Detection of an anti-angina therapeutic module in the effective population treated by a multi-target drug Danhong injection: a randomized trial
Authors: Liu Jun , Li Dan-Dan , Dong Wei , Liu Yu-Qi , Wu Yang , Tang Da-Xuan , Zhang Fu-Chun , Qiu Meng , Hua Qi , He Jing-Yu , Li Jun , Du Bai , Du Ting-Hai , Niu Lin-Lin , Jiang Xue-Jun , Cui Bo , Chen Jiang-Bin , Wang Yang-Gan , Wang Hai-Rong , Yu Qin , He Jing , Mao Yi-Lin , Bin Xiao-Fang , Deng Yue , Tian Yu-Dan , Han Qing-Hua , Liu Da-Jin , Duan Li-Qin , Zhao Ming-Jun , Zhang Cui-Ying , Dai Hai-Ying , Li Ze-Hua , Xiao Ying , Hu You-Zhi , Huang Xiao-Yu , Xing Kun , Jiang Xin , Liu Chao-Feng , An Jing , Li Feng-Chun , Tao Tao , Jiang Jin-Fa , Yang Ying , Dong Yao-Rong , Zhang Lei , Fu Guang , Li Ying , Huang Shu-Wei , Dou Li-Ping , Sun Lan-Jun , Zhao Ying-Qiang , Li Jie , Xia Yun , Liu Jun , Liu Fan , He Wen-Jin , Li Ying , Tan Jian-Cong , Lin Yang , Zhou Ya-Bin , Yang Jian-Fei , Ma Guo-Qing , Chen Hui-Jun , Liu He-Ping , Liu Zong-Wu , Liu Jian-Xiong , Luo Xiao-Jia , Bin Xiao-Hong , Yu Ya-Nan , Dang Hai-Xia , Li Bing , Teng Fei , Qiao Wang-Min , Zhu Xiao-Long , Chen Bing-Wei , Chen Qi-Guang , Shen Chun-Ti , Wang Yong-Yan , Chen Yun-Dai , Wang Zhong 
Published: September 2021

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 Zsummary 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 (r2: 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).