Atrial Fibrillation Patients Face Elevated Bleeding Risks with Diltiazem Combined with Common Anticoagulants
Individuals diagnosed with atrial fibrillation who receive prescriptions for diltiazem to manage their heart rate, in conjunction with anticoagulant medications such as apixaban or rivaroxaban, encounter a substantially increased likelihood of experiencing severe bleeding events when compared to those who are prescribed metoprolol instead. This concerning discovery emerges from a comprehensive investigation conducted by researchers at Vanderbilt Health, in collaboration with experts from the Perelman School of Medicine.
Diltiazem serves as a widely utilized initial treatment option for regulating heart rates among patients suffering from atrial fibrillation. Similarly, apixaban and rivaroxaban represent established standards in preventing strokes for these individuals. Nevertheless, the concurrent administration of these drugs raises significant safety issues that warrant careful consideration by healthcare providers.
The United States Food and Drug Administration has long recognized interactions between drugs facilitated by cytochrome enzymes as one of the primary contributors to avoidable adverse reactions in patients. Given that diltiazem acts as an inhibitor of these critical enzymes, the research team aimed to explore whether this property leads to heightened levels of anticoagulants in the bloodstream, consequently amplifying the chances of major bleeding incidents.
The study in question, which appeared in the prestigious journal Annals of Internal Medicine, encompassed data from approximately 46,000 patients with atrial fibrillation. All participants possessed commercial health insurance coverage and were utilizing either apixaban or rivaroxaban alongside either diltiazem or metoprolol during the observation period.
“These results carry substantial implications when viewed through the lens of public health on a broad scale,” explained Ghadeer Dawwas, Ph.D., MBA, who holds positions as an assistant professor in both Medicine and Health Policy at Vanderbilt University. “People living with atrial fibrillation often contend with numerous co-existing health conditions and require management through a variety of pharmaceuticals taken concurrently. For those classified as high-risk, medical professionals must meticulously evaluate the possibilities of adverse drug interactions prior to recommending diltiazem paired with apixaban or rivaroxaban.”
Dawwas further emphasized, “Even though diltiazem continues to be a viable and potent choice for heart rate management in certain patient profiles, our data strongly highlight the necessity of prioritizing bleeding risks in the decision-making process for therapeutic regimens.”
She continued by noting the particular vulnerabilities in specific scenarios: “This guidance holds special weight for individuals on elevated dosages of diltiazem surpassing 120 mg per day or those concurrently using other medications known to interact. Under these circumstances, opting for metoprolol could prove to be a more secure pathway.”
Atrial fibrillation, characterized by irregular and often rapid heart rhythms originating in the upper chambers of the heart, affects millions worldwide and significantly heightens the risk of stroke due to blood clot formation. Anticoagulants like apixaban and rivaroxaban work by inhibiting clotting factors to mitigate this danger, but their potency can be altered by concurrent therapies.
Diltiazem, a calcium channel blocker, not only controls heart rate but also impacts the metabolism of other drugs through its inhibition of cytochrome P450 enzymes, particularly CYP3A4. This mechanism slows the breakdown of apixaban and rivaroxaban, leading to higher systemic exposure and thus a greater propensity for bleeding complications such as gastrointestinal hemorrhages or intracranial bleeds.
In contrast, metoprolol, a beta-blocker, does not exhibit this inhibitory effect on the same enzymes, allowing for more predictable pharmacokinetics when combined with these oral anticoagulants. The study’s large cohort size and real-world data from insured patients provide robust evidence that supports a shift in clinical practice toward safer combinations where feasible.
Healthcare providers are encouraged to review patient profiles holistically, considering factors like age, renal function, concurrent medications, and bleeding history before initiating diltiazem. Dose adjustments, alternative rate-control agents, or enhanced monitoring protocols may be necessary to safeguard patient outcomes.
This research underscores the ongoing need for pharmacovigilance in polypharmacy scenarios, especially among the elderly population where atrial fibrillation prevalence is highest. Future studies could explore genetic variations in enzyme activity or long-term outcomes to refine these recommendations further.
Publication Information
The detailed findings were documented by Ghadeer K. Dawwas and colleagues in their article titled “The Risk for Bleeding in Patients With Atrial Fibrillation From Concomitant Use of Apixaban or Rivaroxaban With Diltiazem Compared With Metoprolol,” published in Annals of Internal Medicine in 2026. The study’s DOI is 10.7326/annals-25-01408, offering access to the full methodology, statistical analyses, and supplementary data for deeper scrutiny by clinicians and researchers alike.
Key medical concepts central to this work include atrial fibrillation, a common arrhythmia; rivaroxaban, a direct factor Xa inhibitor; and apixaban, another potent anticoagulant in the same class. These fall under broader clinical categories such as cardiology and clinical pharmacology, where drug safety profiles are perpetually under evaluation.
The research was supported by Vanderbilt University Medical Center, a leading institution in cardiovascular research and patient care. Their contributions highlight the importance of interdisciplinary collaboration in translating laboratory insights into practical clinical guidance.
Patients and providers alike should remain vigilant about these interactions. Discussing all current medications with pharmacists or physicians can prevent unintended consequences. Tools like drug interaction checkers and personalized risk assessments are invaluable in modern medicine for optimizing therapy while minimizing harms.
As the medical community digests these findings, it is anticipated that guidelines from bodies like the American Heart Association may incorporate updated recommendations on rate-control strategies in anticoagulated atrial fibrillation patients. This evolution in practice promises to enhance safety and efficacy across diverse patient populations.
