Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin

 

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Summary

Knowledge of pharmacogenetics may help clinicians predict their patients’ therapeutic dose of warfarin, thereby decreasing the risk of bleeding during warfarin initiation. Our goal was to use pharmacogenetics to develop an algorithm that uses genetic, clinical, and demographic factors to estimate the warfarin dose a priori. We collected a blood sample, demographic variables, laboratory values, smoking status, names of medications, and dietary history from 369 patients who were taking a maintenance dose of warfarin. Using polymerase chain reaction, we genotyped each participant for the presence of 8 polymorphisms in the cytochrome P450 2C9 system. Using multiple regression, we quantified the association between warfarin dose and all factors. Advanced age, lower body surface area (BSA), and the presence of cytochrome P450 2C9 *2 or *3 single nucleotide polymorphisms were strongly associated (P < 0.001) with lower warfarin dose: the maintenance dose decreased by 8% per decade of age, by 13% per standard deviation decrease in BSA, by 19% per 2C9*2 allele, and by 30% per 2C9*3 allele. Warfarin doses were 29% lower in patients who took amiodarone, 12% lower in patients who took simvastatin, 21% lower in patients whose target INR was 2.5 rather than 3.0, and 11% lower in white rather than African-American participants (P < 0.05 for these comparisons). An algorithm that included these factors and one of borderline significance (sex), explained 39% of the variance in the maintenance warfarin dose. Use of this pharmacogenetic model had potential to prevent patients from being overdosed when initiating warfarin: we estimate that only 24 (6.5%) patients would have been overdosed by >2 mg/day with pharmacogenetic dosing compared to 59 (16%) patients who would have been overdosed if they had been prescribed the empirical dose of 5 mg/day (P < 0.001). In conclusion, the maintenance warfarin dose can be estimated from demographic, clinical, and pharmacogenetic factors that can be obtained at the time of warfarin initiation.

• References

• 1 Evans WE, McLeod HL. Pharmacogenomicsdrug disposition, drug targets, and side effects. N Engl J Med 2003; 348: 538-49.
  CrossrefPubMedGoogle Scholar
• 2 Evans WE, Relling MV. Pharmacogenomics: translating functional genomics into rational therapeutics. Science 1999; 286: 487-91.
  CrossrefPubMedGoogle Scholar
• 3 Phillips K, Veenstra D, Oren E. et al.. Potential role of pharmacogenomics in reducing adverse drug reactions: A systematic review. JAMA 2001; 286: 2270-79.
  CrossrefPubMedGoogle Scholar
• 4 Aithal GP, Day CP, Kesteven PJL. et al.. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 1999; 353: 717-9.
  CrossrefPubMedGoogle Scholar
• 5 Takahashi H, Kashima T, Nomizo Y. et al.. Metabolism of warfarin enantiomers in Japanese patients with heart disease having different CYP2C9 and CYP2C19 genotypes. Clin Pharmacol Ther 1998; 63: 519-28.
  CrossrefPubMedGoogle Scholar
• 6 Furuya H, Fernandez-Salguero P, Gregory W. et al.. Genetic polymorphism of CYP2C9 and its effect on warfarin maintenance dose requirement in patients undergoing anticoagulation therapy. Pharmacogenetics 1995; 05: 389-92.
  CrossrefPubMedGoogle Scholar
• 7 Stubbins MJ, Harries LW, Smith G. et al.. Genetic analysis of the human cytochrome P450 CYP2C9 locus. Pharmacogenetics 1996; 06: 429-39.
  CrossrefPubMedGoogle Scholar
• 8 Yamazaki H, Inoue K, Shimada T. Roles of two allelic variants (Arg144Cys and Ile359Leu) of cytochrome P4502C9 in the oxidation of tolbutamide and warfarin by human liver microsomes. Xenobiotica 1998; 28: 103-15.
  CrossrefPubMedGoogle Scholar
• 9 Rogers JF, Nafziger AN, Bertino J. et al.. Pharmacogenetics affects dosing, efficacy, and toxicity of cytochrome P450-metabolized drugs. The American Journal of Medicine 2002; 113: 746-50.
  CrossrefPubMedGoogle Scholar
• 10 Margaglione M, Colaizzo D, D’Andrea G. et al.. Genetic modulation of oral anticoagulation with warfarin. Thromb Haemost 2000; 84: 775-8.
  Article in Thieme ConnectPubMedGoogle Scholar
• 11 Taube J, Halsall D, Baglin T. Influence of cytochrome P-450 CYP2C9 polymorphisms on warfarin sensitivity and risk of over-anticoagulation in patients on long-term treatment. Blood 2000; 96: 1816-9.
  PubMedGoogle Scholar
• 12 Loebstein R, Yonath H, Peleg D. et al.. Interindividual variability in sensitivity to warfarin-Nature or nurture?. Clin Pharmacol Ther 2001; 70: 159-64.
  CrossrefPubMedGoogle Scholar
• 13 Higashi MK, Veenstra DL, Kondo LM. et al.. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. JAMA 2002; 287: 1690-8.
  CrossrefPubMedGoogle Scholar
• 14 Imai J, Ieiri I, Mamiya K. et al.. Polymorphism of the cytochrome P450 (CYP) 2C9 gene in Japanese epileptic patients: genetic analysis of the CYP2C9 locus. Pharmacogenetics 2000; 10: 85-9.
  CrossrefPubMedGoogle Scholar
• 15 Dickmann LJ, Rettie AE, Kneller MB. et al.. Identification and Functional Characterization of a New CYP2C9 Variant (CYP2C9*5) Expressed among African Americans. Mol Pharmacol 2001; 60: 382-7.
  CrossrefPubMedGoogle Scholar
• 16 Leung AY, Chow HC, Kwong YL. et al.. Genetic polymorphism in exon 4 of cytochrome P450 CYP2C9 may be associated with warfarin sensitivity in Chinese patients. Blood 2001; 98: 2584-7.
  CrossrefPubMedGoogle Scholar
• 17 White RH, Beyth RJ, Zhou H. et al.. Major bleeding after hospitalization for deep-venous thrombosis. Am J Med 1999; 107: 414-24.
  CrossrefPubMedGoogle Scholar
• 18 Landefeld SC, Beyth R. Anticoagulant-related bleeding: Clinical epidemiology, prediction and prevention. Am J Med 1993; 95: 315-28.
  CrossrefPubMedGoogle Scholar
• 19 Fihn SD, McDonell M, Martin D. et al.. Risk factors for complications of chronic anticoagulation. A multicenter study. Ann Intern Med 1993; 118: 511-20.
  CrossrefPubMedGoogle Scholar
• 20 Douketis JD, Foster GA, Crowther MA. et al.. Clinical Risk Factors and Timing of Recurrent Venous Thromboembolism During the Initial 3 Months of Anticoagulant Therapy. Arch Intern Med 2000; 160: 3431-6.
  CrossrefPubMedGoogle Scholar
• 21 Beyth RJ, Quinn L, Landefeld CS. A Multicomponent Intervention To Prevent Major Bleeding Complications in Older Patients Receiving Warfarin. A Randomized, Controlled Trial. Ann Intern Med 2000; 133: 687-95.
  CrossrefPubMedGoogle Scholar
• 22 Gurwitz J, Avorn J, Ross-Degnan D. et al.. Aging and the anticoagulant response to warfarin therapy. Ann Intern Med 1992; 116: 901-4.
  CrossrefPubMedGoogle Scholar
• 23 Routledge P, Chapman P, Davies D. et al.. Factors affecting warfarin requirements: a prospective population study. Eur J Clin Pharmacol 1979; 15: 319-22.
  CrossrefPubMedGoogle Scholar
• 24 Absher RK, Moore ME, Parker MH. Patientspecific factors predictive of warfarin dosage requirements. Ann Pharmacother 2002; 36: 1512-7.
  CrossrefPubMedGoogle Scholar
• 25 Blann A, Hewitt J, Siddiqui F. et al.. Racial background is a determinant of average warfarin dose required to maintain the INR between 2.0 and 3.0. Br J Haematol 1999; 107: 207-9.
  CrossrefPubMedGoogle Scholar
• 26 Garten S, Wosilait WD. Comparative study of the binding of coumarin anticoagulants and serum albumins. Biochem Pharmacol 1971; 20: 1661-8.
  CrossrefPubMedGoogle Scholar
• 27 Mungall DR, Ludden TM, Marshall J. et al.. Population kinetics of racemic warfarin. Journal of Pharmacokinetics and Biopharmaceutics 1985; 13: 213-27.
  CrossrefPubMedGoogle Scholar
• 28 James AH, Britt RP, Raskino CL. et al.. Factors affecting the maintenance dose of warfarin. J Clin Pathol 1992; 45: 704-6.
  CrossrefPubMedGoogle Scholar
• 29 Ristola P, Pyorala K. Determinants of the response to coumarin anticoagulants in patients with acute myocardial infarction. Acta Med Scand 1972; 192: 183-8.
  PubMedGoogle Scholar
• 30 Fergusson RJ, Eade OE, Logie AW. et al.. A flexible loading dose schedule for warfarin therapy. Scott Med J 1987; 32: 169-71.
  CrossrefPubMedGoogle Scholar
• 31 Gage BF, Fihn SD, White RH. Management and dosing of warfarin therapy. Am J Med 2000; 109: 481-8.
  CrossrefPubMedGoogle Scholar
• 32 Shibata Y, Hashimoto H, Kurata C. et al.. Influence of physical activity on warfarin therapy. Thromb Haemost 1998; 80: 203-4.
  Article in Thieme ConnectPubMedGoogle Scholar
• 33 Lubetsky A, Dekel-Stern E, Chetrit A. et al.. Vitamin K intake and sensitivity to warfarin in patients consuming regular diets. Thromb Haemost 1999; 81: 396-9.
  Article in Thieme ConnectPubMedGoogle Scholar
• 34 Cushman M, Booth SL, Possidente CJ. et al.. The association of vitamin K status with warfarin sensitivity at the onset of treatment. Br J Haematol 2001; 112: 572-7.
  CrossrefPubMedGoogle Scholar
• 35 Ronaghi M, Uhlen M, Nyren P. A sequencing method based on real-time pyrophosphate. Science 1998; 281: 363-5.
  CrossrefPubMedGoogle Scholar
• 36 Ronaghi M. Pyrosequencing sheds light on DNA sequencing. Genome Res 2001; 11: 3-11.
  CrossrefPubMedGoogle Scholar
• 37 Schechtman KB, Barzilai B, Rost K. et al.. Measuring physical activity with a single question. Am J Public Health 1991; 81: 771-3.
  CrossrefPubMedGoogle Scholar
• 38 DuBois D, DuBois E. Clinical Calorimetry; a formula to estimate the approximate surface area if height and weight be known. Arch Int med 1916; 17: 863-71.
  PubMedGoogle Scholar
• 39 Chan K, Lo AC, Yeung JH. et al.. The effects of Danshen (Salvia miltiorrhiza) on warfarin pharmacodynamics and pharmacokinetics of warfarin enantiomers in rats. J Pharm Pharmacol 1995; 47: 402-6.
  CrossrefPubMedGoogle Scholar
• 40 Page 2nd RL, Lawrence JD. Potentiation of warfarin by dong quai. Pharmacotherapy 1999; 19: 870-6.
  CrossrefPubMedGoogle Scholar
• 41 Booth SL, Centurelli MA. Vitamin K: a practical guide to the dietary management of patients on warfarin. Nutr Rev 1999; 57: 288-96.
  PubMedGoogle Scholar
• 42 Raschke R, Reilly B, Guidry J. et al.. Weightbased heparin dosing nomogram compared with a “standard care” nomogram. Ann Intern Med 1993; 119: 874-81.
  CrossrefPubMedGoogle Scholar
• 43 Efron B, Tibshirani R. An introduction to the bootstrap. 57 vol New York: Chapman & Hall; 1993
  Google Scholar
• 44 Mooney CZ, Duval RD. Bootstrapping: A Nonparametric Approach to Statistical Inference. Newbury Park, CA: Sage Publications, Inc; 1993
  Google Scholar
• 45 Goldford M, Backus J, Triscott M. Solid phase genotyping of the warfarin metabolizing enzyme CYP2C9 with DNA probes [abstract]. Thromb Haemost 2001; July Supp: 674.
  PubMedGoogle Scholar
• 46 Palareti G, Manotti C, DA A. et al.. Thrombotic events during oral anticoagulant treatment: results of the inception-cohort, prospective, collaborative ISCOAT study: ISCOAT study group (Italian Study on Complications of Oral Anticoagulant Therapy). Thromb Haemost 1997; 78: 1438-43.
  Article in Thieme ConnectPubMedGoogle Scholar
• 47 AGS Clinical Practice Committee. The use of oral anticoagulants (warfarin) in older people. AGS Clinical Practice Committee. J Am Geriatr Soc 1996; 44: 1112-3.
  PubMedGoogle Scholar
• 48 Ezekowitz MD, James KE, Radford MJ. et al.. Initiating and maintaining patients on warfarin anticoagulation: the importance of monitoring. J Cardiovasc Pharmacol Ther 1999; 04: 3-8.
  CrossrefPubMedGoogle Scholar
• 49 Ansell J, Hirsh J, Dalen J. et al.. Managing oral anticoagulant therapy. Chest 2001; 119: 22S-38S.
  CrossrefPubMedGoogle Scholar
• 50 Horton JD, Bushwick BM. Warfarin therapy: evolving strategies in anticoagulation. Am Fam Physician 1999; 59: 635-46.
  PubMedGoogle Scholar
• 51 Gunnarsson PS, Sawyer WT, Montague D. et al.. Appropriate use of heparin. Empiric vs nomogram-based dosing. Arch Intern Med 1995; 155: 526-32.
  CrossrefPubMedGoogle Scholar
• 52 Wynne H, Cope L, Kelly P. et al.. The influence of age, liver size and enantiomer concentrations on warfarin requirements. Br J Clin Pharmacol 1995; 40: 203-7.
  PubMedGoogle Scholar
• 53 Shepherd AM, Hewick DS, Moreland TA. et al.. Age as a determinant of sensitivity to warfarin. Br J Clin Pharmacol 1977; 04: 315-20.
  CrossrefPubMedGoogle Scholar
• 54 Fennerty A, Dolben J, Thomas P. et al.. Flexible induction dose regimen for warfarin and prediction of maintenance dose. Br Med J (Clin Res Ed) 1984; 288: 1268-70.
  CrossrefPubMedGoogle Scholar
• 55 Gedge J, Orme S, Hampton KK. et al.. A comparison of a low-dose warfarin induction regimen with the modified Fennerty regimen in elderly inpatients. Age Ageing 2000; 29: 31-4.
  CrossrefPubMedGoogle Scholar
• 56 Gladman JR, Dolan G. Effect of age upon the induction and maintenance of anticoagulation with warfarin. Postgrad Med J 1995; 71: 153-5.
  CrossrefPubMedGoogle Scholar
• 57 Roberts GW, Druskeit T, Jorgensen LE. et al.. Comparison of an age adjusted warfarin loading protocol with empirical dosing and Fennerty’s protocol. Aust N Z J Med 1999; 29: 731-6.
  CrossrefPubMedGoogle Scholar
• 58 Rettie AE, Tai G, Veenstra DL. et al.. CYP2C9 exon 4 mutations and warfarin dose phenotype in Asians. Blood 2003; 101: 2896-7.
  CrossrefPubMedGoogle Scholar
• 59 Zarza J, Hermida J, Montes R. et al.. Leu208Val and Ile181Leu variants of cytochrome P450 CYP2C9 are not related to the acenocoumarol dose requirement in a Spanish population. Blood 2002; 100: 734.
  CrossrefPubMedGoogle Scholar
• 60 Sanoski CA, Bauman JL. Clinical observations with the Amiodarone/Warfarin Interaction: Dosing relationships with long-term therapy. Chest 2002; 121: 19-23.
  CrossrefPubMedGoogle Scholar
• 61 Harrell Jr FE, Lee KL, Mark DB. Multivariable prognostic models: issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med 1996; 15: 361-87.
  CrossrefPubMedGoogle Scholar
• 62 Ageno W, Turpie AG. Exaggerated initial response to warfarin following heart valve replacement. Am J Cardiol 1999; 84: 905-8.
  CrossrefPubMedGoogle Scholar
• 63 Kidd RS, Curry TB, Gallagher S. et al.. Identification of a null allele of CYP2C9 in an African-American exhibiting toxicity to phenytoin. Pharmacogenetics 2001; 11: 803-8.
  CrossrefPubMedGoogle Scholar
• 64 Harrison L, Johnston M, Massicotte MP. et al.. Comparison of 5-mg and 10-mg loading doses in initiation of warfarin therapy. Ann Intern Med 1997; 126: 133-6.
  CrossrefPubMedGoogle Scholar
• 65 Hylek EM, Singer D. Risk factors for intracranial hemorrhage in outpatients taking warfarin. Ann Intern Med 1994; 120: 897-902.
  CrossrefPubMedGoogle Scholar
• 66 Hiratsuka M, Agatsuma Y, Mizugaki M. Rapid detection of CYP2C9*3 alleles by real-time fluorescence PCR based on SYBR Green. Mol Genet Metab 1999; 68: 357-62.
  CrossrefPubMedGoogle Scholar