Dabigatran with P-glycoprotein inhibitors may increase bleeding risk in AF, normal kidney function
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Patients with nonvalvular atrial fibrillation and normal kidney function had increased bleeding risk with dabigatran when used alongside P-glycoprotein inhibitors diltiazem and verapamil, according to a retrospective comparative effectiveness cohort study published in JAMA Network Open.
“The primary unique finding of this study is in regards to FDA-approved prescribing information for dabigatran (Pradaxa, Boehringer Ingelheim) which recommends reducing dabigatran’s dose if it is being used with a P-glycoprotein inhibitor only if there is also impaired kidney function,” Joshua D. Brown, PharmD, PhD, assistant professor in the department of pharmaceutical outcomes and policy at the University of Florida College of Pharmacy and Center for Drug Evaluation and Safety in Gainesville, told Healio. “However, European guidelines recommend dose reduction regardless of kidney function. Our study agrees with European guidelines in regards to dabigatran and its interaction with verapamil/diltiazem and confirm both U.S. and European guidelines for rivaroxaban and apixaban, which are not greatly impacted by this interaction.”
Patients with nonvalvular AF
Phuong Pham, MS, PhD student in the department of pharmaceutical outcomes and policy at University of Florida College of Pharmacy, and colleagues analyzed data from 1,764 patients who took direct oral anticoagulants with diltiazem or verapamil and 3,105 patients who took direct oral anticoagulants with amlodipine. Comparisons were also made with 1,793 patients who took direct oral anticoagulants with diltiazem or verapamil and 3,224 patients taking direct oral anticoagulants with metoprolol. All patients had nonvalvular AF.
Direct oral anticoagulants assessed in this study included dabigatran, apixaban (Eliquis, Bristol-Myers Squibb) and rivaroxaban (Xarelto, Bayer/Janssen). Outcomes of interest included minor, moderate and major bleeding.
Approximately 60% of cohorts were younger than 65 years and men depending on the comparison.
For patients taking dabigatran, the overall bleeding rate was 43% higher with diltiazem or verapamil compared with metoprolol (HR = 1.43; 95% CI, 1.02-2). The rate was also 52% higher in those taking diltiazem or verapamil compared with amlodipine (HR = 1.52; 95% CI, 1.05-2.2).
Bleeding rates associated with dabigatran with diltiazem or verapamil were higher overall for other bleeding types (244.9 per 1,000 person-years vs. 158.4 per 1,000 person-years) including minor bleeding (HR = 1.56; 95% CI, 1.07-2.27), overall gastrointestinal bleeding (HR = 2.16; 95% CI, 1.3-3.6) and minor gastrointestinal bleeding (HR = 2.16; 95% CI, 1.29-3.63).
Results were consistent in sensitivity analyses when dabigatran was used with diltiazem and verapamil, as HRs increased from 50% to 100%. There were no significant bleeding risks associated with apixaban or rivaroxaban.
Medication suggestions
“Since P-glycoprotein inhibitors are quite common (eg, antibiotics, antidepressants and over 250 other drugs), it may be impossible to avoid these interactions,” Brown said in an interview. “In those cases, we suggest DOACs with less potential for interaction (like rivaroxaban or apixaban) be selected over dabigatran. Otherwise, for the other medications, prescribers could select other medications that don’t interact with dabigatran similar to our use of amlodipine or metoprolol as comparisons in our study.” – by Darlene Dobkowski
For more information:
Joshua D. Brown, PharmD, PhD, can be reached at joshua.brown@ufl.edu; Twitter: @drxbrown.
Disclosures: Brown reports he received consulting fees and educational funding from Pfizer. Pham reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.
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