More Evidence Rivaroxaban May Carry Higher Bleeding Risk Than Other NOACs

LOS ANGELES, CA—Another real-world study has suggested that there may be differences among the non-vitamin K antagonist oral anticoagulants (NOACs) in terms of the risk of major bleeding.

Among patients with nonvalvular A-fib initiating treatment for the first time within the US Department of Defense Military Health System, dabigatran 150 mg bid was associated with lower risks of overall major bleeding (HR 0.82; 95% CI 0.70-0.97) and major intracranial bleeding (HR 0.65; 95% CI 0.44-0.98) when compared with rivaroxaban 20 mg/day, according to Todd Villines, MD (Walter Reed National Military Medical Center, Bethesda, MD).

Efficacy outcomes were similar with the two agents, he reported at the International Stroke Conference here.

Some differences in outcomes emerged when new users of dabigatran were compared with those starting on apixaban 5 mg bid, although Villines said those findings should be considered exploratory because of limited statistical power.

The study adds to a growing body of literature comparing the NOACs “by using a non-Medicare population—a population that has limited barriers to care and high compliance rates, generally speaking, due to the low cost of drug acquisition,” he said.

Several NOACs are now available as alternatives to warfarin for preventing stroke or systemic embolism in patients with nonvalvular A-fib, and it is a daily challenge for clinicians to choose between them because of the lack of head-to-head randomized trials, Villines said.

Three Agents Compared

To explore the relative safety and effectiveness of the three most commonly used NOACs— dabigatran (Pradaxa; Boehringer Ingelheim), rivaroxaban (Xarelto; Bayer/Janssen), and apixaban (Eliquis; Bristol-Myers Squibb)—he and his colleagues turned to electronic health records from the US Department of Defense Military Health System, which provides healthcare for military service members and their families, as well as retirees.

After propensity-score matching, the analysis included 12,763 matched pairs of patients for the comparison of dabigatran 150 mg bid with rivaroxaban 20 mg/day and 4,802 matched pairs for the comparison of dabigatran with apixaban 5 mg/day.

When comparing dabigatran and rivaroxaban, there were no differences in risks of overall or ischemic stroke, TIA, all-cause mortality, MI, or venous thromboembolism, although dabigatran users carried a lower risk of hemorrhagic stroke (HR 0.22; 95% CI 0.09-0.59). Risks of overall major bleeding (which included hemorrhagic stroke) and major intracranial bleeding were higher with rivaroxaban.

When compared with apixaban, dabigatran was associated with elevated risks of MI (HR 2.72; 95% CI 1.19-6.18) and major GI bleeding (HR 1.50; 95% CI 1.02-2.23), with no differences for the other outcomes.

Villines said the findings from the apixaban comparisons should be considered exploratory because of low event rates—MI occurred in 20 patients in the dabigatran group and eight in the apixaban group—and limited statistical power. “I would not draw firm conclusions from that,” he said. He noted, too, that potential residual confounding is a limitation of all observational studies.

If somebody has a high risk for bleeding, probably in my mind rivaroxaban should not be their first choice. Nada El Husseini

Nada El Husseini, MD (Wake Forest Baptist Medical Center, Winston-Salem, NC), who was not involved in the study, agreed that definitive conclusions cannot be made based on retrospective data. She pointed out, however, that other analyses have similarly suggested that rivaroxaban might carry a higher bleeding risk than the other NOACs.

That plays into how she chooses treatment for her patients in the absence of clear guidelines on differentiating between the NOACs, she said, noting that the decision involves several factors. These include dosing, what a patient’s insurance will cover, patient preference, and side effects.

El Husseini said she tends to go with apixaban because the American Heart Association/American Stroke Association guidelines on secondary stroke prevention make a stronger recommendation for that drug than for rivaroxaban (Class I versus IIa); there is also a Class I recommendation for dabigatran. Also, apixaban seemed to fare a bit better in its pivotal trial versus warfarin than did the other NOACs, she said.

If a patient is adamant about wanting to take a once-a-day NOAC, El Husseini said she will consider using rivaroxaban if the patient does not have a high risk of GI bleeding and has insurance that will cover it. “If somebody has a high risk for bleeding, probably in my mind rivaroxaban should not be their first choice,” she said.