Download PDF
Semin Thromb Hemost 2012; 38(07): 661-666
DOI: 10.1055/s-0032-1326789
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Warfarin Pharmacogenetics: Does More Accurate Dosing Benefit Patients?

Charles Eby
1   Department of Pathology & Immunology, Washington University School of Medicine, St. Louis, Missouri
› Author Affiliations
Further Information

Publication History

Publication Date:
09 October 2012 (online)

    Permissions and Reprints

Abstract

After a decade of clinical investigation, pharmacogenetic-guided initial dosing of warfarin is at a crossroads. Genotypes for two single nucleotide polymorphisms (SNPs) in the cytochrome P 450 2C9 gene, affecting warfarin metabolism, and one SNP in vitamin K reductase complex 1 gene, affecting warfarin sensitivity, account for approximately 30% of therapeutic warfarin dosing variability in whites and Asians. Incorporating this genetic information, along with patient's age, body size, and other clinical information improves the accuracy of initial warfarin dosing. Currently, there is insufficient evidence to support the clinical benefits and cost effectiveness of routine warfarin pharmacogenetics. Results from ongoing international randomized clinical trials should provide clarity about the place of warfarin pharmacogenetics in personalized medicine.

Keywords

warfarin - oral anticoagulant therapy - vitamin K antagonist - pharmacogenetics
 

  • References

  • 1 Witt DM. Approaches to Optimal Dosing of Vitamin K Antagonists. Semin Thromb Hemost 2012; 38 (7) 667-672
    Thieme ConnectPubMedSearch in Google Scholar
  • 2 Lindh JD, Holm L, Dahl ML, Alfredsson L, Rane A. Incidence and predictors of severe bleeding during warfarin treatment. J Thromb Thrombolysis 2008; 25 (2) 151-159
    CrossrefPubMedSearch in Google Scholar
  • 3 Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 2003; 139 (11) 893-900
    CrossrefPubMedSearch in Google Scholar
  • 4 Fihn SD, McDonell M, Martin D , et al; Warfarin Optimized Outpatient Follow-up Study Group. Risk factors for complications of chronic anticoagulation. A multicenter study. Ann Intern Med 1993; 118 (7) 511-520
    CrossrefPubMedSearch in Google Scholar
  • 5 Lubitz SA, Scott SA, Rothlauf EB , et al. Comparative performance of gene-based warfarin dosing algorithms in a multiethnic population. J Thromb Haemost 2010; 8 (5) 1018-1026
    PubMedSearch in Google Scholar
  • 6 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 (1) 54-59
    CrossrefPubMedSearch in Google Scholar
  • 7 Kaminsky LS, Zhang ZY. Human P450 metabolism of warfarin. Pharmacol Ther 1997; 73 (1) 67-74
    CrossrefPubMedSearch in Google Scholar
  • 8 Takahashi H, Echizen H. Pharmacogenetics of warfarin elimination and its clinical implications. Clin Pharmacokinet 2001; 40 (8) 587-603
    CrossrefPubMedSearch in Google Scholar
  • 9 Lee CR, Goldstein JA, Pieper JA. Cytochrome P450 2C9 polymorphisms: a comprehensive review of the in-vitro and human data. Pharmacogenetics 2002; 12 (3) 251-263
    CrossrefPubMedSearch in Google Scholar
  • 10 Marsh S, King CR, Porche-Sorbet RM, Scott-Horton TJ, Eby CS. Population variation in VKORC1 haplotype structure. J Thromb Haemost 2006; 4 (2) 473-474
    CrossrefPubMedSearch in Google Scholar
  • 11 Cavallari LH, Langaee TY, Momary KM , et al. Genetic and Clinical Predictors of Warfarin Dose Requirements in African Americans. Clin Pharmacol Ther 2010; 87: 459-464
    CrossrefPubMedSearch in Google Scholar
  • 12 Rost S, Fregin A, Ivaskevicius V , et al. Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 2004; 427 (6974) 537-541
    CrossrefPubMedSearch in Google Scholar
  • 13 Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW. Identification of the gene for vitamin K epoxide reductase. Nature 2004; 427 (6974) 541-544
    CrossrefPubMedSearch in Google Scholar
  • 14 Rieder MJ, Reiner AP, Gage BF , et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 2005; 352 (22) 2285-2293
    CrossrefPubMedSearch in Google Scholar
  • 15 Yuan HY, Chen JJ, Lee MT , et al. A novel functional VKORC1 promoter polymorphism is associated with inter-individual and inter-ethnic differences in warfarin sensitivity. Hum Mol Genet 2005; 14 (13) 1745-1751
    CrossrefPubMedSearch in Google Scholar
  • 16 Voora D, Koboldt DC, King CR , et al. A polymorphism in the VKORC1 regulator calumenin predicts higher warfarin dose requirements in African Americans. Clin Pharmacol Ther 2010; 87 (4) 445-451
    CrossrefPubMedSearch in Google Scholar
  • 17 King CR, Deych E, Milligan P , et al. Gamma-glutamyl carboxylase and its influence on warfarin dose. Thromb Haemost 2010; 104 (4) 750-754
    Thieme ConnectPubMedSearch in Google Scholar
  • 18 Cooper GM, Johnson JA, Langaee TY , et al. A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose. Blood 2008; 112 (4) 1022-1027
    CrossrefPubMedSearch in Google Scholar
  • 19 Takeuchi F, McGinnis R, Bourgeois S , et al. A genome-wide association study confirms VKORC1, CYP2C9, and CYP4F2 as principal genetic determinants of warfarin dose. PLoS Genet 2009; 5 (3) e1000433
    CrossrefPubMedSearch in Google Scholar
  • 20 Teichert M, Eijgelsheim M, Rivadeneira F , et al. A genome-wide association study of acenocoumarol maintenance dosage. Hum Mol Genet 2009; 18 (19) 3758-3768
    CrossrefPubMedSearch in Google Scholar
  • 21 Caldwell MD, Awad T, Johnson JA , et al. CYP4F2 genetic variant alters required warfarin dose. Blood 2008; 111 (8) 4106-4112
    CrossrefPubMedSearch in Google Scholar
  • 22 Liang R, Wang C, Zhao H, Huang J, Hu D, Sun Y. Influence of CYP4F2 genotype on warfarin dose requirement—a systematic review and meta-analysis. Thromb Res 2012; 130 (1) 38-44
    CrossrefPubMedSearch in Google Scholar
  • 23 McDonald MG, Rieder MJ, Nakano M, Hsia CK, Rettie AE. CYP4F2 is a vitamin K1 oxidase: An explanation for altered warfarin dose in carriers of the V433M variant. Mol Pharmacol 2009; 75 (6) 1337-1346
    CrossrefPubMedSearch in Google Scholar
  • 24 Perera MA, Gamazon E, Cavallari LH , et al. The missing association: sequencing-based discovery of novel SNPs in VKORC1 and CYP2C9 that affect warfarin dose in African Americans. Clin Pharmacol Ther 2011; 89 (3) 408-415
    CrossrefPubMedSearch in Google Scholar
  • 25 Moreau C, Bajolle F, Siguret V , et al. Vitamin K antagonists in children with heart disease: height and VKORC1 genotype are the main determinants of the warfarin dose requirement. Blood 2012; 119 (3) 861-867
    CrossrefPubMedSearch in Google Scholar
  • 26 Biss TT, Avery PJ, Brandão LR , et al. VKORC1 and CYP2C9 genotype and patient characteristics explain a large proportion of the variability in warfarin dose requirement among children. Blood 2012; 119 (3) 868-873
    CrossrefPubMedSearch in Google Scholar
  • 27 Klein TE, Altman RB, Eriksson N , et al; International Warfarin Pharmacogenetics Consortium. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 2009; 360 (8) 753-764
    CrossrefPubMedSearch in Google Scholar
  • 28 Gage BF, Eby C, Johnson JA , et al. Use of pharmacogenetic and clinical factors to predict the therapeutic dose of warfarin. Clin Pharmacol Ther 2008; 84 (3) 326-331
    CrossrefPubMedSearch in Google Scholar
  • 29 Anderson JL, Horne BD, Stevens SM , et al; Couma-Gen Investigators. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation 2007; 116 (22) 2563-2570
    CrossrefPubMedSearch in Google Scholar
  • 30 Lenzini P, Wadelius M, Kimmel S , et al. Integration of genetic, clinical, and INR data to refine warfarin dosing. Clin Pharmacol Ther 2010; 87 (5) 572-578
    CrossrefPubMedSearch in Google Scholar
  • 31 Horne BD, Lenzini PA, Wadelius M , et al. Pharmacogenetic warfarin dose refinements remain significantly influenced by genetic factors after one week of therapy. Thromb Haemost 2012; 107 (2) 232-240
    PubMedSearch in Google Scholar
  • 32 Finkelman BS, Gage BF, Johnson JA, Brensinger CM, Kimmel SE. Genetic warfarin dosing: tables versus algorithms. J Am Coll Cardiol 2011; 57 (5) 612-618
    CrossrefPubMedSearch in Google Scholar
  • 33 Epstein RS, Moyer TP, Aubert RE , et al. Warfarin genotyping reduces hospitalization rates results from the MM-WES (Medco-Mayo Warfarin Effectiveness study). J Am Coll Cardiol 2010; 55 (25) 2804-2812
    CrossrefPubMedSearch in Google Scholar
  • 34 Millican EA, Lenzini PA, Milligan PE , et al. Genetic-based dosing in orthopedic patients beginning warfarin therapy. Blood 2007; 110 (5) 1511-1515
    CrossrefPubMedSearch in Google Scholar
  • 35 Lenzini PA, Grice GR, Milligan PE , et al. Laboratory and clinical outcomes of pharmacogenetic vs. clinical protocols for warfarin initiation in orthopedic patients. J Thromb Haemost 2008; 6 (10) 1655-1662
    CrossrefPubMedSearch in Google Scholar
  • 36 Burmester JK, Berg RL, Yale SH , et al. A randomized controlled trial of genotype-based Coumadin initiation. Genet Med 2011; 13 (6) 509-518
    CrossrefPubMedSearch in Google Scholar
  • 37 Hillman MA, Wilke RA, Yale SH , et al. A prospective, randomized pilot trial of model-based warfarin dose initiation using CYP2C9 genotype and clinical data. Clin Med Res 2005; 3 (3) 137-145
    PubMedSearch in Google Scholar
  • 38 Caraco Y, Blotnick S, Muszkat M. CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study. Clin Pharmacol Ther 2008; 83 (3) 460-470
    CrossrefPubMedSearch in Google Scholar
  • 39 McMillin GA, Melis R, Wilson A , et al. Gene-based warfarin dosing compared with standard of care practices in an orthopedic surgery population: a prospective, parallel cohort study. Ther Drug Monit 2010; 32 (3) 338-345
    CrossrefPubMedSearch in Google Scholar
  • 40 Holbrook A, Schulman S, Witt DM , et al. Evidence-based management of anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST 2012; 141: e152S-84S
    CrossrefPubMedSearch in Google Scholar
  • 41 French B, Joo J, Geller NL , et al; COAG (Clarification of Optimal Anticoagulation through Genetics) Investigators. Statistical design of personalized medicine interventions: the Clarification of Optimal Anticoagulation through Genetics (COAG) trial. Trials 2010; 11: 108
    CrossrefPubMedSearch in Google Scholar
  • 42 Do EJ, Lenzini P, Eby CS , et al. Genetics informatics trial (GIFT) of warfarin to prevent deep vein thrombosis (DVT): rationale and study design. Pharmacogenomics J 2011; . [Epub ahead of print]
    PubMedSearch in Google Scholar
  • 43 van Schie RM, Wadelius MI, Kamali F , et al. Genotype-guided dosing of coumarin derivatives: the European pharmacogenetics of anticoagulant therapy (EU-PACT) trial design. Pharmacogenomics 2009; 10 (10) 1687-1695
    CrossrefPubMedSearch in Google Scholar
  • 44 Anderson JL, Horne BD, Stevens SM , et al. A randomized and clinical effectiveness trial comparing two pharmacogenetic algorithms and standard care for individualizing warfarin dosing (CoumaGen-II). Circulation 2012; 125 (16) 1997-2005
    CrossrefPubMedSearch in Google Scholar
  • 45 Maurice CB, Barua PK, Simses D, Smith P, Howe JG, Stack G. Comparison of assay systems for warfarin-related CYP2C9 and VKORC1 genotyping. Clin Chim Acta 2010; 411 (13-14) 947-954
    CrossrefPubMedSearch in Google Scholar
  • 46 Langley MR, Booker JK, Evans JP, McLeod HL, Weck KE. Validation of clinical testing for warfarin sensitivity: comparison of CYP2C9-VKORC1 genotyping assays and warfarin-dosing algorithms. J Mol Diagn 2009; 11 (3) 216-225
    CrossrefPubMedSearch in Google Scholar
  • 47 King CR, Porche-Sorbet RM, Gage BF , et al. Performance of commercial platforms for rapid genotyping of polymorphisms affecting warfarin dose. Am J Clin Pathol 2008; 129 (6) 876-883
    CrossrefPubMedSearch in Google Scholar
  • 48 Poe BL, Haverstick DM, Landers JP. Warfarin genotyping in a single PCR reaction for microchip electrophoresis. Clin Chem 2012; 58 (4) 725-731
    CrossrefPubMedSearch in Google Scholar
  • 49 Carlquist JF, Anderson JL. Using pharmacogenetics in real time to guide warfarin initiation: a clinician update. Circulation 2011; 124 (23) 2554-2559
    CrossrefPubMedSearch in Google Scholar
  • 50 Schulman S, Crowther MA. How I treat with anticoagulants in 2012: new and old anticoagulants, and when and how to switch. Blood 2012; 119 (13) 3016-3023
    CrossrefPubMedSearch in Google Scholar