Less Bleeding on Rivaroxaban for AF if Fewer Concomitant Meds

Deborah Brauser

January 11, 2016

DURHAM, NC — Up to two-thirds of patients with nonvalvular atrial fibrillation (AF) are taking at least five medications, with many taking up to nine, suggests a new analysis from the ROCKET AF study[1]. While increasing polypharmacy wasn't associated with an increased risk of stroke, it was associated with a higher risk of bleeding.

In addition, the primary efficacy and safety outcomes did not differ significantly between the participants who took the novel oral anticoagulant (NOAC) rivaroxaban (Xarelto, Bayer Pharma/Janssen Pharmaceuticals) for stroke prevention as part of their polypharmacy and those who took warfarin.

However, the new analysis showed that among the patients taking zero to four medications, rivaroxaban was associated with significantly less major bleeding than warfarin.

"This is the first study examining concomitant medications and polypharmacy in patients with AF," write the investigators, led by Dr Jonathan P Piccini (Duke Clinical Research Center, Durham, NC).

"In summary, rivaroxaban was tolerated across complex patients on multiple medications," they add.

The findings were published online December 16, 2015 in Circulation.

Polypharmacy Assessments

In the original ROCKET AF study, 14,264 patients with nonvalvular AF were randomly assigned to treatment with either 20 mg once daily of the direct factor Xa inhibitor rivaroxaban or adjusted doses of the vitamin-K antagonist warfarin. As reported by heartwire from Medscape, rivaroxaban was noninferior to warfarin for preventing stroke and systemic embolism. In addition, major and nonmajor clinically relevant bleeding rates were not significantly different between the two treatments.

As reported this past fall, a retrospective analysis of the trial showed that the rivaroxaban-treated group had more incidence of gastrointestinal bleeding vs the warfarin-treated group. But there were no between-group differences in severe and fatal bleeds—and event rates were low.

For the current analysis, the investigators assessed all ROCKET-AF participants for possible associations between overall polypharmacy and clinical outcomes and to compare safety and efficacy of polypharmacy with rivaroxaban vs warfarin.

At the study's start, 98% of the participants were taking at least one concomitant medication. Among the entire patient population, 36% of the participants were taking up to four concomitant medications, 51% were taking between five and nine medications, and the remaining 13% were taking 10 or more medications.

This latter practice was significantly associated with a higher risk of major or nonmajor bleeding vs only taking up to four medications (adjusted hazard ratio [HR] 1.47, 95% CI 1.31–1.65; P<0.0001). It was also associated with a greater risk of the combined end point of MI, non–central nervous system (CSN) embolism, vascular death, or stroke (HR 1.41, P=0.0009), of MI alone (HR 2.28, P=0.0002), and of all-cause mortality (HR 1.44, P=0.0005).

Taking the high number of medications was not, however, associated with increased risk of stroke by itself (HR 1.02).

Combined Inhibitor Findings "Reassuring"

"Patients taking more medications were older, more often diabetic, more often had a diagnosis of [chronic obstructive pulmonary disease] COPD, and more likely to have taken prior vitamin-K antagonists" but were less likely to have had a prior stroke or transient ischemic attack, note the researchers.

"Of note, the type of AF and the presence of heart failure did not correlate with the number of concomitant medications," they add.

In the patients receiving zero to four medications, the HR for major bleeding was 0.71 for those treated with rivaroxaban vs warfarin (95% CI 0.5–0.95; P=0.007). However, "this reduced risk was not evident" in those taking more than four medications.

Among the participants who were taking at least one mild to moderate combined CYP3A4 and P-glycoprotein inhibitor, there were no differences in outcomes between the assigned treatment groups.

The investigators note that current package inserts caution that using rivaroxaban with these combined inhibitors could potentially increase bleeding, drug absorption, and concentrations. But "we saw no evidence of differential outcomes," they write, adding that "this should be reassuring for clinicians."

ROCKET AF was funded by Johnson & Johnson Pharmaceutical Research & Development and Bayer Healthcare. Piccini receives clinical research grants from ARCA Biopharma, Boston Scientific, Gilead, Janssen Pharmaceuticals, ResMed, and St Jude Medical. He also serves as a consultant to GlaxoSmithKline, Johnson & Johnson, Laguna Pharmaceuticals, Medtronic, and Spectranetics. Disclosures for the coauthors are listed in the article.

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