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Bleeding Risk with Combination Amiodarone and Direct-Acting Oral Anticoagulants

Among patients with atrial fibrillation who were taking a direct-acting oral anticoagulant, there was a significant association between major bleeding and amiodarone use within 60 days, but no association with amiodarone use longer than 60 days before the bleed.

By Michael H. Crawford, MD, Editor

SYNOPSIS: Among patients with atrial fibrillation who were taking a direct-acting oral anticoagulant, there was a significant association between major bleeding and amiodarone use within 60 days, but no association with amiodarone use longer than 60 days before the bleed.

SOURCE: Shurrab M, Jackevicius CA, Austin PC, et al. Association between concurrent use of amiodarone and DOACs and risk of bleeding in patients with atrial fibrillation. Am J Cardiol 2023;186:58-65.

Drug use guidelines recommend against combining direct-acting oral anticoagulants (DOACs) with amiodarone because it may interfere with the metabolism of DOACs, raise their serum level, and increase the risk of bleeding.1 However, there are limited data on the bleeding risk of co-administering amiodarone and DOACs. That means this population-based, nested case-controlled study of registry data from Ontario, Canada, is of interest.

Shurrab et al included all patients with atrial fibrillation (AF) age 66 years and older who received a DOAC between 2011 and 2018. Within this population, those who experienced a spontaneous major bleed were identified and matched 2:1 with controls based on age, sex, and date of the bleeding episode. Exposure was defined as concurrent use of amiodarone and a DOAC, categorized as current (amiodarone within 60 days of the episode), past (61 to 140 days prior), or unexposed (no amiodarone prescription for longer than 140 days prior). All the regression models were adjusted for relevant clinical covariates. The resulting study population included 201,404 patients with AF, of whom 86,679 were on a DOAC (54% apixaban), and 2,766 were admitted to a hospital for a first major bleeding event. These 2,766 patients were matched with 5,532 controls without a major bleed at the same time. The median age of the cases and controls was 80 years, and 48% were women. The cases were more likely than controls to be living with comorbidities, but the median CHA2DS2-VASc scores was the same (score of 4). Current amiodarone use among the cases was 6.2% vs. 4% of controls. In these patients, current amiodarone use was associated with a major bleeding episode (HR, 1.53; 95% CI, 1.24-1.89; P < 0.001). In patients who had used amiodarone, there was no association with major bleeding (HR, 1.13; 95% CI, 0.76-1.68; P = 0.55). The authors concluded the risk of major bleeding was higher by 53% with concomitant use of amiodarone in patients with AF on a DOAC.


The absorption, metabolism, and elimination of DOACs are dependent on the permeability of the glycoprotein (P-gp) transporter system and cytochrome P450 3A4 (CYP3A4) enzymes. Because amiodarone is a weak CYP3A4 inhibitor and a moderate P-gp competitor, there has been concern about its use with DOACs. Drug-drug interaction studies have shown that the serum levels of DOACs can rise by 40% to 60% with the coadministration of amiodarone.2 However, a subanalysis of the ARISTOTLE study of apixaban in AF patients did not demonstrate more bleeding episodes in those on amiodarone.3 Thus, more information on the potential interactions between DOACs and amiodarone is important clinically, since amiodarone is a commonly prescribed drug in AF patients.

The Shurrab et al study showed a significant association with major bleeding in AF patients on a DOAC between those who used amiodarone within 60 days of a major bleed compared to those who never used amiodarone or used it more than 60 days prior. This study supports the notion of using caution with the combined use of DOACs and amiodarone, and should encourage clinicians to consider alternatives for patients at higher risk of bleeding. Unfortunately, these authors did not suggest alternatives. Three come to my mind: switch to warfarin, which also is a CYP3A4 inhibitor and is not recommended to use with amiodarone; reduce the DOAC dose, but that might compromise effectiveness; or use a different anti-arrhythmic drug, such as sotalol.

There were some other limitations to the Shurrab et al study. Since it was retrospective, residual confounding cannot be excluded, but they did adjust their analysis for many clinical factors. Still, the authors did not specify whether the patients had been diagnosed with paradoxical, persistent, or permanent AF. There were no data available on adherence to the study drugs. Study patients all were older than age 66 years, so the implication for younger patients is unknown. Those with major bleeding were living with more comorbidities, although researchers did try to adjust for these. There were four DOACs in use in Canada at the time of the study; the power for each agent was insufficient to analyze each drug separately. Finally, the authors only considered major bleeding that led to a hospitalization, not less severe episodes.

Despite these limitations, the message from this study is clear: caution is advised in combining DOACs with amiodarone, especially for patients with a higher risk of bleeding. However, alternatives probably should not include reducing the dose of the DOAC to accommodate amiodarone, since most patients would rather bleed than experience a stroke.


1. Chen A, Stecker E, A Warden B. Direct oral anticoagulant use: A practical guide to common clinical challenges. J Am Heart Assoc 2020;9:e017559.

2. Shurrab M, Koh M, Jackevicius CA, et al. Prescribing of two potentially interacting cardiovascular medications in atrial fibrillation patients on direct oral anticoagulants. Int J Cardiol Heart Vasc 2021;34:100788.

3. Easton JD, Lopes RD, Bahit MC, et al. Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: A subgroup analysis of the ARISTOTLE trial. Lancet Neurol 2012;11:503-511.