|Year : 2018 | Volume
| Issue : 4 | Page : 132-137
The traditional Chinese medication nuanxin capsule aids in the treatment of chronic heart failure
Qing Zhou1, Yun Zhang2, Zhongwen Zhang3, Panpan Hao1
1 Shenzhen Research Institute of Shandong University, Shenzhen, Guangdong; Shandong University Qilu Hospital and School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
2 Shandong University Qilu Hospital and School of Basic Medical Sciences, Shandong University, Jinan, Shandong, China
3 Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, Shandong, China
|Date of Web Publication||19-Dec-2018|
Shenzhen Research Institute of Shandong University, Shenzhen 518057, Guangdong; Department of Cardiology, The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Shandong University Qilu Hospital, Jinan 250012, Shandong
Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan 250014, Shandong
Source of Support: None, Conflict of Interest: None
Background: Nuanxin capsule is a standardized Chinese herbal medication that is commonly used alongside conventional treatment for chronic heart failure (CHF) in China. However, whether or not it improves outcomes is unknown due to the lack of high-quality randomized controlled trials (RCTs). Methods: We did a patient-level pooled-analysis of 14 RCTs in which 1112 CHF patients from nine medical centers in China were enrolled. These patients were randomly assigned to treatment with Nuanxin capsule in addition to conventional treatment, conventional treatment with placebo, or conventional treatment alone. Our primary outcomes were mortality and rehospitalization rate. Secondary outcomes included New York Heart Association (NYHA) functional classification, plasma brain natriuretic peptide, 6-min walking distance, echocardiographic parameters, and noninvasive hemodynamic parameters. Results: Treatment with Nuanxin capsule significantly decreased mortality (risk ratio [RR] = 0.30, 95% confidence interval [CI] 0.15–0.58, P = 0.0003, I2 = 0%) and rehospitalization rate (RR = 0.47, 95% CI 0.36–0.62, P < 0.00001, I2 = 0%). Nuanxin capsule therapy also had favorable effects on secondary outcomes. Fail-safe = 0.05 value for NYHA functional classification showed negligible publication bias, with a very low probability that future studies can change the current conclusion. Conclusion: We provided conclusive evidence for the beneficial effects of Nuanxin capsule in patients with CHF.
Keywords: Chinese herbal medication, chronic heart failure, left ventricular function, Nuanxin
|How to cite this article:|
Zhou Q, Zhang Y, Zhang Z, Hao P. The traditional Chinese medication nuanxin capsule aids in the treatment of chronic heart failure. Cardiol Plus 2018;3:132-7
| Introduction|| |
Chronic heart failure (CHF) is a serious global health problem and a major cause of death. As the effectiveness of available therapies is limited, many clinicians adopted traditional Chinese medicine as an adjuvant treatment to modern therapy.
Nuanxin capsule is a standardized Chinese herbal treatment that is commonly used in China for CHF alongside conventional treatment. It is prepared from seven Chinese herbs including Panax Ginseng (Renshen), Radix Aconiti Laterailis Prepareata (Fuzi), Semen Coicis (Yiyiren), Citri Exocarpium Rubrum (Juhong), Panax Notoginseng (Sanqi), Poria Cocos (Fuling), and Rhizoma Pinellinae Praeparata (Fabanxia). Each capsule weighs 0.5 g and standard dosage is three capsules thrice daily. According to previous studies, Nuanxin capsule relieved symptoms and improved prognosis through numerous mechanisms, including positive inotropic action on myocardia and inducing myocardia regeneration. In a study on rats with adriamycin-induced heart failure, Nuanxin capsule significantly reduced serum angiotensin II level and increased superoxide dismutase activity, therefore antagonizing the activation of the renin–angiotensin system (RAS) and oxidative stress caused by heart failure. This may explain why it reduced heart rate and decreased heart size in rats with heart failure. However, available clinical trials were insufficient to draw definite conclusions about the efficacy and safety of this traditional Chinese medication. This study aimed to provide comprehensive and sound evidence of the benefits and harms of Nuanxin capsule in treating CHF.
| Methods|| |
Relevant studies were identified by searching the following data sources: MEDLINE, Global Health, EMBASE, EBSCOhost, Cochrane library, China National Knowledge Internet, VIP, Wanfang and SinoMed databases with the following terms: (“Nuanxin” OR “Nuan Xin”) and (“heart failure” OR “heart decompensation” OR “cardiac failure.”) We also searched for trials from mainstream registries including the World Health Organization International Clinical Trials Registry Platform, Current Controlled Trials and Clinicaltrials.gov trials registry. No language limitation was imposed to literature search.
Selection criteria, data abstraction, and quality assessment
All the included studies were randomized controlled trials (RCTs), and the patients were diagnosed as CHF based on international criteria including Framingham criteria and the criteria of the New York Heart Association (NYHA), the American College of Cardiology, and the American Heart Association., The patients in the traditional Chinese medicine group received Nuanxin capsule and conventional medical therapy, and those in the control group received conventional medical therapy with or without placebo. We excluded trials that were not RCTs or without appropriate data to retrieve. Trials in which patients received other Chinese herbs were also excluded. Primary outcomes were all-cause mortality and rehospitalization rate. Secondary outcomes included NYHA functional classification, plasma brain natriuretic peptide (BNP), 6-min walking distance (6MWD), heart rate, cardiac output, mean arterial pressure, cardiac index, left ventricular ejection fraction (LVEF), left ventricular end-systolic dimension (LVESD), left ventricular end-diastolic dimension (LVEDD), diastolic time, Isovolumic relaxation time, ratio of early to late left ventricular filling velocity (E/A), stroke index, and stroke volume. Two authors (Q. Z. and Z. Z.) independently and in duplicate searched and selected available citations, abstracted data and assessed the methodological quality of the trials. All disagreements were resolved by consensus or third-party adjudication.
Data were analyzed using RevMan version 5.3.5 software (Cochrane Collaboration, London, UK). Heterogeneity between trials was tested by Chi-square and I2 tests. Fixed effects model was adopted for nonheterogeneous results and random effects model for heterogeneous results. A two-tailed P < 0.05 was regarded as statistically significant. Moreover, we assessed publication bias using the fail-safe number (Nfs). Any calculated Nfs value smaller than the number of eligible studies demonstrated obvious publication bias. Nfs = 0.05 was calculated as (ΣZ/1.64)2-κ (κ means the number of eligible studies).
| Results|| |
A comprehensive search identified 41 citations. After deduplication, 35 unique citations were screened by title and abstract, and 23 of these were reviewed at full-text screening. Fourteen RCTs enrolling 1112 patients met the inclusion criteria and were included in our analysis.,,,,,,,,,,,,,,,,,, The reports were published between 2005 and 2017, and all of them were full-text available.
The number of patients enrolled in each study ranged from 40 to 144. The proportion of men was 54.95%. In seven trials, the duration of treatment was 3 months,,,,,,,, and in the remaining seven trials, the durations varied from 2 weeks to 12 months.,,,,,,,,, Patients were randomly administrated Nuanxin capsule or placebo at a dosage of three capsules thrice daily. Four trials were placebo-controlled,,,, and in the remaining 10 trials, the control groups received conventional treatment alone.,,,,,,,,,,,,
Only 5 of the eligible 14 RCTs had a low selection bias in which random number tables were used to generate random sequences.,,,,, One study did well in allocation concealment. In four trials, participants and investigators were blinded to treatment assignment.,,,,
Pooled data of six studies with 627 participants (314 in Nuanxin group and 313 in control group) indicated a statistically significant reduction in death rate in patients treated with Nuanxin capsule as compared with control (risk ratio [RR] = 0.30, 95% confidence interval [CI] 0.15–0.58, P = 0.0003).,,,,,, No significant heterogeneity among the six studies existed (I2 = 0%, P = 1.00) [Table 1]. Treatment with Nuanxin capsule was also associated with a significant decrease in rehospitalization rate as compared with control (RR = 0.47, 95% CI 0.36–0.62, P < 0.00001) without significant heterogeneity among the eligible five trials,,,,, (I2 = 0%, P = 0.80) [Table 1]. Rehospitalization was caused by recurrence of heart failure, acute myocardial infarction, angina pectoris, and stroke.
Analyses from 12 eligible studies,,,,,,,,,,, enrolling 905 patients (454 in Nuanxin group and 451 in control group) showed that Nuanxin group exhibited a significant increase in NYHA functional class compared with control group (odds ratio [OR] = 2.90, 95% CI 1.98–4.26, P < 0.00001) without significant heterogeneity (I2 = 0%, P = 0.98) [Table 1]. Treatment with Nuanxin capsule was associated with a significant reduction in plasma BNP level compared with control group (result from three trials,,, mean difference = −295.15 pg/ml, 95% CI-367.55 to-150.74, P < 0.00001, I2 = 98%). Random effects model was used in this analysis as heterogeneity existed among studies (I2 = 98%, P < 0.00001) [Table 2]. Moreover, treatment with Nuanxin capsule exhibited a significant improvement in 6MWD (result from 5 trials,,,,,,, mean difference = 40.71 m, 95% CI 29.73–51.70, P < 0.00001) without significant heterogeneity among studies (I2 = 46%, P = 0.12) [Table 2]. In addition, results of the pooled analyses demonstrated that LVEF,, mean arterial pressure,, cardiac output,,, cardiac index,,, stroke volume,,, stroke index,, diastolic time,,,, and Isovolumic relaxation time,,, were significantly increased, as well as LVESD,, LVEDD,, and E/A,,, were significantly decreased, in the Nuanxin group in comparison with the control group. Nuanxin capsule had no significant effect on heart rate [Table 2].,
In three studies,, quality of life was measured: Yao used both 36-item Short Form Health Survey (SF-36) and the Minnesota Living with Heart Failure Questionnaire (MHFQ) to evaluate quality of life; Liu et al. only adopted SF-36; and Zou et al. only adopted MHFQ. All of them reported that Nuanxin capsule significantly improved quality of life. No serious adverse events were reported in the Nuanxin group in all the 14 studies.
Nfs = 0.05 for improvement in NYHA functional class was calculated to be 115 and was much greater than the number of included studies, indicating a negligible publication bias.
| Discussion|| |
Our results reveal that Nuanxin capsule is beneficial as an adjuvant to improve not only hard endpoints, including death and rehospitalization but also surrogate endpoints, including symptomatic status, exercise capacity, plasma BNP, echocardiography, and noninvasive hemodynamic monitoring. Treatment with Nuanxin capsule did not increase adverse drug reaction.
Nuanxin capsule appeared to increase cardiac output by positive inotropic action instead of positive chronotropic action as the heart rate remained unchanged. Consistent with our findings, Zhou et al. found that both Nuanxin capsule and digoxin were associated with an elevation in the left ventricular systolic pressure and + dp/dtmax, and no statistically significant difference appeared between the two drugs in a rat model of abdominal aorta narrowing-induced heart failure. In addition, treatment with either Nuanxin or digoxin increased both the left ventricular diastolic pressure and-dp/dtmax, and Nuanxin capsule exerted a stronger effect than digoxin. Thus, both Nuanxin capsule and digoxin could improve left the ventricular systolic function, but Nuanxin capsule improved left ventricular diastolic function to a greater degree. Another study used a rat model of heart failure induced by adriamycin to explore the underlying mechanisms. In this experiment, Nuanxin capsule significantly alleviated cardiomyocyte damage such as sarcoplasmic dissolution and vacuolar degeneration. It reduced circulating angiotensin II and aldosterone concentrations to lower preload and afterload of the heart, and thereafter reverse myocardial remodeling. Nuanxin capsule also elevated SERCA2a activity to facilitate calcium re-uptake into the sarcoplasm. Furthermore, it effectively balanced matrix metalloproteinase (MMP) and tissue inhibitor of metalloproteinase (TIMP) to reverse the structural and component change of the extracellular matrix in myocardia, with increases of MMP-1 and MMP-9 and a decrease of TIMP-1, which were measured by immunohistochemical staining.
Nuanxin capsule is prepared from 7 Chinese herbs. Panax Ginseng is one herb prevalent in China and Korea as a dietary supplement or complementary medication with multiple pharmacological actions and low health risk. Panax Ginseng contains ginsenosides, a class of natural steroid glycosides and triterpene saponins which have been confirmed to upregulate antioxidant enzymes and act as a free-radical scavenger. They are so similar in their structure to some steroid hormones that it is highly likely they act in a similar manner. For example, 60 μM ginsenoside-Rh1 reduced opening frequencies and increased closing times of B, L, and T types of calcium channels in the somatic membrane of cardiomyocytes, and thus mimicked the function of calcium antagonists such as verapamil. In addition, it decreased CK-MB and troponin T levels at a dose of 10 mg/kg. Ginsenoside-Rh1 also exerted anti-atherogenic action by attenuating adhesion of monocytes to human umbilical vein endothelial cells (HUVEC) exposed to 10 ng/mL tumor necrosis factor-alpha through inhibiting the expression of ICAM-1, VCAM-1 and E-selectin in HUVEC and α4/β1 integrin VLA-4 in monocytes. In addition, ginsenoside-Rh1 exerted immunomodulatory, neuroprotective, and anti-microorganism effects as well as estrogenic activity. Ginsenoside-Rh1-related adverse reactions included dyspepsia, flash, insomnia, constipation, and so on. Radix Aconiti Laterailis Prepareata is another important constituent of Nuanxin capsule. Diterpenoid alkaloids, isolated from aconiti, were regarded as its main active ingredients. The alkaloids were effective for neuralgia, rheumatalgia, and cardianeuria due to their significant analgesic activity. This may account for why Nuanxin capsule could alleviate pain and improve quality of life in patients with cardiovascular diseases. Another important component, Semen Coicis, is the seed of adlay which is abundant in China. The amount of amino acids in Semen Coicis accounts for 19.72% of the total weight, 2.2 times of rice, including many branched chain amino acids (17.5%) like leucine and valine, as well as antioxidant amino acids (10.8%) such as tyrosine, cysteine, methionine, and tryptophan. Coix oil, coisenolide, and coisxol extracted from Semen Coicis were demonstrated to exert anticancer, anti-thrombosis and vasodilation effects. Wang et al. found that norcantharidin combined with coix oil suppressed hepatocellular carcinoma growth by inducing apoptosis and regulating cellular immunity. Moreover, Semen Coicis contains various vitamins and mineral elements especially phosphate and zinc. Citri Exocarpium Rubrum, the dried exocarp of Citrus Reticulata Blanco and its cultivars, has long been used in traditional Chinese medicine to protect the stomach and make expectoration easy. Its bioactive ingredients mainly consist of hesperidin, nobiletin, and tangeretin. Hesperidin (3, 5, 7-trihydroxy-4-methoxy-flavanone-7-rhamnglucoside) has been demonstrated to exert antioxidant, anti-inflammatory, and anti-cancer effects in clinical trials. Two recent studies revealed that hesperidin effectively lowered blood pressure, reduced inflammation, and alleviated oxidative DNA damage as well as lipid peroxidation in patients with type 2 diabetes. In addition, it reduced endogenous glucose production and increased glucose transport to pancreatic β cells, and peripheral tissues thus could act as an adjuvant in the treatment of diabetes. Panax Notoginseng is called as “miracle root for the preservation of life” in Asia and its one bioactive ingredient, Panax Notoginseng Saponin, proved to reduce D-galactose-induced apoptosis of rat cardiomyoblasts H9c2 cell line by upregulation of antioxidative ability. In addition, Panax Notoginseng Saponin exerted anti-inflammation effects by controlling Th17 cell proliferation and differentiation through downregulating the expression of inflammatory cytokines and cell-cycle genes. The drug-drug interaction was found to exist between Panax Notoginseng and salicylic acid. Salicylic acid could destroy tight junction protein to broaden the intercellular space and enhance absorption of Panax Notoginseng, and serum salicylic acid concentration was elevated when Panax Notoginseng was given as a supplement. Ethanol and ethyl acetate was extracted from the surface layer of Poria Cocos and had diuretic and anti-fibrotic effects. Three types of poricoic acids, isolated from ethyl acetate extract were recognized as novel RAS inhibitors and suppressed TGF-β/Smad3 and Wnt/β-catenin pathways. Therefore, Poria Cocos could exert cardioprotective and diuretic effects, mimicking the function of angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers to benefit circulation. Rhizoma Pinellinae Praeparata contains alkaloids, cerebrosides, lectins, fatty acids, volatile oils, flavonoids, and so on. Its pharmacological actions include antitussive, expectorant, antiemetic and antioxidant.
Our study provided the first comprehensive and rigorous evaluation of the efficacy and safety of Nuanxin capsule as an adjuvant treatment for CHF. Compared with other supplementary therapies, the low price of Nuanxin capsule makes it an attractive adjuvant for patients. However, as the number of published RCTs on Nuanxin capsule is limited and most of the included studies had a low methodological quality, the conclusions drawn from this pooled analysis should be interpreted with caution, though our study included almost all the available data.
Further standardized RCTs are warranted to evaluate the efficacy and safety of Nuanxin capsule to accumulate significant evidence and reach a definitive conclusion. In this study, we found some problems in published RCTs and have some suggestions on future research. First, prolongation of intervention and follow-up is recommended so that the long-term benefits and harms of this drug can be disclosed and the mortality results are more meaningful. Second, double-blind or triple-blind should be adopted to reduce selective bias and improve methodological quality. Third, complete trial protocols and methods such as random sequence generation and allocation concealment should be given to assure comparability between groups. Fourth, we encourage oversea clinicians to perform such RCTs to identify individual potential differences between population demographics in traditional Chinese therapies.
| Conclusion|| |
Nuanxin capsule had favorable effects in treating CHF as a supplemental strategy for conventional therapy. It significantly reduced mortality and improved prognosis through various mechanisms. This pooled analysis should be interpreted with caution as available data were limited. Further RCTs with high methodological quality and large samples are warranted to verify our findings.
Financial support and sponsorship
This work was supported by the Shenzhen Science and Technology Research and Development Fund (No. JCYJ20160331183804137) and the Planned Science and Technology Project of Guangdong Province (No. 2017A020215005).
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]