Efficacy and safety of Chinese herbal medicine Wen Xin granules for the treatment of unstable angina pectoris with Yang deficiency and blood stasis syndrome: study protocol for a randomized controlled trial

Coronary heart disease (CHD), aka ischemic heart disease, has remained as the leading cause of death worldwide over the past decade (WHO 2018) [1]. As one of the risk types of CHD, unstable angina pectoris (UAP) is a clinical syndrome intermediate in severity between stable angina and acute myocardial infarction (AMI). It is also referred to as crescendo or pre-infarction angina [2]. UAP is thought to be caused by a progression in the severity and extent of coronary atherosclerosis, coronary artery spasm, or bleeding into non-occlusive plaques in the coronary artery. It eventually can result in complete occlusion of the artery [3]. The medication therapy for UAP mainly includes antiplatelet, anticoagulation, vasodilation, and relieving coronary constriction. Revascularization including coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI) is indicated effective in certain high-risk individuals and also has been shown to improve angina. However, even after revascularization, a substantial percentage of patients return with recurrent or continued angina, requiring newer and better therapies [4‐6]. Standard drug therapy and invasive revascularizatio​n are effective in decreasing progression to infarction, reducing symptoms and multiple hospitalizations, but without a decrease in the long-term mortality rate in most cases [7]. There are still many patients suffering from persistent or recurrent angina after standard medical therapy and/or revascularization [8, 9]. The causes may be related to coronary spasm, thrombosis, in-stent restenosis, untreated vascular stenosis, coronary microvascular lesions, or psychological factors [10]. Chinese herbal medicine (CHM) either in single herb or in herbal formula has been commonly used for treating UAP in China for many years. And more and more researches are focusing on the exploration of effective Chinese herbal formula for the prevention and treatment of UAP. According to the theory of traditional Chinese medicine (TCM), all the related symptoms and signs in a certain disease phase are generalized to a syndrome (Zheng in Chinese), a basic unit and key concept of TCM [11]. Based on years of clinical experience and previous researches, we identified that Yang deficiency and blood stasis syndrome is the main pathogenesis of UAP. In TCM theory, Yang and Yin are the most fundamental concepts, which represent two inter-opposite aspects existing within one object or the two inter-opposite things or forces. Yang is generally associated with items or concepts that are warm, bright, moving, and ascending [12]. Yang has the function of promoting blood circulation. If Yang is deficient and unable to promote blood circulation, the blood stasis syndrome will be formed. Therefore, we consider ‘Warming Yang and activating blood circulation’ as the main principle of treatment. As an experienced prescription, Professor Li Jun has used Wen Xin decoction for the treatment of UAP with Yang deficiency and blood stasis syndrome in the clinic for about 20 years. Previous studies showed that Wen Xin decoction could regulate blood lipid, improve hemodynamics and the clinical symptoms, and reduce inflammation and the incidence of non-fatal myocardial infarction [13‐16]. However, due to the small sample size and the relatively short follow-up period, the curative effect of Wen Xin decoction still needs to be verified by large-scale clinical trials. This multi-center, double-blind, randomized, placebo-controlled trial aims to evaluate the efficacy and safety of Wen Xin granules in patients with UAP.

Syndrome differentiation and treatment is a central focus of TCM. According to the theory of TCM, UAP can be divided into a variety of syndromes according to different clinical manifestations. Among these syndromes, Yang deficiency and blood stasis syndrome is the most common type in middle-aged and elderly patients who generally manifest as chest tightness, chest pain, aversion to cold, lack of warmth in the limbs, shortness of breath, tiredness, palpitation, and loose stool. Wen Xin decoction is a compound prescription of TCM which contains 13 Chinese herbs. Most of the herbs have been proved to have cardiovascular pharmacological effects. For instance, the extracts of Codonopsis pilosula can protect myocardial cells, enhance hematopoietic function, inhibit platelet aggregation, and improve heart function [22]. Pericarpium trichosanthis extract, Rhizoma Chuanxiong extract and tanshinone, Danshensu, catecholamine, and salvianolic acid A in Salvia miltiorrhiza have effects of protecting myocardium, anticoagulant, antiplatelet aggregation, antiatherosclerosis, and anti-inflammatory [23‐25]. Although previous studies have identified that Wen Xin decoction was effective in improving clinical symptoms of patients with UAP. However, its long-term effect still needs further observation. Besides, the sample sizes of those studies were small and no studies reported the method of random sequence generation or described allocation concealment. Blinding is an essential method for preventing research outcomes from being influenced by either the placebo effect or the observer bias. However, no study reported the blinding of participants. Moreover, no placebo control was used to mask researchers and participants. This double-blind, randomized, placebo-controlled trial was carried out to test the short-term and long-term effects of Wen Xin granular through the comparison between an intervention group and a placebo group. To ensure appropriate high-quality methodology and strict quality control, this protocol was developed in accordance with the Standard Protocol Items: Recommendations for Interventional Trials 2013 [26]. The method of recruitment, randomization and allocation concealment, and data collection are described in detail.

Our study has some limitations. One limitation is that decoctions were used in previous studies, but granules are applied in this study. Because placebo decoction is more difficult to make than granular placebo. In another way, compared with decoctions, granules are more convenient for patients, and patient compliance may be increased. Another limitation is that the intervention time is relatively short since the prescription always needs to be adjusted according to the change of patients’ symptoms.