Prospective evaluation of a pharmacogenetics-guided warfarin loading and maintenance dose regimen for initiation of therapy

Inna Y Gong,Rommel G Tirona,Ute I Schwarz,Natalie Crown,George K Dresser,Samantha Larue,Nicole Langlois,Alejandro Lazo-Langner,Guangyong Zou,Dan M Roden,C Michael Stein,Marc Rodger,Marc Carrier,Melissa Forgie,Philip S Wells,Richard B Kim

doi:10.1182/blood-2011-03-345173

Abstract

AbstractSingle-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.

Highlights

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
We demonstrate the clinical utility of geneticsguided warfarin initiation with the WRAPID protocol to provide safe and optimal anticoagulation therapy for patients with atrial fibrillation or venous thromboembolism. (Blood. 2011;118(11):3163-3171)
The time to first stable anticoagulation was significantly different between vitamin K epoxide reductase complex subunit 1 (VKORC1) (P Ͻ .05) genotype groups, whereas there were no differences between cytochrome P450 2C9 (CYP2C9) groups (P ϭ .37; Figure 2)

Summary

Introduction

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. Time spent within or above the therapeutic range did not differ among VKORC1 and CYP2C9 genotype groups. The overall time course of the anticoagulation response among the genotype groups was similar and predictable. We demonstrate the clinical utility of geneticsguided warfarin initiation with the WRAPID protocol to provide safe and optimal anticoagulation therapy for patients with atrial fibrillation or venous thromboembolism. (Blood. 2011;118(11):3163-3171)

Methods

Results

Conclusion