Meta analysis of the efficacy of western medicine combined with Qiliqiangxin capsule versus western medicine alone in the treatment of chronic heart failure

YANG Min, LU Jian-qi, PANG Yan, ZHOU Jia-tan, LUO Wen-kuan

1. Guangxi University of Traditional Chinese Medicine, Nanning 530001, China

2. National Center for Clinical Medical Research of Cardiovascular Diseases of Traditional Chinese Medicine, Department of Cardiology, First Affiliated Hospital of Guangxi University of Traditional Chinese Medicine, Nanning 530023, China

Keywords:

ABSTRACT Objective: To compare the clinical efficacy of conventional Western medicine combined with Qiliqiangxin capsule and western medicine alone in the treatment of chronic heart failure, and to prove that Qiliqiangxin capsule combined treatment has more advantages,providing reference for clinical decision-making in the treatment of chronic heart failure.Methods: Randomized controlled trials (RCTs) of conventional Western medicine treatment and Western medicine combined with Qiliqiangxin capsule in the treatment of chronic heart failure were searched in databases such as PubMed, Embase, Webofscience, CNKI, WanFang,VIP, and CBM.The bias risk assessment was conducted using the RCT tool recommended by Cochrane, and then the meta-analysis was performed using RevMan5.4 and Stata17 software.Compare the efficacy evaluation of cardiac function, left ventricular ejection fraction (LVEF),left ventricular end diastolic diameter (LVEDD), cardiac stroke output (SV), 6-minute walking test (6MWT), and N-terminal proBNP in the conventional western medicine combined with Qiliqiangxin capsule group (hereinafter referred to as the treatment group) and the conventional western medicine group (hereinafter referred to as the control group).Results: A total of 20 RCTs meeting the criteria were included, including 2953 patients, including 1508 in the treatment group and 1445 in the control group.The results of meta-analysis showed that the treatment group had significantly better cardiac function evaluation, LVEF, LVEDD, SV,6MWT, and NT-proBNP improvement than the control group.Its central functional efficacy evaluation (OR=2.09,95% CI: 1.71-2.55, P<0.001), LVEF (WMD=7.05,95% CI: 5.30-8.79,P<0.00001), LVEDD (WMD=6.73, 95% CI: 3.18-10.29, P=0.0002), SV (WMD=6.73, 95%CI: 3.18-10.29, P=0.0002), 6MWT (SMD=0.70,95% CI: 0.54-0.87, P<0.00001), NT-proBNP(SMD=-1.95,95% CI: -2.5 2 to 1.38 (P<0.0001), with statistically significant differences.Conclusion: Conventional western medicine combined with Qiliqiangxin capsule can significantly improve the clinical efficacy of heart failure, improve LVEF, LVEDD, SV, and NT-proBNP index, and improve exercise tolerance.It is worth using for reference in the treatment.

1.Introduction

Chronic heart failure (CHF) is a clinical syndrome characterized by difficulty breathing, lower limb edema, and fatigue.It is the end-stage manifestation and main cause of death of cardiovascular disease.According to epidemiological reports, the incidence rate of CHF is increasing every year, and the mortality rate has risen sharply in recent years, reaching 20% in one year and 53% in five years[1,2].As the population of CHF patients continues to grow,research literature on how to reduce cardiovascular adverse events,improve quality of life, and extend lifespan in CHF patients is also increasing year by year[3].The 2022 AHA/ACC/HFSA Heart

Failure Management Guidelines[4] changed the CHF basal drug to“new quadruple”[5], including renin angiotensin system inhibitors(such as Shakubatravalsartan, Enalapril, etc.) β Receptor blockers(such as bisoprolol, metoprolol succinate sustained-release agents,etc.), mineralocorticoid receptor antagonists (such as eplerenone,spironolactone, etc.), sodium glucose cotransporter 2 inhibitors(recommended when CHF has symptoms, regardless of the presence of type 2 diabetes, such as daggliflozin, enggliflozin, etc.).

Traditional medicine categorizes chronic heart failure into categories such as asthma, cardiac fluid, and edema based on clinical manifestations.For the first time in the “Twelfth Five Year Plan” textbook of “Internal Medicine of Traditional Chinese Medicine”, the concept of “heart decline disease” has been added.Its pathogenesis is based on deficiency and excess, with heart qi and heart yang deficiency as the foundation, and tangible solid pathogens such as stasis of blood, water consumption, and phlegm turbidity as the standard.Therefore, in clinical practice, warming yang and supplementing qi, promoting blood circulation and diuresis are the main treatment methods.Qili Qiangxin Capsule has the effects of tonifying qi, warming yang, promoting blood circulation,unblocking collaterals, promoting diuresis, and reducing swelling.Research has shown that Qiliqiangxin Capsules contain effective ingredients such as astragaloside A, hairy stamen isoflavone glucoside, and mangiferin, which can inhibit myocardial fibrosis,improve myocardial energy metabolism, regulate inflammatory reactions, and control blood pressure, and can delay the development of CHF[8].This study used meta-analysis to collect RCTs literature on the treatment of CHF with Qiliqiangxin capsules combined with Western medicine and simple Western medicine.The efficacy of the two was evaluated and compared, providing evidence-based medical evidence for the combination of Qiliqiangxin capsules to improve the quality of life, reduce readmission, and reduce mortality in CHF patients.

2.Materials and Methods

2.1 Literature Retrieval Strategy

The research object is RCTs that have been publicly published both domestically and internationally with the addition of Qiliqiangxin Capsules for the treatment of CHF.Computer retrieval of publicly published literature on PubMed, Embase, Webofscience, CNKI,Wanfang, VIP, and China Biomedical Literature Database is set from the establishment of the database until 2023.The retrieval adopts a combination of subject words and free words, and adjustments are made based on specific data bases.English search terms include: Heartfailure, qiliqiangxincapsule, randomized controlled trial, randomized, etc; Chinese search terms include: heart failure,heart failure, chronic heart failure, chronic heart failure, chronic heart failure, Qiliqiangxin capsule, randomized controlled trial,randomized trial, RCT, etc.

2.2 Literature inclusion criteria

2.2.1 Document type

Clinical observation related RCTs research is limited to both Chinese and English.

2.2.2 Research subjects

For patients who meet the diagnosis of CHF, the diagnostic criteria refer to the AHA/ACC/HFSA Heart Failure Management Guidelines in 2022[4] issued by the United States, and the Chinese Medicine Diagnosis and Treatment Guidelines for Chronic Heart Failure(2022) issued by the Cardiovascular Branch of the China Association of Chinese Medicine in 2023[9], and patients with cardiac functionⅡ - Ⅳ and left ventricular ejection fraction (LVEF) 50% are included according to the NYHA classification.

2.2.3 Intervention measures

The control group was treated with conventional Western medicine,with the treatment method referring to the 2022 AHA/ACC/HFSA Heart Failure Management Guidelines[4].The treatment group was supplemented with Qili Qiangxin capsules on the basis of conventional Western medicine.

2.2.4 Efficacy indicators

Evaluation of cardiac function efficacy (significant effect: cardiac function is improved by Level II or above or reaches Level I, and all symptoms of the patient basically disappear; effective: cardiac function is improved by Level I, and all symptoms of the patient are significantly relieved; ineffective: all symptoms and cardiac function of the patient are not improved or even worsened), left ventricular ejection fraction (LVEF), left ventricular end diastolic diameter(LVEDD), cardiac stroke volume (SV), 6-minute walk test (6MWT),and N-terminal brain natriuretic peptide precursor (NT proBNP).

2.3 Exclusion criteria for literature

(1) Literature that does not meet RCT requirements; (2) Literature with inconsistent or imprecise experimental design (such as: the treatment group using other drugs or methods for intervention in addition to the control group using Qiliqianxin capsules; the general description of the sample data is not clear, etc.); (3) Repeated publications or data with repetitive, systematic reviews, animal experiments, conferences, and other literature; (5) Literature with inconsistent efficacy indicators; (6) Patients with acute heart failure,acute attack of chronic heart failure, acute myocardial infarction,pulmonary heart disease, hypertrophic cardiomyopathy, congenital heart disease, and patients with atrial fibrillation, sick sinoatrial node syndrome, high atrioventricular block, diabetes, and severe liver and kidney dysfunction.(7) Literature with a treatment period of less than 4 weeks[10] and a sample size of less than 120 cases[11].

2.4 Literature Screening and Data Extraction

Two researchers independently screen and extract the extracted data, and after completion, exchange and verify the extracted data with each other.If there are any differences, please ask a third researcher to discuss and make a decision together.The first step is to search the Chinese and English databases, download literature that meets the requirements, import all literature into NoteExpress to check for duplicates and eliminate duplicate parts.The second step is to read the literature title and abstract for preliminary exclusion.The third step is to read the entire text of the preliminarily selected literature, eliminate literature with incomplete data and inconsistent experimental design, and record the reasons for the exclusion.Step 4: Excel 2010 is used to extract data from the finally included literature, including the name of the lead author, publication time,number of patients, intervention measures, treatment course, efficacy indicators and other information.

2.5 Literature Quality Evaluation

Use the RCT bias risk assessment tool recommended by CochraneHandbook5.1.0 to evaluate the quality of the final included literature.The evaluation contents mainly include: random allocation method, allocation concealment, subject blindness, research result blindness, data integrity, selective reporting and other biases.And the literature quality was rated as three levels: “l(fā)ow risk bias,” “high risk bias,” and “unclear.”

2.6 Statistical Methods

RevMan5.4 and Stata17.0 software were used for analysis.Counting data were expressed using odds ratio (OR) and 95%confidence interval (95% CI), while econometric data were analyzed using weighted mean difference (WMD) and its 95% CI.Q-test and I2test were used to assess the heterogeneity of the included literature.When I250% and P>0.1, a fixed effects model was used for analysis, while a random effects model was used for analysis.When P<0.05, the difference is statistically significant.

3.Results

3.1 Literature Screening Results

A total of 2920 relevant literature were obtained through preliminary computer search, and 20 RCTs were ultimately included through screening[12-31], all of which are Chinese literature.The literature screening process is shown in Figure 1.

Fig 1 Literature screening flow chart for comparison of clinical efficacy between Western medicine combined with Qiliqiangxin capsule and Western medicine alone in the treatment of CHF

3.2 Basic characteristics of inclusion in the study

A total of 20 RCTs were ultimately included[12-31], including 2953 patients, including 1 508 in the treatment group and 1 445 in the control group.The basic characteristics of the included research literature are shown in Table 1.

3.3 Literature quality evaluation

The included RCTs were evaluated for literature quality using CochraneHandbook5.1.0, and 7 of them[13,18,22,26,28,29,31] did not exhibit any high risk.In the random allocation scheme, 6 articles [12-14,16,19,20] were allocated using the random number table method,1 article[24] was randomly allocated according to the order of visits,and the rest only mentioned the word “random” without describing the allocation method.In terms of allocation concealment, one article[29] provided a control group with the same appearance as Qiliqiangxin capsules in the experiment.In terms of the completeness of the results data, one article[20] reported that one case withdrew from the study due to surgical treatment for trauma, while the remaining literature did not drop out during the study process.The evaluation results are shown in Figures 2 and 3.

3.4 Meta analysis results

3.4.1 Evaluation of cardiac function efficacy

A total of 11 articles[15,19-25,27,28,31] evaluated the efficacy of cardiac function, as shown in Table 2.After heterogeneity testing,I2=0%<50%, Q test P=0.946>0.1, indicating that there is no heterogeneity (heterogeneity is not statistically significant) betweenthese 11 articles.Therefore, fixed effects were chosen to merge the effects.Result: There was a statistically significant difference in efficacy evaluation between the two groups (OR=2.09,95% CI: 1.71-2.55, P<0.001), indicating that the efficacy of conventional Western medicine combined with Qiliqianxin capsules in the treatment of CHF is significantly better than that of simple Western medicine.As shown in Figure 4.

Fig 2 Comparison of the efficacy of Western medicine combined with Qiliqiangxin capsule and western medicine alone in the treatment of CHF:risk ratio of bias included in the literature

3.4.2 LVEF

A total of 20 articles[12-31] reported LVEF.After heterogeneity testing, there was significant heterogeneity between the studies(P<0.1, I2=94%).Sensitivity analysis showed no significant decrease in heterogeneity, so a random effects model was used for meta-analysis.The results showed that the treatment group could significantly improve the LVEF of patients, and there was a statistically significant difference compared to the control group(WMD=7.05, 95% CI: 5.30-8.79, P<0.000 01).This suggests that the combination of Qiliqiangxin capsules on the basis of conventional Western medicine treatment can effectively improve the heart function of CHF patients, and its effect is better than that of simple Western medicine treatment.As shown in Figure 5.

Fig 3 Comparison of clinical efficacy of western medicine combined with Qiliqiangxin capsule and western medicine alone in the treatment of CHF

Tab 2 RCT intervention results compared with the efficacy of the treatment group and the control group after treatment of CHF

Fig 4 Comparison of therapeutic effects between treatment group and control group after treatment of CHF

3.4.3 LVEDD

A total of 13 articles[13,15-17,20,21,23-29] reported LVEDD, with a total of 1979 cases.After heterogeneity testing, there was significant heterogeneity between the studies (P<0.1, I2=87%).After sensitivity analysis, it was found that no article had a significant impact on heterogeneity.Therefore, a random effects model was used for meta-analysis.The results showed that the treatment group could significantly reduce the LVEDD level of patients, and the difference was statistically significant compared to the control group (WMD=-4.20, 95% CI: -5.29-3.12, P<0.000 01).Please refer to Figure 6 for details.

3.4.4 SV

A total of 4 articles[12,15,22,31] reported SV before and after treatment, with a total of 551 cases.After heterogeneity testing, there was statistical heterogeneity between the studies (P<0.1, I2=89%).Sensitivity analysis found that no article had a significant impact on heterogeneity, so random effects were used to merge the effect measures.The results showed that the SV of the treatment group after treatment was significantly higher than that of the control group, with a statistically significant difference compared with the control group (WMD=6.73, 95% CI: 3.18～10.29, P=0.000 2).It showed that the combination of western medicine and Qiliqiangxin capsule could significantly increase the stroke volume of patients’hearts, improve the decline of cardiac function, and the effect was better than that of western medicine alone.As shown in Figure 7.

Fig 5 Comparison of LVEF between treatment group and control group after treatment of CHF

Fig 6 Comparison of LVEDD levels between the treatment group and the control group after treatment of CHF

3.4.5 6MWT

A total of 5 articles[13,18,25,29,30] used 6MWT as the outcome indicator, with a study population of 803 cases.Due to the significant difference in the mean and standard deviation of baseline 6MWT between different literature, standardized mean difference (SMD)was used as the effect measure.Heterogeneity testing showed significant heterogeneity among the studies (P=0.01, I2=68%).Sensitivity analysis of the included studies found that Li Zheng’s study[25] had a significant impact on heterogeneity, and after excluding the literature, heterogeneity decreased (P=0.18, I2=38%).The fixed effects model was used to merge the effects, and the results showed that the treatment group could significantly improve the exercise tolerance (6-minute walking distance) of CHF patients, with a statistically significant difference compared to the control group(SMD=0.70, 95% CI: 0.54-0.87, P<0.000 01).As shown in Figure 8.

Tab 3 Main Effective Components and Pharmacological Effects of Qiliqiangxin Capsule

3.4.6 NT-proBNP

A total of 14 articles[12,16,17,19,20,22-27,29-31] used NT proBNP as the evaluation indicator, with a total of 2087 participants.Due to the different units used to test serum NT proBNP between studies,SMD was used as the effect measure.After heterogeneity testing,it was found that there was significant heterogeneity among the literature (P<0.1, I2=97%), and there was no significant decrease in heterogeneity after sensitivity analysis.Therefore, a random effects model was used to merge the effect quantities.The results showed that the treatment group could significantly reduce serum TNproBNP levels, with a statistically significant difference compared to the control group (SMD=-1.95,95% CI: -2.52-1.38, P<0.000 1).As shown in Figure 9.

Fig 8 Comparison of 6 MWT between the treatment group and the control group after trea-tment of CHF

Fig 9 Comparison of NT-proBNP levels between the treatment group and the control group after treatment of CHF

4.Discussion

CHF is a clinical syndrome characterized by various causes of abnormal cardiac structure or function, resulting in dysfunction of ventricular contraction or diastolic function.It is the ultimate destination of most cardiovascular diseases[32].Traditional Chinese medicine believes that CHF is based on the deficiency of heart qi and heart yang, and is marked by the blockage of tangible solid and pathogenic factors such as blood stasis, water intake, and phlegm turbidity.In treatment, it is necessary to supplement deficiency and eliminate solid.CHF can cause myocardial hypertrophy and fibrosis, leading to ventricular remodeling, thereby stimulating proinflammatory cytokines to enhance their secretion ability, which in turn exacerbates ventricular remodeling and leads to a vicious cycle[33].The “Guidelines for the Diagnosis and Treatment of Chronic Heart Failure in Traditional Chinese Medicine (2022)”strongly recommends Qili Qiangxin Capsule as a treatment drug for heart failure with reduced ejection fraction.Qili Qiangxin Capsules contain 11 traditional Chinese medicines, including Astragalus membranaceus, Ginseng, Aconite, Chenpi, Danshen, Guizhi,Tinglizi, Alisma orientalis, Safflower, Yuzhu, and Xiangjiapi.Among them, Huangqi and Fuzi are the foundation for treating deficiency of qi and yang, and are the rulers; Ginseng, Danshen, and Tinglizi all play the role of tonifying qi, promoting blood circulation, and promoting diuresis, serving as ministers.Modern pharmacology finds that these five drugs can improve myocardial energy metabolism, reduce myocardial injury, inhibit cardiac remodeling,protect vascular endothelial cells, promote angiogenesis, and inhibit inflammatory reaction, as shown in Table 3 below.

Research[57,58] has shown that Qiliqiangxin capsules have functions such as reducing cardiac volume load, increasing myocardial contractility and cardiac output, expanding blood vessels, protecting myocardial endothelial cells, inhibiting myocardial fibrosis and apoptosis, inhibiting ventricular remodeling, improving myocardial energy metabolism, regulating immune and endocrine functions.Ji Xiaodi et al.[59] found that Qili Qiangxin Capsules can regulate miRNA-133a/TGF by regulating- β 1/Smads signaling pathway improves myocardial tissue fibrosis in rats with myocardial infarction.Wang Shikai et al.[60] found that Qiliqiangxin capsule can improve the left ventricular end systolic diameter (LVESD),interventricular septum thickness (IVS), LVEF and LVEDD levels in rats with heart failure, thereby reversing ventricular remodeling.Chen Jun et al.[61] found that Qiliqiang Xin Capsule can reduce the damage caused by oxygen free radicals to myocardial cells through the renin angiotensin aldosterone (RAAS) system, thereby improving the anti hypoxia ability of myocardial cells and delaying heart failure.

This study showed that the treatment group significantly improved the evaluation of cardiac function efficacy, LVEF, SV, and 6MWT compared to the control group, while the LVEDD and NT proBNP indices decreased, all of which were statistically significant,reflecting the good therapeutic effect of Qili Qiangxin Capsule.However, there are still the following limitations in this study: (1)According to the analysis of the composition, Qiliqiangxin Capsule is suitable for patients with Yang deficiency and blood stasis syndrome.However, most of the selected studies have not been included according to the syndrome type.It is recommended to conduct comparative studies on whether to differentiate symptoms and further clarify the applicable symptoms to improve the research value; (2) The quality of the included literature is relatively low.Except for a small portion describing the random allocation method, most of the other literature did not describe the random allocation method, and only one study used control capsules in the experiment, while the rest did not use placebo.I hope that in future clinical design, more attention will be paid to random allocation methods, hidden allocation schemes, and blind methods; (3) In the literature included in this study, there were differences in the causes and proportions of CHF, as well as differences in the drugs used for Western medicine treatment and the duration of medication.However, the combination of Qiliqiangxin capsules significantly improved the relevant indicators, proving that Qiliqiangxin capsules combined with conventional Western medicine are effective in treating CHF caused by different causes.

Author’s contribution and conflict of interest explanation: Yang Min: overall concept, data extraction and management, software operation, and paper writing; Lu Jianqi: topic selection, guidance and supervision, paper review and revision; Pang Yan: Paper review and revision, overall control; Zhou Jiatan: Methodology design,data extraction and management; Luo Wenkuan: Data review, paper revision.All authors declare that there is no conflict of interest relationship.