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

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.

Conflict of interest statement

Ethics approval and consent to participate

The ethics review committees at participating centers approved the study protocol (Additional file 1). The study was conducted in accordance with Good Clinical Practice guidelines, and patients provided written informed consent prior to enrollment. All serious adverse events were reported to the Domain Specific Review Board and the Medical Clinical Research Committee, Ministry of Health in accordance with published guidelines. The study is registered at Consent for publication

Obtained as part of informed consent taking.

Competing interests

The authors declare that they have no competing interests.

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Figures

Fig. 1

Flow of participants through the study of genotype-guided versus traditional-dosing of warfarin. aFurther tests were negative for thrombus. bPotential drug interaction with concomitant corticosteroid medications. cPatients were started on conventional dose of warfarin while awaiting genotype results

Fig. 2

a Number of dose titrations within first 2 weeks of therapy. Dark horizontal lines indicate median values. The circle represents the mean. The top line of the box indicates the 75th percentile, and the bottom line of the box indicates the 25th percentile. The top and bottom whiskers indicate the 97.5th and 2.5th percentiles, respectively. b Non-inferiority and superiority comparison for the primary endpoint of mean difference in number of dose titrations within first 2 weeks of therapy. Error bars indicate two-sided 90% or 95% CI, respectively. Since the upper bound of the 90% CI of the difference in treatment (genotype-guided vs. traditional dosing) was less than 0.5, the genotype-guided strategy was non-inferior to the traditional dosing approach. The upper bound of the 95% CI did not exceed 0, indicating that superiority was also demonstrated

Fig. 3

Secondary endpoints in the study. a Median international normalized ratio (INR) trajectory and 20–80th percentile bands over a 90-day period. b Kaplan–Meier failure functions for the proportion of patients who achieved stable INR, which was not significantly different between treatment groups. Spikes on the Kaplan–Meier curves represent censoring. c and d Number of dose titrations and INR monitoring at 1, 2, and 3 months, predicted using STATA’s post-estimation command

Fig. 4

a Scatterplot of predicted versus actual maintenance dosage. The solid line indicates the line of equivalence, while the dashed line represents the linear fit between algorithm-predicted and actual maintenance warfarin dosages. The plot includes only patients who have achieved stable international normalized ratio (INR), which is defined as attaining therapeutic INR (≥ 1.9 and ≤ 3.1) for two consecutive measurements that are at least 7 days apart. b Bland–Altman assessment of pharmacogenetic dosing model’s predictive performance. Shaded area indicates 95% confidence limits