Association of drug-warfarin interactions and supratherapeutic international normalized ratio of prothrombin time in the emergency department
Keywords:
warfarin, drug interaction, emergency room, abnormal bleedingAbstract
Introduction Warfarin is a vitamin K antagonist anticoagulant that is widely used for prophylaxis and treatment of thromboembolism. Several factors can cause the international normalized ratio (INR) of the prothrombin time to exceed the target ranges of treatment, including drug-drug interactions, leading to abnormal bleeding and potential fatality.
Objectives The primary objective was to evaluate the association of drug-drug interactions between drugs on the warfarin interaction list and warfarin for the supra-therapeutic INR. Additionally, the study aimed to assess how frequently drugs from the warfarin interaction list were prescribed to patients in the emergency department (ED) and to evaluate the severity of bleeding resulting from these interactions.
Method This was a retrospective medical record review study of patients aged 15 years or older who were currently taking warfarin during the index ED visits from 1 January 2015, and 30 June 2017 and had at least one INR blood test.
Results From 530 ED visits included, at least one drug on the warfarin interaction drug list was prescribed in 378 ED visits (71.3%). Overall, 133 of 530 visits (25.1%) had supratherapeutic INR. From these 133 visits, 50 had abnormal bleeding, gastrointestinal and intracranial bleeding were found in 12% and 5%, respectively. Univariable logistic regression analysis revealed that taking warfarin with more than one drug in the highly probable group on the warfarin drug interaction list was associated with supratherapeutic INR (OR 2.6; 95% CI: 1.27-5.32; P-value = 0.01), as well as taking warfarin with paracetamol and another drug on the list (OR 2.25; 95% CI: 1.06-4.78; P-value = 0.03).
Conclusions Approximately three-fourths of patients received at least one drug on the warfarin interaction drug list. Warfarin-drug interactions were associated with supra-therapeutic INR and bleeding. Hospitals should seek prevention strategies for this issue in the future.
References
Witt DM, Clark NP, Kaatz S, Schnurr T, Ansell JE. Guidance for the practical management of warfarin therapy in the treatment of venous thromboembolism. J Thromb Thrombolysis 2016;41(1):187–205. doi: 10.1007/s11239-015-1319-y.
Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy - antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141(2 suppl.):e44S-e88S. doi: 10.1378/chest.11-2292.
Guyatt GH, Akl EA, Crowther M, Gutterman DD, Schünemann HJ. Executive Summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012;141 (2 Suppl):7S-47S. doi: 10.1378/chest.1412S3.
Pourafkari L, Ghaffari S, Khaki N, Hobika GH, Masnadi-Shirazi K, Nader ND. Predictors of hospital mortality and serious complications in patients admitted with excessive warfarin anticoagulation. Thromb Res 2016;137:79–84. doi: 10.1016/j.thromres.2015.11.014.
Gungorer B. Risk factors associated with warfarin overdose and complications related to warfarin overdose in the emergency department. Drug Chem Toxicol 2022;45(4):1732–8. doi: 10.1080/01480545.2020.1868493.
Piatkov I, Rochester C, Jones T, Boyages S. Warfarin toxicity and individual variability clinical case. Toxins (Basel) 2010;2(11):2584– 92. doi: 10.3390/toxins2112584. 7. สมาคมแพทย์โรคหัวใจแห่งประเทศไทยใน พระบรมราชูปถัมภ์. แนวทางการรักษาผู้ป่วยด้วยยาต้านการแข็งตัวของเลือดชนิดรับประทาน. กรุงเทพฯ: สมาคมแพทย์โรคหัวใจแห่งประเทศไทย; 2553.
Sittinateskul P, Angchaisuksiri P, Sasanakul W, Chuansumrit A. Genetic determinants of response to warfarin in Thai patients. Rama Med J 2009;32(4):177–86.
Holbrook AM, Pereira JA, Labiris R, McDonald H, Douketis JD, Crowther M, 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.
Charan J, Biswas T. How to calculate sample size for different study designs in medical research? Indian J Psychol Med 2013;35(2): 121–6. doi: 10.4103/0253-7176.116232.
Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005 ; 3(4) : 692 – 4. doi : 10.1111/j.1538-7836.2005.01204.x.
Teklay G, Shiferaw N, Legesse B, Bekele ML. Drug-drug interactions and risk of bleeding among inpatients on warfarin therapy: a prospective observational study. Thromb J 2014;12(1):20. doi: 10.1186/1477-9560-12-20.
Tadesse TA, Alebachew M, Woldu A. Prevalence of Warfarin Drug Interaction and Warfarin Education Practice in Outpatient Setups of University Teaching Hospital: A Retrospective Chart Review and an Observational Study. J Basic Clin Pharm. 2018;10(1):262–6.
Takamoto K, Sakamoto JI, Ito S, Kimura T, Manabe E, Shikata T, et al. Low quality of warfarin therapy is associated with female gender but not with polypharmacy in patients with atrial fibrillation. Front Pharmacol 2021;12:651799. doi: 10.3389/fphar.2021.651799.
Absher RK, Moore ME, Parker MH. Patient-specific factors predictive of warfarin dosage requirements. Ann Pharmacother 2002;36(10):1512–7. doi: 10.1345/aph.1C025.
Choi JR, Kim JO, Kang DR, Yoon SA, Shin JY, Zhang XH, et al. Proposal of pharmacogenetics-based warfarin dosing algorithm in Korean patients. J Hum Genet 2011;56(4):290–5. doi: 10.1038/jhg.2011.4.
Barcellona D, Schirru P, Mameli A, Cornacchini S, Fenu L, Marongiu F. Overanticoagulation by vitamin K antagonists and gender differences. Int J Cardiol 2022;362:147–51. doi: 10.1016/j.ijcard.2022.05.003.
Harris RZ, Benet LZ, Schwartz JB. Gender effects in pharmacokinetics and pharmacodynamics. Drugs 1995;50(2):222– 39. doi: 10.2165/00003495-199550020-00003.
Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with STsegment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018;39(2):119– 77. doi: 10.1093/eurheartj/ehx393.
Gibson CM, Mehran R, Bode C, Halperin J, Verheugt FW, Wildgoose P, et al. Prevention of bleeding in patients with atrial fibrillation undergoing PCI. N Engl J Med 2016;375(25): 2423–34. doi: 10.1056/NEJMoa1611594.
Caldeira D, Costa J, Barra M, Pinto FJ, Ferreira JJ. How safe is acetaminophen use in patients treated with vitamin K antagonists? A system¬atic review and meta-analysis. Thromb Res 2015;135(1):58–61. doi: 10.1016/j.thromres.2014.10.011.
Thijssen HHW, Soute BA, Vervoort LM, Claessens JG. Paracetamol (acetaminophen) warfarin interaction: NAPQI, the toxic metabolite of paracetamol, is an inhibitor of enzymes in the vitamin K cycle. Thromb Haemost 2004;92(4):797–802. doi: 10.1160/TH04-02-0109.
Forfar JC. A 7-year analysis of haemorrhage in patients on long-term anticoagulant treatment. Br Heart J 1979;42(2):128–32. doi: 10.1136/hrt.42.2.128
Saour JN, Sieck JO, Mamo LAR, Gallus AS. Trial of Different Intensities of Anticoagulation in Patients with Prosthetic Heart Valves. N Engl J Med 1990;322(7):428–32. doi: 10.1056/NEJM199002153220703
Suzuki S, Yamashita T, Kato T, Fujino T, Sagara K, Sawada H, et al. Incidence of major bleeding complication of warfarin therapy in japanese patients with atrial fibrillation. Circ J 2007;71(5):761–5. doi: 10.1253/circj.71.761.
Launiainen T, Sajantila A, Rasanen I, Vuori E, Ojanperä I. Adverse interaction of warfarin and paracetamol: evidence from a postmortem study. Eur J Clin Pharmacol 2010; 66(1):97–103. doi: 10.1007/s00228-009-0727- 3
Downloads
Published
How to Cite
License
Copyright (c) 2025 Thai Collage of Emergency Physicians
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
บทความที่ได้รับตีพิมพ์ในวารสารเวชศาสตร์ฉุกเฉินแห่งประเทศไทย ถือเป็นเป็นลิขสิทธิ์ของ วิทยาลัยแพทย์เวชศาสตร์ฉุกเฉินแห่งประเทศไทย
กรณีที่บทความได้รับการตีพิมพ์ในวารสารเวชศาสตร์ฉุกเฉินแห่งประเทศไทยแล้ว จะตีพิมพ์ในรูปแบบอิเล็กทรอนิกส์ ไม่มีสำเนาการพิมพ์ภายหลังหนังสือเผยแพร่เรียบร้อยแล้ว ผู้นิพนธ์ไม่สามารถนำบทความดังกล่าวไปนำเสนอหรือตีพิมพ์ในรูปแบบใดๆ ที่อื่นได้ หากมิได้รับคำอนุญาตจากวารสารเวชศาสตร์ฉุกเฉินแห่งประเทศไทย
