New England Journal of Medicine October 05, 2017

Rivaroxaban with or without Aspirin in Stable Cardiovascular Disease (COMPASS)

John W. Eikelboom, Stuart J. Connolly, Jackie Bosch, et al.

Bottom Line

A landmark randomized controlled trial demonstrating that the addition of low-dose rivaroxaban (2.5 mg twice daily) to aspirin significantly reduces the risk of major adverse cardiovascular events and improves overall survival compared to aspirin alone in patients with stable cardiovascular disease, albeit with an increased risk of major bleeding.

Key Findings

1. Combination therapy (rivaroxaban 2.5 mg twice daily plus aspirin 100 mg daily) significantly reduced the primary composite outcome of cardiovascular death, stroke, or myocardial infarction compared to aspirin alone (4.1% vs. 5.4%; HR 0.76; 95% CI, 0.66-0.86; P<0.001).

2. Rivaroxaban monotherapy (5 mg twice daily) did not significantly reduce the primary outcome compared to aspirin alone (4.9% vs. 5.4%; HR 0.90; 95% CI, 0.79-1.03; P=0.12).

3. All-cause mortality was significantly lower in the combination therapy group than in the aspirin-alone group (3.4% vs. 4.1%; HR 0.82; 95% CI, 0.71-0.96; P=0.01).

4. Major bleeding events were significantly higher in the combination group compared to the aspirin group (3.1% vs. 1.9%; HR 1.70; 95% CI, 1.40-2.05; P<0.001), primarily driven by gastrointestinal bleeding.

5. There was no significant increase in the incidence of intracranial or fatal bleeding between the combination therapy and aspirin-alone groups.

6. The prespecified net clinical benefit (a composite of cardiovascular death, stroke, myocardial infarction, fatal bleeding, or symptomatic critical organ bleeding) significantly favored the combination therapy over aspirin alone (HR 0.80; P=0.0005).

Study Design

Design

Factorial RCT

Double-Blind

Sample

27,395

Patients

Duration

23 mo

Median

Setting

33 countries

Population Patients with stable atherosclerotic vascular disease (coronary artery disease, peripheral artery disease, or both)

Intervention Rivaroxaban 2.5 mg twice daily plus aspirin 100 mg once daily, OR rivaroxaban 5 mg twice daily (with matching placebos)

Comparator Aspirin 100 mg once daily (plus placebo)

Outcome Composite of cardiovascular death, stroke, or myocardial infarction

Study Limitations

• Early termination of the trial by the Data and Safety Monitoring Board at a mean follow-up of 23 months may have led to an overestimation of the true treatment effect size and restricted the ability to evaluate long-term cumulative safety, particularly bleeding risks.

• The strict inclusion criteria excluded patients with a high risk of bleeding, severe heart failure, or severe renal impairment (eGFR <15 mL/min), limiting the generalizability of the findings to frailer, multi-morbid patient populations.

• A mandatory active run-in period filtered out non-adherent patients and those who immediately developed adverse effects, which likely led to an underestimation of bleeding events compared to unselected real-world clinical practice.

• The trial excluded patients requiring dual antiplatelet therapy (e.g., due to a recent acute coronary syndrome or recent stent implantation), meaning the regimen cannot be directly applied during the immediate high-risk post-event phase.

Clinical Significance

The COMPASS trial established a paradigm-shifting 'dual-pathway inhibition' strategy for the secondary prevention of stable atherosclerotic vascular disease. By demonstrating a 24% relative risk reduction in major cardiovascular events and a significant survival benefit over standard aspirin monotherapy, it filled a major therapeutic gap for patients with chronic coronary and peripheral artery disease. The clear efficacy of 'vascular-dose' rivaroxaban (2.5 mg twice daily) combined with aspirin prompted swift updates to international cardiology and vascular guidelines, making it a standard-of-care option for selected high-ischemic, low-bleeding risk patients.

Historical Context

Prior to COMPASS, standard secondary prevention for stable cardiovascular disease relied heavily on single antiplatelet therapy, predominantly aspirin. Attempts to augment anti-thrombotic protection by combining full-dose oral anticoagulation (e.g., warfarin) with antiplatelet therapy—such as in the WARIS II trial—proved too hazardous due to excessive major bleeding risks and complex monitoring requirements. The advent of direct oral anticoagulants (DOACs) offered a more predictable safety profile. The earlier ATLAS ACS 2-TIMI 51 trial demonstrated that low-dose rivaroxaban (2.5 mg twice daily) could reduce ischemic events when added to dual antiplatelet therapy following an acute coronary syndrome, though with heightened bleeding. COMPASS successfully extended this dual-pathway approach to a broader, stable population of chronic CAD and PAD patients, proving that targeting both thrombin generation and platelet activation could safely confer a survival advantage over aspirin alone.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does the combination of low-dose rivaroxaban and aspirin conceptually target different pathophysiological pathways of thrombosis in stable cardiovascular disease compared to traditional dual antiplatelet therapy (DAPT)?

Key Response

This question tests foundational knowledge of the coagulation cascade versus platelet activation. Aspirin inhibits COX-1 to prevent thromboxane A2-mediated platelet aggregation, while low-dose rivaroxaban inhibits Factor Xa, reducing thrombin generation. Because thrombin is a potent platelet activator and essential for fibrin cross-linking, this 'dual pathway inhibition' (DPI) targets both the cellular (platelet) and humoral (coagulation) arms of thrombus formation more comprehensively than DAPT, which only targets two platelet pathways.

Resident

Based on the COMPASS trial results, how should you balance the Number Needed to Treat (NNT) for major adverse cardiovascular events (MACE) against the Number Needed to Harm (NNH) for major bleeding when deciding to initiate dual pathway inhibition in the outpatient clinic?

Key Response

Residents must apply trial data to clinical risk-benefit analysis. The trial showed a 1.3% absolute risk reduction in MACE and a 1.2% absolute risk increase in major bleeding. However, fatal bleeding and intracranial hemorrhage did not significantly increase, and there was an overall mortality benefit. The resident should recognize that patient selection is critical: the regimen is best suited for patients with high ischemic risk (e.g., polyvascular disease) and unequivocally low bleeding risk.

Fellow

The COMPASS trial included a substantial cohort of patients with peripheral artery disease (PAD). How do the specific ischemic benefits (e.g., reduction in major adverse limb events [MALE]) of the rivaroxaban and aspirin combination in this subgroup alter our traditional approach to medical management in severe claudicants?

Key Response

Fellows should understand subspecialty nuances and subgroup data. The PAD cohort in COMPASS demonstrated a significant reduction in MALE, including major amputations. Traditionally, PAD management relied heavily on single antiplatelet agents (aspirin or clopidogrel) or cilostazol. Recognizing that DPI protects against microvascular and macrovascular limb thrombosis fundamentally shifts PAD medical management from merely preventing systemic MACE to actively preserving limb viability.

Attending

Given that the COMPASS trial was stopped early for efficacy, how should we counsel our patients and trainees regarding the potential overestimation of treatment effect, and in which specific clinical phenotypes do you feel the net clinical benefit truly justifies the lifetime bleeding risk?

Key Response

Attendings must teach critical appraisal alongside practical wisdom. Trials stopped early for efficacy often succumb to the 'random high' effect, potentially overestimating benefits. The attending should guide trainees to reserve this therapy for 'COMPASS-like' high-risk patients (e.g., multivessel CAD with diabetes or PAD) rather than broadly applying it, carefully weighing the lifetime, cumulative risk of bleeding against the potential ischemic benefit.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The COMPASS trial utilized an active run-in period where patients received a placebo and aspirin prior to randomization to exclude those who were non-adherent or experienced early adverse events. How does this enrichment strategy impact the internal validity versus the external generalizability of the trial's safety outcomes?

Key Response

PhD-level critique requires evaluating trial design choices. A run-in period increases statistical power and internal validity by ensuring high adherence and minimizing early noise (e.g., minor bleeding or GI intolerance to aspirin). However, it threatens external validity because the real-world 'intention-to-treat' clinical population includes non-adherent patients and those sensitive to early bleeding, meaning real-world bleeding rates are likely higher than those reported in the trial.

Journal Editor

As a peer reviewer evaluating the COMPASS manuscript, how would you scrutinize the investigators' choice of the modified ISTH major bleeding criteria, and how might this custom definition influence the perceived net clinical benefit of the intervention?

Key Response

Editors look for methodological rigor and endpoint definitions. COMPASS used a modified International Society on Thrombosis and Haemostasis (ISTH) bleeding criteria which included bleeding leading to hospitalization without an overnight stay. A reviewer would flag this to determine if it inflates minor/moderate bleeding relative to fatal/intracranial bleeding, or if it accurately captures the patient-centered burden. Understanding how custom endpoints skew net clinical benefit calculations is central to editorial peer review.

Guideline Committee

Considering the COMPASS trial data alongside the baseline risks of chronic coronary syndromes (CCS), how should current AHA/ACC and ESC guidelines formally integrate low-dose rivaroxaban plus aspirin into treatment algorithms, specifically regarding Class of Recommendation (COR) and defining the 'high ischemic risk' patient?

Key Response

Guideline committees translate evidence into broad clinical algorithms. The ESC guidelines for CCS have incorporated this strategy (Class IIa, LOE A) for patients at high ischemic risk and low bleeding risk. The committee must debate how to standardize the definition of 'high ischemic risk' (e.g., multivessel CAD + diabetes, CKD, or PAD) to justify recommending DPI over the historical paradigm of single antiplatelet therapy, ensuring guidelines provide clear, actionable patient selection criteria for clinicians.

Clinical Landscape

Noteworthy Related Trials

2012

ATLAS ACS 2-TIMI 51

n = 15,526 · NEJM

Tested

Rivaroxaban (2.5 mg or 5 mg BID) + Standard antiplatelet therapy

Population

Patients with recent acute coronary syndrome (ACS)

Comparator

Placebo + Standard antiplatelet therapy

Endpoint

Composite of CV death, MI, or stroke (MACE)

Key result: Low-dose rivaroxaban significantly reduced cardiovascular events and mortality but increased the risk of major bleeding and intracranial hemorrhage.

2015

PEGASUS-TIMI 54

n = 21,162 · NEJM

Tested

Ticagrelor (90 mg or 60 mg BID) + Aspirin

Population

Patients with a history of myocardial infarction (1-3 years prior) and high cardiovascular risk

Comparator

Placebo + Aspirin

Endpoint

Composite of CV death, MI, or stroke (MACE)

Key result: Long-term use of ticagrelor in addition to aspirin significantly reduced the risk of MACE but increased the risk of major bleeding.

2020

VOYAGER PAD

n = 6,564 · NEJM

Tested

Rivaroxaban 2.5 mg BID + Aspirin 100 mg QD

Population

Patients with symptomatic PAD undergoing lower-extremity revascularization

Comparator

Aspirin 100 mg QD + Placebo

Endpoint

Composite of acute limb ischemia, major amputation, MI, ischemic stroke, or CV death

Key result: Rivaroxaban plus aspirin significantly reduced the composite outcome of severe limb and cardiovascular events compared to aspirin alone.

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