Direct oral anticoagulants (DOACs; dabigatran, rivaroxaban, apixaban, edoxaban) are increasingly prescribed for prevention of stroke in the setting of atrial fibrillation. These agents are popular because they do not require laboratory coagulation monitoring (i.e., international normalized ratio [INR]), have fewer dietary restrictions, and are associated with a lower risk of intracranial bleeding in patients with atrial fibrillation. An additional important advantage is the limited number of drugs that interact with DOACs compared with the extensive list of interactions with warfarin. However, there are some important DOAC-drug interactions that can lead to serious consequences for patients.
Dr. Shang-Hung Chang and colleagues conducted a retrospective cohort study of a Taiwan national health insurance database to examine the association between concomitant prescription of DOACs with other selected agents and the risk of major bleeding. They focused on agents that share the same metabolic pathways as DOACs, in particular CYP3A4 (fluconazole, ketoconazole, itraconazole, voriconazole, or posaconazole); the same P-glycoprotein drug transport system (P-glycoprotein; digoxin, verapamil, diltiazem, amiodarone, or cyclosporine); or both mechanisms (atorvastatin, erythromycin or clarithromycin, dronedarone, rifampin, or phenytoin).
Major bleeding was defined as bleeding that required hospitalization or an emergency department visit with a primary diagnosis of intracranial bleeding or gastrointestinal, urogenital, or other bleeding. Comorbidities were included in the model as covariates (e.g., components of Charlson comorbidity index, CHA2DS2-VASc scores), and a propensity score was used to adjust for confounding by indication for medications ordered for the same condition.
DOAC-Selected Drug Combinations Associated With Increased Risk of Major Bleeding
|Concurrent Drug||Adjusted Rate Ratio for Major Bleeding*||Adjusted Incidence Rate Difference per 1,000 Person-years*|
|Fluconazole||2.35 (99% CI, 1.80-3.07)||138 (99% CI, 81-196)|
|Phenytoin#||1.94 (99% CI, 1.59-2.36)||52 (99% CI, 32-72)|
|Rifampin||1.57 (99% CI, 1.02-2.41)||37 (99% CI, 2-72)|
|Amiodarone#||1.37 (99% CI, 1.25-1.50)||14 (99% CI, 10-18)|
*Reference was DOAC alone. #Not significant for apixaban, but smaller proportion for users.
A total of 91,330 patients with nonvalvular atrial fibrillation who received a DOAC were identified (rivaroxaban, 59.1%; dabigatran, 49.7%; apixaban, 14.1%; edoxaban not available). The mean age of the cohort was 74.7 years, 55 percent were men, and baseline average CHA2DS2-VASc score was 3.9. The DOAC-selected drug combinations associated with an increased risk of major bleeding are summarized in the Table.
Some of these results run contrary to available pharmacokinetic interaction data.1 For example, phenytoin and rifampin are combined P-glycoprotein (P-gp)/strong CYP3A4 inducers; therefore, they would be expected to decrease DOAC levels. In the case of phenytoin, the rate of major bleeding was only significantly increased for intracranial bleeding, which suggests that an increased risk of head injury due to seizures may be a confounding factor in this association. Conversely, fluconazole is a moderate CYP3A4 inhibitor, which would be expected to increase DOAC levels and thereby potentially increase the risk of bleeding.
Of special interest to hematologists, neither cyclosporine (P-gp inhibitor) nor the other azole antifungal agents (strong CYP3A4/P-gp inhibitors) were associated with an increased risk of bleeding in the Taiwan cohort. However, the number of prescriptions for these agents was limited, and other studies suggest the interaction could be clinically significant.2-5
Although this cohort provides some real-world data on the potential for interaction between DOACs and selected drugs, the results should be interpreted with caution. Important risk factors for bleeding, such as creatinine clearance and liver function, could not be accounted for in this study, and propensity scores can only adjust for known variables. As a general rule, until further data are available, hematologists should use caution when prescribing anticonvulsants, antifungal agents, cyclosporine, and certain antibiotics (i.e., rifampin, erythromycin, or clarithromycin) for patients taking a DOAC. On the flip side, patients who require the above medications for more than a few days may be better off taking warfarin instead of a DOAC. Although warfarin interacts with some of the same drugs, the impact on coagulation can be easily monitored with an INR.
Mueck W, Kubitza D, Becka M. Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol. 2013;76:455-466.
Wannhoff A, Weiss KH, Schemmer P, et al. Increased levels of rivaroxaban in patients after liver transplantation treated with cyclosporine A. Transplantation. 2014;98:e12-e13.
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Conflict of Interests
Dr. Linkins indicated no relevant conflicts of interest.
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