Log in to MyACC
Rivaroxaban Plus Amiodarone Increases Bleeding
Quick Takes
- Amiodarone and rivaroxaban interact because both are major substrates for CYP3A4 and minor substrates for P-glycoprotein transport, while amiodarone is also a CYP3A4 and P-glycoprotein inhibitor.
- Amiodarone may increase the concentration of rivaroxaban, thereby increasing the risk of bleeding.
- In this prospective observational study, the combination of rivaroxaban plus amiodarone versus rivaroxaban alone in patients with AF was associated with an almost threefold increased risk of clinically relevant nonmajor bleeding.
Study Questions:
Is the incidence of bleeding higher in patients taking amiodarone plus rivaroxaban versus rivaroxaban alone when adjusted for baseline differences?
Methods:
This was a single-center prospective study. Patients were included if they were newly diagnosed with atrial fibrillation (AF) and receiving rivaroxaban. Patients receiving other P-glycoprotein or strong CYP3A4 inhibitors or inducers were excluded. Patients were stratified into two groups: those receiving rivaroxaban without amiodarone (rivaroxaban group) and those receiving rivaroxaban and amiodarone (combination group). Patients were receiving 10-20 mg of rivaroxaban daily and a loading dose of amiodarone followed by 200 mg daily. Patients were followed prospectively by telephone call for 3 months to collect data on bleeding events. Medication adherence was verified by prescription drug fills. The primary outcome was the first occurrence of any International Society on Thrombosis and Hemostasis (ISTH) bleeding over 3 months. Results were provided for ISTH major, clinically relevant nonmajor (CRNM) and minor bleeding.
Results:
Of the 498 patients enrolled, 17 patients were lost to follow-up during the 3 months. There were multiple differences between groups in baseline characteristics including age, sex, prior myocardial infarction, renal function, antiplatelet use, and rivaroxaban dose. Propensity-score matching resulted in 154 patients per group with balanced demographics. The primary outcome, any ISTH bleeding, occurred in 26.0% in the combination group and 10.4% in the rivaroxaban group (hazard ratio, 2.76; 95% confidence interval, 1.55-4.93). Major bleeding only occurred in one patient in the rivaroxaban group. CRNM bleeding (13.0% vs. 4.5%, p = 0.014) and minor bleeding (13.0% vs. 5.2%, p = 0.028) were also significantly higher in the combination group. Subgroup analysis comparing lower versus a 20 mg rivaroxaban dose showed no significant difference in the primary endpoint, whereas bleeding was higher in the combination group in patients with chronic kidney disease (CKD) and no increase in those without CKD.
Conclusions:
In this prospective single-center observational study, coadministration of amiodarone with rivaroxaban increased the risk of any ISTH, CRNM and minor bleeding, but not major bleeding during the first 3 months of use in patients with a new diagnosis of AF.
Perspective:
It is well known that the highest risk for major bleeding in patients with AF occurs within the first 6 months to 1 year following initiation of anticoagulation. We also know that amiodarone significantly increases the international normalized ratio (INR) when added to warfarin and increases bleeding risk if the dose of warfarin is not adjusted downward. Could there be a similar effect when combining amiodarone with rivaroxaban? Results from prior retrospective observational studies have been mixed.
One important difference between prior observational studies and this work is that only newly diagnosed patients with AF were included and patients were prospectively asked to report bleeding in contrast to using electronic health records or hospitalization reports. Therefore, it is not surprising that ISTH bleeding rates were higher than those reported in prior observational studies. Nevertheless, it is concerning that use of amiodarone augmented the risk of CRNM bleeding. Therefore, we should be more vigilant in terms of patient education and reinforcement of bleeding management as well as monitoring (such as monthly phone calls or messages) in patients initiating the combination of amiodarone and rivaroxaban. A significant limitation of this study is that no rivaroxaban anti-Xa levels were measured, so a direct connection between increased bleeding risk and increased rivaroxaban levels could not be ascertained.
Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Anticoagulation Management and Atrial Fibrillation, Atrial Fibrillation/Supraventricular Arrhythmias, Cardiovascular Care Team
Keywords: Anticoagulants, Atrial Fibrillation
< Back to Listings
