Rivaroxaban With or Without Aspirin for the Secondary Prevention of Cardiovascular Disease

Clinical Implications of the COMPASS Trial

Stephen J. Nicholls; Adam J. Nelson

Disclosures

Am J Cardiovasc Drugs. 2019;19(4):343-348. 

In This Article

The Compass Trial

The COMPASS (Cardiovascular Outcomes for People Using Anti-coagulation Strategies) trial tested the hypothesis that treatment with rivaroxaban either in combination with aspirin or as monotherapy would be more effective than aspirin monotherapy at reducing cardiovascular events and would have an acceptable bleeding profile in patients with stable atherosclerotic disease.[29] Eligible patients had established coronary artery disease, peripheral arterial disease, or both. Patients aged < 65 years were also required to have either evidence of polyvascular disease or additional cardiovascular risk factors. Following study entry, patients entered a run-in period receiving rivaroxaban-matched placebo BID and aspirin 100 mg OD for 2 weeks to assess for patient adherence and lack of adverse events. Patients who successfully completed this run-in period were randomized to treatment with (1) rivaroxaban 2.5 mg BID and aspirin 100 mg OD, (2) rivaroxaban 5 mg BID and aspirin-matched placebo OD, or (3) aspirin 100 mg OD and rivaroxaban-matched placebo BID. Importantly, randomization was stratified according to concomitant use of proton pump inhibitors (PPIs).

The primary efficacy endpoint of the study was the composite of cardiovascular death, myocardial infarction, or stroke (MACE). The major safety endpoint included a modification of the International Society on Thrombosis and Haemostasis (ISTH) criteria for major bleeding.[30] The net clinical benefit outcome for the study included the composite of cardiovascular death, myocardial infarction, stroke, fatal bleeding, or symptomatic bleeding into a critical organ. The study was designed to recruit 27,400 patients, with an expected event rate of 3.3 per 100 person-years in the control group, and to continue until at least 2200 patients had experienced a primary efficacy endpoint. The sample size provided 90% power to demonstrate a 20% reduction in cardiovascular risk in each rivaroxaban group compared with aspirin monotherapy.

In total, 27,395 patients were randomized; the mean age was 68 years and 22% were women. Participants had a high prevalence of cardiovascular risk factors (smoking 21%, hypertension 75%, diabetes 37%) and a mean total cholesterol of 162 mg/dL and blood pressure of 136/78 mmHg. Qualifying atherosclerotic disease included coronary artery disease in 90% and peripheral arterial disease in 27% of patients. Concomitant medical therapy included lipid-lowering agents in 90% and renin–angiotensin–aldosterone system inhibitors in 71% of patients.

At the first of two planned interim efficacy analyses, based on accrual of 50% of planned primary endpoint events, the independent data and safety monitoring committee recommended early termination of the comparison of rivaroxaban and aspirin on the basis of clear evidence of clinical benefit in favor of the rivaroxaban groups. The primary endpoint occurred in 4.1% in the rivaroxaban/aspirin group, 4.9% in the rivaroxaban monotherapy group, and 5.4% in the aspirin monotherapy group. This equated to a 24% reduction in MACE in the low-dose rivaroxaban/aspirin group compared with aspirin alone (HR 0.76; 95% CI 0.66–0.86; p < 0.001). In contrast, the HR of 0.90 (95% CI 0.79–1.03) observed with rivaroxaban 5 mg BID compared with aspirin did not meet statistical significance (p = 0.12). An 18% reduction in mortality was observed in the rivaroxaban/aspirin group compared with aspirin alone (3.4 vs. 4.1%; p = 0.01). Subgroup analysis demonstrated no statistical heterogeneity, suggesting this clinical benefit was observed in all subgroups studied. Not surprisingly, major bleeding occurred more frequently in patients treated with either rivaroxaban/aspirin (3.1 vs. 1.9%; p < 0.001) or rivaroxaban monotherapy (2.8 vs. 1.9%; p < 0.001) compared with aspirin monotherapy. Gastrointestinal source made up over half of the major bleeding events, with no significant difference in the rates of fatal bleeding. Patients who were not receiving a PPI at study entry were further randomized to receive PPI or placebo in a nested trial; the results are likely to inform the degree to which this bleeding can be easily mitigated. In a further analysis, when cardiovascular and bleeding events were combined in the net clinical benefit outcome, fewer events were observed with low-dose rivaroxaban in combination with aspirin (4.7 vs. 5.9%; p < 0.001). In contrast, treatment with rivaroxaban 5 mg did not result in a significant reduction in MACE compared with aspirin alone and thus, did not enjoy the same net clinical benefit observed in the arm receiving 2.5 mg. A similar phenomenon was observed in the ATLAS trial and may be driven, in part, by increased rates of nonfatal bleeding, an evolving independent predictor of MACE.[31] Although incompletely understood, this may be mediated through a requirement for antiplatelet therapy cessation, compensatory platelet activation associated with bleeding, or a deleterious oxygen supply–demand curve driven by blood loss and anemia.[32]

A subsequent prespecified analysis of the 7470 patients with an established clinical history of peripheral arterial disease further studied the impact of treatment with rivaroxaban and aspirin on cardiovascular and major adverse limb events (MALE).[33] In this cohort, treatment with rivaroxaban/aspirin resulted in a 28% lower risk in MACE and 46% lower risk in MALE. In a similar fashion, rivaroxaban monotherapy also resulted in a 33% reduction in MALE. Increased bleeding rates were observed with both doses of rivaroxaban compared with aspirin monotherapy in the patients with peripheral arterial disease.

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