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Thromb Haemost 2018; 118(03): 461-470
DOI: 10.1055/s-0038-1627100
Coagulation and Fibrinolysis
Schattauer GmbH Stuttgart

Population Impact of Drug Interactions with Warfarin: A Real-World Data Approach

Mar Martín-Pérez
,
David Gaist
,
Francisco J. de Abajo
,
Luis A. García Rodríguez
Further Information

Publication History

16 October 2017

17 December 2017

Publication Date:
12 February 2018 (online)

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Abstract

Objective To investigate the population impact of previously reported interactions between warfarin and other drugs on international normalized ratio (INR) levels.

Methods Using The Health Improvement Network (THIN), a United Kingdom primary care database, a cohort of warfarin users between 2005 and 2013 (N = 121,962) was followed until the first qualifying prescription for the potential interacting drugs was evaluated. Sixteen sub-cohorts, one for each study drug, and a control sub-cohort of warfarin were ascertained. Short-term changes in INR levels were assessed by comparing INR values measured before and after initiation of the interacting drug with paired Student's t-test. We also evaluated the proportion of patients with INR values outside the therapeutic range (INR: 2–3).

Results Miconazole use was associated with the highest mean increase in INR (+3.35), followed by amiodarone (+1.28), fluconazole (+0.79), metronidazole (+0.75) and nystatin (+0.65). After subtracting the natural INR variation observed in the control sub-cohort, supra-therapeutic levels (INR > 3) were found in 53.2% (miconazole), 45.5% (amiodarone), 23.3% (metronidazole), 23.2% (fluconazole) and 17.6% (nystatin) of patients initiating treatment with these drugs. Carbamazepine use was associated with a mean INR decrease of –0.63 and infra-therapeutic levels (INR < 2) were observed in 46.2% of patients initiating carbamazepine. For all other drugs, the change was small to moderate, in absolute INR units (+0.23 to +0.55) and in the proportion of patients with INR levels out of therapeutic range (<16%).

Conclusions Clinically potentially important interactions were observed in several study drugs. The majority of them, although confirmed, had little impact after adjusting for standard INR variability in the general population of warfarin users.

Keywords

anticoagulant drugs - warfarin - drug interactions - INR - database

Addendum

F.J. de Abajo, D. Gaist, L.A. García Rodríguez and M. Martín-Pérez designed the study and performed the literature search. F.J. de Abajo, D. Gaist, L.A. García Rodríguez and M. Martín-Pérez acquired, analysed and interpreted data. F.J. de Abajo, D. Gaist, L.A. García Rodríguez and M. Martín-Pérez drafted the manuscript and critically reviewed the manuscript for important intellectual content.


Supplementary Material

 

  • References

  • 1 Link KP. The discovery of dicumarol and its sequels. Circulation 1959; 19 (01) 97-107
    CrossrefPubMedGoogle Scholar
  • 2 Hirsh J, Fuster V, Ansell J, Halperin JL. ; American Heart Association; American College of Cardiology Foundation. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. Circulation 2003; 107 (12) 1692-1711
    CrossrefPubMedGoogle Scholar
  • 3 Keeling D, Baglin T, Tait C. , et al; British Committee for Standards in Haematology. Guidelines on oral anticoagulation with warfarin - fourth edition. Br J Haematol 2011; 154 (03) 311-324
    CrossrefPubMedGoogle Scholar
  • 4 Holbrook AM, Pereira JA, Labiris R. , et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 2005; 165 (10) 1095-1106
    CrossrefPubMedGoogle Scholar
  • 5 Greenblatt DJ, von Moltke LL. Interaction of warfarin with drugs, natural substances, and foods. J Clin Pharmacol 2005; 45 (02) 127-132
    CrossrefPubMedGoogle Scholar
  • 6 Juurlink DN. Drug interactions with warfarin: what clinicians need to know. CMAJ 2007; 177 (04) 369-371
    CrossrefPubMedGoogle Scholar
  • 7 Fischer HD, Juurlink DN, Mamdani MM, Kopp A, Laupacis A. Hemorrhage during warfarin therapy associated with cotrimoxazole and other urinary tract anti-infective agents: a population-based study. Arch Intern Med 2010; 170 (07) 617-621
    PubMedGoogle Scholar
  • 8 Kurdyak PA, Juurlink DN, Kopp A, Herrmann N, Mamdani MM. Antidepressants, warfarin, and the risk of hemorrhage. J Clin Psychopharmacol 2005; 25 (06) 561-564
    CrossrefPubMedGoogle Scholar
  • 9 Battistella M, Mamdami MM, Juurlink DN, Rabeneck L, Laupacis A. Risk of upper gastrointestinal hemorrhage in warfarin users treated with nonselective NSAIDs or COX-2 inhibitors. Arch Intern Med 2005; 165 (02) 189-192
    CrossrefPubMedGoogle Scholar
  • 10 Pincus D, Gomes T, Hellings C. , et al. A population-based assessment of the drug interaction between levothyroxine and warfarin. Clin Pharmacol Ther 2012; 92 (06) 766-770
    CrossrefPubMedGoogle Scholar
  • 11 Lam J, Gomes T, Juurlink DN. , et al. Hospitalization for hemorrhage among warfarin recipients prescribed amiodarone. Am J Cardiol 2013; 112 (03) 420-423
    CrossrefPubMedGoogle Scholar
  • 12 Fattinger K, Frisullo R, Masche U, Braunschweig S, Meier PJ, Roos M. No clinically relevant drug interaction between paracetamol and phenprocoumon based on a pharmacoepidemiological cohort study in medical inpatients. Eur J Clin Pharmacol 2002; 57 (12) 863-867
    CrossrefPubMedGoogle Scholar
  • 13 Henriksen DP, Stage TB, Hansen MR, Rasmussen L, Damkier P, Pottegård A. The potential drug-drug interaction between proton pump inhibitors and warfarin. Pharmacoepidemiol Drug Saf 2015; 24 (12) 1337-1340
    CrossrefPubMedGoogle Scholar
  • 14 Mannheimer B, Andersson ML, Järnbert-Pettersson H, Lindh JD. The effect of carbamazepine on warfarin anticoagulation: a register-based nationwide cohort study involving the Swedish population. J Thromb Haemost 2016; 14 (04) 765-771
    CrossrefPubMedGoogle Scholar
  • 15 Pottegård A, dePont Christensen R, Wang SV, Gagne JJ, Larsen TB, Hallas J. Pharmacoepidemiological assessment of drug interactions with vitamin K antagonists. Pharmacoepidemiol Drug Saf 2014; 23 (11) 1160-1167
    CrossrefPubMedGoogle Scholar
  • 16 Pottegård A, Henriksen DP, Madsen KG, Hellfritzsch M, Damkier P, Stage TB. Change in international normalized ratio among patients treated with dicloxacillin and vitamin K antagonists. JAMA 2015; 314 (03) 296-297
    CrossrefPubMedGoogle Scholar
  • 17 Stage TB, Pottegård A, Henriksen DP. , et al. Initiation of glucose-lowering treatment decreases international normalized ratio levels among users of vitamin K antagonists: a self-controlled register study. J Thromb Haemost 2016; 14 (01) 129-133
    CrossrefPubMedGoogle Scholar
  • 18 Blak BT, Thompson M, Dattani H, Bourke A. Generalisability of The Health Improvement Network (THIN) database: demographics, chronic disease prevalence and mortality rates. Inform Prim Care 2011; 19 (04) 251-255
    PubMedGoogle Scholar
  • 19 Lewis JD, Schinnar R, Bilker WB, Wang X, Strom BL. Validation studies of the health improvement network (THIN) database for pharmacoepidemiology research. Pharmacoepidemiol Drug Saf 2007; 16 (04) 393-401
    CrossrefPubMedGoogle Scholar
  • 20 Ltd. IPS. Gemscript A^ The new DM. D drug dictionary for Vision. http://www.inps4.co.uk/my-vision/news/gemscript-%C3%82%C2%96-new-dmd-drug-dictionary-vision . Accessed September 16, 2017.
    PubMed
  • 21 Stuart-Buttle CD, Read JD, Sanderson HF, Sutton YM. A language of health in action: Read Codes, classifications and groupings. Proc AMIA Annu Fall Symp 1996; 75-79
    PubMedGoogle Scholar
  • 22 Venkatakrishnan K, von Moltke LL, Greenblatt DJ. Effects of the antifungal agents on oxidative drug metabolism: clinical relevance. Clin Pharmacokinet 2000; 38 (02) 111-180
    CrossrefPubMedGoogle Scholar
  • 23 Rettie AE, Korzekwa KR, Kunze KL. , et al. Hydroxylation of warfarin by human cDNA-expressed cytochrome P-450: a role for P-4502C9 in the etiology of (S)-warfarin-drug interactions. Chem Res Toxicol 1992; 5 (01) 54-59
    CrossrefPubMedGoogle Scholar
  • 24 Miki A, Ohtani H, Sawada Y. Warfarin and miconazole oral gel interactions: analysis and therapy recommendations based on clinical data and a pharmacokinetic model. J Clin Pharm Ther 2011; 36 (06) 642-650
    CrossrefPubMedGoogle Scholar
  • 25 Drug Safety Update. Topical miconazole, including oral gel: reminder of potential for serious interactions with warfarin. Available at: https://www.gov.uk/drug-safety-update/topical-miconazole-including-oral-gel-reminder-of-potential-for-serious-interactions-with-warfarin . Accessed September 6, 2016
    PubMedGoogle Scholar
  • 26 Kovac M, Mitic G, Kovac Z. Miconazole and nystatin used as topical antifungal drugs interact equally strongly with warfarin. J Clin Pharm Ther 2012; 37 (01) 45-48
    CrossrefPubMedGoogle Scholar
  • 27 Ufondu CC, Ferrins P, Cushen A, Quinn J. Warfarin and topical miconazole: the potential for a clinically significant interaction. Ir J Med Sci 2013; 182 (01) 153-154
    CrossrefPubMedGoogle Scholar
  • 28 Thirion DJ, Zanetti LA. Potentiation of warfarin's hypoprothrombinemic effect with miconazole vaginal suppositories. Pharmacotherapy 2000; 20 (01) 98-99
    CrossrefPubMedGoogle Scholar
  • 29 Devaraj A, O'Beirne JP, Veasey R, Dunk AA. Interaction between warfarin and topical miconazole cream. BMJ 2002; 325 (7355): 77
    CrossrefPubMedGoogle Scholar
  • 30 Garcia-Cuesta C, Sarrion-Pérez MG, Bagán JV. Current treatment of oral candidiasis: a literature review. J Clin Exp Dent 2014; 6 (05) e576-e582
    PubMedGoogle Scholar
  • 31 Pemberton MN. Nystatin and miconazole: pharmacological and clinical evidence regarding interactions with warfarin. Oral Dis 2016; 22 (08) 761-765
    CrossrefPubMedGoogle Scholar
  • 32 Hellfritzsch M, Pottegård A, Pedersen AJT. , et al. Topical antimycotics for oral candidiasis in warfarin users. Basic Clin Pharmacol Toxicol 2017; 120 (04) 368-372
    CrossrefPubMedGoogle Scholar
  • 33 Hamer A, Peter T, Mandel WJ, Scheinman MM, Weiss D. The potentiation of warfarin anticoagulation by amiodarone. Circulation 1982; 65 (05) 1025-1029
    CrossrefPubMedGoogle Scholar
  • 34 Sanoski CA, Bauman JL. Clinical observations with the amiodarone/warfarin interaction: dosing relationships with long-term therapy. Chest 2002; 121 (01) 19-23
    CrossrefPubMedGoogle Scholar
  • 35 Raebel MA, Witt DM, Carroll NM, Magid DJ. Warfarin monitoring in ambulatory older individuals receiving antimicrobial therapy. Pharmacotherapy 2005; 25 (08) 1055-1061
    CrossrefPubMedGoogle Scholar
  • 36 Yacobi A, Lai CM, Levy G. Pharmacokinetic and pharmacodynamic studies of acute interaction between warfarin enantiomers and metronidazole in rats. J Pharmacol Exp Ther 1984; 231 (01) 72-79
    PubMedGoogle Scholar
  • 37 Thi L, Shaw D, Bird J. Warfarin potentiation: a review of the “FAB-4” significant drug interactions. Consult Pharm 2009; 24 (03) 227-230
    CrossrefPubMedGoogle Scholar
  • 38 Powers A, Loesch EB, Weiland A, Fioravanti N, Lucius D. Preemptive warfarin dose reduction after initiation of sulfamethoxazole-trimethoprim or metronidazole. J Thromb Thrombolysis 2017; 44 (01) 88-93
    CrossrefPubMedGoogle Scholar
  • 39 Gadisseur AP, Van Der Meer FJ, Rosendaal FR. Sustained intake of paracetamol (acetaminophen) during oral anticoagulant therapy with coumarins does not cause clinically important INR changes: a randomized double-blind clinical trial. J Thromb Haemost 2003; 1 (04) 714-717
    CrossrefPubMedGoogle Scholar
  • 40 Mahé I, Bertrand N, Drouet L. , et al. Interaction between paracetamol and warfarin in patients: a double-blind, placebo-controlled, randomized study. Haematologica 2006; 91 (12) 1621-1627
    PubMedGoogle Scholar
  • 41 Parra D, Beckey NP, Stevens GR. The effect of acetaminophen on the international normalized ratio in patients stabilized on warfarin therapy. Pharmacotherapy 2007; 27 (05) 675-683
    CrossrefPubMedGoogle Scholar
  • 42 Zhang Q, Bal-dit-Sollier C, Drouet L. , et al. Interaction between acetaminophen and warfarin in adults receiving long-term oral anticoagulants: a randomized controlled trial. Eur J Clin Pharmacol 2011; 67 (03) 309-314
    CrossrefPubMedGoogle Scholar
  • 43 Lopes RD, Horowitz JD, Garcia DA, Crowther MA, Hylek EM. Warfarin and acetaminophen interaction: a summary of the evidence and biologic plausibility. Blood 2011; 118 (24) 6269-6273
    CrossrefPubMedGoogle Scholar
  • 44 Thijssen HH, 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 (04) 797-802
    Article in Thieme ConnectPubMedGoogle Scholar
  • 45 Richens A. Anticonvulsant Drugs and Enzyme Induction. Amsterdam: World Food Programme; 1976
    Google Scholar
  • 46 Kimmel SE, Chen Z, Price M. , et al. The influence of patient adherence on anticoagulation control with warfarin: results from the International Normalized Ratio Adherence and Genetics (IN-RANGE) Study. Arch Intern Med 2007; 167 (03) 229-235
    CrossrefPubMedGoogle Scholar
  • 47 Lurie Y, Loebstein R, Kurnik D, Almog S, Halkin H. Warfarin and vitamin K intake in the era of pharmacogenetics. Br J Clin Pharmacol 2010; 70 (02) 164-170
    CrossrefPubMedGoogle Scholar
  • 48 Kimmel SE. Warfarin therapy: in need of improvement after all these years. Expert Opin Pharmacother 2008; 9 (05) 677-686
    CrossrefPubMedGoogle Scholar
  • 49 Johnson JA, Gong L, Whirl-Carrillo M. , et al; Clinical Pharmacogenetics Implementation Consortium. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011; 90 (04) 625-629
    CrossrefPubMedGoogle Scholar
  • 50 de Abajo FJ. Effects of selective serotonin reuptake inhibitors on platelet function: mechanisms, clinical outcomes and implications for use in elderly patients. Drugs Aging 2011; 28 (05) 345-367
    CrossrefPubMedGoogle Scholar
  • 51 Lin KJ, Hernández-Díaz S, García Rodríguez LA. Acid suppressants reduce risk of gastrointestinal bleeding in patients on antithrombotic or anti-inflammatory therapy. Gastroenterology 2011; 141 (01) 71-79
    CrossrefPubMedGoogle Scholar