CNS Drugs

pp 1–6 | Cite as

Ischemic and Thrombotic Events Associated with Concomitant Xa-inhibiting Direct Oral Anticoagulants and Antiepileptic Drugs: Analysis of the FDA Adverse Event Reporting System (FAERS)

  • Amichai Perlman
  • Maor Wanounou
  • Rachel Goldstein
  • Lotan Choshen Cohen
  • Daniel E. Singer
  • Mordechai MuszkatEmail author
Short Communication



Factor Xa-inhibiting direct oral anticoagulants (FXa-DOACs) undergo hepatic metabolism via cytochrome P-450 (CYP450). Concomitant use of rifampicin, an inducer of these enzymes, with FXa-DOACs, has been shown to decrease FXa-DOAC concentrations in healthy subjects. Several common antiepileptic drugs (AEDs) are known to induce CYP450 enzymes as well. However, little is known regarding the impact of this potential interaction on treatment outcomes with FXa-DOACs.


We analyzed adverse event cases submitted to the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) from January 2013 to December 2018. We compared the proportion of cases reporting thromboembolic and ischemic adverse events (TAIAEs) with the concomitant use of FXa-DOACs and enzyme-inducing AEDs to the proportion of cases with FXa-DOACs and other AEDs.


During this period, 9693 adverse event cases reported concomitant use of FXa-DOACs and AEDs. Almost all reports (> 99%) involved the use of rivaroxaban or apixaban. Compared with other AEDs, enzyme-inducing AEDs were associated with an 86% increase in the odds of reporting TAIAEs [reporting odds ratio (ROR) 1.86, 95% confidence interval (CI) 1.61–2.15; p < 0.0001]. In secondary separate analyses of rivaroxaban and apixaban, enzyme-inducing AEDs were similarly associated with increased reporting of a TAIAE (ROR 1.79, 95% CI 1.50–2.12, and ROR 1.88, 95% CI 1.41–2.48, respectively).


Using real world data, we observed an increase in the odds of reporting anticoagulation treatment failure among patients treated with FXa-DOACs and concomitant enzyme-inducing AEDs compared to those treated with other AEDs.


Compliance with Ethical Standards


No external funding was used in the preparation of this article.

Conflict of interest

A Perlman is a doctoral student at the Hebrew University of Jerusalem and an employee at K-health Inc. The work presented in this article is not related to his work at K-health. M. Wanounou, R. Goldstein, L. Choshen Cohen, D. Singer, and M. Muszkat declare that they have no potential conflicts of interest that might be relevant to this work.

Supplementary material

40263_2019_677_MOESM1_ESM.docx (19 kb)
Supplementary material 1 (DOCX 18 kb)


  1. 1.
    Yao X, Abraham NS, Sangaralingham LR, et al. Effectiveness and safety of dabigatran, rivaroxaban, and apixaban versus warfarin in nonvalvular atrial fibrillation. J Am Heart Assoc. 2016. Scholar
  2. 2.
    Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–51. Scholar
  3. 3.
    Granger CB, Alexander JH, McMurray JJV, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–92. Scholar
  4. 4.
    Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–91. 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(3):516–22. Scholar
  6. 6.
    Steffel J, Verhamme P, Potpara TS, 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. Scholar
  7. 7.
    Vakkalagadda B, Frost C, Byon W, et al. Effect of rifampin on the pharmacokinetics of apixaban, an oral direct inhibitor of factor Xa. Am J Cardiovasc Drugs. 2016;16(2):119–27. Scholar
  8. 8.
    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(1):10. Scholar
  9. 9.
    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. Scholar
  10. 10.
    Serra W, Li Calzi M, Coruzzi P. Left atrial appendage thrombosis during therapy with rivaroxaban in elective cardioversion for permanent atrial fibrillation. Clin Pract. 2015;5(3):788. Scholar
  11. 11.
    Stöllberger C, Finsterer J. Recurrent venous thrombosis under rivaroxaban and carbamazepine for symptomatic epilepsy. Neurol Neurochir Pol. 2017;51(2):194–6. Scholar
  12. 12.
    Risselada AJ, Visser MJ, van Roon EN. Pulmonary embolism due to interaction between rivaroxaban and carbamazepine. Ned Tijdschr Geneeskd. 2013;157(52):A6568.PubMedGoogle Scholar
  13. 13.
    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(1):103–5. Scholar
  14. 14.
    King PK, Stump TA, Walkama AM, Ash BM, Bowling SM. Management of phenobarbital and apixaban interaction in recurrent cardioembolic stroke. Ann Pharmacother. 2018;52(6):605–6. Scholar
  15. 15.
    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. Scholar
  16. 16.
    Perlman A, Hochberg-Klein S, Cohen LC, et al. Management strategies of the interaction between direct oral anticoagulant and drug-metabolizing enzyme inducers. J Thromb Thrombolysis. 2019;47(4):590–5. Scholar
  17. 17.
    Calizo RC, Bhattacharya S, Hasselt JGCV, Wei C, Wong JS, Wiener RJ, et al. Disruption of podocyte cytoskeletal biomechanics by dasatinib leads to nephrotoxicity. Nat Commun. 2019. Scholar
  18. 18.
    Tatonetti NP, Ye PP, Daneshjou R, Altman RB. Data-driven prediction of drug effects and interactions. Sci Transl Med. 2012. Scholar
  19. 19.
    Evans SJW, Waller PC, Davis S. Use of proportional reporting ratios (PRRs) for signal generation from spontaneous adverse drug reaction reports. Pharmacoepidemiol Drug Saf. 2001;10:483–6. Scholar
  20. 20.
    Center for Drug Evaluation and Research. National Drug Code Directory. U.S. Food and Drug Administration. 2019. Accessed 13 June 2019.
  21. 21.
    Cytochrome P-450 CYP3A4 inducers. DrugBank. 2019. Accessed 13 June 2019.
  22. 22.
    Hellwig T, Gulseth M. Pharmacokinetic and pharmacodynamic drug interactions with new oral anticoagulants. Ann Pharmacother. 2013;47(11):1478–87. Scholar
  23. 23.
    Washam JB, Hohnloser SH, Lopes RD, et al. Interacting medication use and the treatment effects of apixaban versus warfarin: results from the ARISTOTLE Trial. J Thromb Thrombolysis. 2019;47(3):345–52. Scholar
  24. 24.
    Medication Guides. 2019. Accessed 13 June 2019.
  25. 25.
    Medicines. European Medicines Agency. 2019. Accessed 13 June 2019.
  26. 26.
    Macha K, Marsch A, Siedler G, Breuer L, Strasser EF, Engelhorn T, Schwab S, Kallmünzer B. Cerebral ischemia in patients on direct oral anticoagulants. Stroke. 2019;50(4):873–9. Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Amichai Perlman
    • 1
    • 2
  • Maor Wanounou
    • 3
  • Rachel Goldstein
    • 1
    • 3
  • Lotan Choshen Cohen
    • 3
  • Daniel E. Singer
    • 4
  • Mordechai Muszkat
    • 3
    Email author
  1. 1.Division of Clinical Pharmacy, School of Pharmacy, Faculty of MedicineThe Hebrew University of JerusalemJerusalemIsrael
  2. 2.K-Health IncTel AvivIsrael
  3. 3.Department of MedicineHadassah Hebrew University HospitalJerusalemIsrael
  4. 4.Division of General Internal MedicineMassachusetts General Hospital, and Harvard Medical SchoolBostonUSA

Personalised recommendations