Combining newer anticoagulants with some other drugs may be risky

By Megan Brooks

NEW YORK (Reuters Health) - Combining several commonly prescribed medications with non-vitamin K oral anticoagulants (NOACs) may increase the risk of major bleeding in patients with nonvalvular atrial fibrillation (AF), suggest results of an observational study from Taiwan.

“Physicians should consider the potential risks associated with the concurrent use of NOACs and other drugs,” Dr. Shang-Hung Chang from Chang Gung Memorial Hospital in Taoyuan told Reuters Health by email. In particular, “combining fluconazole with NOACs looks risky based on the findings. Physicians shall choose alternative whenever possible,” Dr. Chang said.

NOACs are increasingly being used instead of warfarin because of their ease of administration and comparable efficacy in patients with AF. However, they often are prescribed with other medications that share metabolic pathways that may increase the risk of bleeding.

To investigate, Dr. Chang and colleagues analyzed data from the Taiwan National Health Insurance database on 91,330 adults with nonvalvular AF who received at least one NOAC prescription (dabigatran, rivaroxaban, or apixaban).

They estimated the risk of major bleeding associated with or without the concurrent use of medications that share metabolic pathways with NOACs: atorvastatin; digoxin; verapamil; diltiazem; amiodarone; fluconazole; ketoconazole, itraconazole, voriconazole, or posaconazole; cyclosporine; erythromycin or clarithromycin; dronedarone; rifampin; and phenytoin.

During the five-year study period (from 2012 through 2016), there were 4,770 major bleeding events, defined as hospitalization or ED visit with a primary diagnosis of intracranial hemorrhage or gastrointestinal, urogenital, or other bleeding.

Diltiazem and amiodarone were among the most common medications co-prescribed with a NOAC, despite guidance against their combined use, the authors note. Atorvastatin and digoxin were the other two most commonly co-prescribed medications.

According to the study team, the risk of major bleeding was significantly higher when a NOAC was combined with amiodarone, fluconazole, rifampin, or phenytoin rather than with a NOAC alone.

Adjusted incidence rates per 1,000 person-years were 38 for NOAC use alone versus 52 with concurrent use of amiodarone; corresponding rates were 103 versus 242 with fluconazole, 66 versus 103 for rifampin, and 56 vs 109 for phenytoin (P

The other combinations did not confer increased risk of major bleeding, while atorvastatin, digoxin and erythromycin or clarithromycin were associated with a reduced risk of major bleeding.

To the authors' knowledge, this is the first nationwide population-based study to gauge the risk of major bleeding associated with a drug-drug interaction with NOACs.

They note that because the bleeding risk and anticoagulant treatment in the Asian population may differ from that of Western populations, the findings may not generalize to the West. The analyses also did not consider dosages of NOACs and the other medications, and kidney and liver function data were not available.

SOURCE: https://bit.ly/2yFqSLA

JAMA 2017.