroxaban alone, would be superior to aspirin alone for the prevention of major vascular events in patients with stable vascular disease.13, 14 The present paper reports trial results for patients with coronary artery disease in the COMPASS trial.