Contribution to literature

The COMPASS trial showed that rivaroxaban plus aspirin was associated with fewer adverse cardiovascular events, but more major bleeding events vs aspirin alone.

Description

The goal of the trial was to evaluate anticoagulation strategies with rivaroxaban among patients with stable atherosclerosis.

Study design

•Randomized
•Parallel
•Blinded

Patients with stable atherosclerosis were randomized to rivaroxaban 2.5 mg twice daily plus aspirin (n = 9,152) vs rivaroxaban 5 mg twice daily alone (n = 9,117) vs aspirin alone (n = 9,126).

•Total number of enrollees: 27,395
•Duration of follow-up: mean 23 months
•Mean patient age: 68 years
•Percentage female: 23%
•Percentage with diabetes: 38%

Inclusion criteria:

•Atherosclerosis in ≥2 vascular beds or two additional risk factors (current smoking, diabetes, renal insufficiency, heart failure, or nonlacunar ischemic stroke ≥1 month)

Exclusion criteria:

•High bleeding risk
•Recent stroke or previous hemorrhagic or lacunar stroke
•Severe heart failure
•Advanced kidney disease
•Use of dual antiplatelet therapy or anticoagulation
•Limited prognosis

Principal findings

The primary outcome, incidence of cardiovascular death, myocardial infarction, or stroke, occurred in 4.1% of the rivaroxaban plus aspirin group vs 4.9% of the rivaroxaban alone group vs 5.4% of the aspirin alone group (p < 0.001 for rivaroxaban plus aspirin vs aspirin alone; p = 0.12 for rivaroxaban alone vs aspirin alone). The primary efficacy outcome was the same in all tested subgroups.

Secondary outcomes:

•All-cause mortality: 3.4% for rivaroxaban plus aspirin, 4.0% for rivaroxaban alone, vs 4.1% for aspirin alone (p = 0.01 for rivaroxaban plus aspirin vs aspirin alone; p = 0.67 for rivaroxaban alone vs aspirin alone)
•Stroke: 0.9% for rivaroxaban plus aspirin, 1.3% for rivaroxaban alone, vs 1.6% for aspirin alone (p < 0.001 for rivaroxaban plus aspirin vs aspirin alone; p = 0.12 for rivaroxaban alone vs aspirin alone)
•Major bleeding: 3.1% for rivaroxaban plus aspirin, 2.8% for rivaroxaban alone, vs 1.9% for aspirin alone (p < 0.001 for rivaroxaban plus aspirin vs aspirin alone, p < 0.001 for rivaroxaban alone vs aspirin alone)

COMPASS PAD: Among 7,470 participants with peripheral arterial disease (PAD), 4,129 had symptomatic PAD, 1,919 had carotid disease, and 1,422 had coronary artery disease plus ankle-brachial index <0.9.

•Major adverse cardiac events (MACE): 5.0% for rivaroxaban plus aspirin, 6.0% for rivaroxaban alone, vs 7.0% for aspirin alone (p = 0.005 for rivaroxaban plus aspirin vs aspirin alone; p = 0.19 for rivaroxaban alone vs aspirin alone)
•Major adverse limb events (MALE): 1.5% for rivaroxaban plus aspirin, 1.9% for rivaroxaban alone, vs 2.6% for aspirin alone (p = 0.01 for rivaroxaban plus aspirin vs aspirin alone; p = 0.07 for rivaroxaban alone vs aspirin alone)
•Major bleeding: 3.0% for rivaroxaban plus aspirin, 3.0% for rivaroxaban alone, vs 2.0% for aspirin alone (p = 0.009 for rivaroxaban plus aspirin vs aspirin alone; p = 0.004 for rivaroxaban alone vs aspirin alone)

COMPASS CAD: There were 24,824 subjects with coronary artery disease (CAD).

•MACE: 4.0% for rivaroxaban plus aspirin, 5.0% for rivaroxaban alone, vs 6.0% for aspirin alone (p < 0.0001 for rivaroxaban plus aspirin vs aspirin alone; p = 0.094 for rivaroxaban alone vs aspirin alone)
•Major bleeding: 3.0% for rivaroxaban plus aspirin, 3.0% for rivaroxaban alone, vs 2.0% for aspirin alone (p < 0.0001 for rivaroxaban plus aspirin vs aspirin alone; p < 0.0001 for rivaroxaban alone vs aspirin alone)

Overall cost differences: Direct cost savings of event plus procedure costs with rivaroxaban 2.5 BID plus aspirin 100 mg daily vs aspirin 100 mg daily: mean, $682; overall, $6,144,221. Cost savings were robust across the four enrolling countries—United States, Canada, France, and Germany.

Interpretation

Among patients with stable atherosclerosis, rivaroxaban plus aspirin was associated with fewer adverse cardiovascular events, but more major bleeding events compared with aspirin alone. Rivaroxaban alone was not more effective than aspirin alone. Findings were the same among those with PAD and CAD. Rivaroxaban plus aspirin was effective at preventing both MACE and MALE among those with PAD. Bleeding is an important outcome; therefore, net clinical benefit will need to be carefully considered with this strategy.

Directs costs from events and procedures were reduced with low-dose rivaroxaban plus aspirin compared with aspirin alone. However, since the actual cost of this dose of the drug is yet unknown, overall cost savings and cost-effectiveness analyses are unavailable at this time.