By Michael H. Crawford, MD

Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco

SYNOPSIS: An analysis of the COMPASS trial for the secondary endpoint of mortality showed the combination of low-dose rivaroxaban and aspirin significantly lowered the all-cause mortality rate vs. low-dose aspirin alone.

SOURCE: Eikelboom JW, Bhatt DL, Fox KAA, et al. Mortality benefit of rivaroxaban plus aspirin in patients with chronic coronary or peripheral artery disease. J Am Coll Cardiol 2021;78:14-23.

The Cardiovascular Outcomes for People Using Anticoagulant Strategies (COMPASS) trial compared rivaroxaban 2.5 mg twice a day plus aspirin 100 mg/day (RA group) to aspirin alone (AA group) in patients with known coronary or peripheral vascular disease. The combined primary endpoint was cardiovascular (CV) death, stroke, or myocardial infarction (MI). After 1,323 events, the trial ended early because of favorable outcomes in the RA group.

Subsequently, it was approved for this secondary prevention goal in more than 100 countries, including the United States. The components of the combined primary endpoint constituted the three secondary endpoints of the trial. One was mortality, both all-cause and CV. COMPASS mortality and the factors that influenced mortality were the subject of this report by Eikelboom et al. Mortality was classified as CV when no other clear cause of death was discovered. The potential risk factors for death considered were the extent of polyvascular disease, chronic kidney disease (estimated GFR less than 60 mL/minute), mild to moderate heart failure (EF > 30% or New York Heart Association class I or II), and diabetes.

There were 18,278 patients enrolled in COMPASS at 602 sites in 33 countries who were followed for a mean of 23 months. All-cause mortality was reduced significantly (1.8 for RA vs. 2.2% for AA; HR, 0.82; 95% CI, 0.71-0.96; P = 0.01). CV mortality was reduced by 18% in the RA group compared to the AA group (3.4% vs. 4.1%, respectively; HR, 0.82; 95% CI, 0.71-0.96; P = 0.01). Coronary heart disease mortality was reduced (0.5% for RA vs. 0.7% for AA; HR, 0.73; 95% CI, 0.55-0.96; P = 0.03). There was no appreciable effect on non-CV mortality (1.7% for RA vs. 1.9% for AA; HR, 0.87; 95% CI, 0.71-1.08; P = 0.20).

When analyzing specific causes of death, there was no observed effect on non-cerebral bleeding, MI, stroke, heart failure, or sudden death. The overall number needed to treat (NNT) to prevent one death in 30 months was 81. Patient subgroups with risk factors that reduced this NNT included chronic kidney disease (NNT = 59), diabetes (NNT = 53), polyvascular disease (NNT = 47), and heart failure (NNT = 23). In those with more than one of these risk factors, the more that were present the lower the NNT: two risk factors (NNT = 40); three risk factors (NNT = 19). The authors concluded the combination of low-dose rivaroxaban and aspirin vs. low-dose aspirin alone reduced all-cause mortality, mainly because of significant reductions in CV mortality. The authors also observed that the magnitude of the mortality benefit was greater in patients at the highest risk for a CV event.

COMMENTARY

The combined endpoint of mortality, stroke, and MI in the overall COMPASS trial was reduced by 24% in the RA group compared to the AA group. The secondary endpoint analysis by Eikelboom et al demonstrated this was caused mainly by a reduction in CV mortality since non-CV mortality was not affected. This reduction in CV mortality coincided with a decrease in all CV events except stroke and heart failure death. This lack of effect on heart failure death is not surprising since heart failure deaths probably are caused by arrhythmias or pump failure. These would not be expected to be influenced by rivaroxaban or aspirin. Cerebral vascular disease probably caused stroke deaths in these patients, not atrial fibrillation.

Also of interest is the fact rivaroxaban alone was not superior to aspirin in COMPASS. This suggests ischemic events drive the reduction in CV mortality. The finding that higher-risk patients benefitted more from the rivaroxaban/aspirin combination suggests patients with more advanced disease are those in whom plaque rupture more likely would result in thrombus formation. Whereas in patients with milder disease, antiplatelet drugs would be sufficient, and the higher risk of an anticoagulant would not result in net clinical benefit.

In the overall COMPASS trial, major bleeding was more common in the RA group compared to the AA group, but intracranial hemorrhage and fatal bleeding were not. Also, in the mortality analysis by Eikelboom et al, fatal bleeding other than that caused by hemorrhagic stroke was rare and not different between the RA and AA groups. Although rarely fatal, major bleeding is a concern of patients and physicians. This represents a major obstacle to recommending RA for secondary prevention. The message of the Eikelboom et al analysis is patients with demonstrated atherosclerosis and two or more risk factors for a CV event are those who should be targeted for RA therapy. The authors believe the mortality benefit they have shown should tip the equilibrium between benefits and risks.