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Genotype-guided versus traditional clinical dosing of warfarin in patients of Asian ancestry: a randomized controlled trial. (BMC Med, Jul 2018)

Syn NL1,2, Wong AL1,2, Lee SC1,2, Teoh HL3, Yip JWL4, Seet RC3,5, Yeo WT4, Kristanto W4, Bee PC6, Poon LM1, Marban P1, Wu TS7, Winther MD8, Brunham LR9,10, Soong R2,11, Tai BC12, Goh BC13,14,15.

Author information
1 Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.
2 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
3 Division of Neurology, Department of Medicine, National University Health System, Singapore, Singapore.
4 Department of Cardiology, National University Heart Centre, Singapore, Singapore.
5 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
6 Department of Medicine, University of Malaya Medical Centre, Kuala Lumpur, Malaysia.
7 Department of Pharmacy, National University Hospital, Singapore, Singapore.
8 Genome Institute of Singapore, Agency for Science, Technology and Research, Singapore, Singapore.
9 Translational Laboratory in Genetic Medicine, Agency for Science, Technology and Research, Singapore, Singapore.
10 Department of Medicine, Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada.
11 Department of Pathology, Yong Loo Lin School of Medicine, National University Health System, Singapore, Singapore.
12 Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore.
13 Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.
14 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. .
15 Department of Pharmacology, Yong Loo Lin School of Medicine, National University Health System, Singapore, 119228, Singapore.

Abstract
BACKGROUND:
Genotype-guided warfarin dosing has been shown in some randomized trials to improve anticoagulation outcomes in individuals of European ancestry, yet its utility in Asian patients remains unresolved.

METHODS:
An open-label, non-inferiority, 1:1 randomized trial was conducted at three academic hospitals in South East Asia, involving 322 ethnically diverse patients newly indicated for warfarin (NCT00700895). Clinical follow-up was 90 days. The primary efficacy measure was the number of dose titrations within the first 2 weeks of therapy, with a mean non-inferiority margin of 0.5 over the first 14 days of therapy.

RESULTS:
Among 322 randomized patients, 269 were evaluable for the primary endpoint. Compared with traditional dosing, the genotype-guided group required fewer dose titrations during the first 2 weeks (1.77 vs. 2.93, difference -1.16, 90% CI -1.48 to -0.84, P < 0.001 for both non-inferiority and superiority). The percentage of time within the therapeutic range over 3 months and median time to stable international normalized ratio (INR) did not differ between the genotype-guided and traditional dosing groups. The frequency of dose titrations (incidence rate ratio 0.76, 95% CI 0.67 to 0.86, P = 0.001), but not frequency of INR measurements, was lower at 1, 2, and 3 months in the genotype-guided group. The proportions of patients who experienced minor or major bleeding, recurrent venous thromboembolism, or out-of-range INR did not differ between both arms. For predicting maintenance doses, the pharmacogenetic algorithm achieved an R2 = 42.4% (P < 0.001) and mean percentage error of -7.4%.

CONCLUSIONS:
Among Asian adults commencing warfarin therapy, a pharmacogenetic algorithm meets criteria for both non-inferiority and superiority in reducing dose titrations compared with a traditional dosing approach, and performs well in prediction of actual maintenance doses. These findings imply that clinicians may consider applying a pharmacogenetic algorithm to personalize initial warfarin dosages in Asian patients.

TRIAL REGISTRATION: ClinicalTrials.gov NCT00700895 . Registered on June 19, 2008.

KEYWORDS: Anticoagulants; Anticoagulation; CYP2C9; Cytochrome P450; Pharmacogenetics; Pharmacogenomics; Polymorphism; Precision medicine; VKORC1; Warfarin

PMID: 29986700