Detection of an anti-angina therapeutic module in the effective population treated by a multi-target drug Danhong injection: a randomized trial

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 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).

Traditional Chinese medicine injections: where we are after 80-year development

“…Evidence-based medicine is another powerful method for evaluating the efficacy of TCM injections. A number of TCM injection studies related to randomized control trials (RCTs) and meta-analysis were published every year [39][40][41]. Danhong injection (DHI) is a kind of multitarget drug.…”

“…This study further identified the anti-angina therapeutic modules of DHI on the effective population by developing a systemic modular approach. This approach will be helpful to facilitate the modernization of Chinese medicine in confirming therapeutic effects and revealing therapeutic mechanisms [40]. Moreover, the professional TCM clinical evidence database (EVDS) which has been established in 2016 can act as a very powerful tool to provide a reference for the TCM injection clinical effectiveness evaluation [42].…”

Toward better translation of clinical research evidence into rapid recommendations for traditional Chinese medicine interventions: A methodological framework

“…In another example, a recently published RCT found that 14 days of Danhong injection (i.e., a type of Chinese patent medicine) in combination with standard western medicine treatment was more effective than western medicine alone for relieving angina in patients with coronary artery disease, with an increased proportion of patients with clinically significant changes on the angina-frequency, as assessed by the Seattle Angina Questionnaire (difference in proportion: 12.78% [95% CI, 5.86%-19.71%] at day 30 since treatment initiation, 13.82% [95% CI, 6.82%-20.82%] at day 60, and 8.95% [95% CI, 2.06%-15.85%] at day 90). 18 Moreover, a post-market surveillance study showed good tolerance of Danhong injection in a real-world setting, with an incidence rate of adverse drug events (ADEs) being 0.35%, among which 92.6% events were mild to moderate (e.g., pruritus, dizziness, headache, superficial phlebitis, flushing). 19 These studies may not make up sufficient evidence ground for a guideline about the overall clinical application of Danhong injection.…”

“… 19 These studies may not make up sufficient evidence ground for a guideline about the overall clinical application of Danhong injection. But the RCT 18 exploring Danhong injection's improvement of angina may serve as a triggering study, and would be analyzed in combination with the RWE evidence, using the MESERT approach, to develop a rapid recommendation for Danhong injection use in angina management.…”

Molecular Basis Underlying Hepatobiliary and Renal Excretion of Phenolic Acids of Salvia miltiorrhiza Roots (Danshen)

“…DanHong is approved by the Chinese National Medical Products Administration (NMPA) for the treatment of atherosclerotic coronary artery disease and acute ischemic stroke. In a recent adaptive, 31-center, double-blind, randomized controlled trial in 920 patients with stable angina, treatment with 14-days DanHong significantly reduced the number of angina episodes and improved angina-specific health status for at least 90 days, particularly for patients with severe angina, faster heart rate, or diabetes ( Liu et al, 2021 ). It is reassuring that no substantial harm was observed in the clinical trial.…”