Clinically significant drug interactions with warfarin: bleeding risk


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Abstract

Drug interactions with the available oral anticoagulant warfarin are prominent in clinical practice, with more than 50% of patients taking potentially warfarin-interacting drugs. The objective of this review is to summarize data on drug interactions with warfarin in relation to the bleeding risk, their mechanisms and significance, and to present new data on the current problem. In 2021, the results of the largest systematic review and meta-analysis of 72 studies evaluating clinically significant drug interactions with warfarin leading to bleeding were published. The most significant groups of drugs that in combined use with warfarin increase the risk of bleeding include antiplatelets, non-steroidal anti-inflammatory drugs (NSAIDs), some antibiotics, selective serotonin reuptake inhibitors (SSRIs), and the mechanism of these interactions is largely pharmacodynamic. There was no statistically sig-nificant increase in the bleeding risk when warfarin was combined with amiodarone, but an increase in all-cause mortality was found. A decrease in clinically significant bleeding when warfarin was combined with proton pump inhibitors was found. Thus, antiplatelets, NSAIDs, SSRIs may increase the risk of bleeding when combined with warfarin, and their concomitant use should be routinely evaluated. Data on drug interactions with warfarin is constantly updated and replenished, so it is very important for clinicians to regularly receive up-to-date information to address issues of rational and safe treatment of patients receiving warfarin. Qualified management of drug interactions with warfarin will help improve clinical outcomes and prevent adverse complications in patients taking warfarin.

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About the authors

M. V Leonova

Interregional Public Organization «Association of Clinical Pharmacologists»

Email: anti23@mail.ru
Dr. Sci. (Med.), Prof., Corresponding Member of the RANS, Clinical Pharmacologist, Member of the Moscow Regional Branch Volgograd, Russia

References

  1. Crader M.F, Johns Т., Arnold J.K. Warfarin drug interactions. [Updated 2021 Jul 19]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021.
  2. Rydberg DM, Linder M., Malmstrm R.E., et al. Risk factors for severe bleeding events during warfarin treatment: the influence of sex, age, comorbidity and comedication. Eur J Clin Pharmacol. 2020;76:867-76. Doi: 10.1007/ s00228-020-02856-6.
  3. Comoretto R.I., Rea F, Lucenteforte E., et al. Bleeding events attributable to concurrent use of warfarin and other medications in high-risk elderly: meta-analysis and Italian population-based investigation. Eur. J. Clin. Pharmacol. 2018;74:1061-70. doi: 10.1007/s00228-018-2467-8.
  4. Holbrook A.M., Pereira J.A., Labiris R., et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med. 2005;165(10):1095-106. Doi: 10.1001/ archinte.165.10.1095.
  5. Kean M, Krueger K.K., Parkhurst B.L., et al. Assessment of potential drug interactions that may increase the risk of major bleeding events in patients on warfarin maintenance therapy. J Pharm Soc Wis. 2018;21:44-8.
  6. Wang M, Zeraatkar D., Obeda M., et al. Drug-drug interactions with warfarin: a systematic review and meta-analysis. Br J Clin Pharmacol. 2021;87(11):4051-100. Doi: 10.1111/ bcp.14833.
  7. Rothberg M.B., Celestin C., Fiore L.D., et al. Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit. Ann Intern Med. 2005;143(4):241-50. doi: 10.7326/00034819-143-4-200508160-00005
  8. Dentali F., Douketis J.D., Lim W., Crowther M.Combined aspirin-oral anticoagulant therapy compared with oral anticoagulant therapy alone among patients at risk for cardiovascular disease: a meta-analysis of randomized trials. Arch Intern Med. 2007;167(2):117-24. doi: 10.1001/ archinte.167.2.117.
  9. Hansen M.L., Sorensen R., Clausen M.T., et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med. 2010;170:1433-41. Doi: 10.1001/ archinternmed.2010.271.
  10. Lamberts M., Olesen J.B., Ruwald M.H., et al. Bleeding after initiation of multiple antithrombotic drugs, including triple therapy, in atrial fibrillation patients following myocardial infarction and coronary intervention: a nationwide cohort study. Circulation. 2012;126(10):1185-93. doi: 10.1161/CIRCULATIONAHA.112.114967.
  11. van Rein N., Heide-J rgensen U., Lijfering W.M., et al. Major bleeding rates in atrial fibrillation patients on single, dual, or triple antithrombotic therapy. Circulation. 2019;139(6):775-86. doi: 10.1161/CIRCULATIONAHA.118.036248.
  12. Carpenter M., Berry H., Pelletier A.L. Clinically relevant drug-drug interactions in primary care. Am Fam Physician. 2019;99(9):558-64.
  13. Baillargeon J., Holmes H.M., Lin Y.l., et al. Concurrent use of warfarin and antibiotics and the risk of bleeding in older adults. Am J Med. 2012;125(2):183-89. Doi: 10.1016/j. amjmed.2011.08.014.
  14. Horn J.R., Hansten PD. Enhanced warfarin response and antibiotics. Pharmacy Times. 2004;70(6):70. https://www.pharmacytimes.com/view/2004-06-8003
  15. Lane M.A., Zeringue A., McDonald J.R. Serious bleeding events due to warfarin and antibiotic coprescription in a cohort of veterans. Am J Med. 2014;127(7):657-63.e2. Doi: 10.1016/j. amjmed.2014.01.044.
  16. Fischer H.D., Juurlink D.N., Mamdani M.M., et al. Hemorrhage during warfarin therapy associated with cotrimoxazole and other urinary tract anti-infective agents: a population-based study. Arch Intern Med. 2010;170(7):617-21. doi: 10.1001/archinternmed.2010.37.
  17. Hale S.F., Lesar T.S.Interaction of vitamin K antagonists and trimethoprim-sulfamethoxazole: ignore at your patient's risk. Drug Metabol Drug Interact. 2014;29(1):53-60. Doi: 10.1515/ dmdi-2013-0049.
  18. Schelleman H., Bilker W.B., Brensinger C.M., et al. Warfarin, fluoroquinolones, sulfonamides, or azole antifungals interactions and the risk of hospitalization for gastrointestinal bleeding. Clin Pharmacol Ther. 2008;84:581-88. doi: 10.1038/clpt.2008.150.
  19. Carroll D.N., Carroll D.G.Interactions between warfarin and three commonly prescribed fluoroquinolones. Ann Pharmacother. 2008;42(5):680-85. doi: 10.1345/aph.1K605.
  20. Goldstein J.L., Cryer B. Gastrointestinal injury associated with NSAID use: a case study and review of risk factors and preventative strategies. Drug Healthc Patient Saf. 2015;7:31-41. doi: 10.2147/DHPS.S71976.
  21. Cheetham T.C., Levy G., Niu F., Bixler F. Gastrointestinal safety of nonsteroidal anti-inflammatory drugs and selective cyclooxygenase-2 inhibitors in patients on warfarin. Ann Pharmacother. 2009;43:1765- 73. doi: 10.1345/aph.1M284.
  22. Zapata L.V, Hansten PD., Panic J., et al. Risk of bleeding with exposure to warfarin and nonsteroidal anti-inflammatory drugs: a systematic review and meta-analysis. Thromb Haemost. 2020;120(7):1066-74. doi: 10.1055/s-0040-1710592.
  23. Moore N, Pollack C., Butkerait P. Adverse drug reactions and drug-drug interactions with over-the-counter NSAIDs. Ther Clin Risk Manag. 2015;11:1061-75. doi: 10.2147/TCRM. S79135
  24. Vazquez S.R. Drug-drug interactions in an era of multiple anticoagulants: a focus on clinically relevant drug interactions. Blood. 2018;132(21):2230-39. doi: 10.1182/blood-2018-06-848747.
  25. Andrade C., Sharma E. Serotonin reuptake inhibitors and risk of abnormal bleeding. Psychiatr Clin North Am. 2016;39(3):413-26. doi: 10.1016/j.psc.2016.04.010.
  26. Yuet W.C., Derasari D., Sivoravong J., et al. Selective serotonin reuptake inhibitor use and risk of gastrointestinal andiIntracranial bleeding. J Osteopathic Medicine. 2019;119(2):102-11. doi: 10.7556/jaoa.2019.016.
  27. Bixby A.L., VandenBerg A., Bostwick J.R. Clinical management of bleeding risk with antidepressants. Ann Pharmacother. 2019;53(2):186-94. doi: 10.1177/1060028018794005.
  28. Schelleman H., Brensinger C.M., Bilker W.B., Hennessy S. Antidepressant-warfarin interaction and associated gastrointestinal bleeding risk in a case-control study. PloS one. 2011;6:e21447. doi: 10.1371/journal.pone.0021447.
  29. Quinn G.R., Singer D.E., Chang Y., et al. Effect of selective serotonin reuptake inhibitors on bleeding risk in patients with atrial fibrillation taking warfarin. Am J Cardiol. 2014;114(4):583-86. doi: 10.1016/j.amjcard.2014.05.037.
  30. Renoux C, Vahey S., Dell'Aniello S., Boivin J.F. Association of selective serotonin reuptake inhibitors with the risk for spontaneous intracranial hemorrhage. JAMA Neurol. 2017;74(2):173-80 doi: 10.1001/jamaneurol.2016.4529.
  31. Shaik A.N., Bohnert T., Williams D.A., et al. Mechanism of drug-drug interactions between warfarin and statins. J Pharm Sci. 2016;105(6):1976-86. Doi: 10.1016/j. xphs.2016.03.01.1
  32. Douketis J.D., Melo M., Bell C.M., Mamdani M.M. Does statin therapy decrease the risk for bleeding in patients who are receiving warfarin? Am J Med. 2007;120:369 e9-69 e14. Doi: 10.1016/j. amjmed.2006.06.008.
  33. Schelleman H., Bilker W.B., Brensinger C.M., et al. Fibrate/Statin initiation in warfarin users and gastrointestinal bleeding risk. Am J Med. 2010;123:151-57. Doi: 10.1016/j. amjmed.2009.07.020.
  34. Andersson M.L., Mannheime B., Lindh J.D. The effect of simvastatin on warfarin anticoagulation: a Swedish register-based nationwide cohort study. Eur J Clin Pharmacol. 2019;75:1387-92. doi: 10.1007/s00228-019-02703-3.
  35. Shin D., Yoon D., Lim S.G., et al.Comparison of the risk of gastrointestinal bleeding among different statin exposures with concomitant administration of warfarin: electronic health record-based retrospective cohort study. PloS one. 2016;11(7): e0158130. doi: 10.1371/journal. pone.0158130.
  36. Wiggins B.S., Saseen J.J., Page R.L, et al. Recommendations for management of clinically significant drug-drug interactions with statins and select agents used in patients with cardiovascular disease: a scientific statement from the American Heart Association. Circulation. 2016;134:e468- doi: 10.1161/CIR.0000000000000456.
  37. Undas A., Brummel-Ziedins K.E., Mann K.G. Anticoagulant effects of statins and their clinical implications. Thromb Haemost. 2014;111(3):392-400. doi: 10.1160/TH13-08-0720.
  38. McDonald M.G., Au N.T., Wittkowsky A.K., Rettie A.E. Warfarin-amiodarone drug-drug interactions: determination of [I](u)/K(I,u) for amiodarone and its plasma metabolites. Clin Pharmacol Ther. 2012;91(4):709-17. Doi: 10.1038/ clpt.2011.283.
  39. Miano T.A., Yang W., Shashaty M.G.S., et al. The Magnitude of the warfarin-amiodarone drug-drug interaction varies with renal function: a propensity-matched cohort study. Clin Pharmacol Ther. 2020;107(6):1446-56. Doi: 10.1002/ cpt.1819.
  40. Flaker G., Lopes R.D., Hylek E., et al. Amiodarone, anticoagulation, and clinical events in patients with atrial fibrillation: insights from the ARISTOTLE trial. J Am Coll Cardiol. 2014;64(15):1541-50. doi: 10.1016/j.jacc.2014.07.967
  41. Holm J., Lindh J.D., Andersson M.L., Mannheimer B. The effect of amiodarone on warfarin anticoagulation: a register-based nationwide cohort study involving the Swedish population. J Thromb Haemost. 2017;15(3):446-53. doi: 10.1111/jth.13614.
  42. Ray W.A., Chung C.P, Murray K.T., et al. Association of proton pump inhibitors with reduced risk of warfarin-related serious upper gastrointestinal bleeding. Gastroenterology. 2016;151(6):1105-12e10. doi: 10.1053/j.gastro.2016.08.054.
  43. Ray W.A., Chung C.P, Murray K.T., et al. Association of oral anticoagulants and proton pump inhibitor cotherapy with hospitalization for upper gastrointestinal tract bleeding. JAMA 2018;320:2221-30. Doi: 10.1001/ jama.2018.17242.

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