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

Abstract

BackgroundGenotype-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.MethodsAn 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.ResultsAmong 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%.ConclusionsAmong 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 registrationClinicalTrials.gov NCT00700895. Registered on June 19, 2008.Electronic supplementary materialThe online version of this article (10.1186/s12916-018-1093-8) contains supplementary material, which is available to authorized users.

Artificial Intelligence, Machine Learning, and Cardiovascular Disease

“…standard dosing. Similar results were found by Syn et al 24 in Asian patient population on warfarin therapy. Li et al 25 have also utilized back propagation neural network model for predicting the warfarin maintenance dose after heart valve replacement.…”

“…[19][20][21][22] There are several cardiovascular drugs which are being explored as therapeutic targets including clopidogrel, warfarin, and statins particularly simvastatin. [21][22][23][24] Interestingly, pharmacogenomics and precision medicine has already made a big impact on the warfarin dosing in different patient populations as shown in the randomized clinical trials done by Pirmohamed et al 23 and Syn et al 24 Pirmohamed et al 23 showed that the patients on pharmacogenetic-based warfarin dosing had greater time in the therapeutic international normalized ratio (INR) range than the patients with Hidden layers can be from one to several layers.…”

Effect of Gene-Based Warfarin Dosing on Anticoagulation Control and Clinical Events in a Real-World Setting

“…Subsequently, GBWD had less of an effect on anticoagulation control, and multiple-dose titrations might have had a greater role. The finding that the TTR was shorter in the GBWD group is similar to that observed in the GIFT, EU-PACT, and COUMAGEN-II trials Wen et al, 2017) but different from that in the COAG study and other Asian-based studies Gage et al, 2017;Syn et al, 2018;Zhe et al, 2018). Our study revealed that GBWD resulted in a lower prevalence of bleeding events related to anticoagulation therapy, which may have been due to superior primary outcomes.…”

Genetic and phenotypic frequency distribution of CYP2C9, CYP2C19 and CYP2D6 in over 3200 Han Chinese

“…Consistent with these findings, a more recent randomized clinical trial by Syn et al, 9 involving 322 patients of Asian ancestry, found that, when starting anticoagulation, PGx algorithms were superior to traditional dosing at guiding warfarin therapy during the first 2 weeks, and also accurately predicted maintenance dosing. As more time passes, many of the current controversies regarding PGx testing may be settled, and the growing body of convincing evidence emerging from clinical trials will likely reiterate the need to conduct preemptive PGx testing 9 …”

“…Additionally, the Genetic Informatics Trial (GIFT) demonstrated that genotype‐guided dosing of warfarin was able to lower the risk of major haemorrhage, venous thrombus/embolism and death among patients undergoing elective hip/knee joint replacement and receiving warfarin therapy during the perioperative period, when compared with routine clinical drug dosing 8 . Consistent with these findings, a more recent randomized clinical trial by Syn et al, 9 involving 322 patients of Asian ancestry, found that, when starting anticoagulation, PGx algorithms were superior to traditional dosing at guiding warfarin therapy during the first 2 weeks, and also accurately predicted maintenance dosing. As more time passes, many of the current controversies regarding PGx testing may be settled, and the growing body of convincing evidence emerging from clinical trials will likely reiterate the need to conduct preemptive PGx testing 9 …”