Estimation of the warfarin dose with a pharmacogenetic refinement algorithm in Chinese patients mainly under low-intensity warfarin anticoagulation

Qiang Xu; Bin Xu; Yuxiao Zhang; Jie Yang; Lei Gao; Yan Zhang; Hongjuan Wang; Caiyi Lu; Yusheng Zhao; Tong Yin

doi:10.1160/TH12-05-0362

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2012; 108(06): 1132-1140
DOI: 10.1160/TH12-05-0362

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Estimation of the warfarin dose with a pharmacogenetic refinement algorithm in Chinese patients mainly under low-intensity warfarin anticoagulation

Qiang Xu^*

¹Institute of Geriatric Cardiology, General Hospital of People’s Liberation Army, Beijing, China

,

Bin Xu^*

¹Institute of Geriatric Cardiology, General Hospital of People’s Liberation Army, Beijing, China

,

Yuxiao Zhang^*

¹Institute of Geriatric Cardiology, General Hospital of People’s Liberation Army, Beijing, China

,

Jie Yang

¹Institute of Geriatric Cardiology, General Hospital of People’s Liberation Army, Beijing, China

,

Lei Gao

¹Institute of Geriatric Cardiology, General Hospital of People’s Liberation Army, Beijing, China

,

Yan Zhang

¹Institute of Geriatric Cardiology, General Hospital of People’s Liberation Army, Beijing, China

,

Hongjuan Wang

¹Institute of Geriatric Cardiology, General Hospital of People’s Liberation Army, Beijing, China

,

Caiyi Lu

¹Institute of Geriatric Cardiology, General Hospital of People’s Liberation Army, Beijing, China

,

Yusheng Zhao

¹Institute of Geriatric Cardiology, General Hospital of People’s Liberation Army, Beijing, China

,

Tong Yin

¹Institute of Geriatric Cardiology, General Hospital of People’s Liberation Army, Beijing, China

› Author Affiliations

Abstract

Summary

Pharmacogenetic (PG) dosing algorithms have been confirmed to predict warfarin therapeutic dose more accurately;however, most of them are based on standard intensity of warfarin anticoagulation, and their utility outside this range is limited. This study was designed to develop and validate a PG refinement algorithm in Chinese patients mainly under low-intensity warfarin anticoagulation. Consented Chinese-Han patients (n=310) under stable warfarin treatment were randomly divided into a derivation (n=207) and a validation cohort (n=103), with 83% and 80% of the patients under low-intensity anticoagulation, respectively. In the derivation cohort, a PG algorithm was constructed on the basis of genotypes (CYP2C9^*3 and VKORC1–1639A/G) and clinical data. After integrating additional covariates of international normalised ratio (INR) values (INR on day 4 of therapy and target INR) and genotype of CYP4F2 (rs2108622), a PG refinement algorithm was established and explained 54% of warfarin dose variability. In the validation cohort, warfarin dose prediction was more accurate (p <0.01) with the PG refinement algorithm than with the PG algorithm and the fixed dose approach (3 mg/day). In the entire cohort, the PG refinement algorithm could accurately identify larger proportions of patients with lower dose requirement (≤2 mg/day) and higher dose requirement (≥4 mg/day) than did the PG algorithm. In conclusion, PG refinement algorithm integrating early INR response and three genotypes CYP2C9^*3, VKORC1–1639A/G, CYP4F2 rs2108622) improves the accuracy of warfarin dose prediction in Chinese patients mainly under low-intensity anticoagulation.

Keywords

Warfarin - pharmacogenetics - dosing algorithm - low-intensity anticoagulation

Full Text

References

References
1 Pirmohamed M. Warfarin: almost 60 years old and still causing problems. Br J Clin Pharmacol 2006; 62: 509-511.
2 Budnitz DS, Pollock DA, Weidenbach KN. et al. National surveillance of emergency department visits for outpatient adverse drug events. J Am Med Assoc 2006; 296: 1858-1866.
3 Higashi MK, Veenstra DL, Kondo LM. et al. Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy. J Am Med Assoc 2002; 287: 1690-1698.
4 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.
5 Wadelius M, Chen LY, Lindh JD. et al. The largest prospective warfarin-treated cohort supports genetic forecasting. Blood 2009; 113: 784-792.
6 Carlquist JF, Anderson JL. Using pharmacogenetics in real time to guide warfarin initiation: a clinician update. Circulation 2011; 124: 2554-2559.
7 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: 1018-1026.
8 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.
9 Sagreiya H, Berube C, Wen A. et al. Extending and evaluating a warfarin dosing algorithm that includes CYP4F2 and pooled rare variants of CYP2C9. Pharmacogenet Genomics 2010; 20: 407-413.
10 Lenzini P, Wadelius M, Kimmel S. et al. Integration of genetic, clinical, and INR data to refine warfarin dosing. Clin Pharmacol Ther 2010; 87: 572-578.
11 Shin J, Cao D. Comparison of warfarin pharmacogenetic dosing algorithms in a racially diverse large cohort. Pharmacogenomics 2010; 12: 125-134.
12 Roper N, Storer B, Bona R. et al. Validation and comparison of pharmacogenetics-based warfarin dosing algorithms for application of pharmacogenetic testing. J Mol Diagn 2010; 12: 283-291.
13 Suzuki S, Yamashita T, Kato T. et al. Incidence of major bleeding complication of warfarin therapy in Japanese patients with atrial fibrillation. Circ J 2007; 71: 761-765.
14 Dong L, Shi YK, Tian ZP. et al. Low intensity anticoagulation therapy after mechanical heart valve replacement. Zhonghua Wai Ke Za Zhi 2003; 41: 250-252.
15 Yasaka M, Minematsu K, Yamaguchi T. Optimal intensity of international normalized ratio in warfarin therapy for secondary prevention of stroke in patients with non-valvular atrial fibrillation. Intern Med 2001; 40: 1183-1188.
16 You JH, Chan FW, Wong RS. et al. Is INR between 2.0 and 3.0 the optimal level for Chinese patients on warfarin therapy for moderate-intensity anticoagulation?. Br J Clin Pharmacol 2005; 59: 582-587.
17 Haibo Z, Jinzhong L, Yan L. et al. Low-intensity international normalized ratio (INR) oral anticoagulant therapy in Chinese patients with mechanical heart valve prostheses. Cell Biochem Biophys 2012; 62: 147-151.
18 Ridker PM, Goldhaber SZ, Danielson E. et al. Long-term, low-intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003; 348: 1425-1434.
19 Johnson JA, Gong L, Whirl-Carrillo M. et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for CYP2C9 and VKORC1 genotypes and warfarin dosing. Clin Pharmacol Ther 2011; 90: 625-629.
20 Liu Y, Yang J, Xu Q. et al. Comparative performance of warfarin pharmacogenetic algorithms in Chinese patients. Thromb Res 2012. Epub ahead of print.
21 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.
22 Caldwell MD, Awad T, Johnson JA. et al. CYP4F2 genetic variant alters required warfarin dose. Blood 2008; 111: 4106-4112.
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.
24 Yin T, Maekawa K, Kamide K. et al. Genetic variations of CYP2C9 in 724 Japanese individuals and their impact on the antihypertensive effects of losartan. Hypertens Res 2008; 31: 1549-1557.
25 Klein TE, Altman RB, Eriksson N. et al. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med 2009; 360: 753-764.
26 Tham LS, Goh BC, Nafziger A. et al. A warfarin-dosing model in Asians that uses single-nucleotide polymorphisms in vitamin K epoxide reductase complex and cytochrome P450 2C9. Clin Pharmacol Ther 2006; 80: 346-355.
27 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.
28 Kimura R, Miyashita K, Kokubo Y. et al. Genotypes of vitamin K epoxide reductase, gamma-glutamyl carboxylase, and cytochrome P450 2C9 as determinants of daily warfarin dose in Japanese patients. Thromb Res 2007; 120: 181-186.
29 Wen MS, Lee M, Chen JJ. et al. Prospective study of warfarin dosage requirements based on CYP2C9 and VKORC1 genotypes. Clin Pharmacol Ther 2008; 84: 83-89.
30 Lee MT, Chen CH, Chou CH. et al. Genetic determinants of warfarin dosing in the Han-Chinese population. Pharmacogenomics 2009; 10: 1905-1913.
31 Ohno M, Yamamoto A, Ono A. et al. Influence of clinical and genetic factors on warfarin dose requirements among Japanese patients. Eur J Clin Pharmacol 2009; 65: 1097-1103.
32 Huang SW, Chen HS, Wang XQ. et al. Validation of VKORC1 and CYP2C9 genotypes on interindividual warfarin maintenance dose: a prospective study in Chinese patients. Pharmacogenet Genomics 2009; 19: 226-234.
33 Harada T, Ariyoshi N, Shimura H. et al. Application of Akaike information criterion to evaluate warfarin dosing algorithm. Thromb Res 2010; 126: 183-190.
34 You JH, Wong RS, Waye MM. et al. Warfarin dosing algorithm using clinical, demographic and pharmacogenetic data from Chinese patients. J Thromb Thrombolysis 2011; 31: 113-118.
35 Choi JR, Kim JO, Kang DR. et al. Proposal of pharmacogenetics-based warfarin dosing algorithm in Korean patients. J Hum Genet 2011; 56: 290-295.
36 Wei M, Ye F, Xie D. et al. 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. Thromb Haemost 2012; 107: 1083-1091.
37 Liang R, Li L, Li C. et al. Impact of CYP2C9*3, VKORC1-1639, CYP4F2rs2108622 genetic polymorphism and clinical factors on warfarin maintenance dose in Han-Chinese patients. J Thromb Thrombolysis 2012; 34: 120-125.
38 Yin T, Miyata T. Warfarin dose and the pharmacogenomics of CYP2C9 and VKORC1 - rationale and perspectives. Thromb Res 2007; 120: 1-10.
39 Schwarz UI, Ritchie MD, Bradford Y. et al. Genetic determinants of response to warfarin during initial anticoagulation. N Engl J Med 2008; 358: 999-1008.
40 Li C, Schwarz UI, Ritchie MD. et al. Relative contribution of CYP2C9 and VKORC1 genotypes and early INR response to the prediction of warfarin sensitivity during initiation of therapy. Blood 2009; 113: 3925-3930.
41 Ferder NS, Eby CS, Deych E. et al. Ability of VKORC1 and CYP2C9 to predict therapeutic warfarin dose during the initial weeks of therapy. J Thromb Haemost 2010; 8: 95-100.
42 Millican EA, Lenzini PA, Milligan PE. et al. Genetic-based dosing in orthopedic patients beginning warfarin therapy. Blood 2007; 110: 1511-1515.
43 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: 1655-1662.
44 Chan SL, Goh BC, Chia KS. et al. Effects of CYP4F2 and GGCX genetic variants on maintenance warfarin dose in a multi-ethnic Asian population. Thromb Haemost 2011; 105: 1100-1102.
45 Limdi NA, Wadelius M, Cavallari L. et al. Warfarin pharmacogenetics: a single VKORC1 polymorphism is predictive of dose across 3 racial groups. Blood 2010; 2010; 115: 3827-3834.
46 Rosove MH, Grody WW. Should we be applying warfarin pharmacogenetics to clinical practice? No, not now. Ann Intern Med 2009; 151: 270-273 W295
47 Johnson EG, Horne BD, Carlquist JF. et al Genotype-based dosing algorithms for warfarin therapy: data review and recommendations. Mol Diagn Ther 2011; 15: 255-264.
48 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.
49 French B, Joo J, Geller NL. et al. Statistical design of personalized medicine interventions: the Clarification of Optimal Anticoagulation through Genetics (COAG) trial. Trials 2010; 11: 108.
50 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.