Journal Article

Genotype-guided versus traditional clinical dosing of warfarin in patients of Asian ancestry: a randomized controlled trial

Teoh, Hock-Luen, Syn, Nicholas L., Seet, Raymond CS, Bee, Ping-Chong, Wu, Tuck Seng, Poon, LM, Winther, Michael D., Marban, Patrick, Kristanto, William, Lee, Soo-Chin, Yeo, Wee Tiong, Soong, Richie, Wong, Andrea Li-Ann, Yip, James Wei Luen, Goh, Boon-Cher, Brunham, Liam R., Tai, Bee-Choo

2018

Overview

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 R 2  = 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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adult / Age / Aged / Aged, 80 and over / Algorithms / Anticoagulants / Anticoagulants - administration & dosage / Anticoagulants - pharmacology / Anticoagulants - therapeutic use / Asian Continental Ancestry Group / Asian people / Biomedicine / Clinical medicine / CYP2C9 / Cytochrome / Cytochrome P-450 / Cytochrome P450 / Dosage and administration / Drug therapy / Evidence-based medicine / Female / Genetic polymorphisms / Genotype / Genotype & phenotype / Genotypes / Haplotypes / Humans / Male / Maximum Tolerated Dose / Medicine / Medicine & Public Health / Middle Aged / Patients / Pharmacogenetics / Pharmacogenomics / Precision medicine / Research Article / Thromboembolism / Thrombosis / VKORC1 / Warfarin / Warfarin - administration & dosage / Warfarin - pharmacology / Warfarin - therapeutic use / Young Adult