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

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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.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40263-021-00795-z.

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Author and article information

Contributors

Mordechai Muszkat:

ORCID: http://orcid.org/0000-0002-9520-1379

muszkatm@hadassah.org.il

Journal

Journal ID (nlm-ta): CNS Drugs

Journal ID (iso-abbrev): CNS Drugs

Title: CNS Drugs

Publisher: Springer International Publishing (Cham )

ISSN (Print): 1172-7047

ISSN (Electronic): 1179-1934

Publication date (Electronic): 17 February 2021

Publication date PMC-release: 17 February 2021

Publication date (Print): 2021

Volume: 35

Issue: 3

Pages: 305-316

Affiliations

[1 ]GRID grid.17788.31, ISNI 0000 0001 2221 2926, Department of Medicine, , Hadassah Hebrew University Medical Center, ; Mount Scopus, 91540 Jerusalem, Israel

[2 ]GRID grid.17788.31, ISNI 0000 0001 2221 2926, Department of Pharmacy, , Hadassah Hebrew University Medical Center, ; Jerusalem, Israel

[3 ]GRID grid.9619.7, ISNI 0000 0004 1937 0538, Division of Clinical Pharmacy, Faculty of Medicine, Institute for Drug Research, School of Pharmacy, , Hebrew University of Jerusalem, ; Jerusalem, Israel

[4 ]GRID grid.17788.31, ISNI 0000 0001 2221 2926, Department of Cardiology, , Hadassah Hebrew University Medical Center, ; Jerusalem, Israel

[5 ]GRID grid.17788.31, ISNI 0000 0001 2221 2926, Department of Hematology, , Hadassah-Hebrew University Medical Center, ; Jerusalem, Israel

[6 ]GRID grid.9619.7, ISNI 0000 0004 1937 0538, Faculty of Medicine, , Hebrew University of Jerusalem, ; Jerusalem, Israel

[7 ]GRID grid.38142.3c, ISNI 000000041936754X, Division of General Internal Medicine Massachusetts General Hospital, , Harvard T.H. Chan School of Public Health, ; Boston, MA USA

Author information

Mordechai Muszkat http://orcid.org/0000-0002-9520-1379

Article

Publisher ID: 795

DOI: 10.1007/s40263-021-00795-z

PMC ID: 8332574

PubMed ID: 33595834

SO-VID: 30cb188d-8aee-47bd-a737-d17b1810e3ff

License:

Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.

History

Date accepted : 16 January 2021

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

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Abstract

Background

Objective

Methods

Results

Conclusions

Supplementary Information

Related collections

cGMP: Generators, Effectors and Therapeutic Implications Conference

Most cited references 36

A new equation to estimate glomerular filtration rate.

Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.

Apixaban versus Warfarin in Patients with Atrial Fibrillation

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Cited by 10

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