Dabigatran Bleeding Risk Increased in Patients Also on Verapamil or Diltiazem

By Lisa Rapaport

April 29, 2020

(Reuters Health) - Patients with nonvalvular atrial fibrillation and normal kidney function who are prescribed dabigatran may have an increased risk of bleeding when they also take verapamil or diltiazem, a comparative effectiveness study suggests.

Direct oral anticoagulants (DOACS) are presumed to have fewer drug-drug interactions than warfarin, but co-prescriptions remain a safety concern, researchers note in JAMA Network Open. The current analysis focused on one potential safety issue: that the combined P-glycoprotein (P-gp) and CYP3A-4 inhibitors verapamil hydrochloride and diltiazem hydrochloride may be associated with an increased bleeding risk in patients also taking DOACs.

Researchers examined a database of 48,442 patients with nonvalvular atrial fibrillation who had received an index prescription of dabigatran, rivaroxaban, or apixaban between October 2010 and July 2015. They restricted their analysis to people without any history of kidney disease who received standard doses of DOACs.

Then, researchers analyzed bleeding rates for 1764 patients receiving DOACs with verapamil or diltiazem compared with 3105 receiving amlodipine, and 1793 patients receiving DOACs with verapamil or diltiazem compared with 3224 receiving metoprolol.

Among patients on dabigatran, the overall bleeding rate was 52% higher with verapamil or diltiazem than with amlodipine. And these patients on dabigatran had a bleeding rate 43% higher with verapamil or diltiazem than with metoprolol.

"Our findings for dabigatran actually disagree with FDA-approved labeling and would lead to recommending lower doses of dabigatran or using alternative anticoagulants whenever any moderate-to-strong P-glycoprotein inhibitor is present," said senior study author Joshua Brown of the Center for Drug Evaluation & Safety at the University of Florida College of Pharmacy, in Gainesville.

"While we only studied verapamil and diltiazem, there are over 200 P-glycoprotein inhibitors which include many common medications such as antibiotics, antidepressants, and cardiovascular medications," Brown said by email. "While we cannot extrapolate our results to these other medications, I consider it highly likely that any inhibition of P-glycoprotein can have similar effects."

The study didn't find an increased bleeding risk for patients on rivaroxaban or apixaban who also took verapamil or diltiazem, compared with individuals who took these DOACs along with amlodipine or metoprolol.

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).

Researchers only looked at people who used verapamil, diltiazem, amlodipine, and metoprolol before DOAC initiation. They also restricted their analysis to patients who had 90 days of cumulative use of these medications during the previous six months.

One limitation of this approach is that it left a small sample size, the study team notes. But it also left a more homogenous population of patients for the analysis. Due to the small sample size, researchers combined data on verapamil and diltiazem instead of looking at these drugs separately.

Even so, verapamil and diltiazem are known to be combined P-gp inhibitors and CYP3A4 inhibitors, and P-gp is involved in the metabolism of dabigtran, noted Dr. Harpreet Bhatia, a cardiovascular medicine fellow at the University of California, San Diego, who wasn't involved in the study.

"This study is novel in that it suggests there is increased bleeding risk in a real world setting when using these medications with dabigatran, presumably due to increased drug levels in the blood due to inhibition of these metabolic mechanisms," Dr. Bhatia said by email.

These results are important because patients with atrial fibrillation are often prescribed anticoagulation as well as rate control using medications such as diltiazem and verapamil, Dr. Bhatia added. The results suggest that caution is needed when using verapamil or diltiazem for rate control in combination with dabigatran, and alternative medication combinations may need to be considered.

Clinicians may not have considered the need for alternatives in patients with normal kidney function, said Eric Nemec, director of research and assessment at Sacred Heart University in Fairfield, Connecticut and a pharmacist at Stamford Hospital, in Connecticut.

"However, the results of this study suggest that it may be reasonable to consider the use of an alternative to dabigatran such as apixaban or rivaroxaban in patients with normal kidney function who require concomitant therapy with a P-gp inhibitor (like verapamil, nifedipine, etc…)," Nemec, who wasn't involved in the study, said by email.

It might also make sense to consider alternative rate control options such as beta-blockers for patients on dabigatran, Nemec said. More research would be needed to investigate alternative treatment regimens.

The study was funded by PhARMA. Dr. Brown reported consulting fees and educational funding from Pfizer unrelated to the present work. Another study author, Dr. Gregory Lip, also reported funding unrelated to the present work from consultant services for Bayer/Janssen, BMS/Pfizer, Medtronic, Boehringer Ingelheim, Novartis, Verseon, and Daiichi-Sankyo; and from serving as a speaker for Bayer, BMS/Pfizer, Medtronic, Boehringer Ingelheim, and Daiichi-Sankyo.

SOURCE: https://bit.ly/3bI7Zvr JAMA Network Open, online April 24, 2020.