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Warfarin drug interactions: a comparative evaluation of the lists provided by five information sources

  • Pharmacoepidemiology and Prescription
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Abstract

Purpose

Detecting potential drug interactions can lead to early interventions that protect patients from serious drug-related problems. The aim of this study was to evaluate the agreement among the lists of warfarin interactions provided by five information sources.

Methods

The lists of warfarin interactions and the corresponding severity ratings and documentation levels presented by the three compendia and by the World Health Organization (WHO) Model Formulary were all compared, and each list was compared to that provided on the package insert of Marevan, a brand of warfarin. The compendia used were: Drug Interaction Facts, Drug Interactions: Analysis and Management and DRUG–REAX. A kappa coefficient was used to calculate the agreement among the sources.

Results

A total of 537 interactions were listed. Only 13 (2.4%) were common to the five sources. The global Fleiss’ kappa coefficient was −0.0080, which indicated poor agreement. Eleven warfarin interactions appeared only in the Marevan package insert. Importantly, 243 interactions (45.3% of the total) were deemed significant in at least one compendium. Only two warfarin interactions were reported as critical by all three compendia and by WHO. The most critical interactions cited by the compendia were missing from the package insert.

Conclusions

Poor agreement was found among five sources listing warfarin interactions. Potentially severe clinical consequences might occur due to these discrepant recommendations. Finally, the lack of standard terminology and clinical guidance, as well as the possible inaccuracy of severity ratings and documentation might contribute to heterogeneous procedures in clinical practice.

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References

  1. Kohn LT, Corrigan JM, Donaldson MS (2000) To err is human: building a safer health system. National Academy Press, Washington D.C.

    Google Scholar 

  2. Raschetti R, Morgutti M, Menniti-Ippolito F, Belisari A, Rossignoli A, Longhini P, La Guidara C (1999) Suspected adverse drug events requiring emergency department visits or hospital admissions. Eur J Clin Pharmacol 54:959–963

    Article  PubMed  CAS  Google Scholar 

  3. Zhan C, Correa-de-Araujo R, Bierman AS, Sangl J, Miller MR, Wickizer SW, Stryer D (2005) Suboptimal prescribing in elderly outpatients: potentially harmful drug-drug and drug-disease combinations. J Am Geriatr Soc 53:262–267

    Article  PubMed  Google Scholar 

  4. Malone DC, Abarca J, Hansten PD, Grizzle AJ, Armstrong EP, Van Bergen RC, Duncan-Edgar BS, Solomon SL, Lipton RB (2004) Identification of serious drug-drug interactions: results of the partnership to prevent drug-drug interactions. J Am Pharm Assoc 44:142–151

    Article  Google Scholar 

  5. Cruciol-Souza JM, Thomson JC (2006) A pharmacoepidemiologic study of drug interactions in a Brazilian teaching hospital. Clinics (Sao Paulo) 61:515–520

    Article  Google Scholar 

  6. Hu TM, Hayton WL (2009) Architecture of the drug–drug interaction network. J Clin Pharm Ther 34:1–9

    Article  Google Scholar 

  7. Stockley IH (2010) Drug interactions. The Pharmaceutical Press, London

    Google Scholar 

  8. Pirmohamed M, James S, Meakin S, Green C, Scott AK, Walley TJ, Farrar K, Park BK, Breckenridge AM (2004) Adverse drug reactions as cause of admission to hospital: prospective analysis of 18 820 patients. Br Med J 329:15–19

    Article  Google Scholar 

  9. Ansell JE, Buttaro ML, Thomas OV, Knowlton CH (1997) Consensus guidelines for coordinated outpatient oral anticoagulation therapy management. Anticoagulation guidelines task force. Ann Pharmacother 31:604–615

    PubMed  CAS  Google Scholar 

  10. Ansell J, Hirsh J, Hylek E, Jacobson A, Crowther M, Palareti G (2008) Pharmacology and management of the vitamin K antagonists: American college of chest physicians evidence-based clinical practice guidelines, 8th edn. Chest 133:160S–198S

    Article  PubMed  CAS  Google Scholar 

  11. Micromedex. Drug–Reax System (2010) Internet database. Available at: http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/hcs.Interactions.WordWheel. Accessed 31 Oct 2010

  12. Hansten PD, Horn JR (2010) Drug interactions analysis & management. Wolters Kluwer, Saint Louis

    Google Scholar 

  13. Hirsh J, Fuster V, Ansell J, Halperin JL, American Heart Association/American College of Cardiology Foundation (2003) American Heart Association/American College of Cardiology Foundation guide to warfarin therapy. J Am Coll Cardiol 41:1633–1652

    Article  PubMed  CAS  Google Scholar 

  14. Lindh JD, Holm L, Andersson ML, Rane A (2009) Influence of CYP2C9 genotype on warfarin dose requirements–a systematic review and meta-analysis. Eur J Clin Pharmacol 65:365–375

    Article  PubMed  CAS  Google Scholar 

  15. Sconce EA, Khan TI, Wynne HA, Avery P, Monkhouse L, King BP, Wood P, Kesteven P, Daly AK, Kamali F (2005) The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 106:2329–2333

    Article  PubMed  CAS  Google Scholar 

  16. Harrington DJ, Gorska R, Wheeler R, Davidson S, Murden S, Morse C, Shearer MJ, Mumford AD (2008) Pharmacodynamic resistance to warfarin is associated with nucleotide substitutions in VKORC1. J Thromb Haemost 6:1663–1670

    Article  PubMed  CAS  Google Scholar 

  17. Klein TE, Altman RB, Eriksson N, Gage BF, Kimmel SE, Lee MT, Limdi NA, Page D, Roden DM, Wagner MJ, Caldwell MD, Johnson JA (2009) Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 360:753–764

    Article  PubMed  Google Scholar 

  18. Muszkat M, Blotnik S, Elami A, Krasilnikov I, Caraco Y (2007) Warfarin metabolism and anticoagulant effect: a prospective, observational study of the impact of CYP2C9 genetic polymorphism in the presence of drug-disease and drug-drug interactions. Clin Ther 29:427–437

    Article  PubMed  CAS  Google Scholar 

  19. Schelleman H, Chen Z, Kealey C, Whitehead AS, Christie J, Price M, Brensinger CM, Newcomb CW, Thorn CF, Samaha FF, Kimmel SE (2007) Warfarin response and vitamin K epoxide reductase complex 1 in African Americans and Caucasians. Clin Pharmacol Ther 81:742–747

    Article  PubMed  CAS  Google Scholar 

  20. Scott SA, Edelmann L, Kornreich R, Desnick RJ (2008) Warfarin pharmacogenetics: CYP2C9 and VKORC1 genotypes predict different sensitivity and resistance frequencies in the Ashkenazi and Sephardi Jewish populations. Am J Hum Genet 82:495–500

    Article  PubMed  CAS  Google Scholar 

  21. Perini JA, Struchiner CJ, Silva-Assuncao E, Santana IS, Rangel F, Ojopi EB, Dias-Neto E, Suarez-Kurtz G (2008) Pharmacogenetics of warfarin: development of a dosing algorithm for brazilian patients. Clin Pharmacol Ther 84:722–728

    Article  PubMed  CAS  Google Scholar 

  22. Oner Ozgon G, Langaee TY, Feng H, Buyru N, Ulutin T, Hatemi AC, Siva A, Saip S, Johnson JA (2008) VKORC1 and CYP2C9 polymorphisms are associated with warfarin dose requirements in Turkish patients. Eur J Clin Pharmacol 64:889–894

    Article  PubMed  CAS  Google Scholar 

  23. Loebstein R, Dvoskin I, Halkin H, Vecsler M, Lubetsky A, Rechavi G, Amariglio N, Cohen Y, Ken-Dror G, Almog S, Gak E (2007) A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance. Blood 109:2477–2480

    Article  PubMed  CAS  Google Scholar 

  24. Limdi NA, McGwin G, Goldstein JA, Beasley TM, Arnett DK, Adler BK, Baird MF, Acton RT (2008) Influence of CYP2C9 and VKORC1 1173C/T genotype on the risk of hemorrhagic complications in African–American and European–American patients on warfarin. Clin Pharmacol Ther 83:312–321

    Article  PubMed  CAS  Google Scholar 

  25. Orensky IA, Holdford DA (2005) Predictors of noncompliance with warfarin therapy in an outpatient anticoagulation clinic. Pharmacotherapy 25:1801–1808

    Article  PubMed  CAS  Google Scholar 

  26. Kaufman DW, Kelly JP, Rosenberg L, Anderson TE, Mitchell AA (2002) Recent patterns of medication use in the ambulatory adult population of the United States: the Slone survey. JAMA 287:337–344

    Article  PubMed  Google Scholar 

  27. Polinski JM, Schneeweiss S, Levin R, Shrank WH (2009) Completeness of retail pharmacy claims data: implications for pharmacoepidemiologic studies and pharmacy practice in elderly patients. Clin Ther 31:2048–2059

    Article  PubMed  Google Scholar 

  28. Fulda TR, Valuck RJ, Zanden JV, Parker S, Byrns PJ (2000) Disagreement among drug compendia on inclusion and ratings of drug–drug interactions. Curr Ther Res 61:540–548

    Article  Google Scholar 

  29. Abarca J, Malone DC, Armstrong EP, Grizzle AJ, Hansten PD, Van Bergen RC, Lipton RB (2004) Concordance of severity ratings provided in four drug interaction compendia. J Am Pharm Assoc 44:136–141

    Article  Google Scholar 

  30. Chao SD, Maibach HI (2005) Lack of drug interaction conformity in commonly used drug compendia for selected at-risk dermatologic drugs. Am J Clin Dermatol 6:105–111

    Article  PubMed  Google Scholar 

  31. Vitry AI (2007) Comparative assessment of four drug interaction compendia. Br J Clin Pharmacol 63:709–714

    Article  PubMed  CAS  Google Scholar 

  32. Wong CM, Ko Y, Chan A (2008) Clinically significant drug–drug interactions between oral anticancer agents and nonanticancer agents: profiling and comparison of two drug compendia. Ann Pharmacother 42:1737–1748

    Article  PubMed  CAS  Google Scholar 

  33. Anthony M, Romero K, Malone DC, Hines LE, Higgins L, Woosley RL (2009) Warfarin interactions with substances listed in drug information compendia and in the FDA-approved label for warfarin sodium. Clin Pharmacol Ther 86:425–429

    Article  PubMed  CAS  Google Scholar 

  34. Olvey EL, Clauschee S, Malone DC (2010) Comparison of critical drug-drug interaction listings: the Department of Veterans Affairs medical system and standard reference compendia. Clin Pharmacol Ther 87:48–51

    Article  PubMed  CAS  Google Scholar 

  35. Wang LM, Wong M, Lightwood JM, Cheng CM (2010) Black box warning contraindicated comedications: concordance among three major drug interaction screening programs. Ann Pharmacother 44:28–34

    Article  PubMed  CAS  Google Scholar 

  36. Tatro DS (2011) Drug interaction facts. Wolters Kluwer, Saint Louis

    Google Scholar 

  37. Stuart MC, Kouimtzi M, Hill SR (eds) (2009) WHO Model Formulary 2008. World Health Organization. Available at http://whqlibdoc.who.int/publications/2009/9789241547659_eng.pdf. Accessed 21 May 2011

  38. Fleiss JL (1971) Measuring nominal scale agreement among many raters. Psychol Bull 76:378–382

    Article  Google Scholar 

  39. Cohen J (1968) Weighted kappa: nominal scale agreement with provision for scaled disagreement or partial credit. Psychol Bull 70:213–220

    Article  PubMed  CAS  Google Scholar 

  40. Landis JR, Koch GG (1977) The measurement of observer agreement for categorical data. Biometrics 33:159–174

    Article  PubMed  CAS  Google Scholar 

  41. Grizzle AJ, Mahmood MH, Ko Y, Murphy JE, Armstrong EP, Skrepnek GH, Jones WN, Schepers GP, Nichol WP, Houranieh A, Dare DC, Hoey CT, Malone DC (2007) Reasons provided by prescribers when overriding drug-drug interaction alerts. Am J Manag Care 13:573–578

    PubMed  Google Scholar 

  42. Levêque D, Lemachatti J, Nivoix Y, Coliat P, Santucci R, Ubeaud-Séquier G, Beretz L, Vinzio S (2010) Mechanisms of pharmacokinetic drug-drug interactions. Rev Med Interne 31:170–179

    Article  PubMed  Google Scholar 

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Acknowledgments

This study was partially supported by the Programa de Pós-Graduação em Ciências da Saúde: Infectologia e Medicina Tropical da Universidade Federal de Minas Gerais. ALP RIBEIRO, MOC ROCHA and CC CÉSAR are fellows of the Conselho Nacional de Desenvolvimento Científico e Tecnológico.

Conflict of interest

The authors state that they have no conflict of interest.

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Authors and Affiliations

  1. Faculdade de Medicina, Hospital das Clínicas, Universidade Federal de Minas Gerais, Av. Prof. Alfredo Balena, 190, Belo Horizonte, MG, 30130-100, Brazil

    Maria A. P. Martins, Daniel D. Ribeiro, Vandack A. Nobre, Manoel O. C. Rocha & Antonio L. P. Ribeiro

  2. Faculdade de Farmácia, Universidade Federal de Minas Gerais, Av. Presidente Antônio Carlos, 6627, Pampulha, Belo Horizonte, MG, 31270-901, Brazil

    Paula P. S. Carlos

  3. Departamento de Estatística, Instituto de Ciências Exatas, Universidade Federal de Minas Gerais, Av. Presidente Antônio Carlos, 6627, Pampulha, Belo Horizonte, MG, 31270-901, Brazil

    Cibele C. César

  4. Rua Campanha 98/101, Carmo, Belo Horizonte, MG, 30.310-770, Brazil

    Antonio L. P. Ribeiro

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  1. Maria A. P. Martins
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Correspondence to Antonio L. P. Ribeiro.

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Martins, M.A.P., Carlos, P.P.S., Ribeiro, D.D. et al. Warfarin drug interactions: a comparative evaluation of the lists provided by five information sources. Eur J Clin Pharmacol 67, 1301–1308 (2011). https://doi.org/10.1007/s00228-011-1086-4

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  • DOI: https://doi.org/10.1007/s00228-011-1086-4

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