Journal of Thrombosis and Thrombolysis

, Volume 30, Issue 2, pp 220–225 | Cite as

Accuracy assessment of pharmacogenetically predictive warfarin dosing algorithms in patients of an academic medical center anticoagulation clinic

  • Paul B. Shaw
  • Jennifer L. Donovan
  • Maichi T. Tran
  • Stephenie C. Lemon
  • Pamela Burgwinkle
  • Joel Gore


The objectives of this retrospective cohort study are to evaluate the accuracy of pharmacogenetic warfarin dosing algorithms in predicting therapeutic dose and to determine if this degree of accuracy warrants the routine use of genotyping to prospectively dose patients newly started on warfarin. Seventy-one patients of an outpatient anticoagulation clinic at an academic medical center who were age 18 years or older on a stable, therapeutic warfarin dose with international normalized ratio (INR) goal between 2.0 and 3.0, and cytochrome P450 isoenzyme 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) genotypes available between January 1, 2007 and September 30, 2008 were included. Six pharmacogenetic warfarin dosing algorithms were identified from the medical literature. Additionally, a 5 mg fixed dose approach was evaluated. Three algorithms, Zhu et al. (Clin Chem 53:1199–1205, 2007), Gage et al. (J Clin Ther 84:326–331, 2008), and International Warfarin Pharmacogenetic Consortium (IWPC) (N Engl J Med 360:753–764, 2009) were similar in the primary accuracy endpoints with mean absolute error (MAE) ranging from 1.7 to 1.8 mg/day and coefficient of determination R2 from 0.61 to 0.66. However, the Zhu et al. algorithm severely over-predicted dose (defined as ≥2× or ≥2 mg/day more than actual dose) in twice as many (14 vs. 7%) patients as Gage et al. 2008 and IWPC 2009. In conclusion, the algorithms published by Gage et al. 2008 and the IWPC 2009 were the two most accurate pharmacogenetically based equations available in the medical literature in predicting therapeutic warfarin dose in our study population. However, the degree of accuracy demonstrated does not support the routine use of genotyping to prospectively dose all patients newly started on warfarin.


Warfarin Pharmacogenetics Pharmacogenomics Genotype 


  1. 1.
    Lamb E (May 2009) Top 200 drugs of 2008. Pharmacy Times web site. Accessed June 14, 2009
  2. 2.
    Gage BF, Eby C, Johnson JA et al (2008) Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. J Clin Ther 84:326–331CrossRefGoogle Scholar
  3. 3.
    Kaminsky LS, Zhang ZY (1997) Human P450 metabolism of warfarin. Pharmacol Ther 73:67–74CrossRefPubMedGoogle Scholar
  4. 4.
    Higashi MK, Veenstra DL, Kondo LM et al (2002) Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 287:1690–1698CrossRefPubMedGoogle Scholar
  5. 5.
    Reider MJ, Reiner AP, Gage BF et al (2005) Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 352:2285–2293CrossRefGoogle Scholar
  6. 6.
    Bristol-Myers Squibb Company. COUMADIN [warfarin] package insert. Princeton, NJ; August 2007Google Scholar
  7. 7.
    Gage BF, Eby C, Milligan PE et al (2004) Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin. Thromb Haemost 91:87–94PubMedGoogle Scholar
  8. 8.
    Sconce EA, Khan TI, Wynn HA et al (2005) The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics on warfarin dose requirements: proposal for a new dosing regimen. Blood 106:2329–2333CrossRefPubMedGoogle Scholar
  9. 9.
    Zhu Y, Shennan M, Reynolds KK et al (2007) Estimation of warfarin maintenance dose based on VKORC1 (-1639G>A) and CYP2C9 genotypes. Clin Chem 53:1199–1205CrossRefPubMedGoogle Scholar
  10. 10.
    Wadelius M, Chen LY, Lindh JD et al (2008) The largest prospective warfarin-treated cohort supports genetic forecasting. Blood 113:784–792CrossRefPubMedGoogle Scholar
  11. 11.
    International Warfarin Pharmacogenetics Consortium (2009) Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 360:753–764CrossRefGoogle Scholar
  12. 12.
    Voora D, Eby C, Linder MW et al (2005) Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype. Thromb Haemost 93:700–705PubMedGoogle Scholar
  13. 13.
    Kangelaris KN, Bent S, Nussbaum RL et al (2009) Genetic testing before anticoagulation? A systematic review of pharmacogenetic dosing of warfarin. J Gen Intern Med 24:656–664CrossRefPubMedGoogle Scholar
  14. 14.
    Eckman MH, Rosand J, Greenberg SM et al (2009) Cost-effectiveness of using pharmacogenetic information in warfarin dosing for patients with nonvalvular atrial fibrillation. Ann Intern Med 150:73–83PubMedGoogle Scholar
  15. 15.
    Anderson JL, Horne BD, Stevens SM et al (2007) Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation 116:2563–2570CrossRefPubMedGoogle Scholar
  16. 16.
    Lindh JD, Lungren S, Holm L et al (2005) Several-fold increase in risk of overanticoagulation by CYP2C9 mutations. Clin Pharmacol Ther 78:540–550CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Paul B. Shaw
    • 1
    • 2
  • Jennifer L. Donovan
    • 3
  • Maichi T. Tran
    • 4
  • Stephenie C. Lemon
    • 5
  • Pamela Burgwinkle
    • 6
  • Joel Gore
    • 7
  1. 1.Pharmacy Specialty Resident—CardiologyUMass Memorial Medical CenterWorcesterUSA
  2. 2.Clinical Pharmacy Specialist—CardiologyKaiser Permanente of ColoradoLafayetteUSA
  3. 3.Massachusetts College of Pharmacy and Health SciencesWorcesterUSA
  4. 4.Cardiovascular ServicesUMass Memorial Medical CenterWorcesterUSA
  5. 5.Division of Preventive and Behavioral MedicineUniversity of Massachusetts Medical SchoolWorcesterUSA
  6. 6.Anticoagulation CenterUMass Memorial Medical CenterWorcesterUSA
  7. 7.Division of Cardiovascular MedicineUMass Memorial Medical CenterWorcesterUSA

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