Atrial Fibrillation
Lauren Howell, PharmD
There may be a major drug interaction, resulting in serious bleeding, between commonly prescribed medications for patients with AFib, according to a study published in the May 14, 2024, issue of JAMA.
Diltiazem, often prescribed for ventricular rate control in patients with AFib, is a strong inhibitor of CYP3A4 and may also weakly inhibit P-glycoprotein. The most common anticoagulants for patients with AFib, apixaban and rivaroxaban, are substrates of these proteins. Previous studies have shown that diltiazem can increase the area under the time curve of plasma concentration for apixaban by 40%, which in theory would increase the risk of toxicity and adverse effects.
Primary outcome of the study
“Our concern was that diltiazem is a strong inhibitor of CYP3A4, we knew that from other studies, but we wanted to know if it was actually clinically significant,” said Katherine Murray, MD, professor of medicine and pharmacology at Vanderbilt University School of Medicine and coauthor of the study.
Patients with AFib initiating apixaban or rivaroxaban who subsequently began treatment with diltiazem were compared with those who began treatment with metoprolol. The researchers used metoprolol, another commonly prescribed rate control medication, as the control because it is not thought to inhibit the elimination of direct oral anticoagulants.
The primary outcome was the composite of bleeding-related hospitalization and death with recent evidence of bleeding. Secondary outcomes were the components of the primary outcome, ischemic stroke or systemic embolism, major ischemic or hemorrhagic event, and death without recent evidence of bleeding.
The adjusted rates of the primary outcome were 60.3 per 1,000 person-years for the diltiazem group and 49.7 per 1,000 person-years for the metoprolol group. Patients who were prescribed diltiazem had an increased risk for both bleeding-related hospitalization and death with recent evidence of bleeding. There were no significant differences between groups for the other secondary outcomes. The results also indicated that the bleeding risk may be dose dependent, with more bleeding occurring in patients who receive a dose of diltiazem that is greater than 120 mg per day.
What does this mean for clinical practice?
According to Murray, the consistency of results is what she found most surprising about the study. “The percentage of patients experiencing bleeding is not trivial, the magnitude is much greater than we thought,” she said. Based on these results, providers may consider being more selective when choosing which rate control agent to use for a patient. “Be really careful with high-risk patients,” Murray said. “Older adults, patients on doses of diltiazem greater than 120 mg per day, and those with a HAS-BLED score higher than 4, are the types of patients who would be considered high risk for serious bleeding.”
Providers are taught that direct oral anticoagulants, including apixaban and rivaroxaban, do not require therapeutic drug monitoring and this is often listed as an advantage in using these medications over other options, such as warfarin. However, findings from the study indicate that therapeutic drug monitoring may be helpful, particularly in the high-risk population.
While using the Medicare database to collect data for the study allowed for a large sample size, it also limited the generalizability of the results. Murray said that whether this increased bleeding risk applies to younger patients needs to be investigated more, but she believes the results would likely be similar.
Both the FDA labels for apixaban and rivaroxaban and the ACA/AHA/ACCP/HRS guidelines for management of AFib acknowledge that drug–drug interactions should be considered when prescribing and managing anticoagulants. However, neither specifically lists the potential for an increased risk of bleeding when there is concomitant use of diltiazem. More awareness is needed so that pharmacists and other providers are able to effectively and safely manage patients with AFib. ■