title: Prospective evaluation of a pharmacogenetics-guided warfarin loading and maintenance dose regimen for initiation of therapy.
abstract: Single-nucleotide polymorphisms in genes that affect warfarin metabolism (cytochrome P450 2C9 gene, CYP2C9) and response (vitamin K epoxide reductase complex 1 gene, VKORC1) have an important influence on warfarin therapy, particularly during initiation; however, there is a lack of consensus regarding the optimal pharmacogenetics-based initiation strategy. We conducted a prospective cohort study in which patients requiring warfarin therapy for atrial fibrillation or venous thromboembolism were initiated with a novel pharmacogenetics-initiation protocol (WRAPID, Warfarin Regimen using A Pharmacogenetics-guided Initiation Dosing) that incorporated loading and maintenance doses based on genetics, clinical variables, and response (n = 167, followed up for 90 days), to assess the influence of genetic variations on anticoagulation responses. Application of the WRAPID algorithm resulted in a negligible influence of genetic variation in VKORC1 or CYP2C9 on time to achievement of first therapeutic response (P = .52, P = .28) and risk of overanticoagulation (P = .64, P = .96). After adjustment for covariates, time to stable anticoagulation was not influenced by VKORC1 or CYP2C9 genotype. Importantly, time spent within or above the therapeutic range did not differ among VKORC1 and CYP2C9 genotype groups. Moreover, the overall time course of the anticoagulation response among the genotype groups was similar and predictable. We demonstrate the clinical utility of genetics-guided warfarin initiation with the WRAPID protocol to provide safe and optimal anticoagulation therapy for patients with atrial fibrillation or venous thromboembolism.
authors: Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada.
authors: Inna Y
authors: IY
authors: Gong
authors: Rommel G
authors: RG
authors: Tirona
authors: Ute I
authors: UI
authors: Schwarz
authors: Natalie
authors: N
authors: Crown
authors: George K
authors: GK
authors: Dresser
authors: Samantha
authors: S
authors: Larue
authors: Nicole
authors: N
authors: Langlois
authors: Alejandro
authors: A
authors: Lazo-Langner
authors: Guangyong
authors: G
authors: Zou
authors: Dan M
authors: DM
authors: Roden
authors: C Michael
authors: CM
authors: Stein
authors: Marc
authors: M
authors: Rodger
authors: Marc
authors: M
authors: Carrier
authors: Melissa
authors: M
authors: Forgie
authors: Philip S
authors: PS
authors: Wells
authors: Richard B
authors: RB
authors: Kim
mesh_terms: D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D015331:Cohort Studies; D065729:Cytochrome P-450 CYP2C9; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D006899:Mixed Function Oxygenases / Q000235:genetics; D010597:Pharmacogenetics / Q000379:methods*; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D064417:Vitamin K Epoxide Reductases; D014859:Warfarin / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D014914:Whole Blood Coagulation Time
chemical_list: D000925:Anticoagulants; D014859:Warfarin; D006899:Mixed Function Oxygenases; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases; C578523:VKORC1 protein, human; D064417:Vitamin K Epoxide Reductases