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

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

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.

Keywords: atrial fibrillation; control groups; pharmacogenetics; randomized controlled trial; warfarin.

Conflict of interest statement

None.

Figures

Figure 1.
Figure 1.
Consort diagram detailing the total number of participants recruited, withdrawn, and analyzed. *A list of the exclusion criteria appears in the Data Supplement. †Plans for surgery, discovery of cancer, or other health reasons.
Figure 2.
Figure 2.
Percentage of time in the therapeutic international normalized ratio (INR) range, Kaplan-Meier plots of time to reach therapeutic INR, and Kaplan-Meier plots of time to reach a stable warfarin dose.A, Percentage of time in the therapeutic INR range during the first 12 wk by treatment groups (genotype-guided dosing group vs standard dosing group). B, Within 1 to 12 wk, percentages of patients with INR reaching therapeutic range in control and genotype-guided dosing groups. C, Within 1 to 12 wk, percentages of patients reaching a stable warfarin dose in control and genotype-guided dosing groups.

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