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It was not safe to combine dabigatran (Pradaxa) with P-glycoprotein (P-gp) inhibitors in people with atrial fibrillation (Afib), even when they had normal kidney function, researchers determined from real-world evidence.

People taking dabigatran along with the antihypertensive medications verapamil or diltiazem suffered more bleeds than peers whose dabigatran use was accompanied by amlodipine (adjusted HR 1.52, 95% CI 1.05-2.20) or metoprolol (adjusted HR 1.43, 95% CI 1.02-2.00), according to Joshua Brown, PharmD, PhD, of the University of Florida College of Pharmacy, Gainesville, and colleagues.

Bleeding rates for dabigatran with verapamil or diltiazem were higher overall compared against active comparators in terms of GI bleeding, minor bleeding, and minor GI bleeding, the researchers reported in a paper .

Such drug-drug interaction was not applicable to all direct oral anticoagulants (DOACs), however, as rivaroxaban (Xarelto) and apixaban (Eliquis) were not associated with increased rates of bleeding for patients also on verapamil or diltiazem, compared with those receiving amlodipine or metoprolol.

"Clinicians and patients may need to consider alternative DOAC therapy other than dabigatran during concomitant use of moderate to strong P-gp inhibitors regardless of kidney function or find medications that do not interact if dabigatran must be used," the authors said.

Dabigatran is a prodrug that undergoes efflux by P-gp. Therefore, P-gp inhibitors increase the bioavailability of the prodrug, leading to increased serum concentrations of the active metabolite, they explained.

Other moderate-to-strong P-gp inhibitors include amiodarone, proton-pump inhibitors, some antidepressants, and azole antifungals.

"Current U.S. prescribing information only recommends prescribing changes with dabigatran and P-gp inhibitors with lower kidney function," Brown's group noted.

For the study, the investigators compiled U.S. population-based data from IBM Watson MarketScan Databases. They identified 48,442 patients with nonvalvular Afib who had received an index prescription of dabigatran (40%), rivaroxaban (40%), or apixaban (20%) at a standard dose for stroke prophylaxis in 2010-2015. This was a cohort with no history of kidney disease.

Approximately 60% of patients were younger than 65, and most were men. About 40% had a CHA₂DS₂-VASc score of 4 or greater and 70% to 75% had a HAS-BLED score between 0 and 2.

After inverse probability of treatment weighting (IPTW) based on propensity scores, comparisons were made between 1,764 DOAC users taking verapamil or diltiazem versus 3,105 of those on amlodipine; and 1,793 DOAC users taking verapamil or diltiazem versus 3,224 of those on metoprolol.

Comparison groups showed balanced baseline characteristics after IPTW.

Amlodipine and metoprolol were chosen as active comparators because they are not P-gp or CYP3A4 inhibitors and provide similar pharmacologic pathways and therapeutic uses as verapamil and diltiazem, Brown and colleagues said.

They cautioned that because the study was observational, it had the potential for unmeasured confounding.

Moreover, they had a limited sample size, they acknowledged, given that they only included people who were taking verapamil, diltiazem, amlodipine, and metoprolol over at least 90 days in the 6-month period preceding DOAC initiation.

And it was because of the small sample size that the investigators combined data on verapamil and diltiazem.

"Although this combination is not ideal from a study design perspective, both verapamil and diltiazem are categorized as combined P-gp inhibitors and moderate CYP3A4 inhibitors, have similar on-label and off-label indications, and are expected to behave similarly in terms of drug-drug interaction mechanisms," the research team maintained.

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