Xarelto Cuts CV Mortality in Stable Coronary, Peripheral Disease

Low-dose rivaroxaban (Xarelto) plus aspirin held a cardiovascular mortality benefit in the secondary prevention COMPASS trial that was larger for the highest-risk patients, a post hoc analysis showed.

While the previously reported main results from the trial showed a significant reduction in cardiovascular events, with a trend for reduced overall mortality with the combination versus aspirin alone (3.4% vs 4.1% over the median 23 months of follow-up, HR 0.82), the P value of 0.01 didn’t meet the prespecified threshold for significance of 0.0025.

In a new analysis of the 18,278 trial, participants randomized to the dual pathway inhibition regimen or aspirin alone, the combination significantly reduced cardiovascular mortality during that follow-up period (1.7% vs 2.2%, HR 0.78, P=0.02).

Those effects were consistent across myocardial infarction, stroke, and other specific cardiovascular causes of death with the exception of heart failure deaths.

Non-cardiovascular causes of death were not reduced, John Eikelboom, MBBS, of Hamilton General Hospital in Ontario, and colleagues reported online in the Journal of the American College of Cardiology.

All patient subgroups showed at least a numerically lower mortality risk with the combination than with aspirin alone. But while the interaction terms weren’t significant, the absolute magnitude of benefit was greater for those at higher baseline risk.

The absolute additional number of deaths prevented per 1,000 treated with the combination for 30 months climbed from 4.2 for those with none of the highest-risk features (disease in more than one vascular bed, poor kidney function, heart failure, or diabetes) to 4.8 with one such feature, 25.0 with two of the features, and 53.9 with all four features. The number needed to treat correspondingly fell from 236 to 19.

These findings were “consistent with the expected mechanisms of benefit” in chronic coronary and peripheral vascular disease, the researchers noted, and were externally consistent with the mortality benefit of low-dose rivaroxaban in the ATLAS ACS 2 TIMI 51 trial after a recent acute coronary syndrome, where cardiovascular mortality accounted for the overall mortality benefit.

The COMPASS trial overall enrolled patients with chronic coronary artery disease or peripheral artery disease, leading to an expanded indication in those conditions for rivaroxaban in 2018. In addition to the combination regimen of 2.5 mg rivaroxaban twice daily and 100 mg aspirin once daily and the 100 mg aspirin arm, the trial randomized about 9,000 patients to rivaroxaban alone. The direct oral anticoagulant (DOAC) alone did not prove to be better than aspirin alone for the primary endpoint and so was excluded from the mortality-specific analysis, the researchers reported.

The study did not adjust for multiple comparisons. Another limitation was that early termination of the trial for efficacy might have made the combination regimen look better than if the trial had continued.

Nevertheless, “[t]hese findings suggest that targeting both coagulation proteins and platelets can help to maximize the benefits of long-term antithrombotic therapy in patients with chronic atherothrombotic vascular disease,” Eikelboom’s group concluded.

The mortality analysis also has implications for clinical practice in helping sort out which patients are good candidates for a combined approach to prevention, noted an accompanying editorial by Jonathan Halperin, MD, of Mount Sinai Medical Center in New York City, and colleagues.

Showing a reduction in mortality takes away the uncertainty around weighing clinical benefit in preventing events against the risk of bleeding, the editorialists wrote.

Still, physicians should select patients thoughtfully for dual pathway inhibitor therapy, since there is an incremental risk of bleeding with aspirin plus an anticoagulant and cost and complexity to a multidrug regimen, Halperin’s group wrote.

There are still important questions for clinical practice that cannot be answered by COMPASS, particularly whether a more potent antiplatelet agent would be better alone or in combination with a low-dose DOAC.

Eikelboom and co-authors suggested future studies combining rivaroxaban with ticagrelor (Brilinta) rather than aspirin.

“In fact, there are a large number of potential alternatives, most of which have not been evaluated, and few will likely ever undergo the extensive assessment provided by the COMPASS trial investigators,” Halperin and co-authors countered.

“Whereas we might speculate about potentially safer or simpler options, the immediate challenge is to identify patients who are likely to gain survival advantage from the specific dual pathway regimen they validated [in COMPASS],” the editorialists continued. “That regimen is not appropriate for every patient with atherosclerosis, but for many of those with diabetes, involvement of more than one vascular bed, or ischemic heart disease underlying clinical heart failure, such treatment can begin today.”