Articles
Clinical Pharmacology & Therapeutics (2009); advance online publication 30 September 2009. doi:10.1038/clpt.2009.178
Genetic Factors (VKORC1, CYP2C9, EPHX1, and CYP4F2) Are Predictor Variables for Warfarin Response in Very Elderly, Frail Inpatients
E Pautas1,2,3, C Moreau1,3,4,5, I Gouin-Thibault1,3,6, J-L Golmard7, I Mahé8, C Legendre9, E Taillandier-Hériche10, B Durand-Gasselin11, A-M Houllier4, P Verrier5, P Beaune1,4,5, M-A Loriot1,4,5 and V Siguret1,3,6
- 1Université Paris Descartes, Paris, France
- 2Assistance Publique Hôpitaux de Paris, Hôpital Charles Foix, Unité de Gériatrie Aiguë, Ivry-sur-Seine, France
- 3INSERM U765, Paris, France
- 4INSERM UMRS775, Paris, France
- 5Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Pharmacogénétique et Oncologie Moléculaire, Paris, France
- 6Assistance Publique Hôpitaux de Paris, Hôpital Charles Foix, Laboratoire d'Hématologie, Ivry-sur-Seine, France
- 7Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Biostatistiques, Paris, France
- 8Assistance Publique Hôpitaux de Paris, Hôpital Louis Mourier, Service de Médecine Interne, Colombes, France
- 9Assistance Publique Hôpitaux de Paris, Hôpital Charles Foix, Service de Médecine Interne, Ivry-sur-Seine, France
- 10Assistance Publique Hôpitaux de Paris, Hôpital Henri Mondor, Service de Médecine Interne et Gériatrie, Créteil, France
- 11Hôpital Notre-Dame de Bon Secours, Service de Gériatrie, Paris, France
Correspondence: V Siguret, (virginie.siguret@parisdescartes.fr)
The first two authors and the last two authors contributed equally to this work.
Received 5 June 2009; Accepted 23 July 2009; Published online 30 September 2009.
Abstract
Determining the optimal dose of warfarin for frail elderly patients is a challenging task because of the low dose requirements in such patients, the wide interindividual variability of response, and the associated risk of bleeding. The objective of this study was to address the influence of 13 common variations in eight genes on the maintenance dose of warfarin in a cohort of frail elderly inpatients. For our study, we enrolled 300 Caucasian subjects who were hospital inpatients, with a mean age of 86.7 
6 years. In addition to age, genetic variants of VKORC1, CYP2C9, CYP4F2, and EPHX1 were found to be significant predictor variables for the maintenance dose of warfarin, explaining 26.6% of dose variability. Among 132 patients in whom warfarin therapy was initiated with the same low-dose regimen, we studied the relative influences of genetic and nongenetic factors. The time to first international normalized ratio (INR) 
2 was influenced by VKORC1 and CYP2C9 genotypes (P = 0.0003 and P = 0.0016, respectively); individuals with multiple variant alleles were at highest risk for overanticoagulation (INR >4) (odds ratio, 12.8; 95% confidence interval, 2.73–60.0). In this special population of frail elderly patients with multiple comorbidities and polypharmacy, we demonstrated the main impact of genetic factors on warfarin response.
