Download PDF
Thromb Haemost 2012; 107(06): 1083-1091
DOI: 10.1160/TH11-12-0848
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

A new algorithm to predict warfarin dose from polymorphisms of CYP4F2, CYP2C9 and VKORC1 and clinical variables: Derivation in Han Chinese patients with non valvular atrial fibrillation

Meng Wei
1   Department of Clinical Pharmacology, Nanjing First Hospital Affiliated to Nanjing Medical University, and Nanjing Cardiovascular Hospital, Nanjing, Jiangsu, China
3   Department of Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
,
Fei Ye
2   Department of Cardiology, Nanjing First Hospital Affiliated to Nanjing Medical University, and Nanjing Cardiovascular Hospital, Nanjing, Jiangsu, China
,
Dujiang Xie
2   Department of Cardiology, Nanjing First Hospital Affiliated to Nanjing Medical University, and Nanjing Cardiovascular Hospital, Nanjing, Jiangsu, China
,
Yubing Zhu
1   Department of Clinical Pharmacology, Nanjing First Hospital Affiliated to Nanjing Medical University, and Nanjing Cardiovascular Hospital, Nanjing, Jiangsu, China
,
Junrong Zhu
1   Department of Clinical Pharmacology, Nanjing First Hospital Affiliated to Nanjing Medical University, and Nanjing Cardiovascular Hospital, Nanjing, Jiangsu, China
,
Yifu Tao
1   Department of Clinical Pharmacology, Nanjing First Hospital Affiliated to Nanjing Medical University, and Nanjing Cardiovascular Hospital, Nanjing, Jiangsu, China
,
Feng Yu
3   Department of Clinical Pharmacy, China Pharmaceutical University, Nanjing, China
› Author Affiliations Financial support: This study was supported by a grant from Nanjing Technologies R&D Program (No. 2011YX002) and Key Technologies R&D Program of Nanjing Medical University (No. 2011NJMU202).
Further Information

Publication History

Received: 12 December 2011

Accepted after major revision: 14 March 2012

Publication Date:
29 November 2017 (online)

Also available at
    Permissions and Reprints

Summary

Few pharmacogenomic dosing regimens of warfarin have been developed for Chinese patients with non valvular atrial fibrillation (NVAF). The objective of this study was to develop a new algorithm by polymorphisms of CYP2C9, VKORC1 and CYP4F2 to predict the daily stable dose of warfarin in Chinese patients with NVAF. A total of 325 Chinese NVAF patients on stable dose of warfarin with a target international normalised ratio of 1.5 to 3.0 were recruited and divided randomly into two cohorts. CYP2C9*3, VKORC1 –1639, VKORC1 1173 and CYP4F2 were detected by ligase detection reaction method. The new algorithm was developed with multivariate linear regression in cohort 1 (260 patients) and assessed with Pearson Correlation Analysis (PCA) in cohort 2 (65 patients). From 260 enrolled patients, the model (R2 = 51.7%) was developed as: Dose = 3.47 − 0.022 (AGE) + 0.017 (WT) + 0.189 (PTE) − 0.283 (β-blocker) − 0.471 (AMIO) − 0.586 (CYP2C9 *1/*3) − 0.296 (VKORC1 CT) – 0.648 (VKORC1 TT) + 0.219 (CYP4F2 TT). PCA displayed that the algorithm was good (r = 0.658). The residual plots revealed that the predicted doses by the algorithm tend to be overestimated when lower doses were administered to patients and to be underestimated in higher doses. The algorithm developed by us might predict warfarin dose used by Chinese NVAF patients.

Keywords

Warfarin - Chinese - non valvular atrial fibrillation - pharmacogenetics - dosing algorithm

 

  • References

  • 1 Stroke Prevention in Atrial Fibrillation Investigators. Bleeding during antithrombotic therapy in patients with atrial fibrillation. Arch Intern Med 1996; 156: 409-416.
    CrossrefPubMedGoogle Scholar
  • 2 Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose warfarin versus low-intensity, fixed dose warfarin plus aspirin for high risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet 1996; 348: 633-638.
    CrossrefPubMedGoogle Scholar
  • 3 Yang LM, Ge WH, Yu F. et al. Impact of VKORC1 gene polymorphism on interindividual and interethnic warfarin dosage requirement – A systematic review and meta analysis. Thromb Res 2010; 125: e159-e166.
    CrossrefPubMedGoogle Scholar
  • 4 Perlstein TS, Goldhaber SZ, Nelson K. et al. The Creating an Optimal Warfarin Nomogram (CROWN) Study). Thromb Haemost 2012; 107: 59-68.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 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: 232-240.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Namazi S, Azarpira N, Hendijani F. et al. The impact of genetic polymorphisms and patient characteristics on warfarin dose requirements: a cross-sectional study in Iran. Clin Ther 2010; 32: 1050-1060.
    CrossrefPubMedGoogle Scholar
  • 7 Luxembourg B, Luxembourg K, Sittinger K. et al. Impact of pharmacokinetic (CYP2C9) and pharmacodynamic (VKORC1, F7, GGCX, CALU, EPHX1) gene variants on the initiation and maintenance phases of phenprocoumon therapy. Thromb Haemost 2011; 105: 169-180.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 8 Lee CR. CYP2C9 genotype as a predictor of drug disposition in humans. Methods Find Exp Clin Pharmacol 2004; 26: 463-472.
    PubMedGoogle Scholar
  • 9 Aquilante CL, Langaee TY, Lopez LM. et al. Influence of coagulation factor, vitamin K epoxide reductase complex subunit 1, and cytochrome P450 2C9 gene polymorphisms on warfarin dose requirements. Clin Pharmacol Ther 2006; 79: 291-302.
    CrossrefPubMedGoogle Scholar
  • 10 Wu AH, Wang P, Smith A. et al. Dosing algorithm for warfarin using CYP2C9 and VKORC1 genotyping from a multi-ethnic population: comparison with other equations. Pharmacogenomics 2008; 9: 169-178.
    CrossrefPubMedGoogle Scholar
  • 11 Sanderson S, Emery J, Higgins J. CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis. Genet Med 2005; 7: 97-104.
    CrossrefPubMedGoogle Scholar
  • 12 Lindh JD, Holm L, Andersson ML. et al. Influence of CYP2C9 genotype onwarfa-rin dose requirements-a systematic review and meta-analysis. Eur J Clin Pharmacol 2009; 65: 365-375.
    CrossrefPubMedGoogle Scholar
  • 13 Gage BF, Eby C, Milligan PE. et al. Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin. Thromb Haemost 2004; 91: 87-94.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 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: 137-145.
    CrossrefPubMedGoogle Scholar
  • 15 Voora D, McLeod HL, Eby C. et al. The pharmacogenetics of coumarin therapy. Pharmacogenomics 2005; 6: 503-513.
    CrossrefPubMedGoogle Scholar
  • 16 Dumas TE, Hawke RL, Lee CR. Warfarin dosing and the promise of pharmacogenomics. Curr Clin Pharmacol 2007; 2: 11-21.
    CrossrefPubMedGoogle Scholar
  • 17 Rieder MJ, Reiner AP, Gage BF. et al. Effect of VKORC1 haplotypes on transcriptional regulation and warfarin dose. N Engl J Med 2005; 352: 2285-2293.
    CrossrefPubMedGoogle Scholar
  • 18 Veenstra DL, You JH, Rieder MJ. et al. Association of VitaminK epoxide reductase complex 1 (VKORC1) variants with warfarin dose in a Hong Kong Chinese patient population. Pharmacogenet Genomics 2005; 15: 687-691.
    CrossrefPubMedGoogle Scholar
  • 19 Miao L, Yang J, Huang C. et al. Contribution of age, body weight, and CYP2C9 and VKORC1 genotype to the anticoagulant response to warfarin: proposal for a new dosing regimen in Chinese patients. Eur J Clin Pharmacol 2007; 63: 1135-1141.
    CrossrefPubMedGoogle Scholar
  • 20 Caldwell MD, Berg RL, Zhang KQ. et al. Evaluation of genetic factors for warfarin dose prediction. Clin Med Res 2007; 5: 8-16.
    CrossrefPubMedGoogle Scholar
  • 21 McDonald MG, Rieder MJ, Nakano M. et al. CYP4F2 is a vitamin K1 oxidase: an explanation for altered warfarin dose in carriers of the V433m variant. Mol Pharmacol 2009; 75: 1337-1346.
    CrossrefPubMedGoogle Scholar
  • 22 Caldwell MD, Awad T, Johnson JA. et al. CYP4F2 genetic variant alters required warfarin dose. Blood 2008; 111: 4106-4112.
    CrossrefPubMedGoogle Scholar
  • 23 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: e1000433.
    CrossrefPubMedGoogle Scholar
  • 24 Wells PS, Majeed H, Kassem S. et al. A regression model to predict warfarin dose from clinical variables and polymorphisms in CYP2C9, CYP4F2, and VKORC1: Derivation in a sample with predominantly a history of venous thromboembolism. Thromb Res 2010; 125: e259-e264.
    CrossrefPubMedGoogle Scholar
  • 25 Cen HJ, Zeng WT, Leng XY. et al. CYP4F2 rs2108622: a minor significant genetic factor of warfarin dose in Han Chinese patients with mechanical heart valve replacement. Br J Clin Pharmacol 2010; 70: 234-240.
    CrossrefPubMedGoogle Scholar
  • 26 Lip GYH, Andreotti F, Fauchier L. et al. Bleeding risk assessment and management in atrial fibrillation patients Executive Summary of a Position Document from the European Heart Rhythm Association [EHRA], endorsed by the European Society of Cardiology [ESC] Working Group on Thrombosis. Thromb Haemost 2011; 106: 993-1234.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Sanoski CA, Bauman JL. Clinical observations with the amiodarone/warfarin interaction: dosing relationships with long-term therapy. Chest 2002; 121: 19-23.
    CrossrefPubMedGoogle 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: 326-331.
    CrossrefPubMedGoogle Scholar
  • 29 Meijer K, Kim YK, Carter D. et al. A prospective study of an aggressive warfarin dosing algorithm to reach and maintain INR 2 to 3 after heart valve surgery. Thromb Haemost 2011; 105: 232-238.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Sun YH, Hu DY. The efficiency and safety of anticoagulation therapy in atrial fibrillation in Chinese. Clin J Intern Med 2004; 43: 258-260.
    PubMedGoogle Scholar
  • 31 Pengo V, Cucchini U, Denas G. et al. Lower versus standard intensity oral anticoagulant therapy (OAT) in elderly warfarin-experienced patients with non-valvular atrial fibrillation. Thromb Haemost 2010; 103: 442-449.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Lane DA, Lip GYH. Anticoagulation intensity for elderly atrial fibrillation patients: Should we use a conventional INR target (2.0 – 3.0) or a lower range?. Thromb Haemost 2010; 103: 254-256.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Wann LS, January CT, Lowe JE. et al. 2011 ACCF/AHA/HRS Focused Update on the Management of Patients With Atrial Fibrillation. Circulation 2011; 123: 104-123.
    CrossrefPubMedGoogle Scholar
  • 34 The International HapMap Consortium. The International HapMap Project. Nature 2003; 426: 789-796.
    CrossrefPubMedGoogle Scholar
  • 35 Camm AJ, Kirchhof P, Lip GY. et al. Guidelines for the management of atrial fibrillation:the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010; 31: 2369-2429.
    CrossrefPubMedGoogle Scholar
  • 36 Apostolakis S, Lip GYH. Stroke prevention in non-valvular atrial fibrillation: Can warfarin do better?. Thromb Haemost 2011; 106: 753-754.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 Ogilvie LM, Welner SA, Cowell W. et al. Ischaemic stroke and bleeding rates in ‘real-world’ atrial fibrillation patients. Thromb Haemost 2011; 106: 34-44.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 Gage BF, Boechler M, Doggette AL. et al. Adverse outcomes and predictors of underuse of antithrombotic therapy in medicare beneficiaries with chronic atrial fibrillation. Stroke 2000; 31: 822-827.
    CrossrefPubMedGoogle Scholar
  • 39 The International Warfarin Pharmacogenetics Consortium. Estimation of thewarfarin dose with clinical and pharmacogenetic data. N Engl J Med 2009; 360: 753-764.
    CrossrefPubMedGoogle Scholar
  • 40 Wadelius M, Leslie YC, Jonatan DL. et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood 2009; 113: 784-792.
    CrossrefPubMedGoogle Scholar
  • 41 Holbrook AM, Pereira JA, Labiris R. et al. Systematic overview of warfarin and its drug and food interactions. Arch Intern Med 2005; 165: 1095-1106.
    CrossrefPubMedGoogle Scholar
  • 42 Garcia DA, Lopes RD, Hylek EM. New-onset atrial fibrillation and warfarin initiation: High risk periods and implications for new antithrombotic drugs. Thromb Haemost 2010; 104: 1099-1105.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 43 Daniel EJ, Howard LM. Genetic and clinical factors relating to warfarin dosing. Trends Pharmacol Sci 2009; 30: 375-386.
    CrossrefPubMedGoogle Scholar
  • 44 Zhu YS, Shennan M, Reynolds KK. et al. Estimation of Warfarin Maintenance Dose Based on VKORC1 (-1639 G>A) and CYP2C9 Genotypes. Clin Chem 2007; 53: 1199-1205.
    CrossrefPubMedGoogle Scholar
  • 45 King CR, Deych E, Milligan P. et al. Gamma-glutamyl carboxylase and its influence on warfarin dose. Thromb Haemost 2010; 104: 750-754.
    Article in Thieme ConnectPubMedGoogle Scholar