Skip to main content
SpringerLink
Log in

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

  • Short Communication
  • Published:
CNS Drugs Aims and scope Submit manuscript

Abstract

Introduction

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.

Methods

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.

Results

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).

Conclusion

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

References

  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. https://doi.org/10.1161/jaha.116.003725.

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1056/NEJMoa0905561.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1056/NEJMoa1107039.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1056/NEJMoa1009638.

    Article  CAS  Google Scholar 

  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. https://doi.org/10.1007/s00415-014-7462-0.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1093/eurheartj/ehy136.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s40256-015-0157-9.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1186/1477-9560-11-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1007/s40261-015-0298-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.4081/cp.2015.788.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Stöllberger C, Finsterer J. Recurrent venous thrombosis under rivaroxaban and carbamazepine for symptomatic epilepsy. Neurol Neurochir Pol. 2017;51(2):194–6. https://doi.org/10.1016/j.pjnns.2017.01.010.

    Article  PubMed  Google Scholar 

  12. Risselada AJ, Visser MJ, van Roon EN. Pulmonary embolism due to interaction between rivaroxaban and carbamazepine. Ned Tijdschr Geneeskd. 2013;157(52):A6568.

    PubMed  Google Scholar 

  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. https://doi.org/10.7861/clinmedicine.18-1-103.

    Article  Google Scholar 

  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. https://doi.org/10.1177/1060028018759938.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s11239-019-01866-1.

    Article  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s11239-018-01804-7.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1038/s41467-019-09936-x.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Tatonetti NP, Ye PP, Daneshjou R, Altman RB. Data-driven prediction of drug effects and interactions. Sci Transl Med. 2012. https://doi.org/10.1126/scitranslmed.3003377.

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1002/pds.677.

    Article  CAS  PubMed  Google Scholar 

  20. Center for Drug Evaluation and Research. National Drug Code Directory. U.S. Food and Drug Administration. 2019. https://www.fda.gov/drugs/drug-approvals-and-databases/national-drug-code-directory. Accessed 13 June 2019.

  21. Cytochrome P-450 CYP3A4 inducers. DrugBank. 2019. https://www.drugbank.ca/categories/DBCAT003896. Accessed 13 June 2019.

  22. Hellwig T, Gulseth M. Pharmacokinetic and pharmacodynamic drug interactions with new oral anticoagulants. Ann Pharmacother. 2013;47(11):1478–87. https://doi.org/10.1177/1060028013504741.

    Article  CAS  PubMed  Google Scholar 

  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. https://doi.org/10.1007/s11239-019-01823-y.

    Article  CAS  PubMed  Google Scholar 

  24. Medication Guides. accessdata.fda.gov. 2019. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=medguide.page. Accessed 13 June 2019.

  25. Medicines. European Medicines Agency. 2019. https://www.ema.europa.eu/en/medicines. Accessed 13 June 2019.

  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. https://doi.org/10.1161/STROKEAHA.118.023877.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Amichai Perlman, Maor Wanounou and Rachel Goldstein contributed equally to this work.

Authors and Affiliations

  1. Division of Clinical Pharmacy, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel

    Amichai Perlman & Rachel Goldstein

  2. K-Health Inc, Tel Aviv, Israel

    Amichai Perlman

  3. Department of Medicine, Hadassah Hebrew University Hospital, Mt. Scopus, P.O. Box 24035, 91240, Jerusalem, Israel

    Maor Wanounou, Rachel Goldstein, Lotan Choshen Cohen & Mordechai Muszkat

  4. Division of General Internal Medicine, Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA

    Daniel E. Singer

Authors
  1. Amichai Perlman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Maor Wanounou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rachel Goldstein
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lotan Choshen Cohen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Daniel E. Singer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mordechai Muszkat
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mordechai Muszkat.

Ethics declarations

Funding

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.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 18 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Perlman, A., Wanounou, M., Goldstein, R. et al. 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 33, 1223–1228 (2019). https://doi.org/10.1007/s40263-019-00677-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40263-019-00677-5

Search

Navigation