Skip to main content
SpringerLink
Log in

The real world use of combined P-glycoprotein and moderate CYP3A4 inhibitors with rivaroxaban or apixaban increases bleeding

  • Published:
Journal of Thrombosis and Thrombolysis Aims and scope Submit manuscript

Abstract

The use of direct oral anticoagulants for stroke prevention in atrial fibrillation continues to rise. Certain populations may be at higher risk for increased drug exposure and adverse events. Pharmacokinetic studies suggest increased exposure of rivaroxaban and apixaban with combined P-gp and moderate CYP3A4 inhibitors but the clinical relevance of this is unknown. This retrospective cohort study included patients receiving rivaroxaban or apixaban from January 1, 2012 to December 31, 2016 with a moderate inhibitor (amiodarone, dronedarone, diltiazem, verapamil) for at least 3 months in the drug–drug interaction (DDI) group. Propensity matching was used to identify similar control patients without the presence of the DDI. The primary outcome was a time to event analysis of any bleeding episode as defined by the International Society of Thrombosis and Hemostasis. After propensity matching, 213 patients with similar baseline characteristics were included in each group. The mean CHA2DS2-VASc score was 3.0 and median duration of follow-up was 1.45 years. The primary outcome occurred in 26.4% of patients in the DDI group and 18.4% in the control group (hazard ratio 1.8, 95% confidence interval [CI] 1.19 to 2.73; p-value = 0.006). There was no difference in bleeding rates based on type of inhibitor. Use of a combined P-gp and moderate CYP3A4 inhibitor with rivaroxaban or apixaban increased bleeding risk compared to patients without the DDI in this real world, retrospective study. Analysis in a larger patient population is needed to confirm these findings.

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

Similar content being viewed by others

References

  1. January CT, Wann LS, Calkins H et al (2019) AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. JACC 74:132

    Article  Google Scholar 

  2. Kubitza D, Becka M, Mueck W, Halabi A, Maatouk H, Klause N, Lufft V, Wand DD, Philipp T, Bruck H (2010) Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct factor Xa inhibitor. Br J Clin Pharmacol 70(5):703–712

    Article  CAS  Google Scholar 

  3. Chang M, Yu Z, Shenker A, Wang J, Pursley J, Byon W, Boyd RA, LaCreta F, Frost CE (2016) Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of apixaban. J Clin Pharmacol 56(5):637–645

    Article  CAS  Google Scholar 

  4. Chan KE, Edelman ER, Wenger JB, Thadhani RI, Maddux FW (2015) Dabigatran and rivaroxaban use in atrial fibrillation patients on hemodialysis. Circulation 131(11):972–979

    Article  CAS  Google Scholar 

  5. Shin JI, Secora A, Alexander GC, Inker LA, Coresh J, Chang AR, Grams ME (2018) Risks and benefits of direct oral anticoagulants across the spectrum of GFR among incident and prevalent patients with atrial fibrillation. Clin J Am Soc Nephrol Aug 13(8):1144–1152

    Article  CAS  Google Scholar 

  6. Janssen Pharmaceuticals Inc. Xarelto (rivaroxaban) Prescribing information (2014). http://www.xareltohcp.com/sites/default/files/pdf/xarelto_0.pdf

  7. Bristol-Myers Squibb Company and Pfizer Inc. Eliquis (apixaban) Prescribing information (2012). https://packageinserts.bms.com/pi/pi_eliquis.pdf

  8. Vakkalagadda B, Frost C, Byon W, Boyd RA, Wang J, Zhang D, Yu Z, Dias C, Shenker A, LaCreta F (2016) Effect of rifampin on the pharmacokinetics of apixaban, an oral direct inhibitor of factor Xa. Am J Cardiovasc Drugs 16(2):119–127

    Article  CAS  Google Scholar 

  9. Frost CE, Byon W, Song Y, Wang J, Schuster AE, Boyd RA, Zhang D, Yu Z, Dias C, Shenker A, LaCreta F (2015) Effect of ketoconazole and diltiazem on the pharmacokinetics of apixaban, an oral direct factor Xa inhibitor. Br J Clin Pharmacol 79(5):838–846

    Article  CAS  Google Scholar 

  10. Gnoth MJ, Buetehorn U, Muenster U, Schwarz T, Sandmann S (2011) In vitro and in vivo P-glycoprotein transport characteristics of rivaroxaban. J Pharmacol Exp Ther 338(1):372–380

    Article  CAS  Google Scholar 

  11. Mueck W, Kubitza D, Becka M (2013) Co-administration of rivaroxaban with drugs that share its elimination pathways: pharmacokinetic effects in healthy subjects. Br J Clin Pharmacol 2013 76(3):455–466

    Article  CAS  Google Scholar 

  12. Moore KT, Vaidyanathan S, Natarajan J, Ariyawansa J, Haskell L, Turner KC (2014) An open-label study to estimate the effect of steady-state erythromycin on the pharmacokinetics, pharmacodynamics, and safety of a single dose of rivaroxaban in subjects with renal impairment and normal renal function. J Clin Pharmacol 54(12):1407–1420

    Article  CAS  Google Scholar 

  13. Cockcroft DW, Gault MH (1976) Prediction of creatinine clearance from serum creatinine. Nephron 16:31–41

    Article  CAS  Google Scholar 

  14. Kaatz S, Ahmad D, Spyropoulos C, Schulman S, Subcommittee on Control of Anticoagulation (2015) Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC or the ISTH. J Thromb Haemost 13:2119–2126

    Article  CAS  Google Scholar 

  15. Schulman S, Angeras U, Bergqvist D, Eriksson B, Lassen MR, Fisher W, Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (2010) Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. J Thromb Haemost Jan 8(1):202–204

    Article  CAS  Google Scholar 

  16. Washam JB, Hellkamp AS, Lokhnygina Y, Piccini JP, Berkowitz SD, Nessel CC, Becker RC, Breithardt G, Fox KAA, Halperin JL, Hankey GJ, Mahaffey KW, Singer DE, Patel MR, ROCKET AF Steering Committee and Investigators (2017) Efficacy and safety of rivaroxaban versus warfarin in patients taking nondihydropyridine calcium channel blockers for atrial fibrillation (from the ROCKET AF Trial). Am J Cardiol 120(4):594

    Article  CAS  Google Scholar 

  17. Steinberg BA, Hellkamp AS, Lokhnygina Y, Halperin JL, Breithardt G, Passman R, Hankey GJ, Patel MR, Becker RC, Singer DE, Hacke W, Berkowitz SD, Nessel CC, Mahaffey KW, Fox KA, Califf RM, Piccini JP, ROCKET AF Steering Committee and Investigators (2014) Use and outcomes of antiarrhythmic therapy in patients with atrial fibrillation receiving oral anticoagulation: results from the ROCKET AF trial. Heart Rhythm 11(6):925–932

    Article  Google Scholar 

  18. Flaker G, Lopes RD, Hylek E, Wojdyla DM, Thomas L, Al-Khatib SM, Sullivan RM, Hohnloser SH, Garcia D, Hanna M, Amerena J, Harjola VP, Dorian P, Avezum A, Keltai M, Wallentin L, Granger CB, ARISTOTLE Committees and Investigators (2014) Amiodarone, anticoagulation, and clinical events in patients with atrial fibrillation: insights from the ARISTOTLE trial. J Am Coll Cardiol 64(15):1550

    Article  CAS  Google Scholar 

  19. Tepper PG, Mardekian J, Masseria C, Phatak H, Kamble S, Abdulsattar Y, Petkun W, Lip GYH (2018) Real-world comparison of bleeding risks among non-valvular atrial fibrillation patients prescribed apixaban, dabigatran, or rivaroxaban. PLoS ONE 13(11):e0205989

    Article  CAS  Google Scholar 

  20. Amin A, Keshishian A, Trocio J, Dina O, Le H, Rosenblatt L, Lin X, Mardekian J, Zhang Q, Baser O, Vo L (2017) Risk of stroke/systemic embolism, major bleeding and associated costs in non-valvular atrial fibrillation patients who initiated apixaban, dabigatran or rivaroxaban compared with warfarin in the United States Medicare population. Curr Med Res Opin 33(9):1604

    Article  CAS  Google Scholar 

  21. Cheong EJY, Goh JJN, Hong Y, Kojodjojo P, Chan ECY (2018) Rivaroxaban with and without amiodarone in renal impairment. J Am Coll Cardiol 71(12):1397

    Article  Google Scholar 

  22. Chang SH, Chou IJ, Yeh YH, Chiou MJ, Wen MS, Kuo CT, See LC, Kuo CF (2017) Association between use of non-vitamin K oral anticoagulants with and without concurrent medications and risk of major bleeding in nonvalvular atrial fibrillation. JAMA 318(13):1259

    Article  CAS  Google Scholar 

  23. Friberg L (2018) Safety of apixaban in combination with dronedarone in patients with atrial fibrillation. Int J Cardiol 264:90

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacy, Michigan Medicine, Ann Arbor, MI, USA

    Sarah Hanigan & Kristen Pogue

  2. Department of Clinical Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI, USA

    Sarah Hanigan, Kristen Pogue & Michael P. Dorsch

  3. Department of Pharmacy, University of Michigan College of Pharmacy, Ann Arbor, MI, USA

    Jessica Das

  4. Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA

    Geoffrey D. Barnes

  5. Institute of Healthcare Policy and Innovation, University of Michigan, Ann Arbor, MI, USA

    Geoffrey D. Barnes

Authors
  1. Sarah Hanigan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jessica Das
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kristen Pogue
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Geoffrey D. Barnes
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael P. Dorsch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sarah Hanigan.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hanigan, S., Das, J., Pogue, K. et al. The real world use of combined P-glycoprotein and moderate CYP3A4 inhibitors with rivaroxaban or apixaban increases bleeding. J Thromb Thrombolysis 49, 636–643 (2020). https://doi.org/10.1007/s11239-020-02037-3

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11239-020-02037-3

Keywords

Search

Navigation