Bleeding Risk Assessed With Concomitant Direct Oral Anticoagulants and Verapamil or Diltiazem

Concomitant use of dabigatran with verapamil or diltiazem was found to be associated with an increased risk of bleeding in patients with normal kidney function, according to the findings of a recently published retrospective cohort study.

Although direct oral anticoagulants (DOACs) are believed to have fewer drug-drug interactions compared to warfarin, there is a lack of direct clinical evidence surrounding potential interactions with commonly coadministered medications (ie, verapamil hydrochloride and diltiazem hydrochloride). “Verapamil hydrochloride and diltiazem hydrochloride are combined P-glycoprotein (P-gp) and CYP3A4 inhibitors and may be associated with increases in the risk of bleeding with DOACs,” the study authors stated. 

For this study, the authors used an active comparator design to assess the bleeding risk associated with concomitant use of DOACs and verapamil or diltiazem. The comparison group included patients concomitantly using DOACs and amlodipine or metoprolol. The analysis utilized IBM Watson MarketScan Databases to identify patients in the US with nonvalvular atrial fibrillation and no history of kidney disease who received an index prescription for a standard dose of DOAC (dabigatran, rivaroxaban, or apixaban) between October 2010 and June 2015. Outcomes of the study included primary and secondary diagnoses of major, moderate, and minor bleeding overall, as well as gastrointestinal bleeding.

A total of 48,442 patients were included in the analysis. Comparisons were made between the following cohorts: DOACs plus verapamil or diltiazem (n=1764) vs DOACs plus amlodipine (n=3105) and DOACs plus verapamil or diltiazem (n=1793) vs DOACs plus metoprolol (n=3224). The study authors reported that bleeding rates were not found to be increased in patients receiving rivaroxaban or apixaban in combination with verapamil or diltiazem vs amlodipine or metoprolol. 

Findings did reveal, however, that the overall bleeding rate for patients who received dabigatran etexilate plus verapamil or diltiazem was 52% higher compared with patients who received dabigatran plus amlodipine (hazard ratio [HR] 1.52; 95% CI, 1.05-2.20) and 43% higher compared with those who received dabigatran plus metoprolol (HR 1.43; 95% CI, 1.02-2.00). “Bleeding rates for dabigatran with verapamil or diltiazem were higher overall for other bleeding types (244.9 vs 158.4 per 1000 person-years; adjusted hazard ratios of overall GI bleeding: 2.16; 95% CI, 1.30-3.60; minor bleeding: 1.56; 95% CI, 1.07-2.27; and minor GI bleeding: 2.16; 95% CI, 1.29-3.63),” the study authors added. 

According to the findings of this study, concomitant use of dabigatran and the P-gp inhibitors verapamil and diltiazem is associated with an increased risk of bleeding in patients with normal renal function. “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 study authors concluded.

Reference

Pham P, Schmidt S, Lesko L, Lip GYH, Brown JD. Association of oral anticoagulants and verapamil or diltiazem with adverse bleeding events in patients with nonvalvular atrial fibrillation and normal kidney function. JAMA Network Open. 2020;3(4):e203593.