Chronic heart failure (CHF) is a cardiac diseases caused by heart overload, myocardial damage, and systolic dysfunction. If patients with cardiac diseases are deteriorated, their characteristics of CHF will be shown more distinctly.[1–3] Besides, CHF remains a major reason leading to death all over the world,[4–7] and there are almost 26 million people suffer from CHF throughout world.
In terms of Traditional Chinese Medicine (TCM) theory, CHF pertains to “palpitation,” “edema,” primarily due to the deficiency of Qi and blood, phlegm–dampness, and blood stasis. The therapeutic principle is to strengthen body resistance and eliminate pathogen with TCM. Currently, the emphasis of treating CHF is to suppress myocardial remodeling, and perfect cardiac function. Thus, the combination of angiotensin converting enzyme inhibitor (ACEI), β-blocker, and aldosterone inhibitor becomes common for CHF; however, the problems such as poor compliance and low heart rate of patients may influence the desired effect.
Therefore, Chinese herbal injections (CHIs) are gradually applied to assisting in the treatment of CHF due to its rapid action, high bioavailability, and no digestive tract absorption, especially tonic CHIs. As a representative of tonic CHIs, Huangqi injection (HI) was approved by China Food and Drug Administration (CFDA) and has already achieved positive effect in treating CHF in clinical trials, while the conclusion of single trial was weak and its curative effect has not approved in clinical guideline. Hence, it is necessary to sort out and analyze relevant randomized controlled trials (RCTs) comprehensively. Based on existing clinical evidence, this study conducted a systematic review and meta-analysis to explore HI's effectiveness further and provide reference for adopting HI as well.
2.1 Search strategy
The following electronic databases were searched from its inception to June 6, 2017: the Cochrane Library, PubMed, Embase, China Biology Medicine disc, Chinese National Knowledge Infrastructure Database, China Science and Technology Journal Database, WanFang Database. The search method combining the medical subject headings (MeSH) term and free text word was used and changed into various forms with different database. Take the PubMed as the example, the strategy listed as follows:
#1 Heart Failure [MeSH Terms]
#2 Cardiac Failure[Title/Abstract] OR Heart Decompensation[Title/Abstract] OR Chronic heart failure[Title/Abstract] OR Myocardial Failure[Title/Abstract] OR Left-Sided Heart Failure[Title/Abstract] OR Left Sided Heart Failure[Title/Abstract] OR Right-Sided Heart Failure[Title/Abstract] OR Right Sided Heart Failure[Title/Abstract] OR Myocardial Failure[Title/Abstract] OR Congestive Heart Failure[Title/Abstract] OR Cardio-Renal Syndrome[Title/Abstract] OR Paroxysmal Dyspnea[Title/Abstract] OR Cardiac Edema[Title/Abstract]
#3 #1 OR #2
#4 huangqi OR Astragali radix
#5 #3 AND #4
2.2 Eligibility criteria
Eligible studies were: Types of studied: RCTs reported the effectiveness of HI in the treatment of CHF without limitation in languages. Types of patients: All involved patients should be diagnosed as CHF, the diagnostic standard was conformed to “Guidelines on the Diagnosis and Treatment of Heart Failure” conducted by The Chinese medical association cardiovascular epidemiology branch in 2014 or “Clinical Guideline of New Drugs for Traditional Chinese Medicine” released by CFDA in 2002.[10,11] Included patients had no limitation in age, gender, race, national, and the severity of disease. Interventions: All patients received conventional western medicine (WM), for instance, cardiotonic, diuretic, ACEI, β-blocker, vasodilators, and so on. The experimental group received WM and HI, while the control group adopted the same WM. If patients suffered from others complication, clinician gave them corresponding therapies. Outcomes: Major outcomes contained clinical total effective rate and left ventricular ejection fraction (LVEF). Besides, the incidence of left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV), stroke cardiac output (SV), cardiac output (CO), 6 minutes walk test (6MWT), and safety situation (adverse drug reactions (ADRs)/adverse drug events (ADEs)) were also evaluated and deemed as secondary outcomes. The clinical total effective rate calculated by this formula: (number of remarkable recovery patients + number of basic recovery patients)/total number of patients × 100%. According to cardiac function classification standard issued by New York Heart Association in the United States (NYHA), clinical symptoms disappeared and cardiac function perfected 2 level belonged to the class of remarkable recovery patients, clinical symptoms eased and cardiac function improved 1 level was classified into the part of basic recovery, clinical symptoms and cardiac function were unchanged or worsened pertained to grade of deterioration. The studies were excluded if WM contained rehabilitation therapy and naturopathy. The experimental group and the control group's intervention included others TCM treatments except CHIs, for instance acupuncture, moxibustion, and Chinese patent medicine. The data of outcomes were incomplete. The literature cannot obtain full text. If 2 literatures had the same data, we utilized the data of the literature with the larger sample and relative complete information.
2.3 Data extraction and quality assessment
Two reviewers carried out literature filtration complying with predesigned eligible criteria, and extracted the included RCTs’ information in Microsoft Excel 2010 (Microsoft Crop, Redmond, WA). The necessary information comprised these aspects: The essential information of included RCTs: the first author, public date. The characteristics of patients: the number of the experimental group and the control group, gender proportion, age. The details of intervention: specific therapies and there dosages, treatment courses. The data of outcomes. The key elements of risk assessment: randomization, blinding, and handing of dropouts. All literatures were managed by NoteExpress (Wuhan University Library, Wuhan, China).
Methodological quality assessment of each RCT was conducted by the Cochrane Risk of Bias Assessment Tool, which contained 7 aspects: sequence generation (selection bias), allocation concealment (selection bias), blinding of patients and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective outcome reporting (reporting bias), and other sources of bias. Each aspect was classified into 3 levels: low risk, unclear risk, and high risk. If the RCTs described a correct random generation, implemented blinding and reported complete measure outcomes, the RCTs belonged to low risk. On the contrary, the trails pertained to high risk. Besides, the RCTs were deemed as unclear risk provided that the literature did not provide enough information for judgments. Two reviewers accessed the quality of RCTs separately, and any inconsistency between 2 reviewers was resolved by consulting the third reviewer.
Based on collecting clinical experiments’ data, this study would not leak out patients’ information. Thus, it is unnecessary to conduct the ethical approval for this study.
2.4 Statistical analysis
Review Manager 5.3 (Cochrane Collaboration, Oxford, UK) was utilized to synthesize and analyze data. As for dichotomous outcomes, relative risk (RR) was applied to count data, whereas mean difference (MD) was used to evaluate continuous variable, 95% confidence intervals (95% CIs) was presented as well in order to indicate the range of results. Heterogeneity was given as Chi2, I2, and tau2. And the random-effect model in inverse variance method was applied into meta-analysis. Meanwhile, several methods were used to evaluate publication bias, visual inspection was demonstrated by funnel plot. And Egger test and Begg test were also adopted. In addition, the sensitivity analysis was conducted in clinical total effective rate so as to test the stability of results. The sensitivity analysis was done by excluding one of the RCT at a time and then reconducting meta-analysis. Egger test, Begg test, and sensitivity analysis were estimated by STATA 12.0 (StataCorp LP, College Station, TX).
3.1 Study characteristics
Our search identified 1869 literatures initially in total through the 7 databases. NoteExpress checked duplications automatically, the 999 literatures remained. After reading the titles and abstracts by 2 reviewers respectively, reviews, irrelative literatures, and animals experiments were excluded. Then, 577 literatures remained, of which 561 were excluded by reading the full text due to the following reasons: not diagnosed as CHF (119 literatures), not complied with the intervention of inclusion criteria (287 literatures), not referred to the diagnostic standard or therapeutic criterion (132 literatures), not performed in 2 groups (10 literatures), cannot contain the full text (6 literatures), individual cases (1 literature), the same literature (6 literatures). The final 16 RCTs were included in this study, all of them published in Chinese from 2003 to 2017. The flow diagram about the filtration is depicted in Fig. 1.
Sixteen RCTs involved 1273 patients, among which 656 patients in experimental group and 617 patients in control group. All patients were diagnosed as CHF and conformed to eligible criteria, male patients accounted for 59.1% (752/1273) and the middle-age and elderly patients were majority. In these 16 RCTs, the sample size ranged from 43 to 159. As for intervention, the control groups were digoxin, furosemide, captopril, metoprolol, isosorbide dinitrate, and other WM treatments, the experimental group injected HI plus the same WM. All patients received treatment once a day via mainline, and the period of treatment was within 30 days The period was 14 to 15 days and the dosage of HI was 30 to 40 mL in most RCTs. Characteristics of eligible RCTs are summarized in Table 1.
In 16 RCTs, 1 RCT used random number table to generate the group, and 3 RCTs generated groups by the order of hospitalization.[29–31] The others did not provide the details of randomization in the literatures.[16–27] Thus, the bias resulted from random sequence generation of them was evaluated as “low,” “high,” and “unclear.” The information on allocation concealment, blinding was not observed in the literatures. Hence this study evaluated the bias of allocation concealment bias, performance bias, and detection bias as “unclear.” Besides, none of the included RCTs assessed had incomplete data, so the attrition bias was appraised as “low.” As for the part of reporting bias and other bias, 16 RCTs did not provide relevant contents about selective reporting and mention any factors leading to high risk. Therefore, these 2 items were evaluated as “unclear.” The quality of the included RCTs is demonstrated in Fig. 2.
3.2.1 Clinical total effective rate
All of the 16 RCTs tested the clinical total effective rate. Pooled results showed an improvement in favor of the experimental group on clinical total effective rate (RR = 1.19, 95% CI: 1.14–1.26, P < .00001, I2 = 0%, tau2 = 0.00, Fig. 3).
3.2.2 Sensitivity analysis and publication bias
This study conducted a sensitivity analysis focusing on the clinical total effective rate to verify its stability, which has done by eliminating one item at a time and then reanalysis. The results of sensitivity is shown in Fig. 4, the result of clinical total effective rate did not appear a qualitative transform which meant this outcome had a good stability.
A funnel plot on publication bias for clinical total effective rate is displayed in Fig. 5, and included RCTs distributed evenly. Moreover, the result of Egger test (t = 0.38, P = .707 > .05) and Begg test (z = 0.95, P = .344 > .05) indicated no evidence of significant publication bias.
LVEF was compared with in 10 RCTs. If the MD value of meta-analysis was higher, the improvement of LVEF was relative superior. The aggregated data indicated that HI plus WM had a better impact on increasing LVEF than WM (MD = 4.64, 95% CI: 3.52–5.75, P < .00001, I2 = 30%, tau2 = 1.00, Fig. 6).
3.2.4 Secondary outcomes
Detailed data presented in Table 2.
- LVEDV: 4 RCTs examined the LVEDV.[20,23,28,31] The overall results demonstrated that a combination of HI and WM was excelled at lowering LVEDV than WM.
- LVESV: 4 RCTs reported the LVESV.[20,23,28,31] Pooled results signified that HI plus WM exhibited a perforable effect on decreasing LVESV more effectively compared with WM.
- SV: 3 RCTs investigated SV.[23,24,29] The results manifested that the conjunctive use of HI and WM can perform a good effect on enhancing SV.
- CO: 3 RCTs identified SV.[23,27,29] The results indicated that HI plus WM was more efficient in promoting CO in comparing with WM.
- 6MWT: 1 RCT tested 6MWT. Thus, this study made a qualitative description for it. After treatment, the result of the experimental group was 386 ± 52.06 m, whereas the control group was 326.05 ± 32.14 m, the difference between 2 groups was significant as well.
Among 16 RCTs, a total of 3 RCTs mentioned that there were no obviously ADRs/ADEs.[16,24,31] The other RCTs did not reported about ADRs/ADEs.
HI is a common CHI that manufactured by the extractive Huangqi (Astragali radix) under the guideline of TCM, and its effective constituents are astragaloside, astragalus polysaccharide, and so forth. Huangqi is well known for its characters in removing blood stasis without injuring righteousness and widely used as Qi-tonifying herbal medicine.[33,34] The results of pharmacological experiments manifested that Huangqi can enhance myocardial contractility and myocardial cell excitation–contraction coupling. Then it can generate significant cardiotonic effect, whose functions are similar to the positive inotropic effect of digitalis. Beyond that, Huangqi owns a capacity not only on increasing SOD, but also on cleaning oxygen free radical to prevent them from damaging myocardial cell. In addition, Huangqi is capable of decreasing cardiac pressure load and volume load via vasodilation, which may result in slowing heart rate, reducing release kallikrein from central nervous system and renin angiotensin aldosterone system.[35–38] Theoretically, HI is a better option for treating CHF.
The results of this study suggested that, in terms of CHF patients, an integration of HI and WM can make a remarkable influence than WM in improving clinical effective rate and LVEF, lessening LVEDV and LVESV, perfecting SV and CO as well. Beyond that, HI plus WM also had a notable performance on increasing 6MWT. As for its safety, 3 RCTs reported that there were no serious ADRs/ADEs occurred in the treatment. While due to the small quantity, it cannot draw a robust conclusion that HI had a well safety for treating CHF. Besides, the dosage of included RCTs was above the ruled usage (the specification stipulate 10–20 mL once a day), which was irrational and may engender ADRs/ADEs. In addition, elderly patients were in large proportion among included patients who may likely drive the drug build-up and then arised accumulation of drug. Therefore, clinical should pay more attention on the usage.
There were 3 systemic reviews focused on the efficacy of HI for treating CHF respectively published in 2008, 2009, 2011.[40–42] One of them contained 62 RCTs and quasi-RCTs, the rest literatures contained 10 RCTs and 11 RCTs. All of them compared the effectiveness between HI plus WM with WM, one of them contrasted HI and nitroglycerin as well. Apart that, the clinical total effective rate and LVEF were deemed as primary outcomes. By contrast, this study owned the following advantages: firstly, we updated the search date to June 6, 2017 and made a relative comprehensive retrieval in the Cochrane Library, PubMed, Embase, China Biology Medicine disc, Chinese National Knowledge Infrastructure Database, China Science and Technology Journal Database, WanFang Database by combining MeSH term with free text word. Secondly, in order to lower clinical heterogeneity, we formulated strict eligible criteria. In order to ensure the identical base line, all included patients diagnosed as CHF in specific criteria and evaluated the effectiveness in congruent standard, and received the same interventions as well. Thirdly, besides the clinical total effective rate and LVEF, this study also set LVEDV, LVESV, SV, CO as outcomes aimed to indicate cardiac situation. Meanwhile, because 1 RCT reported 6MWT, we utilized a descriptive method in narrating its results to reflect the recovery of patients.
This study was not without limitations. Firstly, included RCTs’ quality was general, and most items were assessed as unclear risk, which may influence the validity of overall findings and overestimate the effectiveness of HI to some degree. Meanwhile, though the Egger test and Begg test manifested that there was no potential publication bias, the deficiency of the funnel plot's top and bottom may also indicated that this study lack the RCTs with very small or large sample. Besides, the original reports of RCTs did not report the contents of intention-to-treat analysis, the missing of it may affect the strength of this evidence. Secondly, all of the RCTs did not conduct follow-up visit after treatment. Thus, whether there was any significant difference between 2 groups in the long-term curative effect like recurrence rate and mortality cannot figure out. Apart that, it is 6MWT that can reflect patients’ situation directly, while this outcome was examined in 1 RCT. Thirdly, this study cannot draw a tangible conclusion on safety due to inadequate ADRs/ADEs information. On account of foregoing shortcoming, we raised several suggestions towards RCTs on HI. Firstly, in order to ensure the transparency of RCTs’ process, it is necessary that RCTs should be registered in advance and carried out accord with Consort standard.[43,44] Meanwhile, randomization, allocation concealment, and blinding ought to perform as possible. Secondly, clinicians had better chose outcomes that associate closely with patients’ feelings and the long-term effectiveness. Thirdly, the clinicians ought to strengthen monitoring of ADRs/ADEs situation while they concern the effectiveness.
To sum up, this study showed that a combination of HI and WM was beneficial for clinical total effective rate, LVEF, LVEDV, LVESV, and others cardiac indexes. Besides, it also can promote 6MWT. However, due to limitations of included RCTs, high quality RCTs with scientific rigor and strict implement are needed to testify HI's effectiveness further.
. Mao GC. Progress in the treatment of chronic heart failure in Chinese medicine. J Guangxi Coll Tradit Chin Med Univ 2015;18:63–6.
. Pocock SJ, Ariti CA, Mcmurray JJ, et al. Predicting survival in heart failure: a risk score based on 39372 patients from 30 studies. Eur Heart J 2013;34:1404–13.
. Wang MZ, Yao CZ, Jia MJ, et al. Meta-analysis on clinical efficacy of Astragalus
injection combined with Fufang Danshen injection in the treatment of chronic heart failure. Guangming J Chin Med 2016;31:2894–7.
. Song X, Qu H, Yang Z, et al. Efficacy and safety of L-carnitine treatment for chronic heart failure: a meta-analysis of randomized controlled trials. Biomed Res Int 2017;2017:6274854.
. Tevik K, Thürmer H, Husby MI, et al. Nutritional risk is associated with long term mortality in hospitalized patients with chronic heart failure. Clin Nutr ESPEN 2016;12:e20–9.
. Wang YC, Zhuang Y, Gu Y, et al. Progress in the evolution of chronic heart failure syndrome. Guiding J Tradit Chin Med Pharmacol 2016;22:62–8.
. Xia K, Wang Q, Li C, et al. Effect of QSKL on MAPK and RhoA pathways in a rat model of heart failure. Evid Based Complement Alternat Med 2017;2017:3903898.
. Pocock SJ, Wang D, Pfeffer MA, et al. Predictors of mortality and morbidity in patients with chronic heart failure. Eur Heart J 2006;27:65–75.
. Zhu C, Cao H, Zhou X, et al. Meta-analysis of the clinical value of Danshen injection and Huangqi injection in liver cirrhosis. Evid Based Complement Alternat Med 2013;2013:842824.
. Cardiology Branch of the Chinese Medical Association. Guidelines for the diagnosis and treatment of heart failure in China. Chin J Cardiol 2014;42:98–122.
. Zheng YY. Clinical Guideline of New Drugs for Traditional Chinese Medicine. Beijing: Chin Med Sci and Tech Press; 2002.
. Higgins JP, Altman DG, Gøtzsche PC, et al. The Cochrane collaboration's tool for assessing risk of bias in randomized trials. BMJ 2011;343:d5928.
. Higgins JP, Green S. Cochrane handbook for systematic reviews of interventions: Cochrane Book Series. Wiley Online Library; 2008. doi: 10.1002/9780470712184.
. Zheng MH. Meta-Analysis Software Applications and Instance Parsing. Beijing: People's Medical Publishing House; 2013.
. Liu YF, Huang Y, Wen CY, et al. The effects of modified simiao decoction in the treatment of gouty arthritis: a systematic review and meta-analysis. Evid Based Complement Alternat Med 2017;2017:6037037.
. Yuan GP. Clinical efficacy evaluation of the treatment of chronic heart failure by Huangqi injection. Chin J Clin Pharmacol Ther 2003;8:710–1.
. Luo XC. 30 cases of congestive heart failure in treatment of Huangqi injection. J Emerg Syndromes Tradit Chin Med 2003;12:35.
. Gu X, Shang SZ, Guo R. 68 cases on congestive heart failure. Her Med 2003;22:556–7.
. Gao JH. Clinical observation of Huangqi injection for congestive heart failure. Acad J Guangdong Coll Pharm 2005;21:610–1.
. Xing GP, Nie XM. The effects of Astragalus
injection on the hemodynamics of congestive heart failure patients. Chin Med Rep 2006;3:67–8.
. Feng LY, Hao W. 34 clinical observations of the treatment of congestive heart failure. Chin J Integr Med Cardio Dis 2008;6:1362–3.
. Yan FY, Lin HZ. 80 cases of Huangqi injection for chronic congestive heart failure. Jiangxi J Tradit Chin Med 2009;40:27–8.
. Lin Y, Huang CL, Zhu CH. Clinical study on Astragalus
injection in treating chronic congestive heart failure. China Pharm 2009;18:22–3.
. Wang XX. Clinical study on Astragalus
injection in treating chronic heart failure. Chin Foreign Health Abstr 2013;14:53–4.
. Zhang CM, Duan QF, Bian XJ. Clinical observation of Astragalus
injection in the treatment of chronic heart failure. Med Front 2013;17:119–20.
. Jia BQ, Xu L. Clinical observation of Astragalus
injection in the treatment of chronic heart failure. Chin J Clin Res 2013;26:654–6.
. Chen JX. Clinical observation of the treatment in congestive heart failure. World Latest Med Inf 2016;16:133–4.
. Zhang ZB. Clinical observation of Astragalus
injection combined with conventional western medicine for senile patients of chronic congestive heart failure. J New Chin Med 2017;49:25–7.
. Ge CJ. Astragalus
injection was used in 50 cases of chronic heart failure. Chin J Integr Tradit Chin West Med 2002;22:859.
. Lv J. Clinical trials of Astragalus
injection in the treatment of chronic congestive heart failure. J Pract Tradit Chin Med 2008;24:164–5.
. Hou BS, Liu X, Song YQ, et al. Clinical observation combined Astragalus
injection and western medicine in the treatment of chronic heart failure. Mod J Integr Tradit Chin West Med 2015;20:2570–2.
. Wang HL, Zhou QH, Meng MB, et al. Astragaloside IV for experimental focal cerebral ischemia: preclinical evidence and possible mechanisms. Oxid Med Cell Longev 2017;2017:8424326.
. Tang CC. Rationality and safety evaluation of the clinical application of Astragalus
injection. J New Chin Med 2014;46:145–7.
. Yan LH, Shao Y. Progress in clinical application of Astragalu
s injection. Chin Pharm 2013;22:126–8.
. Yu JM, Zhang XB, Zhang YN. Astragaloside attenuates myocardial injury in a rat model of acute myocardial infarction by upregulating hypoxia inducible factor 1α and Notch1/Jagged1 signaling. Mol Med Rep 2017;15:4015–20.
. Han RH, Tang FT, Lu ML, et al. Astragalus
polysaccharide ameliorates H2
-induced human umbilical vein endothelial cell injury. Mol Med Rep 2017;15:4027–34.
. Wang LQ, Yang JH, Zhang YY, et al. Research progress and prospect of mechanisms in treating chronic heart failure with Chinese medicine. J Jiangxi Coll Tradit Chin Med Univ 2015;27:108–11.
. Chu JH, Li CY, Dai GL, et al. Simultaneous determination of five components in Astragalus
injection and Astragalus
oral liquid by LC-MS-MS. Chin Tradit Pat Med 2015;37:2647–51.
. Fu XR. 46 cases of Huangqi injection for chronic congestive heart failure. Asia-Pac Tradit Med 2015;11:2647–51.
. Fu S, Zhang J, Mennitiippolito F, et al. Huangqi injection (a traditional Chinese patent medicine) for chronic heart failure: a systematic review. PLoS ONE 2011;2011:e19604.
. Wen ZH, Nong YB, Pan CX, et al. The meta-analysis of clinical research on chronic heart failure by Astragalus
injection. Chin J Integr Med Cardio Dis 2011;9:770–2.
. Wang LX, Du WX, Zhu MD, et al. The systematic evaluation of the treatment of chronic heart failure by Huangqi injection. Chin J Evid Based Med 2009;1:78–81.
. Hao TT, Xie YM, Liao X, et al. The systematic evaluation and meta-analysis of non-small cell lung cancer were treated by the joint first-line chemotherapy of ginseng and stilbene injection. China J Chin Mater Med 2015;40:4094–107.
. Shen H, Ai QH, Xie YM, et al. The systematic evaluation of the treatment of heart failure by the combined conventional drug treatment and Shenqifuzheng injection. China J Chin Mater Med 2013;38:298–306.