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



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.


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.


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.


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.


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.

This is a preview of subscription content, access via your institution.

Fig. 1
Fig. 2


  1. 1.

    Yao X, Abraham NS, Sangaralingham LR, Bellolio MF, McBane RD, Shah ND, et al. Effectiveness and safety of dabigatran, rivaroxaban, and apixaban versus warfarin in nonvalvular atrial fibrillation. J Am Heart Assoc [Internet]. 2016;15:4. https://doi.org/10.1161/JAHA.116.003725 (cited 2020 Jun 7).

    Article  Google Scholar 

  2. 2.

    Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–51.

    CAS  Article  Google Scholar 

  3. 3.

    Granger CB, Alexander JH, McMurray JJV, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981–92.

    CAS  Article  Google Scholar 

  4. 4.

    Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–91.

    CAS  Article  Google Scholar 

  5. 5.

    Caldeira D, Barra M, Pinto FJ, Ferreira JJ, Costa J. Intracranial hemorrhage risk with the new oral anticoagulants: a systematic review and meta-analysis. J Neurol. 2015;262:516–22.

    CAS  Article  Google Scholar 

  6. 6.

    Macha K, Marsch A, Siedler G, Breuer L, Strasser EF, Engelhorn T, et al. Cerebral ischemia in patients on direct oral anticoagulants: plasma levels are associated with stroke severity. Stroke. 2019;50:873–9.

    CAS  Article  Google Scholar 

  7. 7.

    Testa S, Paoletti O, Legnani C, Dellanoce C, Antonucci E, Cosmi B, et al. Low drug levels and thrombotic complications in high-risk atrial fibrillation patients treated with direct oral anticoagulants. J Thromb Haemost. 2018;16:842–8.

    CAS  Article  Google Scholar 

  8. 8.

    Bhagirath V, Eikelboom J, Hirsh J, Coppens M, Ginsberg J, Vanassche T, et al. Apixaban-calibrated anti-FXa activity in relation to outcome events and clinical characteristics in patients with atrial fibrillation: results from the AVERROES Trial. TH Open. 2017;01:e139–45.

    Article  Google Scholar 

  9. 9.

    Di Gennaro L, Lancellotti S, De Cristofaro R, De Candia E. Carbamazepine interaction with direct oral anticoagulants: help from the laboratory for the personalized management of oral anticoagulant therapy. J Thromb Thrombolysis. 2019;48:528–31.

    Article  Google Scholar 

  10. 10.

    Hager N, Bolt J, Albers L, Wojcik W, Duffy P, Semchuk W. Development of Left Atrial Thrombus After Coadministration of Dabigatran Etexilate and Phenytoin. Can J Cardiol. 2017;33:554.e13-554.e14.

    Article  Google Scholar 

  11. 11.

    Serra W, Li Calzi M, Coruzzi P. Left atrial appendage thrombosis during therapy with rivaroxaban in elective cardioversion for permanent atrial fibrillation. Clin Pract [Internet]. 2015 [cited 2020 Jun 7];5. http://www.clinicsandpractice.org/index.php/cp/article/view/788. Accessed 1 Oct 2020.

  12. 12.

    Burden T, Thompson C, Bonanos E, Medford AR. Lesson of the month 2: pulmonary embolism in a patient on rivaroxaban and concurrent carbamazepine. Clin Med. 2018;18:103–5.

    Article  Google Scholar 

  13. 13.

    King PK, Stump TA, Walkama AM, Ash BM, Bowling SM. Management of phenobarbital and apixaban interaction in recurrent cardioembolic stroke. Ann Pharmacother. 2018;52:605–6.

    Article  Google Scholar 

  14. 14.

    Risselada AJ, Visser MJ, van Roon EN. Pulmonary embolism due to interaction between rivaroxaban and carbamazepine. Ned Tijdschr Geneeskd. 2013;157:A6568.

    PubMed  Google Scholar 

  15. 15.

    Stöllberger C, Finsterer J. Recurrent venous thrombosis under rivaroxaban and carbamazepine for symptomatic epilepsy. Neurol Neurochir Pol. 2017;51:194–6.

    Article  Google Scholar 

  16. 16.

    Perlman A, Wanounou M, Goldstein R, Choshen Cohen L, Singer DE, Muszkat M. Ischemic and thrombotic events associated with concomitant Xa-inhibiting direct oral anticoagulants and antiepileptic drugs: analysis of the FDA Adverse Event Reporting System (FAERS). CNS Drugs. 2019;33:1223–8.

    CAS  Article  Google Scholar 

  17. 17.

    Dagan G, Perlman A, Hochberg-Klein S, Kalish Y, Muszkat M. Managing direct oral anticoagulants in patients with antiepileptic medication. Can J Cardiol. 2018;34:1534.e1-1534.e3.

    Article  Google Scholar 

  18. 18.

    Chin PKL, Wright DFB, Zhang M, Wallace MC, Roberts RL, Patterson DM, et al. Correlation between trough plasma dabigatran concentrations and estimates of glomerular filtration rate based on creatinine and cystatin C. Drugs RD. 2014;14:113–23.

    CAS  Article  Google Scholar 

  19. 19.

    Wiggins BS, Northup A, Johnson D, Senfield J. Reduced anticoagulant effect of dabigatran in a patient receiving concomitant phenytoin. Pharmacother J Hum Pharmacol Drug Ther. 2016;36:e5-7.

    Article  Google Scholar 

  20. 20.

    Becerra AF, Amuchastegui T, Tabares AH. Decreased rivaroxaban levels in a patient with cerebral vein thrombosis receiving phenytoin. Case Rep Hematol. 2017;2017:1–3.

    Article  Google Scholar 

  21. 21.

    Perlman A, Hochberg-Klein S, Choshen Cohen L, Dagan G, Hirsh-Raccah B, Horwitz E, et al. Management strategies of the interaction between direct oral anticoagulant and drug-metabolizing enzyme inducers. J Thromb Thrombolysis. 2019;47:590–5.

    CAS  Article  Google Scholar 

  22. 22.

    Vakkalagadda B, Frost C, Byon W, Boyd RA, Wang J, Zhang D, et al. Effect of rifampin on the pharmacokinetics of apixaban, an oral direct inhibitor of factor Xa. Am J Cardiovasc Drugs. 2016;16:119–27.

    CAS  Article  Google Scholar 

  23. 23.

    Mueck W, Schwers S, Stampfuss J. Rivaroxaban and other novel oral anticoagulants: pharmacokinetics in healthy subjects, specific patient populations and relevance of coagulation monitoring. Thromb J. 2013;11:10.

    CAS  Article  Google Scholar 

  24. 24.

    Mendell J, Chen S, He L, Desai M, Parasramupria DA. The effect of rifampin on the pharmacokinetics of edoxaban in healthy adults. Clin Drug Investig. 2015;35:447–53.

    CAS  Article  Google Scholar 

  25. 25.

    Härtter S, Koenen-Bergmann M, Sharma A, Nehmiz G, Lemke U, Timmer W, et al. Decrease in the oral bioavailability of dabigatran etexilate after co-medication with rifampicin. Br J Clin Pharmacol. 2012;74:490–500.

    Article  Google Scholar 

  26. 26.

    Steffel J, Verhamme P, Potpara TS, Albaladejo P, Antz M, Desteghe L, et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J. 2018;39:1330–93.

    CAS  Article  Google Scholar 

  27. 27.

    January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. J Am Coll Cardiol. 2014;64:e1-76.

    Article  Google Scholar 

  28. 28.

    Perlman A, Horwitz E, Hirsh-Raccah B, Aldouby-Bier G, Fisher Negev T, Hochberg-Klein S, et al. Clinical pharmacist led hospital-wide direct oral anticoagulant stewardship program. Isr J Health Policy Res. 2019;8:19.

    Article  Google Scholar 

  29. 29.

    Rottenstreich A, Zacks N, Kleinstern G, Raccah BH, Roth B, Da’as N, et al. Direct-acting oral anticoagulant drug level monitoring in clinical patient management. J Thromb Thrombolysis. 2018;45:543–9.

    CAS  Article  Google Scholar 

  30. 30.

    Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro AF, Feldman HI, et al. A new equation to estimate glomerular filtration rate. Ann Intern Med. 2009;150:604–12.

    Article  Google Scholar 

  31. 31.

    Eikelboom JW, Quinlan DJ, Hirsh J, Connolly SJ, Weitz JI. Laboratory monitoring of non-vitamin k antagonist oral anticoagulant use in patients with atrial fibrillation: a review. JAMA Cardiol. 2017;2:566.

    Article  Google Scholar 

  32. 32.

    Gosselin R, Adcock D, Bates S, Douxfils J, Favaloro E, Gouin-Thibault I, et al. International Council for Standardization in Haematology (ICSH) recommendations for laboratory measurement of direct oral anticoagulants. Thromb Haemost. 2018;118:437–50.

    Article  Google Scholar 

  33. 33.

    Cytochrome P-450 CYP3A4 Inducers. DrugBank [Internet]. [cited 2020 Jun 9]. https://www.drugbank.ca/categories/DBCAT003896. Accessed 9 June 2020.

  34. 34.

    Cytochrome P-450 CYP3A4 Inhibitors (moderate). DrugBank [Internet]. [cited 2020 Jul 1]. https://www.drugbank.ca/categories/DBCAT002648. Accessed 1 July 2020.

  35. 35.

    Raval AN, Cigarroa JE, Chung MK, Diaz-Sandoval LJ, Diercks D, Piccini JP, et al. Management of patients on non-vitamin K Antagonist oral anticoagulants in the acute care and periprocedural setting: a scientific statement from the American Heart Association. Circulation [Internet]. 2017;13:5. https://doi.org/10.1161/CIR.0000000000000477 (cited 2020 Jul 1).

    CAS  Article  Google Scholar 

  36. 36.

    Acton EK, Willis AW, Gelfand MA, Kasner SE. Poor concordance among drug compendia for proposed interactions between enzyme-inducing antiepileptic drugs and direct oral anticoagulants. Pharmacoepidemiol Drug Saf. 2019;28:1534–8.

    CAS  Article  Google Scholar 

  37. 37.

    Galgani A, Palleria C, Iannone LF, De Sarro G, Giorgi FS, Maschio M, et al. Pharmacokinetic interactions of clinical interest between direct oral anticoagulants and antiepileptic drugs. Front Neurol. 2018;9:1067.

    Article  Google Scholar 

  38. 38.

    Hirsh Raccah B, Rottenstreich A, Zacks N, Muszkat M, Matok I, Perlman A, et al. Drug interaction as a predictor of direct oral anticoagulant drug levels in atrial fibrillation patients. J Thromb Thrombolysis. 2018;46:521–7.

    CAS  Article  Google Scholar 

  39. 39.

    Drouet L, Bal dit Sollier C, Steiner T, Purrucker J. Measuring non-vitamin K antagonist oral anticoagulant levels: When is it appropriate and which methods should be used? Int J Stroke. 2016;11:748–58.

    Article  Google Scholar 

  40. 40.

    Eliquis-EPAR Product information [Internet]. European Medicines Agency; [cited 2020 Jun 9].: https://www.ema.europa.eu/en/documents/product-information/eliquis-epar-product-information_en.pdf. Accessed 9 June 2020.

Download references

Author information



Corresponding author

Correspondence to Mordechai Muszkat.

Ethics declarations



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.


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.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file3 (PDF 143 KB)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation