Abstract
Using pharmacogenetics-based therapy, clinicians can estimate the therapeutic warfarin dose by genotyping patients for single nucleotide polymorphisms (SNPs) that affect warfarin metabolism or sensitivity. SNPs in the cytochrome P450 complex (CYP2C9) affect warfarin metabolism: patients who have the CYP2C9*2 and/or CYP2C9*3 variants metabolize warfarin slowly and are more likely to have an elevated International Normalized Ratio INR or to hemorrhage during warfarin initiation than patients without these variants. SNPs in vitamin K epoxide reductase (VKORC1) correlate with warfarin sensitivity. Patients who are homozygous for a common VKORC1 promoter polymorphism, −1639 G>A (also designated as VKOR 3673, haplotype A, or haplotype*2), are warfarin sensitive and typically require lower warfarin doses. By providing an estimate of the therapeutic warfarin dose, pharmacogenetics-based therapy may improve the safety of anticoagulant therapy. To improve drug safety, the FDA updates labels of previously approved drugs as new clinical and genetic evidence accrues. The labels of medical products serve to inform prescribers and patients about potential ways to improve the benefit/risk ratio and/or optimize doses of medical products. On August 16, 2007, the FDA updated the label of warfarin to include information on pharmacogenetic testing and to encourage, but not require, the use of this information in dosing individual patients initiating warfarin therapy. The FDA completed the label update in August 2007.
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References
White RH, Beyth RJ, Zhou H, Romano PS (1999) Major bleeding after hospitalization for deep-venous thrombosis. Am J Med 107:414–424
Landefeld SC, Beyth R (1993) Anticoagulant-related bleeding: clinical epidemiology, prediction and prevention. Am J Med 95:315–328
Fihn SD, McDonell M, Martin D et al (1993) Risk factors for complications of chronic anticoagulation. A multicenter study. Ann Intern Med 118:511–520
Douketis JD, Foster GA, Crowther MA, Prins MH, Ginsberg JS (2000) Clinical risk factors and timing of recurrent venous thromboembolism during the initial 3 months of anticoagulant therapy. Arch Intern Med 160:3431–3436
Beyth RJ, Quinn L, Landefeld CS (2000) A multicomponent intervention to prevent major bleeding complications in older patients receiving warfarin. A randomized, controlled trial. Ann Intern Med 133:687–695
Linkins LA, Choi PT, Douketis JD (2003) Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 139:893–900
Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S (2007) Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation. Circulation 115:2689–2696
Hirsh J, Fuster V, Ansell J, Halperin JL (2003) American heart association/american college of cardiology foundation guide to warfarin therapy. Circulation 107:1692–1711
Ezekowitz MD, James KE, Radford MJ, Rickles FR, Redmond N (1999) Initiating and maintaining patients on warfarin anticoagulation: the importance of monitoring. J Cardiovasc Pharmacol Ther 4:3–8
Ansell J, Hirsh J, Dalen J et al (2001) Managing oral anticoagulant therapy. Chest 119:22S–38S
Redman AR (2001) Implications of cytochrome P450 2C9 polymorphism on warfarin metabolism and dosing. Pharmacotherapy 21:235–242
Gage BF, Eby CS (2004) The genetics of vitamin K antagonists. Pharmacogenomics J 4:224–225
Margaglione M, Colaizzo D, D’Andrea G et al (2000) Genetic modulation of oral anticoagulation with warfarin. Thromb Haemost 84:775–778
Gage BF, van Walraven C, Pearce L et al (2004) Selecting patients with atrial fibrillation for anticoagulation: stroke risk stratification in patients taking aspirin. Circulation 110:2287–2292
Taube J, Halsall D, Baglin T (2000) Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment. Blood 96:1816–1819
Loebstein R, Yonath H, Peleg D et al (2001) Interindividual variability in sensitivity to warfarin-nature or nurture? Clin Pharmacol Ther 70:159–164
Sanderson S, Emery J, Higgins J (2005) CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis. Genet Med 7:97–104
Voora D, Eby C, Linder MW et al (2005) Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype. Thromb Haemost 93:700–705
Higashi MK, Veenstra DL, Kondo LM et al (2002) Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 287:1690–1698
Allabi AC, Gala JL, Horsmans Y et al (2004) Functional impact of CYP2C95, CYP2C96, CYP2C98, and CYP2C911 in vivo among black Africans. Clin Pharmacol Ther 76:113–118
Kidd RS, Curry TB, Gallagher S, Edeki T, Blaisdell J, Goldstein JA (2001) Identification of a null allele of CYP2C9 in an African-American exhibiting toxicity to phenytoin. Pharmacogenetics 11:803–808
Li T, Chang CY, Jin DY, Lin PJ, Khvorova A, Stafford DW (2004) Identification of the gene for vitamin K epoxide reductase. Nature 427:541–544
Rost S, Fregin A, Ivaskevicius V et al (2004) Mutations in VKORC1 cause warfarin resistance and multiple coagulation factor deficiency type 2. Nature 427:537–541
Hall JG, Pauli RM, Wilson KM (1980) Maternal and fetal sequelae of anticoagulation during pregnancy. Am J Med 68:122–140
Sugiyama T, Takaki T, Sakanaka K et al (2007) Warfarin-induced impairment of cortical bone material quality and compensatory adaptation of cortical bone structure to mechanical stimuli. J Endocrinol 194:213–222
Gage BF, Birman-Deych E, Radford MJ, Nilasena DS, Binder EF (2006) Risk of osteoporotic fracture in elderly patients taking warfarin: results from the national registry of atrial fibrillation 2. Arch Intern Med 166:241–246
Fennerty A, Dolben J, Thomas P et al (1984) Flexible induction dose regimen for warfarin and prediction of maintenance dose. Br Med J (Clin Res Ed) 288:1268–1270
Harrison L, Johnston M, Massicotte MP, Crowther M, Moffat K, Hirsh J (1997) Comparison of 5-mg and 10-mg loading doses in initiation of warfarin therapy. Ann Intern Med 126:133–136
Gedge J, Orme S, Hampton KK, Channer KS, Hendra TJ (2000) A comparison of a low-dose warfarin induction regimen with the modified Fennerty regimen in elderly inpatients. Age Ageing 29:31–34
O’Connell MB, Kowal PR, Allivato CJ, Repka TL (2000) Evaluation of warfarin initiation regimens in elderly inpatients. Pharmacotherapy 20:923–930
Roberts GW, Druskeit T, Jorgensen LE et al (1999) Comparison of an age adjusted warfarin loading protocol with empirical dosing and Fennerty’s protocol. Aust N Z J Med 29:731–736
Oates A, Jackson PR, Austin CA, Channer KS (1998) A new regimen for starting warfarin therapy in out-patients. Br J Clin Pharmacol 46:157–161
Go AS, Hylek EM, Phillips KA et al (2001) Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study. JAMA 285:2370–2375
Gage BF, Fihn SD, White RH (2001) Warfarin therapy for an octogenarian who has atrial fibrillation. Ann Intern Med 134:465–474
Majeed A, Moser K, Carroll K (2001) Trends in the prevalence and management of atrial fibrillation in general practice in England and Wales, 1994–1998: analysis of data from the general practice research database. Heart 86:284–288
Gurwitz J, Avorn J, Ross-Degnan D, Choodnovskiy I, Ansell J (1992) Aging and the anticoagulant response to warfarin therapy. Ann Intern Med 116:901–904
Ageno W, Squizzato A, Dentali F, Crowther M (2005) Tailoring warfarin induction doses to reflect individual and disease-specific factors. Am J Med 118:143–144
Visser LE, van Vliet M, van Schaik RH et al (2004) The risk of overanticoagulation in patients with cytochrome P450 CYP2C9*2 or CYP2C9*3 alleles on acenocoumarol or phenprocoumon. Pharmacogenetics 14:27–33
Gage BF, Eby C, Banet G, Milligan P, McLeod H (2002) Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin (abstract). J Gen Intern Med 17:111
Steward DJ, Haining RL, Henne KR et al (1997) Genetic association between sensitivity to warfarin and expression of CYP2C9*3. Pharmacogenetics 7:361–367
Takahashi H, Kashima T, Nomoto S et al (1998) Comparisons between in-vitro and in-vivo metabolism of (S)-warfarin: catalytic activities of cDNA-expressed CYP2C9, its Leu359 variant and their mixture versus unbound clearance in patients with the corresponding CYP2C9 genotypes. Pharmacogenetics 8:356–373
Tabrizi AR, Zehnbauer BA, Borecki IB, McGrath SD, Buchman TG, Freeman BD (2002) The frequency and effects of cytochrome P450 (CYP) 2C9 polymorphisms in patients receiving warfarin. J Am Coll Surg 194:267–273
Aithal GP, Day CP, Kesteven PJL, Daly AK (1999) Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 353:717–719
Kaminsky LS, de Morais SM, Faletto MB, Dunbar DA, Goldstein JA (1993) *Correlation of human cytochrome P4502C substrate specificities with primary structure: warfarin as a probe. Mol Pharmacol 43:234–239
Gotoh O (1992) Substrate recognition sites in cytochrome P450 family 2 (CYP2) proteins inferred from comparative analyses of amino acid and coding nucleotide sequences. J Biol Chem 267:83–90
Rieder MJ, Reiner AP, Gage BF et al (2005) Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 352:2285–2293
Marsh S, King CR, Porche-Sorbet RM, Scott-Horton TJ, Eby CS (2006) Population variation in VKORC1 haplotype structure. J Thromb Haemost 4:473–474
Reitsma PH, Heijden JF, Groot AP, Rosendaal FR, Buller HR (2005) A C1173T dimorphism in the VKORC1 gene determines coumarin sensitivity and bleeding risk. PLoS Med 2:e312
Osman A, Enstrom C, Arbring K, Soderkvist P, Lindahl TL (2006) Main haplotypes and mutational analysis of vitamin K epoxide reductase (VKORC1) in a Swedish population: a retrospective analysis of case records. J Thromb Haemost 4:1723–1729
Wadelius M, Chen LY, Downes K et al (2005) Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J 5:262–270
Sconce EA, Khan TI, Wynne HA et al (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
Loebstein R, Dvoskin I, Halkin H et al (2007) A coding VKORC1 Asp36Tyr polymorphism predisposes to warfarin resistance. Blood 109:2477–2480
Shikata E, Ieiri I, Ishiguro S et al (2004) Association of pharmacokinetic (CYP2C9) and pharmacodynamic (vitamin K-dependent protein-Factors II, VII, IX, and X, proteins S and C, and {gamma}-glutamyl carboxylase) gene variants with warfarin sensitivity. Blood 103:2630–2635
Chu K, Wu S, Stanley T, Stafford DW, High K (1996) A mutation in the propeptide of factor IX leads to warfarin sensitivity by a novel mechanism. J Clin Invest 98:1619–1625
Oldenburg J, Quenzel EM, Harbrecht U et al (1997) Missense mutations at ALA-10 in the factor IX propeptide: an insignificant variant in normal life but a decisive cause of bleeding during oral anticoagulant therapy. Br J Haematol 98:240–244
Vecsler M, Loebstein R, Almog S et al (2006) Combined genetic profiles of components and regulators of the vitamin K-dependent gamma-carboxylation system affect individual sensitivity to warfarin. Thromb Haemost 95:205–211
Wadelius M, Sorlin K, Wallerman O et al (2004) Warfarin sensitivity related to CYP2C9, CYP3A5, ABCB1 (MDR1) and other factors. Pharmacogenomics J 4(1):40–48
Millican E, Lenzini P, Milligan P et al (2007) Genetic-based dosing in orthopaedic patients beginning warfarin therapy. Blood 110:1511–1515
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Disclosure: A portion of this article was adapted from an education handout that Dr. Gage has retained copyright of: Gage, B.F. (2006). Pharmacogenetics-based coumarin therapy. Hematology Am Soc Hematol Educ Program: 467–473. Dr. Gage has served as a consultant to Bristol-Myers Squibb.
Funding: NIH R01 HL074724.
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Gage, B.F., Lesko, L.J. Pharmacogenetics of warfarin: regulatory, scientific, and clinical issues. J Thromb Thrombolysis 25, 45–51 (2008). https://doi.org/10.1007/s11239-007-0104-y
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DOI: https://doi.org/10.1007/s11239-007-0104-y