Dataset Information

Genotype-Guided Dosing of Warfarin in Chinese Adults: A Multicenter Randomized Clinical Trial.

ABSTRACT: BACKGROUND:Warfarin is an effective treatment for thromboembolic disease but has a narrow therapeutic index; optimal anticoagulation dosage can differ tremendously among individuals. We aimed to evaluate whether genotype-guided warfarin dosing is superior to routine clinical dosing for the outcomes of interest in Chinese patients. METHODS:We conducted a multicenter, randomized, single-blind, parallel-controlled trial from September 2014 to April 2017 in 15 hospitals in China. Eligible patients were ?18 years of age, with atrial fibrillation or deep vein thrombosis without previous treatment of warfarin or a bleeding disorder. Nine follow-up visits were performed during the 12-week study period. The primary outcome measure was the percentage of time in the therapeutic range of the international normalized ratio during the first 12 weeks after starting warfarin therapy. RESULTS:A total of 660 participants were enrolled and randomly assigned to a genotype-guided dosing group or a control group under standard dosing. The genotype-guided dosing group had a significantly higher percentage of time in the therapeutic range than the control group (58.8% versus 53.2% [95% CI of group difference, 1.1-10.2]; P=0.01). The genotype-guided dosing group also achieved the target international normalized ratio sooner than the control group. In subgroup analyses, warfarin normal sensitivity group had an even higher percentage of time in the therapeutic range during the first 12 weeks compared with the control group (60.8% versus 48.9% [95% CI, 1.1-24.4]). The incidence of adverse events was low in both groups. CONCLUSIONS:The outcomes of genotype-guided warfarin dosing were superior to those of clinical standard dosing. These findings raise the prospect of precision warfarin treatment in China. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02211326.

SUBMITTER: Guo C

PROVIDER: S-EPMC7439928 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Genotype-Guided Dosing of Warfarin in Chinese Adults: A Multicenter Randomized Clinical Trial.

Guo Chengxian C Kuang Yun Y Zhou Honghao H Yuan Hong H Pei Qi Q Li Jingle J Jiang Weihong W Ng Chee M CM Chen Xiaoping X Huo Yong Y Cui Yimin Y Wang Xiaobin X Yu Jingjing J Sun Xue X Yu Wanying W Chen Peng P Miao Da D Liu Wenyu W Yu Zaixin Z Ouyang Zewei Z Shi Xiangjiang X Lv Chunmei C Peng Zijing Z Xiong Guozuo G Zeng Gaofeng G Zeng Jianping J Dai Haiying H Peng Jianqiang J Zhang Yuming Y Xu Fanghua F Wu Jie J Chen Xiaoliang X Gong Hao H Yang Zhiyuan Z Wu Xianming X Fang Qiulian Q Yang Liu L Li Haigang H Tan Hongyi H Huang Zhijun Z Tang Xiaohong X Yang Qiong Q Tu Shan S Wang Xiaoyan X Xiang Yuxia Y Huang Jie J Wang Xiaomin X Cai Jingjing J Jiang Shanjie S Huang Lu L Peng Jinfu J Gong Liying L Zou Chan C Yang Guoping G

Circulation. Genomic and precision medicine 20200608 4

<h4>Background</h4>Warfarin is an effective treatment for thromboembolic disease but has a narrow therapeutic index; optimal anticoagulation dosage can differ tremendously among individuals. We aimed to evaluate whether genotype-guided warfarin dosing is superior to routine clinical dosing for the outcomes of interest in Chinese patients.<h4>Methods</h4>We conducted a multicenter, randomized, single-blind, parallel-controlled trial from September 2014 to April 2017 in 15 hospitals in China. Elig ...[more]

PMID: 32510984

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Project description: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.

Project description:ImportanceWarfarin use accounts for more medication-related emergency department visits among older patients than any other drug. Whether genotype-guided warfarin dosing can prevent these adverse events is unknown.ObjectiveTo determine whether genotype-guided dosing improves the safety of warfarin initiation.Design, setting, and patientsThe randomized clinical Genetic Informatics Trial (GIFT) of Warfarin to Prevent Deep Vein Thrombosis included patients aged 65 years or older initiating warfarin for elective hip or knee arthroplasty and was conducted at 6 US medical centers. Enrollment began in April 2011 and follow-up concluded in October 2016.InterventionsPatients were genotyped for the following polymorphisms: VKORC1-1639G>A, CYP2C9*2, CYP2C9*3, and CYP4F2 V433M. In a 2 × 2 factorial design, patients were randomized to genotype-guided (n = 831) or clinically guided (n = 819) warfarin dosing on days 1 through 11 of therapy and to a target international normalized ratio (INR) of either 1.8 or 2.5. The recommended doses of warfarin were open label, but the patients and clinicians were blinded to study group assignment.Main outcomes and measuresThe primary end point was the composite of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Patients underwent a screening lower-extremity duplex ultrasound approximately 1 month after arthroplasty.ResultsAmong 1650 randomized patients (mean age, 72.1 years [SD, 5.4 years]; 63.6% women; 91.0% white), 1597 (96.8%) received at least 1 dose of warfarin therapy and completed the trial (n = 808 in genotype-guided group vs n = 789 in clinically guided group). A total of 87 patients (10.8%) in the genotype-guided group vs 116 patients (14.7%) in the clinically guided warfarin dosing group met at least 1 of the end points (absolute difference, 3.9% [95% CI, 0.7%-7.2%], P = .02; relative rate [RR], 0.73 [95% CI, 0.56-0.95]). The numbers of individual events in the genotype-guided group vs the clinically guided group were 2 vs 8 for major bleeding (RR, 0.24; 95% CI, 0.05-1.15), 56 vs 77 for INR of 4 or greater (RR, 0.71; 95% CI, 0.51-0.99), 33 vs 38 for venous thromboembolism (RR, 0.85; 95% CI, 0.54-1.34), and there were no deaths.Conclusions and relevanceAmong patients undergoing elective hip or knee arthroplasty and treated with perioperative warfarin, genotype-guided warfarin dosing, compared with clinically guided dosing, reduced the combined risk of major bleeding, INR of 4 or greater, venous thromboembolism, or death. Further research is needed to determine the cost-effectiveness of personalized warfarin dosing.Trial registrationclinicaltrials.gov Identifier: NCT01006733.

Project description:Warfarin is the most common oral anticoagulant. Because of a narrow therapeutic range, interindividual differences in drug responses, and the risk of bleeding, there are many challenges in using warfarin. We need to predict the warfarin maintenance dose. However, ethnic-specific algorithms may be required, and some Chinese algorithms do not perform adequately. Therefore, we aimed to establish a Han Chinese appropriate algorithm.We recruited a study group consisting of 361 Han Chinese patients receiving warfarin treatment who had heart valve replacements. Genotyping of 38 single nucleotide polymorphisms (SNPs) in 13 candidate genes was carried out using the MassARRAY. In the derivation cohort, a multiple linear regression model was constructed to predict the warfarin dosage. We evaluated the accuracy of our algorithm in the validation cohort and compared it with the other 5 algorithms based on Han Chinese and other races.We established a Han Chinese-specific pharmacogenetic-guided warfarin dosing algorithm. Warfarin maintenance dosage (mg/day) = 1.787 - 0.023 × (Age) + 1.151 × (BSA [m]) + 0.917 × (VKORC1 AG) + 4.619 × (VKORC1 GG) + 0.595 × (CYP4F2 TT) + 0.707 × (CYP2C19 CC). It explained 58.3% of the variance in warfarin doses in Han Chinese patients and was superior to the other 5 algorithms. The ability of the 6 algorithms which estimate the required dose correctly was tested. Our model had a mean absolute error of 0.74?mg/day, the other 5 models have mean absolute error of 0.81?mg/day,1.05?mg/day, 1.24?mg/day, 1.18?mg/day, and 0.85?mg/day, respectively. Our model had a mean percentage error of 26.9%, the other 5 models have the mean percentage error of 27.7%, 27.2%, 52.3%, 45.7%, and 29.3%, respectively.Physicians can not adopt algorithm from other race directly to predict warfarin dose in patients with heart valve replacements, they should establish a new algorithm or adjust another algorithm to fit their patients. The algorithm established in this study has the potential to assist physicians in determining warfarin doses that are close to the appropriate doses.

Dataset Information

Genotype-Guided Dosing of Warfarin in Chinese Adults: A Multicenter Randomized Clinical Trial.

Publications

Genotype-Guided Dosing of Warfarin in Chinese Adults: A Multicenter Randomized Clinical Trial.

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