Effect of Enzyme-Inducing Antiseizure Medications on the Risk of Sub-Therapeutic Concentrations of Direct Oral Anticoagulants: A Retrospective Cohort Study

Abstract

Background

Stroke and thromboembolic events occurring among patients taking direct oral anticoagulants (DOACs) have been associated with low concentrations of DOACs. Enzyme-inducing antiseizure medications (EI-ASMs) are associated with enhanced cytochrome-P450-mediated metabolism and enhanced P-glycoprotein-mediated transport.

Objective

The aim of this study was to evaluate the effect of concomitant EI-ASM use on DOAC peak concentrations in patients treated in clinical care.

Methods

We performed a retrospective cohort study of patients treated with DOACs for atrial fibrillation and venous thromboembolic disease in an academic general hospital. In total, 307 patients treated with DOACs between August 2015 and January 2020 were reviewed. Clinical characteristics and peak DOAC plasma concentrations of patients co-treated with an EI-ASM were compared with those of patients not treated with an EI-ASM. An apixaban dose score (ADS) was defined to account for apixaban dosage and the number of apixaban dose-reduction criteria.

Results

In total, 177 peak DOAC plasma concentrations (including apixaban, rivaroxaban, and dabigatran) from 131 patients were measured, including 24 patients co-treated with an EI-ASM and 107 controls not treated with an EI-ASM. The proportion of patients with DOAC concentrations below the expected range was significantly higher among EI-ASM users than among patients not taking an EI-ASM (37.5 vs. 9.3%, respectively; p = 0.0004; odds ratio 5.82; 95% confidence interval [CI] 2.03–16.66). Most of these patients were treated with apixaban (85%); however, sensitivity analysis results were also significant (p = 0.031) for patients with non-apixaban DOACs. In patients co-treated with apixaban and an EI-ASM, median apixaban peak concentration was 106 ng/mL (interquartile range [IQR] 71–181) compared with 150 ng/mL (IQR 94–222) in controls (p = 0.019). In multivariable analysis, EI-ASM use was associated with 6.26-fold increased odds for apixaban concentration below the expected range (95% CI 2.19–17.90; p = 0.001). Apixaban concentrations were significantly associated with EI-ASM use, moderate enzyme inhibitor use, and ADS.

Conclusions

Concurrent EI-ASM and DOAC use presents a possible risk for DOAC concentrations below the expected range. The clinical significance of the interaction is currently unclear.

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Correspondence to Mordechai Muszkat.

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Funding

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Conflict of interest

A Perlman is an employee at K-health Inc; the work presented in this manuscript is not related to his work at K-health. DE Singer is an employee of Massachusetts General Hospital. Dr. Singer has received research funding from Bristol Myers Squibb and has served as a paid consultant and/or member of advisory boards for Boehringer Ingelheim, Bristol Myers Squibb, Fitbit, Johnson and Johnson, Merck, and Pfizer. M Muszkat has received honoraria from Roche and a research grant from Pfizer Independent Global Medical Grant. R Goldstein, L Cohen, B Hirsh-Raccah, D Hakimian, I Matok, and Y Kalish have no conflicts of interest that are directly relevant to the content of this article.

Availability of data and material

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethics Approval

The study was approved by the Hadassah Medical Organization Institutional Review Board and was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments.

Consent

This observational study was exempt from obtaining consent from the Hadassah Medical Organization institutional review board.

Author contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by AP, RG, BH-R, LCC, DH, IM, YK, DS, and MM. The first draft of the manuscript was written by AP and RG, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Perlman, A., Goldstein, R., Choshen Cohen, L. et al. Effect of Enzyme-Inducing Antiseizure Medications on the Risk of Sub-Therapeutic Concentrations of Direct Oral Anticoagulants: A Retrospective Cohort Study. CNS Drugs 35, 305–316 (2021). https://doi.org/10.1007/s40263-021-00795-z

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