Detection of an anti-angina therapeutic module in the effective population treated by a multi-target drug Danhong injection: a randomized trial
Jun Liu, Dandan Li, Wei Dong, Yuqi Liu, Yang Wu, Da-Xuan Tang, Fuchun Zhang, Meng Qiu, Qi Hua, Jingyu He, Jun Li, Bai Du, Tinghai Du, Lin-Lin Niu, Xuejun Jiang, Bo Cui, Jiang-Bin Chen, Yang-Gan Wang, Hairong Wang, Qin Yu, Jing He, Yilin Mao, Xiao-Fang Bin, Yue Deng, Yudan Tian, Qinghua Han, Dajin Liu, Liqin Duan, Mingjun Zhao, Cuiying Zhang, Haiying Dai, Ze-Hua Li, Ying Xiao, You-Zhi Hu, Xiaoyu Huang, Kun Xing, Xin Jiang, Chaofeng Liu, Jing An, Fengchun Li, Tao Tao, Tao Tao, Ying Yang, Dong Yao-rong, Lei Zhang, Guang Fu, Ying Li, Shu-Wei Huang, Liping Dou, Lanjun Sun, Yingqiang Zhao, Jie Li, Yun Xia, Jun Liu, Fan Liu, Wen-Jin He, Ying Li, Jiancong Tan, Jian-Cong Tan, Yabin Zhou, Jian-Fei Yang, Guoqing Ma, Huijun Chen, Heping Liu, He-Ping Liu, Jian-Xiong Liu, Xiaojia Luo, Xiao-Hong Bin, Yanan Yu, Haixia Dang, Bing Li, Fei Teng, Wangmin Qiao, Xiaolong Zhu, Bingwei Chen, Qiguang Chen, Chunti Shen, Chun-Ti Shen, Yundai Chen, Zhong Wang, Yundai Chen, Zhong Wang
Abstract
Abstract It’s a challenge for detecting the therapeutic targets of a polypharmacological drug from variations in the responsed networks in the differentiated populations with complex diseases, as stable coronary heart disease. Here, in an adaptive, 31-center, randomized, double-blind trial involving 920 patients with moderate symptomatic stable angina treated by 14-day Danhong injection(DHI), a kind of polypharmacological drug with high quality control, or placebo (0.9% saline), with 76-day following-up, we firstly confirmed that DHI could increase the proportion of patients with clinically significant changes on angina-frequency assessed by Seattle Angina Questionnaire (ΔSAQ-AF ≥ 20) (12.78% at Day 30, 95% confidence interval [CI] 5.86–19.71%, P = 0.0003, 13.82% at Day 60, 95% CI 6.82–20.82%, P = 0.0001 and 8.95% at Day 90, 95% CI 2.06–15.85%, P = 0.01). We also found that there were no significant differences in new-onset major vascular events ( P = 0.8502) and serious adverse events ( P = 0.9105) between DHI and placebo. After performing the RNA sequencing in 62 selected patients, we developed a systemic modular approach to identify differentially expressed modules (DEMs) of DHI with the Z summary value less than 0 compared with the control group, calculated by weighted gene co-expression network analysis (WGCNA), and sketched out the basic framework on a modular map with 25 functional modules targeted by DHI. Furthermore, the effective therapeutic module (ETM), defined as the highest correlation value with the phenotype alteration (ΔSAQ-AF, the change in SAQ-AF at Day 30 from baseline) calculated by WGCNA, was identified in the population with the best effect (ΔSAQ-AF ≥ 40), which is related to anticoagulation and regulation of cholesterol metabolism. We assessed the modular flexibility of this ETM using the global topological D value based on Euclidean distance, which is correlated with phenotype alteration ( r 2 : 0.8204, P = 0.019) by linear regression. Our study identified the anti-angina therapeutic module in the effective population treated by the multi-target drug. Modular methods facilitate the discovery of network pharmacological mechanisms and the advancement of precision medicine. (ClinicalTrials.gov identifier: NCT01681316).