Analysis of potential interactions between warfarin and prescriptions in Estonian outpatients aged 50 years or more
In Estonia, warfarin is widely prescribed by general practitioners to prevent and treat thromboembolic diseases. To date, there has been no systematic analysis of the potential risk of warfarin interactions with other drugs in the outpatient population.
Objective: The aim of the study was to analyze the incidence of potential interactions in prescription schemes in Estonia in a cohort of outpatients receiving warfarin treatment.
Methods: The retrospective study population included 203,646 outpatients aged 50 years or older of whom 7,175 received warfarin therapy. Patients who had used at least one prescription drug for a minimum period of 7 days concomitantly with warfarin were analyzed. Potential drug interactions were analyzed using Epocrates online, Stockley’s Drug Interactions and domestic drug interaction databases.
Results: The average number of drugs used concomitantly with warfarin was 4.8 (SD=1.9) (males: 4.7 SD=2.0, females: 4.9 SD=2.0). No potential interactions in treatment regimens were found in 38% of patients, one potential interaction was observed in 29% and two or more potential interactions were observed in 33% of patients. The mean number of all potential interactions was 1.2 per patient and about the same in men and women. Potential interactions were associated with the number of drugs. Warfarin-related interactions were detected in 57% of patients, and the number of interactions related to warfarin per patient varied from 1 to 5. Most frequent were use of warfarin with NSAIDs (14%), followed by simvastatin (9%) and amiodarone (7%).
Conclusion: This study shows that 57% of outpatients in Estonia receiving warfarin have drugs potentially interacting with warfarin in their treatment schemes. Most interactions (14%) with warfarin are associated with the prescription of NSAIDs.
2. Lip GY, Hart RG, Conway DS. Antithrombotic therapy for atrial fibrillation. BMJ. 2002;325(7371):1022-1025.
3. Lip GY, Agnelli G, Thach AA, Knight E, Rost D, Tangelder MJ. Oral anticoagulation in atrial fibrillation: A pan-European patient survey. Eur J Intern Med. 2007;18(3):202-208.
4. Segal JB, McNamara RL, Miller MR, Kim N, Goodman SN, Powe NR, Robinson KA, Bass EB. Prevention of thromboembolism in atrial fibrillation. A meta-analysis of trials of anticoagulants and antiplatelet drugs. J Gen Intern Med. 2000;15(1):56-67.
5. Hirsh J, Dalen J, Anderson DR, Poller L, Bussey H, Ansell J, Deykin D. Oral Anticoagulants: Mechanism of Action, Clinical Effectiveness, and Optimal Therapeutic Range. Chest. 2001;119(1 Suppl):8S-21S.
6. Johnson JA. Warfarin: an old drug but still interesting. Pharmacotherapy. 2008;28(9):1081-1083.
7. Hanley JP. Warfarin reversal. J Clin Pathol. 2004;57(11):1132-1139.
8. Juurlink DN. Drug interactions with warfarin: what clinicians need to know. CMAJ. 2007;177(4):369-371.
9. Pirmohamed M. Warfarin: almost 60 years old and still causing problems. Br J Clin Pharmacol. 2006;62(5):509-511.
10. Pirmohamed M, James S, Meakin S, Green C, Scott AK, Walley TJ, Farrar K, Park BK, Breckenridge AM. Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. BMJ. 2004;329(7456):15-19.
11. Budnitz DS, Shehab N, Kegler SR, Richards CL. Medication use leading to emergency department visits for adverse drug events in older adults. Ann Intern Med. 2007;147(11):755-765.
12. Baxter K. Stockley’s Drug Interactions (9 Edition). Pharmaceutical Press. 2010.
13. Bachmann KA. Lexi-Comp’s drug interactions handbook: the new standard for drug and herbal interactions. Lexi-Comp. 2004.
14. Narum S, Solhaug V, Myhr K, Johansen PW, Brørs O, Kringen MK. Warfarin-associated bleeding events and concomitant use of potentially interacting medicines reported to the Norwegian spontaneous reporting system. Br J Clin Pharmacol. 2011;71(2):254-262.
15. Holbrook AM, Pereira JA, Labiris R, McDonald H, Douketis JD, Crowther M, Wells PS. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med. 2005;165(10):1095-1106.
16. Spencer FA, Gore JM, Lessard D, Emery C, Pacifico L, Reed G, Gurwitz JH, Goldberg RJ. Venous thromboembolism in the elderly. A community-based perspective. Thromb Haemost. 2008;100(5):780-788.
17. Hylek EM, Heiman H, Skates SJ, Sheehan MA, Singer DE. Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation. 2007;115(21):2689-2696.
18. Wittkowsky AK, Boccuzzi SJ, Wogen J, Wygant G, Patel P, Hauch O. Frequency of concurrent use of warfarin with potentially interacting drugs. Pharmacotherapy. 2004;24(12):1668-1674.
19. Uibokand S, Zarkovski A. A system for analysis and report of drug interactions. Patent No.091803734-1225. European Patent Office 10.05.10.
20. https://online.epocrates.com (accessed May 8, 2011)
21. Clauson KA, Polen HH, Marsh WA Clinical decision support tools: performance of personal digital assistant versus online drug information databases. Pharmacotherapy. 2007;27(12):1651-1658.
22. Ray S, Pramanik J, Bhattacharyya M, Todi S. Prospective observational evaluation of incidences and implications of drug-drug interactions induced adverse drug reactions in critically ill patients. Indian J Pharm Sci. 2010;72(6):787-792.
23. Johnell K, Klarin I. The relationship between number of drugs and potential drug-drug interactions in the elderly: a study of over 600,000 elderly patients from the Swedish Prescribed Drug Register. Drug Saf. 2007;30(10):911-918.
24. Verhovsek M, Motlagh B, Crowther MA, Kennedy C, Dolovich L, Campbell G, Wang L,Papaioannou A. Quality of anticoagulation and use of warfarin-interacting medications in long-term care: A chart review. BMC Geriatr. 2008;8:13.
25. Kotirum S, Chaiyakunapruk N, Jampachaisri K, Wattanasombat S, Rojnuckarin P. Utilization review of concomitant use of potentially interacting drugs in Thai patients using warfarin therapy. Pharmacoepidemiol Drug Saf. 2007;16(2):216-222.
26. Palareti G, Cosmi B. Bleeding with anticoagulation therapy - who is at risk, and how best to identify such patients. Thromb Haemost. 2009;102(2):268-278.
27. Blann AD, Fitzmaurice DA, Lip GY.Anticoagulation in hospitals and general practice. BMJ. 2003;326(7381):153-156.
28. Roughead EE, Kalisch LM, Barratt JD, Gilbert AL. Prevalence of potentially hazardous drug interactions amongst Australian veterans. Br J Clin Pharmacol. 2010;70(2):252-257.
29. Snaith A, Pugh L, Simpson CR, McLay JS. The potential for interaction between warfarin and coprescribed medication: a retrospective study in primary care. Am J Cardiovasc Drugs. 2008;8(3):207-212.
30. Wells PS, Holbrook AM, Crowther NR, Hirsh J. Interactions of warfarin with drugs and food. Ann Intern Med. 1994;121(9):676-683.
31. Westergren T, Johansson P, Molden E. Probable warfarin-simvastatin interaction. Ann Pharmacother. 2007;41(7):1292-1295.
32. Hamer A, Peter T, Mandel WJ, Scheinman MM, Weiss D. The potentiation of warfarin anticoagulation by amiodarone. Circulation. 1982;65(5):1025-1029.
33. Sanoski CA, Bauman JL. Clinical observations with the amiodarone/warfarin interaction: dosing relationships with long-term therapy. Chest. 2002;121(1):19-23.
34. Kates RE, Yee YG, Kirsten EB. Interaction between warfarin and propafenone in healthy volunteer subjects. Clin Pharmacol Ther. 1987;42(3):305-311.
35. Rawlins MD, Smith SE. Influence of allopurinol on drug metabolism in man. Br J Pharmacol. 1973;48(4):693-698.
36. Chute JP, Ryan CP, Sladek G, Shakir KM. Exacerbation of warfarin-induced anticoagulation by hyperthyroidism. Endocr Pract. 1997;3(2):77-79.
37. Bellosta S, Paoletti R, Corsini A. Safety of statins: focus on clinical pharmacokinetics and drug interactions. Circulation. 2004;109(23 Suppl 1):III50-III57.
38. Andrus MR. Oral anticoagulant drug interactions with statins: case report of fluvastatin and review of the literature. Pharmacotherapy. 2004;24(2):285-290.
39. Herman D, Locatelli I, Grabnar I, Peternel P, Stegnar M, Lainscak M, Mrhar A, Breskvar K, Dolzan V. The influence of co-treatment with carbamazepine, amiodarone and statins on warfarin metabolism and maintenance dose. Eur J Clin Pharmacol. 2006;62(4):291-296.
40. Stern R, Abel R, Gibson GL, Besserer J. Atorvastatin does not alter the anticoagulant activity of warfarin. J Clin Pharmacol. 1997;37(11):1062-1064.
41. Almog S, Shafran N, Halkin H, Weiss P, Farfel Z, Martinowitz U, Bank H. Mechanism of warfarin potentiation by amiodarone: dose--and concentration--dependent inhibition of warfarin elimination. Eur J Clin Pharmacol. 1985;28(3):257-261.
42. Lu Y, Won KA, Nelson BJ, Qi D, Rausch DJ, Asinger RW. Characteristics of the amiodarone-warfarin interaction during long-term follow-up. Am J Health Syst Pharm. 2008;65(10):947-952.
43. Heimark LD, Wienkers L, Kunze K, Gibaldi M, Eddy AC, Trager WF, O'Reilly RA, Goulart DA. The mechanism of the interaction between amiodarone and warfarin in humans. Clin Pharmacol Ther. 1992;51(4):398-407.
44. http://medicine.iupui.edu/clinpharm/ddis/table.asp (accessed Nov 8, 2011)
45. Hampel H, Berger C, Kuss HJ, Müller-Spahn F. Unstable anticoagulation in the course of amitriptyline treatment. Pharmacopsychiatry. 1996;29(1):33-37.
46. Wiedermann C, Stockner I. Warfarin-induced bleeding complications -clinical presentation and therapeutic options. Thromb Res. 2008;122(Suppl 2):S13-S18.
47. Wysowski DK, Nourjah P, Swartz L. Bleeding complications with warfarin use: a prevalent adverse effect resulting in regulatory action. Arch Intern Med. 2007;167(13):1414-1419.
48. Sabbe JR, Sims PJ, Sims MH. Tramadol-warfarin interaction. Pharmacotherapy. 1998;18(4):871-873.
49. Hedenmalm K, Lindh JD, Säwe J, Rane A. Increased liability of tramadol-warfarin interaction in individuals with mutations in the cytochrome P450 2D6 gene. Eur J Clin Pharmacol. 2004;60(5):369-372.
50. Penning-van Beest FJ, van Meegen E, Rosendaal FR, Stricker BH. Drug interactions as a cause of overanticoagulation on phenprocoumon or acenocoumarol predominantly concern antibacterial drugs. Clin Pharmacol Ther. 2001;69(6):451-457.
51. Cheetham TC, Levy G, Niu F, Bixler F. Gastrointestinal safety of nonsteroidal antiinflammatory drugs and selective cyclooxygenase-2 inhibitors in patients on warfarin. Ann Pharmacother. 2009;43(11):1765-1773.
52. Malhi H, Atac B, Daly AK, Gupta S. Warfarin and celecoxib interaction in the setting of cytochrome P450 (CYP2C9) polymorphism with bleeding complication. Postgrad Med J. 2004;80(940):107-109.
53. Israel DS, Stotka J, Rock W, Sintek CD, Kamada AK, Klein C, Swaim WR, Pluhar RE, Toscano JP, Lettieri JT, Heller AH, Polk RE. Effect of ciprofloxacin on the pharmacokinetics and pharmacodynamics of warfarin. Clin Infect Dis. 1996;22(2):251-256.
54. Schelleman H, Bilker WB, Brensinger CM, Han X, Kimmel SE, Hennessy S. Warfarin with fluoroquinolones, sulfonamides, or azole antifungals: interactions and the risk of hospitalization for gastrointestinal bleeding. Clin Pharmacol Ther. 2008;84(5):581-588.
55. Angaran DM, Dias VC, Arom KV, Northrup WF, Kersten TG, Lindsay WG, Nicoloff DM. The comparative influence of prophylactic antibiotics on the Ann Surg. 1987;206(2):155-161.
56. Pea F, Furlanut M. Pharmacokinetic aspects of treating infections in the intensive care unit: focus on drug interactions. Clin Pharmacokinet. 2001;40(11):833-868.
57. Ng HJ, Crowther MA. Azathioprine and inhibition of the anticoagulant effect of warfarin: evidence from a case report and a literature review. Am J Geriatr Pharmacother. 2006;4(1):75-77.
58. Whyte IM, Buckley NA, Reith DM, Goodhew I, Seldon M, Dawson AH. Acetaminophen causes an increased International Normalized Ratio by reducing functional factor VII. Ther Drug Monit. 2000;22(6):742-748.
59. Hylek EM, Heiman H, Skates SJ, Sheehan MA, Singer DE. Acetaminophen and other risk factors for excessive warfarin anticoagulation. JAMA. 1998;279(9):657-662.
60. Meeks ML, Mahaffey KW, Katz MD. Danazol increases the anticoagulant effect of warfarin. Ann Pharmacother. 1992;26(5):641-642.
61. O'Reilly RA. The stereoselective interaction of warfarin and metronidazole in man. N Engl J Med. 1976;295(7):354-357.
62. Kim KY, Mancano MA. Fenofibrate potentiates warfarin effects. Ann Pharmacother. 2003;37(2):212-215.
63. de Teresa E, Vera A, Ortigosa J, Pulpon LA, Arus AP, de Artaza M. Interaction between anticoagulants and contraceptives: an unsuspected finding. Br Med J. 1979;2(6200):1260-1261.
64. Zingone MM, Guirguis AB, Airee A, Cobb D. Probable drug interaction between warfarin and hormonal contraceptives. Ann Pharmacother. 2009;43(12):2096-2102.
The authors hereby transfer, assign, or otherwise convey to Pharmacy Practice: (1) the right to grant permission to republish or reprint the stated material, in whole or in part, without a fee; (2) the right to print pr epublish copies for free distribution or sale; and (3) the right to republish the stated material in any format (electronic or printed). In addition, the undersigned affirms that the article described above has not previously been published, in whole or part, is not subject to copyright or other rights except by the author(s), and has not been submitted for publication elsewhere, except as communicated in writing to Pharmacy Practice with this document.
Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License (CC-BY-NC-ND) that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.