| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Circulation. 2007;116:2563-2570.)
© 2007 American Heart Association, Inc.
Genetics |
From the Cardiovascular Department, LDS Hospital, Intermountain Healthcare (J.L.A., B.D.H., S.M.S., A.S.G., S.B., Z.P.N., S.F.S.K., H.T.M., K.M.S., J.B.M., J.F.C.), and University of Utah School of Medicine (J.L.A., B.D.H., S.M.S., J.B.M., J.F.C.), Salt Lake City, Utah.
Correspondence to Jeffrey L. Anderson, MD, Intermountain Medical Center, Cardiovascular Department, 5121 S Cottonwood St, Murray, UT 84157. E-mail jeffrey.anderson{at}intermountainmail.org
Received August 28, 2007; accepted October 5, 2007.
Background— Pharmacogenetic-guided dosing of warfarin is a promising application of "personalized medicine" but has not been adequately tested in randomized trials.
Methods and Results— Consenting patients (n=206) being initiated on warfarin were randomized to pharmacogenetic-guided or standard dosing. Buccal swab DNA was genotyped for CYP2C9 *2 and CYP2C9 *3 and VKORC1C1173T with a rapid assay. Standard dosing followed an empirical protocol, whereas pharmacogenetic-guided dosing followed a regression equation including the 3 genetic variants and age, sex, and weight. Prothrombin time international normalized ratio (INR) was measured routinely on days 0, 3, 5, 8, 21, 60, and 90. A research pharmacist unblinded to treatment strategy managed dose adjustments. Patients were followed up for up to 3 months. Pharmacogenetic-guided predicted doses more accurately approximated stable doses (P<0.001), resulting in smaller (P=0.002) and fewer (P=0.03) dosing changes and INRs (P=0.06). However, percent out-of-range INRs (pharmacogenetic=30.7%, standard=33.1%), the primary end point, did not differ significantly between arms. Despite this, when restricted to wild-type patients (who required larger doses; P=0.001) and multiple variant carriers (who required smaller doses; P<0.001) in exploratory analyses, results (pharmacogenetic=29%, standard=39%) achieved nominal significance (P=0.03). Multiple variant allele carriers were at increased risk of an INR of
4 (P=0.03).
Conclusions— An algorithm guided by pharmacogenetic and clinical factors improved the accuracy and efficiency of warfarin dose initiation. Despite this, the primary end point of a reduction in out-of-range INRs was not achieved. In subset analyses, pharmacogenetic guidance showed promise for wild-type and multiple variant genotypes.
This article has been cited by other articles:
![]() |
T. P. Moyer, D. J. O'Kane, L. M. Baudhuin, C. L. Wiley, A. Fortini, P. K. Fisher, D. M. Dupras, R. Chaudhry, P. Thapa, A. R. Zinsmeister, et al. Warfarin Sensitivity Genotyping: A Review of the Literature and Summary of Patient Experience Mayo Clin. Proc., December 1, 2009; 84(12): 1079 - 1094. [Abstract] [Full Text] [PDF] |
||||
![]() |
P. Gladding, H. White, J. Voss, J. Ormiston, J. Stewart, P. Ruygrok, B. Bvaldivia, R. Baak, C. White, and M. Webster Pharmacogenetic Testing for Clopidogrel Using the Rapid INFINITI Analyzer: A Dose-Escalation Study J. Am. Coll. Cardiol. Intv., November 1, 2009; 2(11): 1095 - 1101. [Abstract] [Full Text] [PDF] |
||||
![]() |
J. F. Meschia Pharmacogenetics and Stroke Stroke, November 1, 2009; 40(11): 3641 - 3645. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Teichert, M. Eijgelsheim, F. Rivadeneira, A. G. Uitterlinden, R. H.N. van Schaik, A. Hofman, P. A.G.M. De Smet, T. van Gelder, L. E. Visser, and B. H.Ch. Stricker A genome-wide association study of acenocoumarol maintenance dosage Hum. Mol. Genet., October 1, 2009; 18(19): 3758 - 3768. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. W. Linder, M. Bon Homme, K. K. Reynolds, B. F. Gage, C. Eby, N. Silvestrov, and R. Valdes Jr. Interactive Modeling for Ongoing Utility of Pharmacogenetic Diagnostic Testing: Application for Warfarin Therapy Clin. Chem., October 1, 2009; 55(10): 1861 - 1868. [Abstract] [Full Text] [PDF] |
||||
![]() |
G. Piazza and S. Z. Goldhaber Computerized Decision Support for the Cardiovascular Clinician: Applications for Venous Thromboembolism Prevention and Beyond Circulation, September 22, 2009; 120(12): 1133 - 1137. [Full Text] [PDF] |
||||
![]() |
D. J. Ellis, M. H. Usman, P. G. Milner, D. M. Canafax, and M. D. Ezekowitz The First Evaluation of a Novel Vitamin K Antagonist, Tecarfarin (ATI-5923), in Patients With Atrial Fibrillation Circulation, September 22, 2009; 120(12): 1029 - 1035. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. R. Patrick, J. Avorn, and N. K. Choudhry Cost-Effectiveness of Genotype-Guided Warfarin Dosing for Patients With Atrial Fibrillation Circ Cardiovasc Qual Outcomes, September 1, 2009; 2(5): 429 - 436. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. H. Rosove and W. W. Grody Should We Be Applying Warfarin Pharmacogenetics to Clinical Practice? No, Not Now Ann Intern Med, August 18, 2009; 151(4): 270 - 273. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. W. Smith Chiral Toxicology: It's the Same Thing...Only Different Toxicol. Sci., July 1, 2009; 110(1): 4 - 30. [Abstract] [Full Text] [PDF] |
||||
![]() |
B. Nochowitz, N. L Shapiro, E. A Nutescu, and L. H Cavallari Effect of a Warfarin Adherence Aid on Anticoagulation Control in an Inner-City Anticoagulation Clinic Population Ann. Pharmacother., July 1, 2009; 43(7): 1165 - 1172. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Valgimigli, G. Campo, N. de Cesare, E. Meliga, P. Vranckx, A. Furgieri, D. J. Angiolillo, M. Sabate, M. Hamon, A. Repetto, et al. Intensifying Platelet Inhibition With Tirofiban in Poor Responders to Aspirin, Clopidogrel, or Both Agents Undergoing Elective Coronary Intervention: Results From the Double-Blind, Prospective, Randomized Tailoring Treatment With Tirofiban in Patients Showing Resistance to Aspirin and/or Resistance to Clopidogrel Study Circulation, June 30, 2009; 119(25): 3215 - 3222. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. A. Garcia, E. Hylek, A. B. Shil, M. P. Strohm, T. E. Klein, S. E. Kimmel, and J. A. Johnson Warfarin pharmacogenetics. N. Engl. J. Med., June 4, 2009; 360(23): 2474 - 2475. [Full Text] [PDF] |
||||
![]() |
D. A. Cios, W. L. Baker, S. D. Sander, O. J. Phung, and C. I. Coleman Evaluating the impact of study-level factors on warfarin control in U.S.-based primary studies: A meta-analysis Am. J. Health Syst. Pharm., May 15, 2009; 66(10): 916 - 925. [Abstract] [Full Text] [PDF] |
||||
![]() |
A. M. Garber and S. R. Tunis Does Comparative-Effectiveness Research Threaten Personalized Medicine? N. Engl. J. Med., May 7, 2009; 360(19): 1925 - 1927. [Full Text] [PDF] |
||||
![]() |
M. R. Langley, J. K. Booker, J. P. Evans, H. L. McLeod, and K. E. Weck Validation of Clinical Testing for Warfarin Sensitivity: Comparison of CYP2C9-VKORC1 Genotyping Assays and Warfarin-Dosing Algorithms J. Mol. Diagn., May 1, 2009; 11(3): 216 - 225. [Abstract] [Full Text] [PDF] |
||||
![]() |
C. Li, U. I. Schwarz, M. D. Ritchie, D. M. Roden, C. M. Stein, and D. Kurnik Relative contribution of CYP2C9 and VKORC1 genotypes and early INR response to the prediction of warfarin sensitivity during initiation of therapy Blood, April 23, 2009; 113(17): 3925 - 3930. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. A. Hlatky and P. A. Heidenreich The Year in Epidemiology, Health Services Research, and Outcomes Research J. Am. Coll. Cardiol., April 21, 2009; 53(16): 1459 - 1466. [Full Text] [PDF] |
||||
![]() |
T. Aomori, K. Yamamoto, A. Oguchi-Katayama, Y. Kawai, T. Ishidao, Y. Mitani, Y. Kogo, A. Lezhava, Y. Fujita, K. Obayashi, et al. Rapid Single-Nucleotide Polymorphism Detection of Cytochrome P450 (CYP2C9) and Vitamin K Epoxide Reductase (VKORC1) Genes for the Warfarin Dose Adjustment by the SMart-Amplification Process Version 2 Clin. Chem., April 1, 2009; 55(4): 804 - 812. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Wadelius Point: Use of Pharmacogenetics in Guiding Treatment with Warfarin Clin. Chem., April 1, 2009; 55(4): 709 - 711. [Full Text] [PDF] |
||||
![]() |
C. S. Eby Counterpoint: Pharmacogenetic-Based Initial Dosing of Warfarin: Not Ready for Prime Time Clin. Chem., April 1, 2009; 55(4): 712 - 714. [Full Text] [PDF] |
||||
![]() |
E. Lyon and C. T. Wittwer LightCycler Technology in Molecular Diagnostics J. Mol. Diagn., March 1, 2009; 11(2): 93 - 101. [Abstract] [Full Text] [PDF] |
||||
![]() |
The International Warfarin Pharmacogenetics Consor Estimation of the Warfarin Dose with Clinical and Pharmacogenetic Data N. Engl. J. Med., February 19, 2009; 360(8): 753 - 764. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Wadelius, L. Y. Chen, J. D. Lindh, N. Eriksson, M. J. R. Ghori, S. Bumpstead, L. Holm, R. McGinnis, A. Rane, and P. Deloukas The largest prospective warfarin-treated cohort supports genetic forecasting Blood, January 22, 2009; 113(4): 784 - 792. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. H. Eckman, J. Rosand, S. M. Greenberg, and B. F. Gage Cost-Effectiveness of Using Pharmacogenetic Information in Warfarin Dosing for Patients With Nonvalvular Atrial Fibrillation Ann Intern Med, January 20, 2009; 150(2): 73 - 83. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. C. Anderson Jr. Pharmacogenomics and warfarin Am. J. Health Syst. Pharm., January 15, 2009; 66(2): 121 - 121. [Full Text] [PDF] |
||||
![]() |
M. P. Gulseth, G. R. Grice, and W. E. Dager Pharmacogenomics of warfarin: Uncovering a piece of the warfarin mystery Am. J. Health Syst. Pharm., January 15, 2009; 66(2): 123 - 133. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. H. Eckman, L. K.S. Wong, Y. O.Y. Soo, W. Lam, S. R. Yang, S. M. Greenberg, and J. Rosand Patient-Specific Decision-Making for Warfarin Therapy in Nonvalvular Atrial Fibrillation: How Will Screening With Genetics and Imaging Help? * Supplemental Appendix Stroke, December 1, 2008; 39(12): 3308 - 3315. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Y. Chan, F. Andreotti, and R. C. Becker Hypercoagulable States in Cardiovascular Disease Circulation, November 25, 2008; 118(22): 2286 - 2297. [Full Text] [PDF] |
||||
![]() |
J. A. Johnson Ethnic Differences in Cardiovascular Drug Response: Potential Contribution of Pharmacogenetics Circulation, September 23, 2008; 118(13): 1383 - 1393. [Full Text] [PDF] |
||||
![]() |
L. M Hynicka, W. D Cahoon Jr, and B. L Bukaveckas Genetic Testing for Warfarin Therapy Initiation Ann. Pharmacother., September 1, 2008; 42(9): 1298 - 1303. [Abstract] [Full Text] [PDF] |
||||
![]() |
S. H. Hohnloser, G. Z. Duray, U. Baber, and J. L. Halperin Prevention of stroke in patients with atrial fibrillation: current strategies and future directions Eur. Heart J. Suppl., September 1, 2008; 10(suppl_H): H4 - H10. [Abstract] [Full Text] [PDF] |
||||
![]() |
G. M. Cooper, J. A. Johnson, T. Y. Langaee, H. Feng, I. B. Stanaway, U. I. Schwarz, M. D. Ritchie, C. M. Stein, D. M. Roden, J. D. Smith, et al. A genome-wide scan for common genetic variants with a large influence on warfarin maintenance dose Blood, August 15, 2008; 112(4): 1022 - 1027. [Abstract] [Full Text] [PDF] |
||||
![]() |
K. W. Phillips, P. P. Dobesh, and S. T. Haines Considerations in using anticoagulant therapy in special patient populations Am. J. Health Syst. Pharm., August 1, 2008; 65(15_Supplement_7): S13 - S21. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. A Garcia, D. M Witt, E. Hylek, A. K Wittkowsky, E. A Nutescu, A. Jacobson, S. Moll, G. J Merli, M. Crowther, L. Earl, et al. Delivery of Optimized Anticoagulant Therapy: Consensus Statement from the Anticoagulation Forum Ann. Pharmacother., July 1, 2008; 42(7): 979 - 988. [Abstract] [Full Text] [PDF] |
||||
![]() |
N. S. Rost, S. M. Greenberg, and J. Rosand The Genetic Architecture of Intracerebral Hemorrhage Stroke, July 1, 2008; 39(7): 2166 - 2173. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. Schillinger, K. A. Neville, B. M. Wicklund, G. L. Kearns, U. P. Kulkarni, D. R. Karnad, N. J. Gogtay, P. M. Mannucci, M. Spreafico, F. Peyvandi, et al. Genetics of Warfarin Response N. Engl. J. Med., June 19, 2008; 358(25): 2741 - 2744. [Full Text] [PDF] |
||||
![]() |
M. D. Caldwell, T. Awad, J. A. Johnson, B. F. Gage, M. Falkowski, P. Gardina, J. Hubbard, Y. Turpaz, T. Y. Langaee, C. Eby, et al. CYP4F2 genetic variant alters required warfarin dose Blood, April 15, 2008; 111(8): 4106 - 4112. [Abstract] [Full Text] [PDF] |
||||
![]() |
M. Stramba-Badiale Atrial fibrillation subtypes, risk of stroke, and antithrombotic therapy Eur. Heart J., April 1, 2008; 29(7): 840 - 842. [Full Text] [PDF] |
||||
![]() |
M. T. Scheuner, P. Sieverding, and P. G. Shekelle Delivery of Genomic Medicine for Common Chronic Adult Diseases: A Systematic Review JAMA, March 19, 2008; 299(11): 1320 - 1334. [Abstract] [Full Text] [PDF] |
||||
![]() |
C. W. Francis New Issues in Oral Anticoagulants Hematology, January 1, 2008; 2008(1): 259 - 265. [Abstract] [Full Text] [PDF] |
||||
|
Circulation Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search Copyright © 2007 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited. |