Shengmai (a traditional Chinese herbal medicine) for heart failure.

Shengmai (a traditional Chinese herbal medicine) for heart failure (Review) Zhou Q, Qin WZ, Liu SB, Kwong JSW, Zhou J, Chen J

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library 2014, Issue 4 http://www.thecochranelibrary.com

Shengmai (a traditional Chinese herbal medicine) for heart failure (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

TABLE OF CONTENTS HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.1. Comparison 1 Shengmai plus usual treatment versus usual treatment alone, Outcome 1 Lack of improvement in heart failure (NYHA class improved < I class or worsening of heart failure). . . . . . . . . . . . . Analysis 1.2. Comparison 1 Shengmai plus usual treatment versus usual treatment alone, Outcome 2 Exercise test (after treatment). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.3. Comparison 1 Shengmai plus usual treatment versus usual treatment alone, Outcome 3 Change in quality of life. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.4. Comparison 1 Shengmai plus usual treatment versus usual treatment alone, Outcome 4 Change in ejection fraction (%). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.5. Comparison 1 Shengmai plus usual treatment versus usual treatment alone, Outcome 5 Change in cardiac output (L/min). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.6. Comparison 1 Shengmai plus usual treatment versus usual treatment alone, Outcome 6 Change in stroke volume (mL). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.7. Comparison 1 Shengmai plus usual treatment versus usual treatment alone, Outcome 7 Change in cardiac index L/min*m². . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.8. Comparison 1 Shengmai plus usual treatment versus usual treatment alone, Outcome 8 Change in left ventricular end-diastolic volume (mL). . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 1.9. Comparison 1 Shengmai plus usual treatment versus usual treatment alone, Outcome 9 Change in left ventricular end-systolic volume (mL). . . . . . . . . . . . . . . . . . . . . . . . . . Analysis 2.1. Comparison 2 Shengmai versus placebo, Outcome 1 Lack of improvement in heart failure (NYHA class improved < I class or worsening of heart failure). . . . . . . . . . . . . . . . . . . . . . . Analysis 2.2. Comparison 2 Shengmai versus placebo, Outcome 2 Change in exercise test (mins). . . . . . . . Analysis 2.3. Comparison 2 Shengmai versus placebo, Outcome 3 Change in ejection fraction (%). . . . . . . Analysis 2.4. Comparison 2 Shengmai versus placebo, Outcome 4 Change in cardiac output (L/min). . . . . . . Analysis 2.5. Comparison 2 Shengmai versus placebo, Outcome 5 Change in stroke volume (mL). . . . . . . . Analysis 2.6. Comparison 2 Shengmai versus placebo, Outcome 6 Change in stroke volume index. . . . . . . . Analysis 2.7. Comparison 2 Shengmai versus placebo, Outcome 7 Change in cardiac index L/min*m². . . . . . Analysis 2.8. Comparison 2 Shengmai versus placebo, Outcome 8 Change in Heather Index. . . . . . . . . . Analysis 2.9. Comparison 2 Shengmai versus placebo, Outcome 9 Change in ECG: Q-Z. . . . . . . . . . . Analysis 2.10. Comparison 2 Shengmai versus placebo, Outcome 10 Change in ECG: Adz/dtMax. . . . . . . Analysis 2.11. Comparison 2 Shengmai versus placebo, Outcome 11 Change in ECG: Q-B/B-X. . . . . . . . ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Shengmai (a traditional Chinese herbal medicine) for heart failure (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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[Intervention Review]

Shengmai (a traditional Chinese herbal medicine) for heart failure Qin Zhou1 , Wen-Zhe Qin2 , Shuai-Bin Liu3 , Joey SW Kwong4 , Jing Zhou5 , Jin Chen1 1

Department of Evidence-Based Medicine and Clinical Epidemiology, West China Hospital, Sichuan University, Chengdu, China. of Evidence-Based Medicine and Clinical Epidemiology, West China Hospital, Sichuan University, Sichuan, China. 3 Department of Obstetrics & Gynaecology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. 4 Institute of Vascular Medicine, Li Ka Shing Institute of Health Sciences, Heart Education And Research Training (HEART) Centre, and Division of Cardiology, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong. 5 West China Medical School, Sichuan University, Sichuan, China 2 Department

Contact address: Jin Chen, Department of Evidence-based Medicine and Clinical Epidemiology, West China Hospital of Sichuan University, No. 37, Guo Xue Xiang, Chengdu, 610041, China. [email protected]. Editorial group: Cochrane Heart Group. Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 4, 2014. Review content assessed as up-to-date: 1 August 2013. Citation: Zhou Q, Qin WZ, Liu SB, Kwong JSW, Zhou J, Chen J. Shengmai (a traditional Chinese herbal medicine) for heart failure. Cochrane Database of Systematic Reviews 2014, Issue 4. Art. No.: CD005052. DOI: 10.1002/14651858.CD005052.pub5. Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT Background Heart failure is a major public health problem worldwide. Shengmai, a traditional Chinese herbal medicine, has long been used as a complementary treatment for heart failure in China. This is an update of a Cochrane Review published in 2012. Objectives To determine the effect (both benefits and harms) of Shengmai in treatment of people with heart failure. Search methods We searched CENTRAL on The Cochrane Library (Issue 5 of 12, April 2013); DARE on The Cochrane Library (Issue 2 of 4, April 2013); MEDLINE (1948 to June Week 1 2013); EMBASE (1980 to 2013 Week 23); AMED (1985 to August 2008); BIOSIS (1969 to 7 June 2013); CBM (1978 to June 2013); VIP (1989 to June 2013); and CNKI (1979 to June 2013). We also handsearched Chinese journals and did not apply any language restrictions. Selection criteria We included randomised controlled trials (RCTs) of Shengmai plus usual treatment for heart failure versus usual treatment alone, or Shengmai versus placebo, irrespective of blinding status. In this update we only included studies with a clear description of randomisation methods and classified as true RCTs. Data collection and analysis Two authors independently selected trials, assessed methodological quality and extracted data. We calculated dichotomous data as risk ratios (RRs) and continuous data as mean differences (MDs) or standardized mean differences (SMDs) with corresponding 95% confidence intervals (CIs). We used a fixed-effect model to perform meta-analysis for outcomes without heterogeneity; and a randomeffects model to perform meta-analysis for outcomes with heterogeneity. Shengmai (a traditional Chinese herbal medicine) for heart failure (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Main results We included a total of 14 RCTs (858 patients) in this review update, four of which were new trials. Of these 14 RCTs, 11 trials compared Shengmai plus usual treatment with usual treatment alone, and three trials compared Shengmai with placebo. Improvement of NYHA functional classification was more common in patients taking Shengmai plus usual treatment than in those receiving usual treatment alone (RR 0.37; 95% CI 0.26 to 0.51; 10 trials, 672 participants; low quality evidence). Beneficial effects of Shengmai in treating heart failure were also observed in other outcomes, including exercise test, ejection fraction and cardiac output. The three RCTs (106 patients) comparing Shengmai with placebo reported improvement in NYHA functional classification and in stroke volume. Three of the 14 RCTs reported a total of six patients with mild adverse effects and two were withdrawn due to the adverse effects. The adverse events rate was 1.21%. Authors’ conclusions Shengmai may exert a positive effect on heart failure, especially for improving NYHA functional classification when Shengmai plus usual treatment is used. The review results should be interpreted with caution due to the high risk of bias of the included studies (particularly regarding allocation concealment and blinding), the small sample size of these studies, and the significant heterogeneity in outcomes such as ejection function, cardiac output and stroke volume. There was no evidence available concerning the effect of Shengmai on mortality, and more high quality studies with long-term follow-up are warranted.

PLAIN LANGUAGE SUMMARY Shengmai (a traditional Chinese herbal medicine) for heart failure Heart failure is a major public health issue worldwide. Despite advances in treatment, many people are affected and hundreds of thousand of people die each year. Shengmai is a traditional Chinese herbal medicine and is a mixture extracted from three herbs: Panax ginseng, Ophiopogon japonicus and Schisandra chinensis. In China it has been used to treat heart failure and ischemiac heart disease. In this Cochrane Review update, we included 14 trials which compared Shengmai plus usual treatment with usual treatment alone, or compared Shengmai with placebo. Shengmai may be beneficial in improving heart function (low quality evidence) and in most trials, people who took Shengmai had few unwanted side effects. However, many of the included trials were of poor quality and included a small number of people. More high quality, large trials of Shengmai of treatment heart failure are needed.


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S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]

Shengmai plus usual treatment compared to usual treatment alone for heart failure Patient or population: patients with heart failure Settings: inpatients and outpatients Intervention: Shengmai plus usual treatment Comparison: usual treatment alone Outcomes

Mortality

Illustrative comparative risks* (95% CI)

Assumed risk

Corresponding risk

Usual treatment alone

Shengmai plus usual treatment

See comment

See comment

Lack of improvement Moderate in heart failure (NYHA class improved 0.05)” (Zhao 2006). Participants All of the 858 participants were Chinese (Table 1), 52.2% (448/ 858) were male and 43.1% (370/858) were female (Note: as Mao 2003a, Part B did not report any information on its participants, the statistical data did not include these 40 participants). The

participants’ ages varied from 23 to 85 years, and the mean age ranged from 41 to 70.4 years. Seven trials reported the duration of heart failure (Zhang 2002; Mao 2003a; Zhao 2006; Liu 2007a; Zhai 2009; Ding 2012; Wan 2012), which varied from 0.5 to 30 years. The spectrum of primary causes for heart failure differed among the 12 trials that reported this data (Fang 1987; Jiang 1988; Zhang 2002; Mao 2003a, Part A; He 2004; Zhao 2006; Liu 2007a; Zhai 2009; Wang 2010a; Ding 2012; Su 2012; Wan 2012). Of these, 328 patients were coronary heart disease patients from nine trials (Fang 1987; Mao 2003a, Part A; He 2004; Liu 2007a; Zhao 2006; Zhai 2009; Wang 2010a; Su 2012; Wan 2012), 157 patients were dilated cardiomyopathy patients from six trials (Jiang 1988; Zhang 2002; He 2004; Liu 2007a; Zhai 2009; Wang 2010a), 44 patients were rheumatic heart disease patients from six trials (Mao 2003a, Part A; He 2004; Zhao 2006; Liu 2007a; Zhai 2009; Su 2012), 187 patients were hypertensive heart disease patients from eight trials (Mao 2003a, Part A; He 2004; Liu 2007a; Zhai 2009; Wang 2010a; Ding 2012; Su 2012; Wan 2012); 18 patients were pulmonary heart disease from four trials (Mao 2003a, Part A; Zhao 2006; Zhai 2009; Su 2012), and two patients were congenital heart disease patients from Zhai 2009. Twenty-five patients had old myocardial infarction in Ding 2012, 65 patients in two trials had diabetes mellitus (Ding 2012; Wan 2012), and 26 patients in one study had hyperlipidaemia (Ding 2012). Two trials did not report the primary cause of heart failure (Mao 2003a, Part B; Liu 2013). All included trials provided baseline data on NYHA function classifications (NYHA FC). There were 207 participants with NYHA class II, 481 with NYHA class III and 170 with NYHA class IV.

Diagnosis Eleven trials stated the diagnostic criteria of heart failure: three based on criteria from the World Health Organization (WHO) ( Fang 1987; Jiang 1988; Zhang 2002), three based on Framingham and Boston (Mao 2003a, Part A; Mao 2003a, Part B; Zhao 2006; Ding 2012); one from Guidelines for diagnosis and treatment of chronic heart failure 2007 (Wang 2010a); one based on Guidelines for treatment of systolic heart failure (Zhai 2009); one based on Reference standards for the treatment of left ventricle diastolic heart failure (Wan 2012); one based on Guidelines for clinical research on the treatment of new Chinese traditional medicine in congestive heart failure (Liu 2013). The remaining three articles did not mention the diagnostic criteria, but provided the NYHA class (He 2004; Liu 2007a; Su 2012). All included trials adopted NYHA class for clinical assessment of patients, and one also used the specific activity scale (SAS) (Zhao 2006).

Intervention Eleven trials administered Shengmai by intravenous infusion (


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Zhang 2002; Mao 2003a,Part A; Mao 2003a, Part B; He 2004; Zhao 2006, Liu 2007a; Zhai 2009; Wang 2010a; Ding 2012; Su 2012; Wan 2012), and three trials gave it as an oral liquid (Fang 1987; Jiang 1988, Liu 2013). All trials but three (Zhai 2009; Su 2012; Liu 2013) reported the manufacturers of Shengmai and included: Huaxi (Zhang 2002; He 2004; Zhao 2006), Shanghai (Fang 1987; Jiang 1988), Shanxi (Liu 2007a; Ding 2012), Yibin (Mao 2003a), Jiangsu (Wang 2010a) and Suzhong (Wan 2012). Shengmai dosage varied: the injection ranged from 20 mL to 180 mL per day and according to Pharmacopoeia of the People’s Republic of China, 10 mL Shengmai injection is extracted based on a standardized formula: Panax ginseng (1.00 g), Ophiopogon japonicu (3.12 g) and Schisandra chinensis (1.56 g); the volume of oral liquid was 20 mL per day (Jiang 1988) (Panax ginseng,Ophiopogon japonicu and Schisandra chinensis were 11 g in total) or 200 mL per day (Liu 2013) (including: Panax ginseng (24.00 g), Ophiopogon japonicu (24.00 g) and Schisandra chinensis (12.00 g)). Treatment duration varied from seven days to 20 days, and the mean duration was 13.79 days (SD 3.81). No study reported the duration of follow up. Eleven trials compared Shengmai plus usual treatment with usual treatment alone. Of the eleven trials, four provided detailed information about usual treatment, including drug names and administration of medicines (Zhang 2002; Mao 2003a, Part A; Zhao 2006; Su 2012). There were some differences amongst them regarding usual treatment. Seven trials (He 2004; Liu 2007a; Zhai 2009; Wang 2010a; Ding 2012; Wan 2012; Liu 2013) described usual treatment as cardiotonic, diuretic and vasodilator instead of giving detailed information. Three trials compared Shengmai with placebo (Fang 1987; Jiang 1988; Mao 2003a, Part B). We have listed the intervention details in Table 2.

Outcomes

Twelve trials reported the NYHA classification of clinical status (Zhang 2002; Mao 2003a,Part A; Mao 2003a, Part B; He 2004; Zhao 2006; Liu 2007a; Zhai 2009; Wang 2010a; Ding 2012; Su 2012; Wan 2012; Liu 2013). Three trials reported mild adverse effects in six patients: in the high-dose (60 mL/d) Shengmai group, two had mild asomnia (2/30, 6.67%) (Liu 2007a), two had dry mouth and were fidgety (2/10, 20%) (Zhao 2006), two patients in the Shengmai group (20 mL/d) had stomach discomfort and hypoglycaemia (2/26 7.69%) and were withdrawn from Jiang 1988. Four trials reported no adverse effects at the end of treatment (He 2004; Zhai 2009; Wang 2010a; Ding 2012). Seven trials did not report on this outcome (Fang 1987; Zhang 2002; Mao 2003a,Part A; Mao 2003a, Part B; Su 2012; Wan 2012; Liu 2013). For secondary outcomes, none of the included trials reported hospitalisation, rehospitalization or costs. Two trials reported exercise test (Jiang 1988; He 2004); one trial reported quality of life (“Minnesota Living with Heart Failure Questionnaire” adopted) (Zhai 2009); eight trials reported the change in haemodynamics (Fang 1987; Jiang 1988; Zhang 2002; Liu 2007a; Zhai 2009; Wang 2010a; Ding 2012, Wan 2012); four trials reported the change in ejection fraction (Zhang 2002; Liu 2007a; Zhai 2009; Ding 2012) and only one trial reported the change of quality of life (Zhai 2009). No trial reported changes in medication due to worsening of symptoms or heart failure. All fourteen trials reported the outcomes measured at the end of treatment.

Risk of bias in included studies We presented the risk of bias of included trials in the Risk of bias tables in the ’Characteristics of included studies’ section. We have summarized the risk of bias in each domain for each included trial in Figure 2 and as percentages across all included trials in Figure 3.

Regarding primary outcomes, only one trial reported on mortality.


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Figure 2. Risk of bias summary: review authors’ judgements about each risk of bias item for each included trial.


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Figure 3. Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included trials.

Although all included trials “randomly allocated” participants, only seven trials reported on sequence generation (Fang 1987; Liu 2007a; Zhai 2009; Wang 2010a; Ding 2012; Wan 2012; Liu 2013). We contacted the authors of the remaining seven trials by telephone for the detailed randomisation method used in their trials. The methods of randomisation sequence generation included computer random number generator (Zhang 2002; Ding 2012), throwing dice (Fang 1987; Jiang 1988; He 2004), and random number table (Mao 2003a, Part A; Mao 2003a, Part B; Zhao 2006; Liu 2007a; Zhai 2009; Wang 2010a; Su 2012; Wan 2012; Liu 2013). None of the included trials reported allocation concealment. Although thirteen of fourteen trials stated there were no significant differences at baseline between treatment and control groups (Fang 1987; Jiang 1988; Zhang 2002; Mao 2003a, Part A; Mao 2003a, Part B; Zhao 2006; Liu 2007a; Zhai 2009; Wang 2010a; Ding 2012; Su 2012; Wan 2012; Liu 2013), only Zhao 2006 detailed baseline characteristics data and He 2004 did not report on baseline comparisons. It was difficult to assess risk of

bias in a domain such as sequence generation as baseline data were not available for 13 of 14 trials, so selection bias was still unclear and likely to exist. Two cross-over trials compared Shengmai to placebo used doubleblinding (Fang 1987; Jiang 1988). He 2004 assessed blindly one of the reported outcomes. Other trials did not provide information about blinding and there was high risk of performance bias and detection bias in these trials. Apart from two participants who were withdrawn due to adverse effects in the Shengmai group in Jiang 1988, trial investigators reported all the other participants’ outcomes. As we could not obtain any original trial protocols, the risk of bias of incomplete outcome assessment was unclear. Also, the risk of selective reporting bias was unclear. We generated a funnel plot for NYHA class (Figure 4), and found no evidence of reporting bias. However, there were too few included trials for other outcomes to generate a funnel plot.


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Figure 4. Funnel plot of comparison: 1. Shengmai plus usual treatment versus usual treatment alone, outcome: 1.1 Lack of improvement in heart failure (NYHA class improved < I class or worsening of heart failure).

Zhao 2006 was funded by State Chinese Medicine Administration Bureau, Zhang 2002 was under the support of the National Science and Technology Department’s Ninth Five-year Plan, and Mao 2003a was funded by the Education Commission of Tianjin Province. The remaining trials were not funded by any institution and all funding was from public authorities. Based on sources of funding, the included trials were unlikely to have had any conflict of interests. We had insufficient information to determine bias from other sources.

Effects of interventions See: Summary of findings for the main comparison Shengmai plus usual treatment compared to usual treatment alone for heart failure; Summary of findings 2 Shengmai compared to placebo for heart failure Shengmai plus usual treatment versus usual treatment alone

Mortality

There were no data available on this outcome.

NYHA class

Ten trials (Zhang 2002; Mao 2003a, Part A; He 2004; Zhao 2006; Liu 2007a; Zhai 2009; Wang 2010a; Su 2012; Wan 2012; Liu 2013), including 672 participants, provided data on NYHA class. A meta-analysis of data on the change of NYHA classification showed that Shengmai plus usual treatment was more beneficial compared with usual treatment alone. The summary relative risk of NYHA FC improved < I class, or worsening of heart failure was 0.37 (95% CI 0.26 to 0.51; 10 trials, 672 participants; Analysis 1.1).

Exercise test or six-minute walk test performance

He 2004 showed that Shengmai plus usual treatment was better than usual treatment alone for improving exercise tolerance (MD 6.00, 95% CI 4.48 to 7.52; one trial, 60 participants; Analysis 1.2).


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Quality of life

Left ventricular end-diastolic volume

Zhai 2009 showed that Shengmai plus usual treatment was not significantly different from usual treatment alone (MD 7.00, 95% CI -1.98 to 15.98; one trial, 60 participants; Analysis 1.3).

Wang 2010a studied this outcome in 74 participants and showed that there was no significant difference between Shengmai plus usual treatment and usual treatment alone (MD 7.20, 95% CI 9.80 to 24.20; one trial, 74 participants; Analysis 1.8).

Ejection fraction

Left ventricular end-systolic volume

Four trials with 354 participants presented data on ejection fraction (Zhang 2002; Liu 2007a; Zhai 2009; Wang 2010a). We detected considerable heterogeneity (P < 0.00001, I² = 91%) and we conducted meta-analysis using the random-effects model. Shengmai plus usual treatment was better than usual treatment alone in improving ejection fraction (MD 9.02, 95% CI 5.95 to 12.08; four trials, 354 participants; Analysis 1.4). The intervention effect on this outcome had statistical significance in each of the four trials.

Wang 2010a, with 74 participants, reported on left ventricular end-systolic volume and showed that Shengmai plus usual treatment was better than usual treatment alone for improving this outcome (MD 14.60, 95% CI 0.50 to 28.70; one trial, 74 participants; Analysis 1.9).

Cardiac output

Costs

Four trials including 360 participants presented data on this outcome (Zhang 2002; Liu 2007a; Zhai 2009; Ding 2012). There was considerable heterogeneity (P < 0.00001, I² = 92%) and we conducted random-effects meta-analysis. Shengmai plus usual treatment was better than usual treatment alone for improving cardiac output (MD 0.94, 95% CI 0.26 to 1.63; four trials, 360 participants; Analysis 1.5) and the intervention effect had statistical significance in each of the four trials.

Stroke volume

Three trials which recruited 240 participants reported on stroke volume (Zhang 2002; Zhai 2009; Ding 2012). Substantial heterogeneity was present (P < 0.00001, I² = 97%) and we conducted random-effects meta-analysis. Shengmai plus usual treatment was not significantly different from usual treatment alone in increasing stroke volume (MD 8.53, 95% CI 0.08 to 16.98; three trials, 240 participants; Analysis 1.6).The intervention effect on this outcome had statistical significance in each of the three trials.

Cardiac index

Two trials with 160 participants reported on this outcome (Zhang 2002; Zhai 2009). There was considerable heterogeneity (P = 0.04, I² = 77%) and we undertook random-effects meta-analysis. Shengmai plus usual treatment was better than usual treatment alone at changing cardiac index (MD 0.79, 95% CI 0.59 to 0.99; two trials, 160 participants; Analysis 1.7).The intervention effect on this outcome had statistical significance in each of the two trials.

Hospitalization/rehospitalization

No data were available on this outcome.


Shengmai versus placebo

Mortality


NYHA class

Mao 2003a, Part B, which included 40 participants, showed that Shengmai treatment was more beneficial than placebo treatment at improving NYHA classification of clinical status. The summary relative risk of NYHA FC improved < I class, or worsening of heart failure was 0.22 (95% CI 0.11 to 0.44; one trial, 40 participants; Analysis 2.1).

Exercise test (time change)

Jiang 1988 demonstrated that Shengmai treatment was not significantly different from placebo treatment changing exercise test (MD -3.56, 95% CI -7.19 to 0.07; one trial, 18 participants; Analysis 2.2).

Ejection fraction

Jiang 1988 showed that Shengmai treatment was better than placebo treatment improving ejection fraction (MD 12.45, 95% CI 8.96 to 15.94; one trial, 52 participants; Analysis 2.3).


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Cardiac output

Jiang 1988 showed that Shengmai treatment was not significantly different from placebo treatment at increasing cardiac output (MD -0.53, 95% CI -1.08 to 0.02; one trial, 52 participants; Analysis 2.4).

B-X (MD 0.03, 95% CI -0.00 to 0.06; one trial, 80 participants; Analysis 2.11).

Hospitalization/rehospitalization


Stroke volume

Fang 1987 demonstrated that Shengmai treatment was better than placebo treatment at increasing stroke volume (MD 5.80, 95% CI 0.16 to 11.44; one trial, 80 participants; Analysis 2.5).

Costs

No data were available on this outcome. Adverse effects

Stroke volume index

Fang 1987 showed that Shengmai treatment was not significantly different from placebo treatment changing stroke volume index (MD 3.95, 95% CI -0.10 to 8.00; one trial, 80 participants; Analysis 2.6).

Cardiac index

Fang 1987 demonstrated that Shengmai treatment was better than placebo treatment for changing cardiac index (MD 0.32, 95% CI 0.04 to 0.60; one trial, 80 participants; Analysis 2.7).

Three trials reported mild adverse effects in six patients: mild asomnia occurred in 2/90 patients (2.22%) within the Shengmai group (Liu 2007a), and both were in the high-dose (60 mL/d) Shengmai group (2/30, 6.67%); dry mouth and fidgety responses occurred in 2/30 patients (6.67%) in the Shengmai group (Zhao 2006), and both occurred in the high-dose (60 mL/d) Shengmai group (2/10, 20%); stomach discomfort and hypoglycaemia occurred in 2/26 patients (7.69%) within the Shengmai group and they were withdrawn from the trial (Jiang 1988). Four trials reported no adverse effects at the end of treatment (He 2004; Zhai 2009; Wang 2010a; Ding 2012). Seven trials did not report on this outcome (Fang 1987; Zhang 2002; Mao 2003a Part A; Mao 2003a Part B; Su 2012; Wan 2012; Liu 2013)

Myocardial contractility

Fang 1987 showed that Shengmai treatment was better than placebo treatment for increasing Heather Index (HI) (MD 1.88, 95% CI 0.38 to 3.38; one trial, 80 participants; Analysis 2.8). Fang 1987 provided data for ECG change and demonstrated that Shengmai treatment was better than placebo treatment for changing Q-Z (MD 10.72, 95% CI 5.10 to 16.34; one trial, 80 participants; Analysis 2.9) and Adz/dtMax (MD 0.10, 95% CI 0.01 to 0.19; one trial, 80 participants; Analysis 2.10), but was not significantly different from placebo treatment at changing Q-B/

Sensitivity analyses and subgroup analyses We did not perform any sensitivity analyses because the included trials were of similar low quality. We were unable to perform any subgroup analyses because of insufficient sample size and incomplete data of heart failure types. We made a thorough investigation of heterogeneity, but there was insufficient information to explain the cause of the heterogeneity, so we still applied the random-effects model for these indexes.


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A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]

Shengmai compared to placebo for heart failure Patient or population: patients with heart failure Settings: inpatients and outpatients Intervention: Shengmai Comparison: placebo Outcomes

Mortality

Illustrative comparative risks* (95% CI)

Assumed risk

Corresponding risk

Placebo

Shengmai

See comment

See comment

Lack of improvement Moderate in heart failure (NYHA class improved 160/90 mmHg (21.3/12 kPa, 1 kPa = 7.5 mmHg)), CHF combined uncontrolled infection; (4) combined with blood system diseases; (5) serious liver or kidney dysfunction; (6) current or past tumour or other deadly diseases that may affect short-term survival; (7) pregnant women, breast-feeding women and psychiatric patients Baseline characteristics: comparable (statistical analysis)

Interventions

Shengmai group: Shengmai injection (agent: Shanxi, 40 mL + 5% glucose solution 250 mL intravenously daily) + co-intervention Control group: co-intervention only Co-intervention: diuretic, cardiotonic, ACEI or adrenergic receptor binder, beta-adrenoceptor blockade, nitrate esters Treatment duration: seven days

Outcomes

LVEF (%): before treatment: 44.83 ± 4.08 in Shengmai group, 45.89 ± 4.51 in control group; after treatment: 52.37 ± 3.53 in Shengmai group, 50.68 ± 3.87 in control group SV(ml/bite): before treatment: 44.46 ± 5.02 in Shengmai group, 46.12 ± 6.38 in control group; after treatment: 56.42 ± 8.51 in Shengmai group, 54.14 ± 8.14 in control group CO (L/min): before treatment: 3.61 ± 0.56 in Shengmai group, 3.56 ± 0.47 in control group; after treatment: 4.88 ± 0.82 in Shengmai group, 4.39 ± 0.55 in control group Adverse reactions: none The outcomes were measured at the end of treatment

Notes Shengmai (a traditional Chinese herbal medicine) for heart failure (Review) Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

29

Ding 2012

(Continued)

Risk of bias Bias

Authors’ judgement

Support for judgement

Random sequence generation (selection Unclear risk bias)

“patients were randomly allocated”. Sequence generation: a computer random number generator. However, baseline data were not available.

Allocation concealment (selection bias)

The method of concealment is not described.

High risk

Blinding (performance bias and detection High risk bias) All outcomes

The trial did not answer this question.

Incomplete outcome data (attrition bias) All outcomes

Unclear risk

Insufficient information.

Selective reporting (reporting bias)

Unclear risk


Other bias

Unclear risk

Insufficient information to assess whether an important risk of bias exists

Fang 1987 Methods

Randomized, double-blind, placebo-controlled, cross-over trial

Participants

Ethnicity: Chinese Participants: 40 patients, M/F 35/5 (20 in Shengmai group, 20 in control group), age: 39 to 80 years, mean age 57.52 ± 10.78 years, stable Angina/old myocardial infarction 9/31. NYHA class 2/3: 37/3 Setting: inpatients Diagnostic criteria: NYHA class; CHD based on WHO criteria 1979(Rapaport 1979) Exclusion criteria: not stated Baseline characteristics: comparable (statistical analysis)

Interventions

Shengmai group: Shengmai oral liquid (10 mL twice a day) Control group: placebo Treatment duration: 50 days in total = Phase I (20 days) + wash-out period (10 days) + Phase II (20 days)

Outcomes

Heart function improvement (ECG) In Shengmai group: HR: before treatment 75.95 ± 10.12, after treatment 75.18 ± 9.22 Contractive pressure (SBP): before treatment 128.9 ± 13.8, after treatment 128.3 ± 12. 1 Diastolic blood pressure (DBP): before treatment 79.25 ± 8.01, after treatment 78.75 ± 6.30 Q-Z: before treatment 173.3 ± 15.1, after treatment 161.5 ± 11.6


30

Fang 1987

(Continued)

HI: before treatment 10.55 ± 3.44, after treatment 12.59 ± 3.67 Q-B/B-X: before treatment 0.4482 ± 0.08, after treatment 0.4064 ± 0.06 Adz/dtMax: before treatment 0.6203 ± 0.1933, after treatment 0.4872 ± 0.1758 SV: before treatment 48.33 ± 13.29, after treatment 54.73 ± 12.56 SVI: before treatment 30.58 ± 9.43, after treatment 34.78 ± 8.98 CI: before treatment 2.2638 ± 0.6140, after treatment 2.6140 ± 0.6488 In placebo group: HR: before treatment 75.83 ± 9.06, after treatment 76.40 ± 9.71 contractive pressure(SBP): before treatment 129.65 ± 12.34, after treatment 129.55 ± 12.55 Diastolic blood pressure (DBP): before treatment 79.30 ± 6.83, after treatment 79.40 ± 6.69 Q-Z: before treatment 169.88 ± 12.75, after treatment 168.40 ± 10.73 HI: before treatment 10.35 ± 3.30, after treatment 10.51 ± 3.26 Q-B/B-X: before treatment 0.4366 ± 0.07, after treatment 0.4262 ± 0.06 Adz/dtMax: before treatment 0.6051 ± 0.2103, after treatment 0.5783 ± 0.2038 SV: before treatment 49.08 ± 12.38, after treatment 49.68 ± 13.19 SVI: before treatment 31.20 ± 9.28, after treatment 31.45 ± 9.25 CI: before treatment 2.3343 ± 0.6400, after treatment 2.3647 ± 0.6203 Adverse reaction: not stated The outcomes were measured at the end of treatment Notes Risk of bias Bias




“patients were randomly allocated by drawing of lots” (pers. communication with trial author) However, baseline data were not available.



High risk

Blinding (performance bias and detection Low risk bias) All outcomes

Double blinding.


Unclear risk



Unclear risk


Other bias

Unclear risk



31

He 2004 Methods

RCT

Participants

Ethnicity: Chinese Participants: 60 patients (32 in Shengmai group, M/F 18/14, mean age 43 years; 28 in control group, M/F 15/13, mean age 42 years), NYHA class: class 2/class 3/class 4:8/ 34/18; CHD/hypertensive heart disease/DCM/RHD:21/15/12/12 Setting: inpatients Diagnostic criteria of heart failure: NYHA class Exclusion criteria: not stated Baseline characteristics: not stated

Interventions

Shengmai group: Shengmai injection (agent: Huaxi, 20 to 40 mL + 5% glucose solution 250 mL intravenously daily) plus co-intervention Control group: co-intervention Co-intervention: cardiotonic, diuretic, vasodilator Treatment duration: 14 days

Outcomes

Heart function improvement < class 1: 3 in Shengmai group, 7 in control group Exercise test after treatment: 12 min ± 3min in Shengmai group, 6 ± 3min in control group Heart rate multiply systolic blood pressure: no difference The activity of Flow Medicated Dilation of brachial artery: before treatment: 3.5 ± 3.1 in Shengmai group, 3.6 ± 3.1 in control group after treatment: 9.6 ± 3.2 in Shengmai group, 4.2 ± 2.8 in control group Adverse reaction: none The outcomes were measured at the end of treatment

Notes

Activity of flow medicated dilation of brachial artery was assessed blindly

Risk of bias Bias




“patients were randomly allocated” Sequence generatIon: drawing of lots (telephone author) However, the baseline data were not available.



High risk


Activity of flow medicated dilation of brachial artery assessed blindly


Unclear risk



Unclear risk



32

He 2004

(Continued)

Other bias

Unclear risk


Jiang 1988 Methods

Randomized, double-blind, placebo-controlled, cross-over trial

Participants

Ethnicity: Chinese Participants: 26 patients, M/F: 23/3 (13 in Shengmai group, 13 in control group), age 23 to 60 years, mean age: 43.8 ± 12.3 years, DCM: 26, NYHA class 2/3: 23/3 Setting: outpatients Diagnostic criteria: NYHA class; DCM based on WHO criteria 1984(WHO 1984) Exclusion criteria: not stated Baseline characteristics: comparable (statistical analysis)

Interventions

Shengmai group: Shengmai oral liquid (10 mL twice a day) Control group: placebo Treatment duration: 50 days in total = Phase I (20 days) + wash out period (10 days) + Phase II (20 days)

Outcomes

Heart function improvement (M-UCG) In Shengmai group: HR (bpm): before treatment 70.7 ± 10.2, after treatment 70.8 ± 10.5 Contractive pressure (SBP) (mmHg): before treatment 120.2 ± 13.1, after treatment 119.5 ± 15.4 DBP (mmHg): before treatment 75.3 ± 5.6, after treatment 76.3 ± 5.1 Left ventricular end-diastolic dimension (Dd) (mm): before treatment 61.5 ± 5.7, after treatment 56.6 ± 6.2 Left ventricular end systolic diameter (Ds) (mm): before treatment 52.9 ± 6.1, after treatment 44.8 ± 6.8 CO (L/min): before treatment 3.97 ± 0.17, after treatment 4.48 ± 0.98 EF (%): before treatment 29.71 ± 5.49, after treatment 29.35 ± 5.30 Left ventricular fractional shortening (1D): before treatment 13.96 ± 2.77, after treatment 14.05 ± 2.82 mVcf (cir/s): before treatment 0.440 ± 0.10, after treatment 0. ± 0.142 Exercise test: before treatment 7.22 ± 3.80, after treatment 10.67 ± 4.24 In placebo group: HR (bpm): before treatment 70.5 ± 10.7,after treatment 69.9 ± 10.8 Contractive pressure (SBP) (mmHg): before treatment 119.4 ± 13.6, after treatment 119.3 ± 13.3 DBP (mmHg): before treatment 75.2 ± 6.1, after treatment 75.1 ± 5.4 Left ventricular end-diastolic dimension (Dd) (mm): before treatment 60.9 ± 6.8, after treatment 61.0 ± 5.9 Left ventricular end-systolic diameter (Ds) (mm): before treatment 52.6 ± 7.1, after treatment 52.5 ± 6.2 CO (L/min): before treatment 3.82 ± 1.2, after treatment 3.80 ± 1.00 EF (%): before treatment 29.15 ± 5.43, after treatment 29.35 ± 5.30


33

Jiang 1988

(Continued)

Left ventricular fractional shortening (1D): before treatment 13.96 ± 2.77, after treatment 14.05 ± 2.82 mVcf (cir/s): before treatment 0.440 ± 0.10, after treatment 0.439 ± 0.09 Exercise test: before treatment 5.33 ± 3.60, after treatment 5.22 ± 4.01 Adverse reaction: one patient with stomach discomfort, one patient with hypoglycaemia Outcomes were measured at the end of treatment Notes Risk of bias Bias




“patients were randomly allocated by drawing of lots”.(contact the author). However, the baseline data were not available



High risk


Double blinding.


High risk

Two missing outcome data in Shengmai group.


Unclear risk


Other bias

Unclear risk


Liu 2007a Methods

RCT

Participants

Ethnicity: Chinese Participants: 120 patients: 30 in low-dose group, M/F 15/15, age 40 to 75 years, duration of heart failure 4 to 12 years, CHD/hypertension heart disease/DCM/RDH: 13/11/3/ 3, NYHA class2/3/4: 7/13/10; 30 in middle-dose group, M/F 17/13, age 39 to 74 years, duration of heart failure 3 to 11 years, CHD/hypertension heart disease/DCM/RDH: 13/10/3/4,NYHA class 2/3/4: 8/13/9 30 in high-dose group, M/F 16/14, age 38 to 75 years, duration of heart failure 5 to 12 years, CHD/hypertension heart disease/DCM/ RDH: 12/11/3/4, NYHA class 2/3/4: 8/14/8 30 in control group, M/F 16/14, age 38 to 73 years, duration of heart failure 3 to 10 years, CHD/hypertension heart disease/DCM/RDH: 14/10/2/4, NYHA class 2/3/4: 8/ 12/10 Setting: inpatients and outpatients Diagnostic criteria: heart function class based on NYHA class


34

Liu 2007a

(Continued)

Exclusion criteria: (1) age > 75, (2) women with pregnancy or in lactation stage; (3) heart failure caused by other organs, such as liver and kidney failure; (4) malignant arrhythmia; (5) diabetes with non controlling serum glucose; (6) acute myocardial infarction; (7) hypertensive patients with non-controlling of blood pressure; (8) patients with treatment discontinued, unable to determine the efficacy Baseline characteristics: comparable (statistical analysis) Interventions

Shengmai group: Shengmai injection (1) in low-dose group (agent: Shanxi, 20 mL + 5% glucose solution 250 mL intravenously daily) (2) in middle-dose group (agent: Shanxi, 40 mL + 5% glucose solution 250 mL intravenously daily) (3) in high-dose group (agent: Shanxi, 60 mL + 5% glucose solution 250 mL intravenously daily) Control group: co-intervention (co-interventions: diuretics, cardiotonics, vasodilators) Treatment duration: 15 days

Outcomes

Symptoms and sign no improvement or worsening of heart failure: 7 in low-dose group, 2 in middle-dose group, 2 in high-dose group, 14 in control group Cardiac function and haemorheology changes: In Shengmai groups: Low-dose group: LV (mm): before treatment 59.87 ± 10.09, after treatment 48.63 ± 6.25 CO (L/min): before treatment 2.61 ± 0.60, after treatment 3.92 ± 0.62 LVEF: before treatment 0.36 ± 0.03, after treatment 0.42 ± 0.03 E/A: before treatment 0.88 ± 0.09, after treatment 1.20 ± 0.13 cardiothoracic ration: before treatment 0.50 ± 0.03, after treatment 0.61 ± 0.06 Middle-dose group: LV (mm): before treatment 60.59 ± 9.26, after treatment 40.13 ± 5.31 CO (L/min): before treatment 2.44 ± 0.79, after treatment 4.86 ± 0.72 LVEF: before treatment 0.36 ± 0.02, after treatment 0.47 ± 0.03 E/A: before treatment 0.87 ± 0.11, after treatment 1.41 ± 0.13 cardiothoracic ratio: before treatment 0.52 ± 0.03, after treatment 0.65 ± 0.06 High-dose group: LV (mm): before treatment 58.05 ± 8.79, after treatment 39.59 ± 6.25 CO (L/min): before treatment 2.44 ± 0.81, after treatment 4.85 ± 0.77 LVEF: before treatment 0.37 ± 0.03, after treatment 0.46 ± 0.02 E/A: before treatment 0.88 ± 0.13, after treatment 1.44 ± 0.15 cardiothoracic ratio:before treatment 0.52 ± 0.04, after treatment 0.65 ± 0.05 Control group: LV (mm): before treatment 62.82 ± 7.66, after treatment 55.95 ± 5.96 CO (L/min): before treatment 2.38 ± 0.78, after treatment 3.17 ± 0.62 LVEF: before treatment 0.35 ± 0.02, after treatment 0.38 ± 0.03 E/A: before treatment 0.86 ± 0.11, after treatment 1.00 ± 0.12 cardiothoracic ratio: before treatment 0.51 ± 0.04, after treatment 0.55 ± 0.05 Adverse reaction: 1 patient with little skin hypersensitiveness in control group, 2 patients with mild somnipathy in high-dose group Outcomes were measured at the end of treatment


35

Liu 2007a

(Continued)

Notes Risk of bias Bias




“patients were randomly allocated by random number table” (telephone author) However, the baseline data were not available.



High risk




Unclear risk



Unclear risk


Other bias

Unclear risk


Liu 2013 Methods

RCT

Participants

Ethnicity: Chinese; Participants: 50 patients (25 in Shengmai group, M/F 16/9, age 67 ± 4 years; NYHA class3/4: 17/8; 25 in control group, M/F 17/8, age 67 ± 6, NYHA class 3/4: 16/9); Diagnostic criteria: Guideline for clinical research on the treatment of new Chinese traditional medicine in congestive heart failure, Reference standard of deficiency syndrome classification in traditional Chinese medicine, heart function class based on NYHA class Setting: inpatients Baseline characteristics: comparable (statistical analysis)

Interventions

Shengmai group: Shengmai oral liquid 100 mL (agent: Panax ginseng Ophiopogon 12 g, japonicus 12 g and Schisandra chinensis 6 g po bid) + co-intervention Control group: co-intervention Co-interventions: diuretic, digitalis, ACEI, beta-adrenoceptor blockade, nitrate esters Treatment duration: 14 days.

Outcomes

Heart function improvement < class 1: 4 in Shengmai, 7 in control group BNP (ng/L): before treatment: 841.21 ± 413.61 in Shengmai group, 839.67 ± 431.79 in control group; after treatment: 371.18 ± 189.27 in Shengmai group, 567.26 ±162.43 in control group


36

Liu 2013

(Continued)

With no obvious improvement or even aggravation of TCM (Traditional Chinese Medicine) syndrome: 3 in Shengmai, 11 in control group Adverse reaction: none Outcomes were measured at the end of treatment Notes Risk of bias Bias




“patients were randomly allocated”. Sequence generation: a computer random number generator. However, the baseline data were not available



High risk




Unclear risk



Unclear risk


Other bias

Unclear risk


Mao 2003a Methods

RCT

Participants

Ethnicity: Chinese Participants: 40 patients (10 in Shengmai A1 group, M/F 3/7, age 59.40 ± 6.24 years, duration of heart failure 6.96 ± 6.24 years, CHD/RDH/PHD: 8/1/1, NYHA class2/3: 4/6;10 in Shengmai A2 group, M/F 4/6, age 59.20 ± 6.83 years, duration of heart failure 6.60 ± 6.22 years, CHD/HBP: 9/1, NYHA class2/3: 3/7; 10 in Shengmai A3 group, M/F 6/4, age 58.80 ± 8.09 years, duration of heart failure 6.35 ± 7.32 years, CHD/ RDH/PHD: 8/1/1, NYHA class2/3: 3/7;10 in control A group, M/F 4/6, age 60.30 ± 7.07 years, duration of heart failure 6.87 ± 6.22 years, CHD/HBP/PHD: 8/1/1, NYHA class2/3: 3/7) 40 patients (10 in Shengmai B1 group,10 in Shengmai B2 group, 10 in Shengmai B3 group, 10 in control B group) Setting: inpatients Diagnostic criteria: heart failure diagnosis based on Framingham and Boston criteria, heart function class based on NYHA class Inclusion criteria: heart failure; (1) age 41 to 70 years; (2) heart failure class 2-3; not taking digitalis or drugs affecting the metabolization of digoxin within one week; liver


37

Mao 2003a

(Continued)

and kidney function were normal, normal electrolyte Exclusion criteria: acute myocardial infarction, acute respiratory insufficiency of PHD, serious mitral stenosis in sinus rhythm, or HCM with obstruction; combined with diabetes, hyperthyroidism Baseline characteristics: comparable (statistical analysis) Interventions

Shengmai + co-intervention A versus co-intervention (Part A) (i) Shengmai A1, A2, A3 groups: Shengmai injection (agent: Yibing, 20, 40, 60 mL intravenously daily ) + co-intervention A Control group: Co-intervention A Co-interventions A: digoxin (0.25 mg + 5% glucose solution 40 mL, intravenously daily) + polarized solution 200 mL intravenously daily Shengmai versus co-intervention B (Part B) (ii) Shengmai B1, B2, B3 groups: Shengmai injection (agent: Yibing 20, 40, 60 mL intravenously daily) + co-intervention B (placebo) Control group: co-intervention B (placebo) Co-interventions B: polarized solution 200 mL intravenously daily Treatment duration: 14 days

Outcomes

Shengmai + co-intervention A versus co-intervention (Part A) Heart function improvement < class 1: 1/30 in Shengmai group, 2/20 in control group Serum TNFα: before treatment: 1.44 ± 0.8 in Shengmai A1 group, 1.53 ± 0.73 in Shengmai A2 group, 1.52 ± 0.66 in Shengmai A3 group, 1.54 ± 0.68 in control A group after treatment: 0.71 ± 0.52 in Shengmai A1 group, 0.63 ± 0.29 in Shengmai A2 group, 0.59 ± 0.36 in Shengmai A3 group, 1.2 ± 0.65 in control A group Serum EDLF: before treatment: 0.17 ± 0.12 in Shengmai B1 group, 0.15 ± 0.08 in Shengmai B2 group, 0.16 ± 0.09 in Shengmai B3 group, 0.18 ± 0.06 in control B group after treatment: 0.29 ± 0.14 in Shengmai B1 group, 0.32 ± 0.11 in Shengmai B2 group, 0.37 ± 0.1 in Shengmai B3 group, 0.14 ± 0.06 in control B group Shengmai + co-intervention A versus co-intervention (Part B) Heart function improvement 70, heart failure caused by acute myocardial infarction, acute pulmonary edema, congenital heart disease, valvular heart disease, hyperthyroid heart, liver/renal failure Baseline characteristics: comparable (statistical analysis)

Interventions

Shengmai group: Shengmai injection (40 mL + 5% GS250ml iv gtt qd ) + co-intervention Control group: co-intervention Co-interventions: diuretic, digitalis, vasodilator, ACEI/adrenergic receptor binder Treatment duration: 15 days

Outcomes

Heart function improvement < class 1: 4 in Shengmai, 9 in control group Hemodynamics CO (L/min): before treatment: 3.7 ± 1.4 in Shengmai group, 3.6 ± 1.7 in control group after treatment: 5.0 ± 0.8 in Shengmai group, 4.1 ± 0.7 in control group SV (mL): before treatment: 38.2 ± 6.1 in Shengmai group, 43.5 ± 4.6 in control group after treatment: 69.5 ± 2.8 in Shengmai group, 57.8 ± 3.3 in control group CI (L/min·m²): before treatment: 1.80 ± 0.50 in Shengmai group, 1.86 ± 0.36 in control group after treatment: 3.15 ± 0.20 in Shengmai group, 2.30 ± 0.20 in control group EF:


43

Zhai 2009

(Continued)

before treatment: 0.42 ± 0.03 in Shengmai group, 0.63 ± 0.05 in control group after treatment: 0.43 ± 0.04 in Shengmai group, 0.51 ± 0.02 in control group Left ventricular fractional shortening (1D) (%): before treatment: 10.6 ± 3.8 in Shengmai group, 11.8 ± 3.6 in control group after treatment: 16.0 ± 3.3 in Shengmai group, 14.3 ± 3.1 in control group 1T (%): before treatment: 23.1 ± 12.6 in Shengmai group, 21.8 ± 15.3 in control group after treatment: 40.2 ± 17.1 in Shengmai group, 31.5 ± 13.7 in control group QOL: using “Minnesota Living with Heart Failure Questionnaire” before treatment: 69.0 ± 20.0 in Shengmai group, 68.0 ± 18.0 in control group after treatment: 42.0 ± 15.0 in Shengmai group, 48.0 ± 17.0 in control group Adverse reaction: none Outcomes were measured at the end of treatment Notes Risk of bias Bias




“patients were randomly allocated” Sequence generation: random number table (telephone the author) However, the baseline data were not available.



High risk




Unclear risk



Unclear risk


Other bias

Unclear risk


Zhang 2002 Methods

RCT

Participants

Ethnicity: Chinese Participants: 100 patients, 50 in Shengmai group, M/F 30/20, mean age 58 years, duration of heart failure 4.8 years, NYHA class 2/3/4: 10/35/5; 50 in control group, M/ F 29/21, mean age 60 years, duration of heart failure 4.9 years, NYHA class 2/3/4: 10/ 36/4


44

Zhang 2002

(Continued)

Setting: inpatients Diagnostic criteria: heart function class based NYHA class. WHO/ISFC classification of cardiomyopathy(WHO/ISFC 1980) Exclusion criteria: CHD, RHD, congenital heart disease Baseline characteristics: comparable (statistical analysis) Interventions

Shengmai group: Shengmai injection (agent: Huaxi, from three herbs/10 mL: Panax ginseng 1 g, Ophiopogon japonicus 3.12 g and Schisandra chinensis 1.56 g. 60 mL + 5% GS250ml iv gtt qd) + co-intervention Control group: co-intervention Co-interventions: oxygen therapy, digoxin 0.125mg daily orally (maintenance therapy) ; hydrochlorothiazide 25 mg twice daily orally, triamterene 50 mg twice daily orally (to interrupt use); isosorbide dinitrate 5 mg three times daily orally Treatment duration: 14 days

Outcomes

Heart function improvement < class 1: 8 in Shengmai, 20 in control group Hemodynamics CO (L/min): before treatment: 3.8 ± 1.0 in Shengmai group, 3.7 ± 1.5 in control group after treatment: 5.1 ± 0.6 in Shengmai group, 4.2 ± 0.3 in control group SV (mL): before treatment: 48.9 ± 6.0 in Shengmai group, 45.4 ± 5.3 in control group after treatment: 70.4 ± 3.2 in Shengmai group, 62.3 ± 3.1 in control group CI(L/min·m²): before treatment: 1.9 ± 0.2 in Shengmai group, 1.9 ± 0.2 in control group after treatment: 3.0 ± 0.2 in Shengmai group, 2.3 ± 0.2 in control group EF: before treatment: 0.45 ± 0.01 in Shengmai group, 0.41 ± 0.02 in control group after treatment: 0.64 ± 0.04 in Shengmai group, 0.51 ± 0.02 in control group SVR (dyn*sec*cm-5): before treatment: 2602 ± 689 in Shengmai group, 2660 ± 638 in control group after treatment: 1886 ± 896 in Shengmai group, 2432 ± 386 in control group D (%): before treatment: 10.2 ± 4.1 in Shengmai group, 12.2 ± 3.2 in control group after treatment: 15.9 ± 3.5 in Shengmai group, 14.0 ± 3.0 in control group T (%): before treatment: 23.2 ± 10.3 in Shengmai group, 22.1 ± 16.0 in control group after treatment: 42.3 ± 23.1 in Shengmai group, 30.6 ± 15.0 in control group Adverse reaction: not stated Outcomes were measured at the end of treatment

Notes

National ’9·5’ Program

Risk of bias Bias




45

Zhang 2002

(Continued)


“patients were randomly allocated” Sequence generation: a computer random number generator (telephone the author). However, the baseline data were not available



High risk




Unclear risk



Unclear risk


Other bias

Unclear risk


Zhao 2006 Methods

Stratified random according to age

Participants

Ethnicity: Chinese Participants: 40 patients, M/F 14/26, age 41 to 70 years, mean age 61.38 ± 8.47 years, duration of heart failure 0.5 to 30 years. 35 CHD, 3 RHD, 2 PHD, heart function class 2/3: 18/22; (10 in low-dose group, 10 in middle-dose group, 10 in high-dose group, 10 in control group) Setting: inpatients Diagnostic criteria: heart failure diagnosis based on Framingham criteria, heart function class based on NYHA Class and SAS criteria Inclusion criteria: (1) age from 40 to 70 years; (2) hear class 2~3; (3) no digitalis used in the last week and no high salt diet; (4) blood electrolytes, liver, kidney no obvious abnormalities Exclusion criteria: (1) age >70 or < 40 years, (2) AMI, hypertrophic obstructive cardiomyopathy, high blood pressure 3 class. (3) combined with diabetes, hyperthyreosis Baseline characteristics: comparable (statistical analysis), specific data on baseline characters were provided

Interventions

Shengmai group: Shengmai injection (1) in low-dose group: (agent: Huaxi, 20 mL + 5% glucose solution 100 mL + 0.25 g KCL + R-I 1u intravenously daily) (2) in middle-dose group:(agent: Huaxi, 40 mL + 5% glucose solution 100 mL + 0.25 g KCL + R-I 1u intravenously daily) (3) in high-dose group:(agent: Huaxi, 60 mL + 5% glucose solution 100 mL + 0.25 g KCL + R-I 1u intravenously daily) Control group: 5% glucose solution 100 mL + 0.25 g KCL + R-I 1u intravenously daily Treatment duration: seven days


46

Zhao 2006

(Continued)

Outcomes

Symptoms and sign no improvement or worsening of heart failure: 5 in low-dose group, 2 in middle-dose group, 0 in high-dose group, 8 in control group Urinary volume change is significant in different groups Adverse reaction: 2 patients with dry mouth and restlessness in high-dose group The outcomes were measured at the end of treatment

Notes

Funding source: A project of State Administration of Traditional Chinese Medicine

Risk of bias Bias



Random sequence generation (selection Low risk bias)

“Stratified random”. Sequence generation: random number table (telephone the author)


Insufficient information to permit judgement.

High risk




Unclear risk



Unclear risk


Other bias

Unclear risk


Angiotensin converting enzyme inhibitors = ACEIs; M/F = Male/female; CHD = coronary heart disease; RHD = rheumatic heart disease; PHD = pulmonary heart disease; DCM = dilated cardiomyopathy; HCM = hypertrophic cardiomyopathy; HR = heart rate; QOL = quality of life; EF = ejection fraction; CO = cardiac output; SV = stroke volume; CI = cardiac index; LVEDV = left ventricular end-diastolic volume; LVESV = left ventricular end-systolic volume; HI = heather index; PaO2 = oxygen partial pressure; PaCO2 = carbon dioxide partial pressure; kPa = blood pressure measure unit, 1kPa = 7.6 mmHg; po = by mouth; NYHA = New York Heart Association; WHO = World Health Organization.

Characteristics of excluded studies [ordered by study ID]

Study

Reason for exclusion

Bu 2007

Not a RCT (”Allocation by the sequence of enrolled in the hospital“)

Cen 1999

Not a RCT (confirmed by contacting author by telephone).


47

(Continued)

Chen 2000

Not a RCT or quasi-RCT (confirmed by contacting author by telephone)

Chen 2003

Not a RCT. Randomisation methods are not mentioned in the paper. We could not contact the study authors

Chen 2008

Not a RCT (confirmed by contacting to the author by telephone. ”Allocated by the sequence of medical record number“)

Chen 2010

The randomisation methods are not mentioned in the paper. We could not contact the authors for details

Chen 2012

The author refused to answer our questions.

Chen 2013

There were many contradictions in their data.

Cheng 2001

Not a RCT (”allocated by the hospital number“).

Cheng 2007

Not a RCT (confirmed by contacting the author by telephone).

Dai 2011

The randomisation methods are not mentioned in the paper. We could not contact the authors for details

Deng 1992

Not a RCT (”Patients were allocated by the sequence of enrolled in the trial“)

Ding 2005

Shengmai group used not only Shengmai but other medicine.

Dou 2010

We could not contact the authors for details.

Duan 2010

The randomisation methods were not mentioned in the paper. We could not contact the authors for details

Fan 2004

We could not contact the author for details.

Feng 2002

Not a RCT or quasi-RCT.

Feng 2003

Not a RCT. Randomization methods are not mentioned in the paper

Feng 2012

Not a RCT or quasi-RCT (”Patients were allocated casually).

Gao 2001


Gong 2006


Gu 2004


Gu 2008


He 2001

Not a RCT (“allocation by the hospital number”).

Hong 2005

Not a RCT (“allocation by sequence of visiting the hospital”)


48

(Continued)

Hong 2009

The number of patients in tables (treatment group 23, control group 27) was not accordance with that in the text treatment group 24, control group 26). Though we contacted the author, we failed to obtain the outcome data on detail

Hou 2012


Hu 1997


Hu 1998


Hu 2005a


Hu 2005b


Hui 2007


Jiang 2005

Shengmai in this study was not used to treat heart failure but to improve symptoms in patients after coronary artery bypass grafting.

Jiang 2010


Kong 2010


Li 1998a


Li 1998b

Not a RCT. The randomisation methods were not mentioned in the paper. We could not contact the authors for details)

Li 2003a

Not a RCT.

Li 2003b


Li 2004

Not a RCT (“allocation by the sequence of visiting the hospital”)

Li 2006a

Not a RCT. The randomisation methods were not mentioned in the paper. We could not contact the authors of this article

Li 2008


Li 2009a


Li 2009b

Not a RCT (confirmed by contacting the author by telephone. “Allocated by the sequence of medical record number”)

Li 2009c

Not a RCT (confirmed by contacting the author by telephone. “Allocated by the sequence of entering hospital”)

Li 2012a



49

(Continued)

Li 2012b


Liang 2006


Liao 1996

Not a RCT. The randomisation methods were not mentioned in the paper. We could not contact the authors for details

Liu 1999

Shengmai plus Chinese drug plus usual treatment versus usual treatment

Liu 2007b

Shengmai versus dobutamine.

Liu 2009

There were no outcomes of interest.

Liu 2010


Lu 2005

Before-and-after study.

Lu 2008


Lu 2009

Not a RCT (confirmed by contacting to the author by telephone. “Allocated by the sequence of entering hospital”)

Lu 2012


Ma 2003

Not a RCT (confirmed by contacting to the author by telephone)

Ma 2006


Ma 2008

Shengmai group used not only Shengmai but other Western medicine

Mao 1998


Mao 2003b


Mao 2006a


Mao 2006b


Miao 2005


Mo 1996

Shengmai versus another drug.

Ni 2004


Ni 2007

Outcome only reported 28 patients in the Shengmai group.

Ni 2012

Not a RCT (confirmed by contacting the author by telephone. “Allocated casually”


50

(Continued)

Peng 2007

Combination of Metoprolol and Shengmai capsule.

Peng 2012


Qiao 2007

Components of Shengmai were more than our intervention specifications

Qiu 1999

Outcome reported from 27 patients, but only 20 patients were included at entry in the control group

Qiu 2007

Shengmai versus captopril.

Shao 2006


Shen 2006


Shi 2006


Shi 2006a


Shi 2006b

Outcome reported 21 patients in the control group, but there were only 20 patients included in the study

Song 2013


Su 2008

Shengmai versus another Chinese drug.

Sun 1998

Not a RCT. The randomisation methods were not mentioned in the paper. We could not contact the authors for details

Sun 1998b


Sun 1999

Not a RCT or quasi-RCT (confirmed by contacting the author by telephone)

Tang 2001

Not a RCT. The randomisation methods were not mentioned in the paper. We could not contact the authors for details)

Tang 2005


Wan 2004

The outcome data did not match the description.

Wan 2007


Wang 1994


Wang 1997

Not a RCT. The randomisation methods were not mentioned in the paper. We could not contact the authors of this article for details

Wang 2002

Outcomes reported from 40 patients, but 50 patients were included in study


51

(Continued)

Wang 2003

Outcome reported from 51 patients, but only 50 patients were included at entry in the Shengmai group

Wang 2004a

No full text article available. We could not obtain any substantial publications to assess these studies for eligibility

Wang 2004b

Not a RCT (we contacted the author: “allocation by the sequence of visiting the hospital”)

Wang 2005a


Wang 2005b


Wang 2005c


Wang 2006a

Not a RCT (“Allocation by sequence of visiting the hospital”)

Wang 2006b


Wang 2008a


Wang 2008b

Shengmai injection versus polarized solution.

Wang 2009


Wang 2010b


Wang 2010c

The randomisation methods were not mentioned in the paper. We could not contact the authors the details

Wu 2009a


Wu 2009b


Wu 2011


Xiao 2004

Not a RCT or quasi-RCT,

Xin 2012


Xu 2009


Xu 2011


Yan 2005

No outcomes of interest.

Yang 2001


Yang 2005



52

(Continued)

Yang 2006a


Yang 2006b

Not a RCT (“Allocation by clinic record number”).

Yang 2010


Ye 2011


Yu 2005


Yuan 2011


Zhan 2007

Shengmai was used to treat chronic pulmonary heart disease without heart failure

Zhang 1990


Zhang 2004a

Only reported the outcomes in Shengmai grou p and did not report the outcomes in co n trol group

Zhang 2004b


Zhang 2006

The treatment drug in this study was Shenmai which is only a partial component of Shengmai

Zhang 2007a


Zhang 2008

We could not contact the author of this article for details.

Zhang 2008a

We could not contact the author of this article for details.

Zhang 2008b

No outcomes of interest reported.

Zhang 2008c

Not a RCT (“Allocated by the sequence of entering hospital”)

Zhang 2009a


Zhang 2009b

Some data in table 2 were wrong. By contacting the author, we could not obtain details of the outcome data

Zhang 2011


Zhao 1998a


Zhao 1998b


Zhao 2000


Zhao 2004

No full text article was available. We could not obtain any substantial publications to assess this study for eligibility


53

(Continued)

Zhao 2005

Disease was low blood pressure.

Zhao 2007

Shengmai versus epinephrine.

Zhao 2008


Zhao 2011

The author said he forgot how he conducted the allocation and then he refused to answer the phone

Zheng 1996

A descriptive study.

Zheng 2005


Zhong 2005


Zhong 2007

The intervention included other drugs besides Shengmai.

Zhou 2006a

Patients with acute myocardial infraction and without heart failure

Zhou 2006b


Zhou 2009


Zhu 2004

No description of randomisation methods. We could not contact the authors for details

Zou 2011

Not a RCT (confirmed by contacting the author by telephone). “Allocated by the sequence of entering hospital”)


54

DATA AND ANALYSES

Comparison 1. Shengmai plus usual treatment versus usual treatment alone

Outcome or subgroup title 1 Lack of improvement in heart failure (NYHA class improved < I class or worsening of heart failure) 2 Exercise test (after treatment) 3 Change in quality of life 4 Change in ejection fraction (%) 5 Change in cardiac output (L/min) 6 Change in stroke volume (mL) 7 Change in cardiac index L/min*m² 8 Change in left ventricular end-diastolic volume (mL) 9 Change in left ventricular end-systolic volume (mL)

No. of studies

No. of participants

10

672

Risk Ratio (M-H, Fixed, 95% CI)

0.37 [0.26, 0.51]

1 1 4 4

354 360

Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI)

Totals not selected Totals not selected 9.02 [5.95, 12.08] 0.94 [0.26, 1.63]

3 2

240 160

Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Random, 95% CI)

8.53 [0.08, 16.98] 0.79 [0.59, 0.99]

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

1

Mean Difference (IV, Fixed, 95% CI)

Totals not selected

Statistical method

Effect size

Comparison 2. Shengmai versus placebo

Outcome or subgroup title 1 Lack of improvement in heart failure (NYHA class improved < I class or worsening of heart failure) 2 Change in exercise test (mins) 3 Change in ejection fraction (%) 4 Change in cardiac output (L/min) 5 Change in stroke volume (mL) 6 Change in stroke volume index 7 Change in cardiac index L/min*m² 8 Change in Heather Index 9 Change in ECG: Q-Z 10 Change in ECG: Adz/dtMax 11 Change in ECG: Q-B/B-X

No. of studies

No. of participants

Statistical method

Effect size

1

Risk Ratio (M-H, Fixed, 95% CI)

Totals not selected

1 1 1

Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI)

Totals not selected Totals not selected Totals not selected

1 1 1

Mean Difference (IV, Random, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI)

Totals not selected Totals not selected Totals not selected

1 1 1 1

Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI) Mean Difference (IV, Fixed, 95% CI)

Totals not selected Totals not selected Totals not selected Totals not selected


55

Analysis 1.1. Comparison 1 Shengmai plus usual treatment versus usual treatment alone, Outcome 1 Lack of improvement in heart failure (NYHA class improved < I class or worsening of heart failure). Review:

Shengmai (a traditional Chinese herbal medicine) for heart failure

Comparison: 1 Shengmai plus usual treatment versus usual treatment alone Outcome: 1 Lack of improvement in heart failure (NYHA class improved < I class or worsening of heart failure)

Study or subgroup

Shengmai

Usual treatment

n/N

n/N

He 2004

3/32

7/28

7.8 %

0.38 [ 0.11, 1.31 ]

Liu 2007a

11/90

14/30

21.9 %

0.26 [ 0.13, 0.51 ]

Liu 2013

4/25

7/25

7.3 %

0.57 [ 0.19, 1.71 ]

Mao 2003a

1/30

2/10

3.1 %

0.17 [ 0.02, 1.65 ]

Su 2012

2/33

4/33

4.2 %

0.50 [ 0.10, 2.55 ]

Wan 2012

2/33

2/29

2.2 %

0.88 [ 0.13, 5.85 ]

Wang 2010a

3/38

10/36

10.7 %

0.28 [ 0.09, 0.95 ]

Zhai 2009

4/30

9/30

9.4 %

0.44 [ 0.15, 1.29 ]

Zhang 2002

8/50

20/50

20.9 %

0.40 [ 0.19, 0.82 ]

Zhao 2006

7/30

8/10

12.5 %

0.29 [ 0.14, 0.60 ]

391

281

100.0 %

0.37 [ 0.26, 0.51 ]

Total (95% CI)

Risk Ratio

Weight

M-H,Fixed,95% CI

Risk Ratio M-H,Fixed,95% CI

Total events: 45 (Shengmai), 83 (Usual treatment) Heterogeneity: Chi2 = 3.74, df = 9 (P = 0.93); I2 =0.0% Test for overall effect: Z = 6.10 (P < 0.00001) Test for subgroup differences: Not applicable

0.001 0.01 0.1 Favours Shengmai

1

10 100 1000 Favours usual treatment


56

Analysis 1.2. Comparison 1 Shengmai plus usual treatment versus usual treatment alone, Outcome 2 Exercise test (after treatment). Review:


Comparison: 1 Shengmai plus usual treatment versus usual treatment alone Outcome: 2 Exercise test (after treatment)

Study or subgroup

He 2004

Shengmai

Mean Difference

Usual treatment

N

Mean(SD)

N

Mean(SD)

32

12 (3)

28

6 (3)

Mean Difference

IV,Fixed,95% CI

IV,Fixed,95% CI 6.00 [ 4.48, 7.52 ]

-20

-10

0

Favours Shengmai

10

20

Favours usual treatment

Analysis 1.3. Comparison 1 Shengmai plus usual treatment versus usual treatment alone, Outcome 3 Change in quality of life. Review:


Comparison: 1 Shengmai plus usual treatment versus usual treatment alone Outcome: 3 Change in quality of life

Study or subgroup

Zhai 2009

Shengmai

Mean Difference

Usual treatment

N

Mean(SD)

N

Mean(SD)

30

27 (18)

30

20 (17.5)

IV,Fixed,95% CI

IV,Fixed,95% CI 7.00 [ -1.98, 15.98 ]

-50

-25

Favours Shengmai


Mean Difference

0

25

50

Favours usual treatment

57

Analysis 1.4. Comparison 1 Shengmai plus usual treatment versus usual treatment alone, Outcome 4 Change in ejection fraction (%). Review:


Comparison: 1 Shengmai plus usual treatment versus usual treatment alone Outcome: 4 Change in ejection fraction (%)

Study or subgroup

Shengmai

Mean Difference

Usual treatment

Weight

N

Mean(SD)

N

Mean(SD)

Liu 2007a

90

9 (3.4)

30

3 (3)

28.1 %

6.00 [ 4.72, 7.28 ]

Wang 2010a

38

21 (8.9)

36

13.1 (11.5)

17.4 %

7.90 [ 3.20, 12.60 ]

Zhai 2009

30

21 (4.3)

30

8 (3.5)

26.3 %

13.00 [ 11.02, 14.98 ]

Zhang 2002

50

19 (4)

50

10 (2)

28.2 %

9.00 [ 7.76, 10.24 ]

100.0 %

9.02 [ 5.95, 12.08 ]

Total (95% CI)

208

IV,Random,95% CI

Mean Difference IV,Random,95% CI

146

Heterogeneity: Tau2 = 8.29; Chi2 = 35.02, df = 3 (P

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