Rivaroxaban Appears to Protect Against MI in Older Men With A-fib, but Not in Women

Patient sex influences the impact of rivaroxaban on MI risk in Medicare beneficiaries with newly diagnosed A-fib, with men—but not women—deriving a benefit, a new analysis suggests.

When it comes to risks of heart failure and all-cause mortality, however, rivaroxaban (Xarelto; Janssen Pharmaceuticals) and dabigatran (Pradaxa; Boehringer Ingelheim) both have the advantage over warfarin in men and women alike, Ghanshyam Palamaner Subash Shantha, MBBS (University of Iowa Hospitals and Clinics, Iowa City), reported during a poster session at Heart Rhythm 2017 in Chicago, IL.

The findings may have implications for personalizing the choice of anticoagulation in patients with A-fib, Shantha told TCTMD. For example, he said, an older man with a history of acute MI may be a good candidate for rivaroxaban over another anticoagulant because of the added protection against recurrent infarction.

“The newer anticoagulants have benefits other than stroke protection,” Shantha said, noting that much of the mortality in patients with A-fib is caused by reasons other than stroke. “So it is time that we start looking into agents which protect from stroke but at the same time have an effect on mortality, acute MI, and heart failure.”

Shantha pointed out that the randomized trials of the non-vitamin K antagonist oral anticoagulants (NOACs) have provided some evidence of beneficial effects on MI, heart failure, and all-cause mortality, in addition to stroke. But potential sex differences had not been explored.

For this study, the investigators looked at data from Medicare Part D beneficiaries ages 66 and older who were newly diagnosed with A-fib; the analysis included 65,734 men and 81,137 women. Rivaroxaban and dabigatran were compared with each other and with warfarin.

There was a distinct sex interaction for MI, but not for heart failure or all-cause mortality, Shantha said.

Among men, rivaroxaban was associated with a 41% lower relative risk of MI compared with warfarin (HR 0.59; 95% CI 0.38-0.91) and 43% lower risk compared with dabigatran (HR 0.57; 95% CI 0.31-0.89). Risk was similar with dabigatran and warfarin.

Among women, on the other hand, there were no significant differences in MI risk for any of the comparisons.

In terms of heart failure and all-cause mortality, both NOACs were associated with lower risks compared with warfarin regardless of sex.

Shantha said he couldn’t explain the interaction with sex observed for MI.

But T. Jared Bunch, MD (Intermountain Heart Institute Heart Rhythm Specialists, Murray, UT), who was not involved in the study, speculated that the differential effect might have to do with the smaller size, lower creatinine clearance, and use of hormone replacement therapy in older women. Hormone replacement therapy, Bunch noted, is known to be prothrombotic and it’s possible that it could mitigate the beneficial effect of rivaroxaban.

As for the reduction in heart failure seen with both NOACs, Shantha pointed to the thrombin theory of heart failure progression for an explanation. The idea is that thrombin causes myocardial inflammation and worsens heart failure.

Bunch said that there could be a direct drug effect responsible for the lower risk of heart failure in the NOAC-treated patients, but pointed out that the finding could be due to bias. When new drugs are introduced, they are costly, which can limit their use to a select group of people who are more likely to be insured and tend to be healthier, he explained. So comparisons of a generic medication (warfarin) and costlier new drugs (NOACs) may be pitting a healthier population against a sicker one. In addition, Bunch said, patients who can afford more expensive A-fib drugs might also be able to afford better medications for heart failure.

“This study doesn’t go into the concurrent use of other medications for heart failure, but I’d worry in that setting that we may be picking up a little bit of bias,” he said, noting that a similar case could be made to explain the mortality findings.

Overall, the study indicates that “we clearly need more women in large randomized prospective trials so we can—upfront—have an understanding of gender variance in drug effect,” Bunch said.