Scholarly article on topic 'A Chinese patent medicine Salvia miltiorrhiza depside salts for infusion combined with conventional treatment for patients with angina pectoris: A systematic review and meta-analysis of randomized controlled trials'

A Chinese patent medicine Salvia miltiorrhiza depside salts for infusion combined with conventional treatment for patients with angina pectoris: A systematic review and meta-analysis of randomized controlled trials Academic research paper on "Clinical medicine"

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Abstract of research paper on Clinical medicine, author of scientific article — Yili Zhang, Yanming Xie, Xing Liao, Qiulei Jia, Yan Chai

Abstract Background: Currently, many trials have been conducted to investigate the beneficial and harmful effects of Salvia miltiorrhiza depside salts for infusion for treating patients with angina pectoris. It is important to systematically and criticallyevaluate the existing literature into providing a pooled effect to examine outcomes of angina pectoris with Salvia miltiorrhiza depside salts for infusion. Purpose: A systematic review and meta-analysis were performed to determine the clinical curative effect and safety of Salvia miltiorrhiza depside salts for infusion for angina pectoris and provide clear evidence to inform clinical practice. Method: The Cochrane Library, MEDLINE, EMBASE, and other four electronic Chinese databases were searched to identify relevant randomized controlled trials. Methodological quality and reporting quality of eligible studies was evaluated by using the Cochrane risk-of-bias tool and CONSORT for traditional Chinese medicine respectively. Meta-analysis was performed by RevMan 5.3 software. Result: Fifty-six randomized controlled trials involving 5503 patients were included. Most of the trials were classified as having an unclear risk of bias because of poor reported methodology. The main outcomes are improvements in angina symptoms, ECG improvement and reduction of nitroglycerin use. CHD mortality or rate of CHD events was not reported in any trial. Meta-analysis showed that Salvia miltiorrhiza depside salts for infusion combined with conventional treatment was better than conventional treatment alone in improving angina symptoms (RR= 1.28, 95% CI 1.24 to 1.31, p  < 0.00001), the frequency of angina attack (time/week)(WMD=−1.47, 95% CI −2.16 to −0.78), reducing clinical symptom scores (WMD=−0.55, 95% CI −0.57 to −0.53, p < 0.000011), increasing physical limitation scores (WMD= 7.68, 95% CI 1.48 to 13.88, p = 0.02), improving ECG (RR= 1.32,95% CI 1.27 to 1.38, p < 0.00001) and reducing dosage of nitroglycerin (RR= 1.50, 95% CI: 1.26 to 1.77, p < 0.00001). In addition, Egger's regression tests was found there was publication bias (Kendall’ tau= 0.36, p < 0.01). Conclusion: The current systematic review indicates relevant evidence for Salvia miltiorrhiza depside salts for infusion combined with conventional treatments treating patient with angina pectoris. However, the results should be interpreted with caution due to the low methodological quality, the risk of publication bias, lack of important clinically relevant outcomes and inadequate reporting on adverse events of the included trials. International methodological and reporting standards could help researchers conduct well designed trials and generate better evidence for Salvia miltiorrhiza depside salts for infusion.

Academic research paper on topic "A Chinese patent medicine Salvia miltiorrhiza depside salts for infusion combined with conventional treatment for patients with angina pectoris: A systematic review and meta-analysis of randomized controlled trials"

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A Chinese patent medicine Salvia miltiorrhiza depside salts for infusion combined with conventional treatment for patients with angina pectoris: a systematic review and meta-analysis of randomized controlled trials

Yili Zhang , Yanming Xie , Xing Liao , Qiulei Jia , Yan Chai

PII: DOI:

Reference:

S0944-7113(17)30002-8 10.1016/j.phymed.2017.01.002 PHYMED 52146

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Phytomedicine

Received date: Revised date: Accepted date:

5 December 2015 22 December 2016 5 January 2017

Please cite this article as: Yili Zhang , Yanming Xie , Xing Liao , Qiulei Jia , Yan Chai, A Chinese patent medicine Salvia miltiorrhiza depside salts for infusion combined with conventional treatment for patients with angina pectoris: a systematic review and meta-analysis of randomized controlled trials, Phytomedicine (2017), doi: 10.1016/j.phymed.2017.01.002

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A Chinese patent medicine Salvia miltiorrhiza depside salts for infusion combined with conventional treatment for patients with angina pectoris: a systematic review and meta-analysis of randomized controlled trials

Yili Zhanga, Yanming Xiea, Xing Liaoa* , Qiulei Jiab, Yan Chai

cademy o:

Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences, Beijing 100700, China;

b Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China;

c Department of Epidemiology, University of California-Los Angeles, California

90095, United States.

Corresponding author. Xing Liao Institute of Basic Research in Clinical Medicine, China Academy of

Chinese Medical Sciences, Beijing 100700, China Tel.: +86-18611002580

E-Mail address: okfrom2008@hotmail.com (XL)

ABSTRACT

Background: Currently, many trials have been conducted to investigate the beneficial and harmful effects of Salvia miltiorrhiza depside salts for infusion for treating patients with angina pectoris. It is important to systematically and critically evaluate the existing literature into providing a pooled effect to examine outcomes of angina pectoris with Salvia miltiorrhiza depside salts for infusion.

Purpose: A systematic review and meta-analysis were performed to determine the clinical curative effect and safety of Salvia miltiorrhiza depside salts for infusion for angina pectoris and provide clear evidence to inform clinical practice. Method: The Cochrane Library, MEDLINE, EMBASE, and other four electronic Chinese databases were searched to identify relevant randomized controlled trials. Methodological quality and reporting quality of eligible studies was evaluated by using the Cochrane risk-of-bias tool and CONSORT for traditional Chinese medicine respectively. Meta-analysis was performed by RevMan 5.3 software. Result: Fifty-six randomized controlled trials involving 5503 patients were included. Most of the trials were classified as having an unclear risk of bias because of poor reported methodology. The main outcomes are improvements in angina symptoms, ECG improvement and reduction of nitroglycerin use. CHD mortality or rate of CHD events was not reported in any trial. Meta-analysis showed that Salvia miltiorrhiza depside salts for infusion combined with conventional treatment was better than conventional treatment alone in improving angina symptoms (RR = 1.28, 95% CI 1.24 to 1.31, p < 0.00001), the frequency of angina attack(time/week)(WMD = -1.47, 95% CI -2.16 to -0.78), reducing clinical symptom scores(WMD = -0.55, 95% CI -0.57 to -0.53, p < 0.000011), increasing physical limitation scores (WMD = 7.68, 95% CI 1.48 to 13.88, p = 0.02), improving ECG (RR = 1.32,95% CI 1.27 to 1.38, p < 0.00001) and reducing dosage of nitroglycerin (RR = 1.50, 95% CI: 1.26 to 1.77, p < 0.00001). In addition, Egger's regression tests was found there was publication bias (Kendall' tau = 0.36,p < 0.01).

Conclusion: The current systematic review indicates relevant evidence for Salvia miltiorrhiza depside salts for infusion combined with conventional treatments treating patient with angina pectoris. However, the results should be interpreted with caution

due to the low methodological quality, the risk of publication bias, lack of important clinically relevant outcomes and inadequate reporting on adverse events of the included trials. International methodological and reporting standards could help researchers conduct well designed trials and generate better evidence for Salvia miltiorrhiza depside salts for infusion.

Keywords:

Salvia miltiorrhiza Bunge; angina pectoris; systematic review; medicine

Abbreviations:

rt disease; MI: myocardial traditional Chinese medicine;

CVD: cardiovascular disease; CHD: coron infarction; ACS: ambulatory care sensitive; T TCPM: traditional Chinese patent medicine; CNED: Chinese National Essential Drug; PPRC: Pharmacopoeia of the People's Republic of China; FDA: Food and Drug Administration; SMDS: Salvia miltiorrhiza depside salts for infusion; CONSORT: Consolidated Standards for Reporting Trials; ADEs/ADRs: adverse drug events/reactions; RCT: randomized controlled trial; CT: conventional treatment;T: treatment group;C: control group;Uap: unstable angina pectoris; Sap: stable angina pectoris; Ap: angina pectoris;)

©: Frequency of ac

ck angina;

©: Duration of angina attack; ®: Severity of angina pectoris; ©: ECG improvement;

©: Nitroglycerine use;

©: ADEs/ADRs;

®: Quality of life;

N: nitroglycerin (Sublingual or intravenous infusion when an attack of angina pectoris);A: anti arrhythmia; NA: not applicable.

Introduction

Cardiovascular disease (CVD) is the leading cause of mortality worldwide, accounting for 31.4% of deaths in 2012 [World Health Organization 2015].To date, about 230 million patients, or approximately one in five adults, suffer from CVD in China [Hu et al. 2012] . Angina pectoris, a symptom of coronary heart disease (CHD), is generally defined as pain or discomfort within (or adjacent to) the chest, which is typically provoked by exertion or anxiety. Stable angina is a primary and the most common symptom of CHD [Fihn et al. 2012].The frequency of angina is a very strong predictor of subsequent ambulatory care sensitive (ACS) hospitalizations [Spertus et al. 2002]. Unstable angina pectoris is a clinical syndrome subset of the ACS, which is usually associated with an increased risk of cardiac death and subsequent myocardial infarction (MI) [Anderson et al. 2013]. The ACC/AHA guidelines recommend antiplatelet therapy, including aspirin and clopidogerl, anticoagulant therapy, including heparin and low-molecular-weight heparin, anti-ischemic therapy, including beta-blocker, calcium channel blockers and nitrates. Beta-blocker and renin-angiotensin-aldosterone blocker therapies are recommended for preventing MI and death together with antiplatelet therapy [Fihn et al. 2012; Anderson et al. 2013]. Two aims of conventional therapy of CHD patients are to obtain relief of symptoms and to prevent cardiovascular events [Fihn et al. 2012]. However, patients in mainland China prefer to seek traditional Chinese medicine (TCM) for the treatment of CHD for a long time. Many kinds of TCM therapies, such as acupuncture [Chen et al. 2012], traditional Chinese herbal medicines [Yang et al. 2013] and traditional Chinese patent medicine (TCPM) [Yi et al. 2014], were reported that having effectiveness on treating patients with angina pectoris by combining with

western medicines. The Chinese National Essential Drug (CNED) (2012 edition, available at http://www.sda.gov.cn), the Pharmacopoeia of the People's Republic of China (PPRC) (2010 edition), and the China Food and Drug Administration (CFDA, http://www.sda.gov.cn) list a variety of TCM preparations (mixtures of multi-herbs) subjected to a relatively strict drug evaluation process and widely used in current clinical practice. These TCM preparations are defined as TCPMs. TCPMs in CNED and PPRC represent the most important therapies listed by China government. Salvia miltiorrhiza depside salts for infusion (SMDS) is one of the TCPMs and widely used as an adjunctive therapy in treating angina pectoris in mainland China [Yang et al. 2014; Jia et al. 2013; Wang et al. 2006].

Salvia miltiorrhiza Depside Salt is extracted from the dried root of Chinese herb

Salvia miltiorrhiza Bunge

(http://www.theplantlist.org/tpl1.1/search?q=Salvia+miltiorrhiza), a traditional Chinese medical herb known as Danshen, consists of a mixture of compounds. The type state of SMDS is lyophilizing powder for infusion. SMDS contain 200 mg of extract (as dry extract, refined) from the dried root of Salvia miltiorrhiza Bunge (about 50:1), corresponding to: 160 mg to 180 mg of magnesium lithospermate B (MLB); 10 mg to 20 mg of lithospermic acid (LA) and rosmarinic acid (RA). First extraction solvent is 70% aqueous EtOH. The main purpose of manufacturing procedure is to enrich this key bioactive constituent, and to remove other inactive constituents as much as possible to reach the promising efficacy and safety. Two key techniques, including the extraction of Depside Salts and enrichment of MLB, were developed. Finally, a procedure with granted patent was established after series of practice from laboratory to industrialized scale. The content of MLB was enriched to be over 80% and the rest was identified as other Depside Salts. The yield of total Depside Salts was about 2% from botanical raw material (Fig. 1).

In 2005, SMDS was approved by China FDA and appeared on the market (License Number: Z20050248) in 2006 for the treatment of stable angina pectoris.

As the major component (about 80%) of S. miltiorrhiza Depside Salt, the pharmacological actions of MLB have been investigated. The fingerprint of SMDS is analyzed by HPLC on Zorbax C18 column (4.6*25 cm, 5 p,m) with MeoH-MeCN-H2O-HCOOH (42:1:59:0.2) as eluent and 254 nm as wavelength. The fingerprint similarity index of each batch should be more than 95%, calculated by the software issued by China Pharmacopoeia Committee (Fig. 2). The markers' chemical structures were provided in Fig. 3.

Experiments in vitro and in vivo showed that MLB has the effects on anti-atherosclerotic and protecting against myocardial ischemia and reperfusion injury (I/R). The mechanisms are as follows: (1) reducing the proliferation and migration of vascular smooth muscle cells after endothelial injury and excessive oxidative stress [Wu and Wang 2012], (2) scavenging of ROS/free radicals [Zhao et al. 2008; Zhang et al. 2006], (3) attenuation of injury of the vascular endothelium [Wu et al. 2009], (4) inhibition of inflammatory reactions [Lin et al. 2007], (5) avoidance of lipid deposition [Yang et al.2011; Bao et al. 2012],(6) and modulation of the immune response [Cheng et al. 2012], (7) increasing capillary density and decreased infarct size [Han et al. 2011], (8) preventing myocardial remodeling by significantly down-regulating the mRNA expression level and activity of MMP-9 [Jiang et al. 2009], (9) decreasing myocardiocyte apoptosis during I/R via elevating superoxide dismutase activity, thioredoxin activity and glutathione concentration [Han et al.

2011]. Also studies in vitro and in vivo demonstrated that RA possesses antioxidant activity as well as anti-inflammatory activities [Bulgakov et al. 2012; Chu et al.

2012], of which mechanism is similar to that described previously for MLB. LA, a competitive inhibitor of xanthine oxidase, is able to directly scavenge superoxide and inhibit superoxide production in vitro and thus exhibits hypouricemic and anti-inflammatory actions in vivo [Liu et al. 2008].

According to its prescription drug labels, the common dosage of SMDS is 200 mg per day, being diluted with 5% glucose solvent or 0.9% normal saline from 250

ml to 500 ml for intravenous administration. In clinic, SMDS is used for treating both stable and unstable angina pectoris. Clinical trials [Miao et al. 2006; Shan et al. 2013] reported that SMDS can effectively relieve angina, improve ECG, and reduce the frequency of angina attack. However, some adverse effects have been reported, such as palpitation, headache and dizziness [Li et al. 2010; Liu et al. 2014]. Therefore, a systematic review and meta-analysis of randomized controlled trials (RCTs) approach

seems to be of interest as it would systematically and objectively evaluate the clinical curative effect and safety of SMDS for angina pectoris.

te the clii

1. Methods

This systematic review was carried out and reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) [Moher et al. 2009] and A Measurement Tool for the 'Assessment of Multiple Systematic Reviews' (AMSTAR) [Shea et al. 2007]. Also, all included trials were appraised by using Consolidated Standards for Reporting Trials of Traditional Chinese Medicine (CONSORT for TCM) [Wu et al. 2007]. 1.1Search Strategy

A comprehensive search strategy was carried out including searching MEDLINE (1950 to April 2016), EMBASE (1974 to April 2016), Cochrane Central Register of Controlled Trials (1996 to April 2016), ClinicalTrials.gov (from inception to April 2016), China Knowledge Resource Integrated Database(CNKI)(1979 to April 2016), Chinese Science and Technique Journals Database(VIP)(1989 to April 2016), Wan Fang Database(Wan Fang)(1990 to April 2016) and the Chinese Biomedical Database(CBM)(1990 to April 2016). The following search terms were used in separate or combined ways: 'angina pectoris', 'danshenduofensuanyan', 'coronary heart disease', 'angina', 'SMDS' and 'Salvia miltiorrhiza Depside Salt'. There were no restrictions on language, the type of publication and participants' characteristics. 1.2 Study Selection

Studies meeting the following criteria were included:(1)Randomized controlled trials (RCTs); (2)Participants diagnosed as chronic angina pectoris;(3) SMDS combined with conventional treatment(CT) versus CT, including aspirin, clopidogrel, ACEI or ARB, beta blockers, calcium channel blockers, statins, nitrate esters, or low weight molecular heparin (LWMH); (4) Primary outcomes including CHD mortality, combined CHD events and morbidity (fatal and non-fatal MI), percutaneous transluminal coronary angioplasty(PTCA), coronary artery bypass graft(CABG), readmission rate; secondary outcomes including angina symptoms frequency, duration of angina attack, severity of angina pectoris and ECG improvement, reduction of nitroglycerin use and quality of life, and any adverse events as a result of treatment. Participants with acute myocardial infarction, heart failure, hepatic failure and renal failure were excluded. Duplicate publications reporting the same groups of participants were excluded.

The titles, abstracts and keywords of records retrieved were scanned to determine whether to be assessed further. Full content of related articles were retrieved for further assessment if the information met the inclusion criteria. If there was any doubt about these criteria from the »rmation given in the title and abstract, the full

content of articles was retrieved for identification. Any disagreement between reviewers was resolved by discussion or by consulting a third party (XL and YMX). 1.3 Data extraction and management

Data concerning details of participants, intervention and outcomes were extracted independently by two reviewers (ZYL and JQL). For binary outcomes, number of events and total number in each group were extracted. For continuous outcomes, mean, standard deviation and sample size of each group were abstracted or imputed. The data extraction form included the following items:(1) general information: title, authors and year of publication.(2) trials characteristics: study design, method of randomization, allocation concealment, blinding (patients, people administering treatment, outcome assessors).(3) patients: total number and number in comparison

groups, age, diagnostic criteria, withdrawals/losses to follow-up (reasons/description), subgroups.(4) intervention: intervention (dose, course of treatment, and frequency), comparison intervention (dose, course of treatment, and frequency). (5) outcomes: outcomes specified above, any other outcomes assessed, other events, length of follow-up, quality of reporting of outcomes.

1.4 Quality Assessment

The methodological quality of trials was assessed independently using criteria from the Cochrane Handbook for Systematic Review of Interventions, Version 5.1.0. [Higgins and Green 2011]Seven domains are considered such as sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective outcome reporting (reporting bias) and other bias. Three levels of 'low risk', 'high risk', or 'unclear risk' were the quality appraisal category. Any disagreements were resolved by mutual consensus.

1.5 Data synthesis

Revman 5.3 software provided by the Cochrane Collaboration was used for data analyses. The model used to pool the data depends on the existence and extent of heterogeneity. If the I statistics were less than 50%, the heterogeneity could be accepted, the fixed-effect model was chosen. While random-effects model was chosen if the I2

statistics exceeded 50%. The random-effect model was also used when subgroup analysis was adopted and heterogeneity among studies was obvious. For dichotomous the pooled relative risk (RR) with 95% confidence interval (CI) was used as the effect measure. For the continuous outcome, weighted mean difference (WMD) was used as the effect measure. If the number of included studies is less than two or heterogeneity is apparent, meta-analysis is neither appropriate nor possible. Under those circumstances, the result of our systematic review will be narratively reported. If included studies have multiple arms, we will identify the relevant intervention and control groups and combine the relevant intervention groups into a

single group, and the relevant control groups into a single group, before synthesizing the data [Higgins and Green 2011]. Publication bias will be assessed with a funnel plot and Egger weighted regression technique. 1.6 Subgroup analysis and sensitivity analysis

In order to deal with heterogeneity and perform secondary analysis, subgroup analysis is necessary. These will focus on two aspects: (1) Types of angina pectoris (stable angina or unstable angina); (2) Duration of treatment. In order to explore the influence of the methodological quality of study on effect size, sensitivity analyses might be performed. Pre-specified sensitivity analyses will be performed by removing one study at a time and determining the influence of a single article on the overall pooled estimate.

2. Results 2. Results

2.1 Literature search results

In total, 547 records were identified. After duplicates among different databases were removed, 247 potentially relevant records were kept for further assessment. The full texts of 85 remaining records were downloaded for careful assessment. All were published in Chinese. Finally, 29 articles were excluded upon further scrutiny for not being randomized controlled trials (n = 4); not conducting intervention measures correctly (n = 2) ; not reporting relevant outcomes (n = 15); unavailable data (n = 5); the same studies (n = 3). There were 56 trials included in the review. The detailed process of search and identification was shown in Fig. 4.

2.2 Trials characteristics

All trials included were of a parallel design with a positive control group and conducted in China. Trials duration ranged from 10 days to 60 days. Sample size ranged from 48 to 210, with a total of 5500 participants included in this review. Average of ages of participants ranged from 56 to 82 years old. There are 343 patients

with stable angina pectoris, 3825 patients with unstable angina pectoris and 1332 angina pectoris patients without clarifying the type of angina.

All of the trials compared SMDS combined with CT vs. CT. SMDS was given by intravenous drip once a day. The treatment regimen of SMDS varied across trials: 20 milligram per day (mg/day) was used in one trial [Chen et al. 2009], 100 mg/day was used in one study [Li et al. 2010], 400 mg/day was used in two trials [Gao et al. 2010; Ye 2013], 200 mg/day was used in the remaining fifty-two trials. The patients in seven trials [Duan et al. 2010; Xu et al. 2011; Jiang et al. 2012; Wu et al. 2012; Han 2013; Liu 2013; Wan and tong 2013] received treatment for 10 days, and the patients in forty-four trials received treatment for 14days. In addition, the patients were treated for 28 days, 40 days and 60 days respectively in three trials [Zhou and Wang 2014; Zhang 2014; Wu et al. 2015]. SMDS was administrated to be diluted in 250 ml 5% GS or 0.9% NS or 5% xylitol. None of the trials assessed CHD mortality, combined CHD events, or readmission rate. Fifty-two trials reported rate of angina symptoms improvement. Eleven trials reported the frequency of angina attack. Two trials [Ren et al. 2012; Wen and Sun 2016] reported changes in angina frequency via the Seattle Angina Questionnaire (SAQ) angina frequency subscale. Five trials [Chen 2008; Chen et al. 2009; Gong et al. 2012; Zhai and Jiao 2013; Yu and Jiao 2014] reported the duration of angina pectoris. One trial [Wang 2013] evaluated the clinical symptom scores. Only one study [Liu 2014] mentioned follow-up visit and reported rate of angina recrudescence. Forty-one trials reported rate of improvement of ECG. Nine trials reported rate of stopping or reducing the dosage of nitroglycerine. One study [Wu et al. 2009] reported the frequency of taking nitroglycerin. Four trials [Chen 2008; Yang et al. 2011; Zhai and Jiao 2013; Yu and Jiao 2014] compared nitroglycerine dosages. Only one trial [Ren et al. 2012] reported quality of life via SAQ physical limitation, disease perception, and treatment satisfaction subscales.

Thirty-five trials observed adverse drug events/reactions. Details of the 56 included trials are listed in the characteristics of included trials table (Table 1).

2.3 Methodological Quality

All the included studies mentioned randomization. However, only six studies [Li 2012; Wan and Tong 2013; Liu and Xiao 2014; Chen 2014; Tang et al. 2015; Hong 2016] described allocation sequence being generated from random number tables and three studies [Chen et al. 2009; Dai 2011; Rao and Xi 2015] used a computer random number generator. Only one of the included studies [Dai 2011] mentioned the allocation concealment carried out by sealed envelopes. None of the others mentioned allocation concealment. Two studies [Chen 2008; Dai 2011] adopted single blinding, where only the patients were blind to the intervention. None of others mentioned blinding. Only three studies mentioned withdrawals and losses to follow up [Chen et al. 2009; Dai 2011; Xie 2011] and two of them [Dai 2011; Xu et al. 2011] reported the reasons, but none of the studies performed intention-to-treat analysis. No study protocols were available for any of the included studies. We believed all included studies to be free of selective reporting because the same outcomes were described in the methods and reported in the results. In all studies the characteristics of participants in different treatment groups were similar at baseline (age, sex, severity of angina). So we considered all to be free of other potential sources of bias (Fig. 5,

The funnel plot was asymmetric when pooling 47 trials on rate of improvement of angina symptoms (Fig. 7). A high proportion of published studies having positive results in China might make the publication bias exist.

investigated CHD mortality, combined CHD events and morbidity or readmission rate as a primary outcome. Symptoms improvement and ECG improvement were the most common outcomes in all included studies.

Fig. 6).

According to the different types of angina pectoris, the studies were divided into two subgroups: stable angina pectoris group and unstable angina pectoris group. The results from thirteen studies were not included in the any pooled estimates of effect due to no clarifying the type of the angina pectoris.

In the pooled estimates of rate of improvement of angina symptoms and improvement of ECG, the studies were separated into three subgroups according to different treatment duration: 10 days group, 14 days and more than 14 days group. Both in the three estimates of effect, none of the stable angina pectoris studies were included in subgroup analysis due to the different dosage of SMDS. And two studies [Li et al. 2010; Wu et al. 2007] about unstable angina pectoris using different dosage of SMDS (100 mg and 400 mg respectively) in the 14 days group were excluded as well.

2.4.1 Angina symptoms frequency (1)Rate of improvement of angina symptoms Three stable angina pectoris studies [39, 64, 67] and forty-six unstable angina pectoris studies assessed the rate of improvement of angina symptoms. The reduction of the frequency of angina attack was the measure. According to the type of angina pectoris, these studies were divided into two subgroups including stable angina group and unstable angina group.

SMDS combined with conventional treatment has a better effect on improving angina symptoms among all patients compared with CT alone (RR = 1.28, 95% CI 1.24 to 1.31, I2 = 0%, p < 0.00001, Fig. 8). The effects of SMDS combined with CT on improving angina symptoms for patients with unstable angina pectoris (RR = 1.29, 95% CI: 1.24 to 1.34, I2 = 9%, p < 0.00001, Fig. 8) , stable angina pectoris (RR = 1.51, 95% CI: 1.23 to 1.84, I2 = 0%; p < 0.0001, Fig 8)are better than CT and angina pectoris (RR = 1.22, 95% CI: 1.15 to 1.28, I2 = 0%; p < 0.0001, Fig. 8)

The effects of SMDS combined with CT on improving angina symptoms in 10 days group (RR = 1.22, 95% CI: 1.12 to 1.33, I2 = 10%, p < 0.0001, Fig. 9), 14 days

group (RR = 1.27, 95% CI: 1.23 to 1.32, I2 = 10%, p < 0.00001, Fig. 9) and more than 14 days group (RR = 1.28, 95% CI: 1.15 to 1.43, I2 = 0%, p < 0.0001, Fig. 9) are better than CT.

(2)The frequency of angina attack

Six unstable angina studies showed that SMDS combined with CT was more effective than CT in decreasing the frequency of angina attack(time/week)(WMD = -1.47, 95% CI -2.16 to -0.78, p < 0.00001, Fig. 10). One stable angina study [39] showed that SMDS combined with CT could reduce the frequency of angina attack (time/day) (WMD = -1.04, 95% CI -1.72 to -0.36, p = 0.003).

In the forest plot, two trials' [Zhai and Jiao 2013; Yu and Jiao 2014] confidence interval do not overlap with other four trials. It was closely related to the poor methodological quality in the design, performance and so on. So, we also pooled other four trials alone. (WMD = -0.85, 95% CI -1.14 to -0.56,p < 0.00001)

(3) SAQ angina frequency scores

Two trials [Ren et al. 2012; Wen and Sun 2016] reported the frequency of angina attack outcome according to SAQ angina frequency scores, SMDS combined with CT resulted in a slight increase of angina frequency scores(WMD = 6.33, 95% CI 4.92 to 7.73, p < 0.00001). 2.4.2 The duration of angina attack

One stable angina study [Chen et al. 2009] and four unstable angina studies [Chen 2008; Dai 2011; Zhai and Jiao 2013; Yu and Jiao 2014] showed that SMDS combined with CT shortened the duration of angina attack (min). SMDS combined with CT is more effective than CT in decreasing the duration of angina pectoris for unstable angina patients (WMD = -1.51, 95% CI -2.54 to -0.49, p < 0.00001, Fig. 11). The stable angina study also showed that SMDS combined with CT could decrease the duration of angina attack (WMD = -2.4, 95% CI -3.58 to -1.22,p < 0.00001). In the forest plot, one trial's [Yu and Jiao 2014] confidence interval do not overlap with other three trials. After reading the original study, we observed that all the participants in this trials came from emergency department with serious and complex illness. We thought that it is the important reason leading to heterogenicity. So, we

also removed it and pooled other three trials alone. (WMD = -0.97, 95% CI -1.53 to -0.41,p < 0.0007)

2.4.3 Severity of angina pectoris: Clinical symptom scores

Data from one study [Wang 2013] showed that SMDS combined with CT was better at reducing clinical symptom(Chest pain, chest tightness, palpitations, shortness of breath) scores than CT alone (WMD = -0.55, 95% CI -0.57 to -0.53,p < 0.000011).

2.4.4 ECG improvement : Rate of improvement of ECG

Two stable angina pectoris studies [Ye 2013; Jin et al. 2014] and thirty-four unstable angina pectoris studies reported rate of improvement of ECG. Improvement of depressed ST segment and normalization of reversal T wave were the most common measures. SMDS combined with CT has a better effect on improving ECG among all patients compared with CT alone (RR = 1.32, 95% CI 1.27 to 1.38, I2 = 6%, p < 0.00001, Fig. 12). The effects of SMDS combined with CT on improving ECG for both patients with unstable angina pectoris (RR = 1.33, 95% CI: 1.27 to 1.40, I = 16%, p < 0.00001, Fig. 12) and with stable angina pectoris (RR = 1.33, 95% CI 1.16

to 1.53, I2 = 0%,p < 0.0001, Fig. 12) are better than CT.

The effects of SMDS combined with CT on improving ECG in 14 days group (RR = 1.33, 95% CI 1.27 to 1.40, I2 = 13%, p < 0.00001, Fig. 13), 10 days group [Duan et al. 2010; Jiang et al. 2012; Wu et al. 2012; Wan and Tong 2013] (RR = 1.44, 95% CI 1.22 to 1.70, I2 = 0%, p < 0.00001, Fig. 13) and more than 14 days [Zhou and Wang 2014] (RR = 1.32, 95% CI 1.07 to 1.64,p = 0.009, Fig. 13) are better than CT.

2.4.5 Nitroglycerine use

(1)Rate of stopping or reducing the dosage of nitroglycerin

There were five unstable angina pectoris studies reported the rate of stopping or reducing the dosage of nitroglycerin. The effect of SMDS combined with CT on increasing the rate of stopping or reducing the dosage of nitroglycerin for unstable angina pectoris is better than CT (RR = 1.50, 95% CI 1.28 to 1.75, p < 0.00001, Fig. 14).

(2)Frequency of nitroglycerin taken

One study [Chen et al. 2009] reported SMDS combined with CT could reduce the frequency of taking nitroglycerin (time/day) (WMD = -2.60, 95% CI -2.93 to -2.27, p < 0.00001). 3.4.7 Quality of life

Only one study [Ren et al. 2012] reported quality of life outcomes according to the SAQ physical limitation, disease perception, and treatment satisfaction subscales. SMDS combined with CT had an advantage of increasing physical limitation scores (WMD = 7.68, 95% CI 1.48 to 13.88, p = 0.02), treatment satisfaction scores (WMD = 11.42, 95% CI 5.00 to 17.84, p = 0.0005) than CT alone. But there was no significant difference between the treatment group and control groups in the disease perception scores (WMD = -0.73, 95% CI -7.44 to 5.98, p = 0.83). 2.5 Adverse drug events/reactions

Out of fifty-six included studies, thirty-five studies observed adverse drug events/reactions (ADEs/ADRs) fifteen studies reported positive results. In treatment group, the most frequently reported ARDs of SMDS combined with CT were dizziness and palpitation. Ten participants had ARDs of dizziness and four participants had ADRs of palpitation. Six participants had ARDs of headache and two participants had ARDs of dry mouth. Eight participants had the ARDs of fatigue, skin pruritus, orthostatic hypotension, digestive system symptoms, facial flushing and abnormal liver and kidney function respectively.

In control group, dizziness was noted as the top ARD of CT. Six participants had ARDs of headache. Six participants respectively had ADRs of nausea, diarrhea, fever and abnormal liver and kidney function. One participants in control group deteriorated into AMI and withdrew from the trial.

One study [Chen et al. 2009] reported that two cases with adverse events which

were not caused by SMDS, while the specific situation and the group in which the events appeared was not illustrated.

ll adverse reactions in two groups were minor or well tolerated, which could be relieved by symptomatic treatment [Liu 2014; Li et al. 2014] or adjusting the dropping speed [Moher et al. 2009; Jin et al. 2014], or could be without additional intervention [Liu et al. 2008; Liu 2013; Tang et al. 2015]. The details of ADEs/ADRs were summarized in Table 2.

3. Discussion

3.1 Summary of therapy effectiveness

SMDS combined with CT appeared to have some benefit showing improving angina symptoms for both stable angina and unstable angina patients, improving ECG, and the injection was associated with a trend in reduction of the need for nitroglycerin. SMDS combined with CT is more effective than CT on improving ECG and reducing nitroglycerin used for both stable angina pectoris and unstable angina pectoris. However, none of the included trials reported the effect of SMDS on CHD mortality, combined CHD events or readmission rate and only one trial reported quality of life, which obviously deviated from the need of real clinical practice. Instead of that, angina symptom reducing, ECG improvement and reduction of nitroglycerin use have become the main outcomes analyzed in this review. Six studies even didn't clarify the type of angina, which are not rigorous clinical trials.

What is more, it is difficult to provide evidence for evaluating the efficacy on severity of angina pectoris, due to few included studies investing this outcome.

In addition, the measurement methods of these outcomes were described in varied forms and this may have caused reporting bias in the studies. Researchers preferred to short term outcomes to outcomes with long-term follow-up such as CHD mortality, combined CHD events and morbidity and the rate of readmission to hospital. Consequently, it is restricted to demonstrate the possible efficacy of SMDS. The SAQ can be used to obtain a valid reliable, and sensitive assessment of patients' symptoms, function, and quality of life from patients' perspectives [Spertus et al. 1994; Spertus et al. 1995]. However, only two studies [Ren et al. 2012; Wen and Sun 2016] reported quality of life after 14days treatment measured by the SAQ, therefore there is insufficient evidence for improving quality of life with SMDS combined with CT.

Also, traditional Chinese medicine injection with or without routine drugs for angina had been proved that they could relieve ischemic symptoms and improve ECG significantly [Dai and Kong 2014]. Further evidence in support of traditional Chinese medicine injection like panaxnoto ginseng saponins injection [9], guanxinning injection [Jia et al. 2013] and puerarin injection [Wang et al. 2006] have beneficial effect for angina pectoris are provided by previous systematic reviews. Conclusions of

these reviewers were that these injections plus routine drugs were helpful to improve symptoms and ECG, but further large-scale high-quality trials would be needed to confirm the efficacy.

We also searched for any other trials that focus on animal studies. Animal experiments indicated that Salvia miltiorrhiza Depside Salt possesses a protective effect in the cardiovascular system such as attenuation of atherosclerosis [Wu and Wang 2012] and protection against myocardial ischemia-reperfusion injury [Han et al. 2011].

3.2 Summary of therapy safety

There is inadequate reporting on ADEs/ADRs in the included trials. The same number of cases with suspected ADRs were reported in both treatment group and control group (32/32). ADRs known on the drug direction of SMDS were headache, dizziness and abnormal liver function. Suspected ADRs in this review we found were new. They were not serious and could be tolerated by patients. However, none of precise and reliable quantitative estimations of relationship likelihood about these ADRs were provided in current review. Further studies to investigate the mechanism and causality assessment on these ADRs are needed. Rapid dropping speed is one of common reasons of ARDs caused by traditional Chinese medicine injections [Dai and Kong 2014]. This indication should be emphasized during the use of SMDS.

Meanwhile, the adverse reactions could be caused by SMDS or combined drugs, such as nitroglycerin, aspirin, if researchers could not give a precise diagnosis of ADRs. However, it may be have different ADR's reports in different reviews depending on the studies' design, the trials' quality and so on. For example, a review [Duan et al. 2013] reported the adverse events of SMDS combined with other drugs were slightly, but another review [Lu et al. 2013] summarized the serious adverse reactions of SMDS, such as shivering, cyanosis and fever. Moreover, incomplete reporting and short duration of treatment make it impossible to detect rare adverse events or related long term safety problems. Therefore, further research exploring factors that might

cause adverse events of SMDS and monitoring related harms in long term use of

SMDS is needed.

3.3 Quality of research

All the included studies were appraised as being low quality. Most of the included studies had an unclear risk of bias according to the Cochrane Collaboration 'Risk of bias's tool. Sample size calculation was not reported in any study. All studies made simple description about statistical analysis of baseline characteristics.

The diagnosis criteria and efficacy evaluation criteria in different trials were rather variable, which brought about the selection bias and clinical heterogeneity that may influence the results of meta-analysis. The criteria of therapeutic effect for the rate of improvement of angina symptoms, ECG, and stopping or reduction of nitroglycerin use were different in included studies in this review, most of which were not commonly used One trial even adopted self-made clinical symptom scores without reliability and validity tests. For instance, six studies evaluated the efficacy of SMDS on the basis of the patients' subjective feeling.

No studies used placebo combined with CT as a control. This type of add-on

design is quite popular in TCM studies in which TCM therapy is added to conventional therapy. Nevertheless, this kind of design may exaggerate the effects of TCPM and is prone to generate false-positive results and significant systemic errors in the assessment of outcomes. All the included studies adopted short-term outcomes to assess curative effect, such as angina symptoms improvement and ECG improvement. The objectives of medical therapy is to prevent MI and death and relieve symptoms [Fihn et al. 2012]. But none of the trials included reported this important result, due to the short-term therapy. And only one trial [Liu 2014] mentioned follow-up visit and reported rate of angina recrudescence, while the guideline recommends follow-up visit should pay attention to changes in physical activity or symptoms, response to therapy, adverse effects, development of relevant, new chronic conditions or changes in existing conditions, BP, heart rate, resting 12-lead ECG and laboratory examination to assess the conditions of patients comprehensively. Quality of life that is satisfactory to the patient is one of the objectives of treatment, which was reported by one trial [Ren et al. 2012]. Therefore, we were not able to know long-term effectiveness and safety of SMDS. No multi-center, large scale RCT was found. Small sample size may

be poor in general representative, which affects promotion and application the therapeutic effects. All of the included studies are published in Chinese. All are small, with positive findings. Though SMDS has been widely used in angina pectoris in mainland China, the efficacy and safety still need strong evidence to prove it.

CONSORT for TCM was used to appraise the reporting quality of included trials from title/abstract, introduction, methods, results and discussion, including 22 items. In general, these trials have poor reporting quality. Most of the included trials had complete reporting on intervention, primary outcomes and inclusive criteria rather than protocol registering, design, randomization, and blinding. Thus this will bring great challenges to readers to aid their critical appraisal and interpretation. 3.4 Compared with pre-studies and systematic reviews

We found out seven Chinese systematic reviews evaluating SMDS for angina pectoris. One review [Shi et al. 2014] assessed the efficacy, safety, and cost-effectiveness of SMDS compared with Danshen injection for patients with angina pectoris. Five reviews analyzed unstable angina pectoris. One review [Zhao et al. 2012] assessed the efficacy and safety of SMDS for angina pectoris without clarifying type of angina pectoris.

Their results and conclusions were similar to ours. Some of the reviews had the same conclusion that SMDS combined with CT was superior to CT alone in reducing unstable angina symptoms [Wu 2013; Yao et al. 2013; Guan et al. 2013], improving ECG [Wu 2013; Yao et al. 2013; Guan et al. 2013]. And they mentioned the conclusion need to be verified by high quality and large sample size RCTs. The conclusions of two reviews [Shi et al. 2014; Yan et al. 2015] showed a better effect of SMDS for angina pectoris compared with other traditional Chinese medicine injection.

However there are still deficiencies as following for these systematic reviews: (1) Two reviews [Shi et al. 2014; Yan et al. 2015] didn't define the type of angina pectoris, which could not give precise evidence for readers. (2) None of the reviews chose or mentioned total CHD mortality or combined CHD events as a primary outcome, which is a highly valued outcome in CHD. The outcome of one review [Shi et al. 2014] was just described as 'efficacy rate' without any explanation. (3) One review [Shi and Hu 2013] had a poor quality judged by PRISMA. In method part of

this review, study selection, data collection process and methodological quality assessment was not reported. Primary outcomes were not mentioned in inclusion criteria. The result of study selection and methodological quality assessment was not reported. Moreover, no summary evidence and limitations were seen in discussion. 3.5 Implications for practice

Based on this systematic review, it appears that SMDS combined with CT may have positive effects on reducing the frequency angina attack, improving ECG and reducing the dosage of nitroglycerin. However, the prescription drug labels of SMDS states that it is used for stable angina pectoris. But it is more generally applied to treating unstable angina pectoris in clinical practice. As to whether both the stable angina and unstable angina can be treated by this injection, it's necessary to be confirmed by more mechanism and clinical research, and be analyzed respectively by systematic reviews in the future. Moreover, due to the low methodological quality of the RCTs and the risk of publication bias, and lack of other clinically relevant outcomes, there is no strong evidence for treating angina pectoris with SMDS combined with conventional treatment.

3.6 Implications for research

ilitv of clinical

Both methodological and reporting quality of clinical trials of treatment with SMDS

s to be

combined with CT for angina needs to be improved. Further research should consider

the following aspects:

> Complete and transparent reporting in quality and methodology should be accordance wit h well -known standards.

> The type of angina pectoris should be illustrated definitely in trials.

> Clinical trial registries should be encouraged to provide the available protocol.

> Participants with withdrawal/drop-out during the trial should be clearly described and performed intention-to-treat analysis.

> Reporting of clinically important outcome measures, such as mortality, combined CHD events and quality of life from long-term follow-up.

> The outcome measures should be assessed by international criteria, especially in the aspect of measuring the subjective feelings of patients, and including more quantifiable outcome measures.

3.7 Limitations

There were some potential limitations in the current systematic review: (1) Just English and Chinese databases were searched because of language barrier, without hand searching. (2) Methodological quality of these included studies was generally poor. (3) We didn't interview the authors of studies by telephone for more detailed information. (4) More useful safety information of SMDS could not be obtained due to inadequate reporting and combination use with other CT.

We could declare that SMDS in all included studies in the current Meta analysis were from the same manufacturer (Shanghai Green Valley Pharmaceutical Co., Ltd.) which is the only one producing this drug in mainland China. Therefore, we do not worry that SMDS in different trials were inconsistent in composition, chemical structure and so on. However we could not assure that different reactions might occur to different individual patients by using different batches of SMDS. 4. Conclusions

Based on this systematic review, there is currently insufficient evidence for treating angina pectoris and safety with SMDS combined with CT, due to the low methodological quality and poor reporting quality which would be a caution to future researchers of TCM. The positive results from this review still needs larger, well designed and high-quality trials to

e results fro confirm.

Conflict of interest

a conflic

No author has declared a conflict of interests with respect to this study. Acknowledgments Yili Zhang: designed the review, and participated in the writing this manuscript. Yanming Xie: participated in the literature search, extracted data and evaluated the quality of papers, Qiulei Jia: participated in the literature search, extracted data and participated in the writing this manuscript. Xing Liao: designed the review, evaluated the quality of papers and analyzed data. Yan Chai: provided language help. All of the authors approved the final version of the manuscript. Xiaomei Zhou: designed and described the graphic abstract.

Funding

The study was financially supported by the Ninth-Science Foundation of Institute of Basic Research in Clinical Medicine, China Academy of Chinese Medical Sciences (no. Z0406); Scientific Research Innovation Team Project of China Academy of Chinese Medical Sciences (no. PY1303), National Natural Science Foundation of China (General Program, No. 81202776) and China Postdoctoral Science Foundation Project (no. 2014T70202).

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Table. 1 Characteristics of included trials

Study ID Type

Sample size Mean age

(T/C) /(year)

Treatment group

Dose of Salvia miltiorrhiza Depside Salt/mg

Duration /day

Combined with treatment

Control group Outcomes

Li 2005 Uap

Chen 2008 Uap 30/30

Ren 2008 Uap 50/50

Chao 2009 Uap 24/24

Chen 2009 Uap 49/48

C:69.5 ± 3.2 T:57.37 ± 8.66

C:56.00 ± 7.4 T:59 ± 6

C:62 ± 5 T:NA

r:56±6

Chen 2009 Sap 44/38

4 ± 5 T:NA

14 CT + N

CT ®,®,©

CT ®,®,©

CT ®,®,©

CT ®,®,©

CT ®,©,©,©

T:70.2 ± 5.1

Gao 2010 Uap

T:58.90 ± 3.14

Liu 2009 Ap 50/50 200 14 CT CT

C:60.80 ± 2.95 T:62.3

Duan 2010 Uap 32/28 200 10 CT + N CT + N

Dai 2011 Uap 37/38

Lun 2011 Uap 30/30

C:61.5 T:NA C:NA T:60.3

C:63.8 T:57.43 ± 8.29

C:56.18 ± 8.30 T:60.11 ± 11

C:62.31 ± 8.30 T:54.64 ± 4.0

C:54 T:

54.86 ± 3 T:83.5 ± 3.5

C:81.2 ± 2.6 52.1 ± 7.9

CT ®,®,©,®

CT + N ®,®,®

200 14 CT + A CT + A

200 14 CT CT

200 14 CT + N CT + N

200 14 CT CT

200 10 CT + N CT + N ®,®

C:54.6 ± 6.3

Dou 2012 Uap 46/46

Gong 2012 Ap

Jiang 2012 Uap

Kang 2012 Uap 35/35

Ren 2012 Uap 30/30

Wu 2012 Uap

Zhao 2012 Uap 105/105

Chen 2013 Ap

C:61.8 ± 4 T:60.3

C:62.2 T:NA

C:NA T:7.56 ± 8.26

C:73.77 ± 8.26 T:NA

C:NA T:61.85 ± 10.37

5.93 ± 9.85

C:66.93 ± 9.85 T:59.91 ± 10.86

C:59.92 ± 9.03 T:70.8 ± 4.1

200 14 CT CT r

200 14 CT CT

200 10 CT + N CT + N

200 14 CT + C CT + C ®,®

200 14 CT + C CT + C

200 k 14 CT CT

200 10 CT + N CT + N

200 14 CT CT ®

200 14 CT CT

T:62.5 ± 5

C:71.8 ± 5.3

C:NA T:57.54 ± 2.12

Han 2013 Uap 62/62 200

C:56.98 ± 2.24

T:51.7 ± 6.5

Liu 2013 Ap 33/33 200

C:51.6 i 6. / T:NA

Liu 2013 Ap 60/60 200

Qi 2013 Uap 35/35 200

Wan 2013 Uap 46/43 200

T:57.48 ± 8.56

Wang 2013 Uap 40/40 200 C:56.05 ± 7.4

Wang 2013 Uap 46/46

Ye 2013 Sap 38/37

T:51.12 ± 9.89

C:54.12 ± 11.01

CT + N

CT + N ®,®,®

CT ®,®,©,®

14 CT + C + N CT + C + N ®,®

14 CT + N

CT + N ®,®

Yin 2013 Uap 45/45 200 14 CT + N CT + N ®,®,©

Zhai 2013 Uap 56/56 200 14 CT + C CT + C ®,©,®,©

CT + C

Uap 92/92 200 14 CT CT ®,®,©

Liu 2014 Uap 83/77 200 14 CT CT ®,®,©

T:70.9 ± 11.0

Liu 2014 Uap 57/56 200 14 CT + N CT + N ®,®,®,©

T:59.2 ± 8.6

C:58.8 ± 8.3

T:50.4 ± 8.9

C:51.3 ± 7.8

Jin 2014

T:58.3 ± 8.6

C:58.9 ± 8.9

T:65.3 ± 12.1

C:63.8 ± 11.3

C:70.0 ± 10.5

CT + N

CT + N

T:50.3 ± 8.8

Yu 2014 Uap 62/62 200 14 CT CT

C:51.4 ± 7.9

T:57.3 ± 5.6

Chen 2014 Uap 36/28 200 14 CT + N CT + N

C:56.9 ± 6.1

T:72 ® ,©,®,©

Zhou 2014 Uap 50/50 200 28 CT CT

C:71.8

T:61.07 ± 1.02 ® ,®,©

Xiong 2014 Ap 39/39 200 14 CT CT

C:60.11 ± 1.03

T:NA ® ,©,©

Zhang 2014 Ap 50/50 200 40 CT CT

T:NA © ,®

Zhuang 2014 Uap 45/45 200 14 CT CT

T:65.6 ± 6.8 ® ,©,©

Tang 2015 Uap 30/30 200 14 CT CT

C:61.1 ± 7.0

T:70.20 ± 6.57

Wu 2015 Uap 69/66 200 60 CT CT

C:68.80 ± 6.44

T:70.2 ± 4.9 V

Wang 2015 Uap 90/90 200 14 CT + C CT + C

C:71.2 ± 5.9 T:68.3 ± 5.4

Rao 2015 Ap 50/50 200 14 CT + N CT + N

C:68.7 ± 5.1 T:NA

Tian 2015 Ap 47/47 200 14 CT CT

C:NA T:NA

Cheng 2015 Ap 65/65 200 14 CT + N CT + N

C:NA T:64.7 ± 10.1

Xia 2016 Uap 44/44 200 14 CT CT

C:63.1 ± 6.1 T:62.30 ± 2.50

Hong 2016 Ap 94/94 200 14 CT CT

C:62.00 ± 2.50

Wen 2016 Ap 48/48 200 14 CT CT

® ,®,© ® ,©,®,

® ,®,© ® ,®,©,© ® ,®,©,©

® ,©

® ,©,

Table. 2 ADEs/ADRs

Study ID Treatment group Dose of Salvia miltiorrhiza Depside Salt/mg Control group Duration/day Treatment group Control group Treatment for ADEs/ADRs

Chen 2009 200 CT 14 A Two adverse events,which were not caused by the test drugs, without other adverse effects related to medicine was found. Palpitation in two NA

Chen 2009 20 CT 14 cases,Facialflushing in one no adverse reaction NA

Duan 2010 200 CT + N 10 case Headache in two cases,Nausea Fatigue in one case one in case NA

Palpitation in one case due to rapid dropping speed, two cases were mild headache

abnormal liver and kidney function in one case

no adverse reaction

abnormal liver and kidney function in one case,

AMI in one case(was eliminated from test)

adjusting the dropping

CT + N

Jiang 2012

Wang 2013

Chen 2014

Tang 2015 Wu 2015

200 CT + N

200 CT

200 CT

200 CT

10 Dizziness in one case no adverse reaction NA

14 Slight dry mouth and dizziness in one case no adverse reaction spontaneous remission

14 Palpitation in one case no adverse reaction adjusting the dropping speed

14 Dizziness in one case,Dry mouth in one case Dizziness in one case,Diarrhea in one case,Fever in one case symptomatic treatment

14 Dizziness in two cases The skin pruritus in one case,orthostatic hypotension in one Dizziness in three cases symptomatic treatment

14 case,digestive system no adverse reaction spontaneous remission

symptoms,which may be related to non-steroidal

anti-inflammatory drugs

14 Dizziness and headache in two cases no adverse reaction drug withdrawal

14 Dizziness in one case Dizziness in one case spontaneous remission

60 headache in one case Nausea and headache in three NA

CT + N

Yin 2013

CT + N

CT + N

Jin 2014

Cheng 2015

Dizziness, headache and digestive system in one

case respectively Chest tightness in two cases; Dizziness, skin itching and low b pressure in respectively; other adverse reaction in three cases

htness in four cases;

Dizzines in three cases; Edema of . . ; ower limbs in one case; skin

itching and low blood pressure in

two cases respectively; other

adverse reaction in five cases

Table 2. Adverse drug events/reactions CT: Conventional treatment: aspirin, clopidogrel, AC nitroglycerin (Sublingual or intravenous infusion when an attack of angina pectoris); NA: not applic

ARB, beta blockers, calcium channel blockers, statins, nitrate esters, or LMWH. N:

CT + N

CT + N

Figure legends

Botanical raw materials of Salvia miltiorrhiza bunge

Quality controlled by fingerprinting

Extracted solution

Macroporous resin absorption

Ethanol eluent

Eluted by ethonal

Concentrated solution

Vacuum concentrate

Filtrate

Quality controlled by fingerprinting

Ethonal precipitation/ ^ centrifuge and fil^^e

Raw materials of SMDS

Quality controlled by fingerprinting

Vacuum conccntratc |

Lyophylfzation

Lyophilized preparation of SMDS

Fig. 1 Manufacturing procedure of SMDS

Fig. 2 The fingerprint of SMDS

Rosraarinic acid

.5 A A .

kl h h coom

--f—^ o coomf

mg** „ , ooo^.-h ||

"OH Lithosperinic, acid

Fig. 3 Markers' chemical structure

Magnesium lithospermate B

CNKI n = 152 Medline n = 23

Wanfang n = 142 EMBASE n = 15

VIP n = 107 Clinicaltrials.gov n = 2

CBM n = 100 Cochrane Library n = 4

Fig. 4 Flow diagram of study selection

Random sequence generation [selection bias) [

Allocation concealment [selection bias) IZ

Blinding of participants and personnel (performance bias) [

Elinding of outcome assessment [detection bias) _

Incomplete outcome data (attrition bias) H

Selective reporting (reporting bias) IZ

Other bias H h

—I-1

75% 100%

Low risk of bias

I | Unclear risk of bias

| High risk of bias

Fig. 5 Risk of bias graph: review authors' judgements aut each risk of bias item presented as percentages across all included studies.

200S «

Cheng Fangchun 2015

Dou Lihua 2012 DuanXingiiang 2010 GaoWenqian 2010 Gorg Liang 2012 Han Changheng 2013 Hong Yu qing 2016 Jiang Zongpeng 2012 Kang Shanping 2012 LiuQiang 2013 Liu XI angling 2009 LiuXincheng 2013

LiYani 2010 ?

RerYufang 20 OS Tang Fang li 2015 TianXiaohua 2015 Wang Jinju 2013 WangLijun 2015 Wang Qiang 2013 WanZhi 2013 Wen He 2016 WuFurcng 2015 WuZeming 2012 Xia Jing wen 2016

Xu Rong 2011 ®

Liwei 2013 #

YeRuiyin 2013 Yin Yuanyuan 2013

Yu Li« Zhai Yanyan 2013 Zhang Li 2014 Zhang Liqiong 2013 Zhao Fuzhong 2012

Zhao Huijun 2011 #

Zhuang Ruijuan 2014

!! iilii

Fig. 6 Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

SE(log[RR])

I— Subgroups-

^ unstable angina pectoris o stable angina pectoris L-l angina pectoris

Fig. 7 Funnel plot of publication bias according to rate of improvement of ang

addition, Egger's regression tests was found there was publication bias (Kendall' tau = I

—i—

SWS +CT CT Risk Ratio Risk Ratio

Studv or Subaroup Everts Total Everts Total Wei a ht MIL Fixed. 95%CI M-H, Fined. 95%CI

1.1.1 unstable angina pectoris

Chao Shengwu 2009 21 24 11 24 0.7% 1.91 [1.20, 3.03]

Chen Chun 2008 26 30 19 30 1.3% 1.37 [1.01,1.86]

Chen Chun 2014 32 36 18 28 1.3% 1.38 [1.03,1.87]

Chen Fei 2009 41 49 31 48 2.1% 1.30 [1.02,1.65]

Dai Dashun 2011 32 37 23 38 1.5% 1.43 [1.07,1.90]

Dou Lihua 2012 41 46 31 46 2.1% 1.32 [1.06,1.66]

DuanXingliang 2010 31 32 20 28 1.4% 1.36 [1.06,1.73]

Gao Wenqian 2010 25 32 16 32 1.1% 1.56 [1.06, 2.31]

Han Changheng 2013 60 62 50 62 3.3% 1.20 [1.05,1.37] •

Jiang Zongpeng 2012 28 30 21 30 1.4% 1.33 [1.04,1.72]

Kang Shanping 2012 32 35 23 35 1.5% 1.39 [1.07,1.80]

Li Xingtio 2005 28 30 24 30 1.6% 1.17 [0.95,1.43]

Li Yan 2012 40 43 28 43 1.9% 1.43 [1.13,1.80]

Li Yani 2010 29 30 23 30 1.5% 1.26 [1.02,1.55]

LiuXincheng 2013 55 60 50 60 3.3% 1.10 [0.96,1.26]

Lun Jia 2011 29 30 22 30 1.5% 1.32 [1.05,1.65]

Qi Jing 2013 34 35 29 35 1.9% 1.17 [1.00,1.38] —

Ren Yufang 2008 47 50 29 50 1.9% 1.62 [1.27, 2.07]

Tang Fang li 2015 26 30 21 30 1.4% 1.24 [0.94,1.63]

WanZhi 2013 41 46 33 43 2.3% 1.16 [0.96,1.41]

Wang Jinju 2013 36 40 26 40 1.7% 1.38 [1.08,1.78]

Wang Lijun 2015 79 90 61 90 4.1% 1.30 [1.10,1.52] —"—

Wu Furong 2015 62 69 50 66 3.4% 1.19 [1.01,1.39] •—

Wu Zerning 2012 29 30 22 30 1.5% 1.32 [1.05,1.65]

Xia Jing wen 2016 40 44 33 44 2.2% 1.21 [1.00,1.47] -

XieXiaoqin 2011 24 28 19 28 1.3% 1.26 [0.94,1.70]

Xu Rong 2011 43 45 38 45 2.5% 1.13 [0.98,1.30]

YinYuanyuan 2013 42 45 32 45 2.1% 1.31 [1.07,1.61] ---

Yu Liwei 2013 25 28 18 28 1.2% 1.39 [1.02,1.88]

Zhai Yanyan 2013 52 56 45 56 3.0% 1.16 [1.00,1.34]

Zhao Fuzhong 2012 93 105 67 105 4.5% 1.39 [1.18,1.63] ■—

Zhao Huijun 2011 35 36 32 36 2.1% 1.09 [0.96,1.24]

Zhou Kun 2014 46 50 32 50 2.1% 1.44 [1.15,1.80]

Subtotal [95%CI) 1433 1415 66,7% 1.29 [1.24,1.34] +

Total events 1 304 997

Heterogeneity: Chi= = 35.11, df= 32 (P = 0.32); l== 9% Test for overall effect: Z= 13.48 (P = 0.00001)

1.1.2 stable angina pectoris

Chen Shu 2009 40 44 21

Ye Ruiyin 201 3 33 38 24

Subtotal [95%CI) 82

Total events 73 45

Heterogeneity: Chi= = 0.76, df= 1 (P= 0.38); l== 0% Test for overall effect: Z= 3.95 (P < 0.0001)

1.1.3 angina pectoris

38 38 76

1.5% 1.6% 31%

1.65 [1.22, 2.22] 1.38 [1.05,1.81] 1.51 [1.23,1.84]

Chen Xia 2013 41 60 39 60 2.6% 1.05 [0.82,1.35]

Cheng Fangchun 2015 54 65 44 65 2.9% 1.23 [1.00,1.50]

Gong Liang 2012 54 60 43 60 2.9% 1.26 [1.05,1.50]

Hong Yu qing 2016 89 94 73 92 4.9% 1.19 [1.06,1.34]

Liu Qiang 2013 31 33 25 33 1.7% 1.24 [1.00,1.53]

LiuXiangling 2009 43 50 34 50 2.3% 1.26 [1.01,1.58]

Rao Guohua 2015 49 50 43 50 2.9% 1.14 [1.01,1.28]

Tian Xiaohua 2015 44 47 33 47 2.2% 1.33 [1.09,1.63]

Wen He 2016 47 48 40 48 2.7% 1.18 [1.03,1.34]

Xiong Guo ying 2014 36 39 28 39 1.9% 1.29 [1.04,1.60]

Xu Weizhong 2011 24 25 19 25 1.3% 1.26 [1.00,1.60]

Zhang Li 2014 41 45 32 45 2.1% 1.28 [1.04,1.58]

Subtotal (95%CI) 616 614 30.2% 1.22 [1.15,1.28]

Total events 553 453

Heterogeneity: Chi= = 4.48, df = 11 (P = 0.95); = = 0%

Test for overall effect: Z = 7.19 (P < 0.00001)

Total (95% CI) 2131 2105 100.0% 1.28 [1.24,1.31]

Total events 1 930 1495

Heterogeneity: Chi= = 44.88, df= 46 (P = 0.52); l== 0%

Test for overall effect: Z= 15.74 (P = 0.00001)

Test for subarouci differences: Chi== 5.97. df= 2 (P = 0.05). I== 66.5%

0.5 1 2 5

Favours [СЦ Favours [SMDS * CI]

Fig. 8 SMDS plus CT versus CT: Rate of improvement of angina symptoms.

SWS + CT CT Risk Ratio

Study or SubarouB Everts Total Everts Total Wei a ht MIL Fixed, 96% CI

1.5.1 10d

DuanXingllang 2010 31 32 20 28 1.6% 1.36 [1.06,1.73]

Han Changheng 2013 60 62 52 60 4.1% 1.12 [1.00,1.25]

Jiang Zongpeng 2012 28 30 21 30 1.6% 1.33 [1.04,1.72]

WanZhl 2013 41 46 33 43 2.6% 1.16 [0.96,1.41]

Wu Zeniing 2012 29 30 22 30 1.7% 1.32 [1.05,1.65]

Subtotal (95%CI) 200 191 11.6% 1.22 [1.12,1.33]

Total events 189 148

Heterogeneity: Chi= = 4.43, df = 4 (P = 0.35); l= = 10%

Test for overall effect: Z = 4.67 (P < 0.00001)

1.5.214d 200mg

Chao Shengwu 2009 21 24 11 24 0.8% 1.91 [1.20, 3.03]

Chen Chun 2003 26 30 19 30 1.5% 1.37 [1.01,1.86]

Chen Chun 2014 32 36 18 28 1.6% 1.38 [1.03,1.87]

Chen Fei 2009 41 49 31 48 2.4% 1.30 [1.02,1.65]

Cheng Fangchun 2015 54 65 44 65 3.4% 1.23 [1.00,1.50]

Dal Dashun 2011 32 37 23 38 1.7% 1.43 [1.07,1.90]

Dou Llhua 2012 41 46 31 46 2.4% 1.32 [1.06,1.66]

Gong Liang 2012 54 60 41 60 3.1% 1.32 [1.09,1.60]

Hong Yu qing 2016 89 94 73 94 5.6% 1.22 [1.08,1.37]

Kang Shanplng 2012 32 35 23 35 1.8% 1.39 [1.07,1.80]

Li Xlngho 2005 28 30 24 30 1.8% 1.17 [0.95,1.43]

Li Yan 2012 40 43 28 43 2.1% 1.43 [1.13,1.80]

LluXincheng 2013 55 60 50 60 3.8% 1.10 [0.96,1.26]

Lun Jia 2011 29 30 22 30 1.7% 1.32 [1.05,1.65]

Ql Jlng 2013 34 35 29 35 2.2% 1.17 [1.00,1.38]

Rao Guohua 2015 49 50 43 50 3.3% 1.14 [1.01,1.28]

Ren Yufang 2008 47 50 29 50 2.2% 1.62 [1.27, 2.07]

Tang Fang li 2015 26 30 21 30 1.6% 1.24 [0.94,1.63]

Tlan Xiaohua 2015 44 47 33 47 2.5% 1.33 [1.09,1.63]

Wang Jinju 2013 34 40 26 40 2.0% 1.31 [1.01,1.70]

Wang Lijun 2015 79 90 61 90 4.7% 1.30 [1.10,1.52]

Wen He 2016 47 48 40 48 3.1% 1.18 [1.03,1.34]

Xla Jlng wen 2016 40 44 33 44 2.5% 1.21 [1.00,1.47]

XleXiaoqin 2011 24 28 19 28 1.5% 1.26 [0.94,1.70]

Xiong Guo ying 2014 32 39 26 39 2.0% 1.23 [0.94,1.61]

Xu Rong 2011 43 45 38 45 2.9% 1.13 [0.98,1.30]

YlnYuanyuan 2013 42 45 32 45 2.5% 1.31 [1.07,1.61]

Yu Liwel 2013 25 28 18 28 1.4% 1.39 [1.02,1.88]

Zhal Yanyan 2013 52 56 45 56 3.5% 1.16 [1.00,1.34]

Zhao Fuihong 2012 93 105 67 105 5.1% 1.39 [1.18,1.63]

Zhao Huijun 2011 35 36 32 36 2.5% 1.09 [0.96,1.24]

Subtotal [95%CI) 1455 1447 79.2% 1.27 [1.23,1.32]

Total events 1320 1030

Heterogeneity: Chi= = 33.27, df= 30 (P = 0.31); l== 10%

Test for overall effect: Z = 13.07 (P = 0.00001)

1.5.3 more than 14d

Wu Furong 2015 62 69 50 66 3.9% 1.19 [1.01,1.39]

Zhang Li 2014 46 50 36 50 2.8% 1.28 [1.06,1.55]

Zhou Kun 2014 46 50 32 50 2.5% 1.44 [1.15,1.80]

Subtotal [95%CI) 159 166 9.1% 1.28 [1.15,1.43]

Total events 154 118

Heterogeneity: ChP= 1.94, df= 2 (P= 0.38); l= = 0%

Test for overall effect: Z = 4.51 (P < 0.00001)

Total (95% CI) 1824 1804 100.0% 1.27 [1.23,1.31]

Risk Ratio M-H. Fixed. 95% CI

Total events 1 663 1296

Heterogeneity: Chi= = 40.82, df= 38 (P = 0.35); l== 7%

Test for overall effect: Z= 14.59 (P = 0.00001)

Test for sutiarouB differences: Chi== 0.95. df= 2 (P = 0.62). I== 0%

0.5 0.7 1 1.5 2 Favours [CT| Favours [SMDS* СЦ

Fig. 9 SMDS plus CT versus CT: Rate of improvement of symptoms, subgroup analysis: according to the treatment duration.

SMDS +CT CT Mean Difference

Study or S Lib a roup Mean SD Total Mean SD Total Weiaht IV. Random, 95%CI

Chen Chun 2008 1.9 1.06 30 2.53 1.14 30 16.4% -0.63 [-1.1 9,-0.07]

Dal Dashun 2011 1.92 0.55 37 2.55 0.55 38 18.0% -0.63 [-0.88,-0.38]

Xla Jing wen 201 6 2.1 0.7 44 3.2 1.1 44 17.4% -1.10 [-1.49,-0.71]

Yu Kerning 2014 2.42 1.61 62 5.16 1.92 62 16.0% -2.74 [-3.36,-2.1 2]

ZhaiYanyan 201 3 2.43 1.62 56 5.17 1.91 56 15.8% -2.74 [-3.40,-2.08]

Zhuang Ruijuan 2014 2 0.86 45 3.16 1.78 45 16.3% -1.1 6 [-1.74,-0.58]

Total [95% CI) 274 275 100.0% -1.47 [-2.16, -0.78]

Heterogeneity: Tau== 0.67; Chl=: = 66.95, df= 5 (P < 0.00001); l== ! 33%

Test for overall effect: Z = 4.18 (P < 0.0001)

Mean Difference IV. Random. 95%CI

-4 -2 0 2 4 Favours [SMDS * CT] Favo u rs [CT[

Fig. 10 SMDS plus CT versus CT among unstable angina studies: The frequency of angina attack.

SMDS +CT CT Mean Difference

Studv or SubarouD Mean SD Total Mean SD Total Weiaht IV. Random. 95% CI

Chen Chun 2008 2.67 1.51 30 3.58 1.82 30 22.8% -0.91 [-1.76,-0.06]

Dal Dashun 2011 2.02 0.64 37 3.37 0.67 38 25.7% -1.35 [-1.65,-1.05]

Yu Kerning 2014 3.87 0.75 62 6.68 0.67 62 25.8% -2.81 [-3.06,-2.56]

Zhai Yanyan 2013 3.84 0.74 56 4.47 0.68 56 25.8% -0.63 [-0.89,-0.37]

Total [95% CI) 185 186 100.0% -1.44 [-2.57, -0.31]

Heterogeneity: Tau= = 1.28; Chl== 147.00, df=3(P « 0.00001); F !=98%

Mean Difference IV. Random. 95%CI

Test for overall effect: Z= 2.50 (P = 0.01)

Favours [SMDS h

0 2 CT] Favours [CT]

Fig. 11 SMDS plus CT versus CT: The duratio

of angina attack.

Study or Subgroup

SKIDS + CT Events Total

CT Events

Risk Ratio Weight M-H. Fined. 95%CI

Risk Ratio M-H. Fixed, 95%CI

1.2.1 unstable angina pectoris

Chao Shengwu 2009 Chen Chun 2008 Chen Chun 2014 Chen Fei 2009 Dai Dashun 2011 Dou Lihua 2012 DuanXingliang 2010 Gao Wenqian 2010 Jiang Zongpeng 2012 Kang Shanping 2012 Li Xingho 2005 Li Yan 2012 Li Yani 2010 LiuXincheng 2013 Lun Jia 2011 Ren Yufang 2008 WanZhi 2013 Wang Jinju 2013 Wang Lijun 2015 Wang Qiang 2013 Wu Zeniing 2012 Xia Jing wen 2016 XieXiaoqin 2011 Xu Rong 2011 Yin Yuanyuan 2013 Yu Liwei 2013 Zhai Yanyan 2013 Zhao Fuzhong 2012 Zhao Huijun 2011 Zhou Kun 2014 Subtotal [95% CI) Total events

18 24 15 24 1.4% 1.20 [0.82 1.77]

25 30 18 30 1.7% 1.39 [1.00 1.94]

30 36 17 28 1.8% 1.37 [0.98 1.91]

37 49 32 48 3.1% 1.13 [0.88 1.46]

30 37 22 38 2.1% 1.40 [1.02 1.91]

38 46 30 46 2.9% 1.27 [0.99 1.63]

30 32 18 28 1.8% 1.46 [1.09 1.95]

22 32 13 32 1.2% 1.69 [1.05 2.73]

22 30 14 30 1.3% 1.57 [1.01 2.44]

31 35 21 35 2.0% 1.48 [1.10 1.98]

25 30 22 30 2.1% 1.14 [0.87 1.49]

28 43 16 43 1.5% 1.75 [1.12 2.73]

28 30 26 30 2.5% 1.08 [0.91 1.28]

56 60 48 60 4.6% 1.17 [1.01 1.35]

28 30 20 30 1.9% 1.40 [1.07 1.83]

44 50 23 50 2.2% 1.91 [1.39 2.63]

34 46 23 43 2.3% 1.38 [1.00 1.92]

32 40 23 40 2.2% 1.39 [1.02 1.89]

85 90 66 90 6.3% 1.29 [1.13 1.47]

44 46 37 46 3.5% 1.19 [1.02 1.39]

28 30 20 30 1.9% 1.40 [1.07 1.83]

39 44 32 44 3.1% 1.22 [0.99 1.50]

18 28 12 28 1.2% 1.50 [0.90 2.50]

42 45 36 45 3.5% 1.17 [0.99 1.38]

39 45 30 45 2.9% 1.30 [1.03 1.65]

23 28 16 28 1.5% 1.44 [1.00 2.07]

50 56 43 56 4.1% 1.16 [0.98 1.38]

98 105 63 105 6.0% 1.56 [1.32 1.83]

33 36 27 36 2.6% 1.22 [0.99 1.51]

45 50 34 50 3.3% 1.32 [1.07 1.64]

1283 1266 78.8% 1,33 [1.27,1,40]

Heterogeneity: Chi= = 34.55, df= 29 (P = 0.22); l== 16% Test for overall effect: Z= 12.37 (P < 0.00001)

1.2.2 stable angina pectoris

Jin Yijing 2014 89 96 63 90 6.2% 1.32 [1.14,1.53]

Ye Ruiyin 2013 29 38 21 37 2.0% 1.34 [0.96,1.87]

Subtotal (95%CI) 134 127 8.3% 1.33 [1.16,1.53]

Total events 118 84

Heterogeneity: Chi== 0.01, df = 1 (P = 0.93); l; != 0%

Test for overall effect: Z = 4.06 (P = 0.0001)

1.2.3 angina pectoris

Chen Xia 2013 43 60 36 60 3.5% 1.19 [0.92,1.55]

Gong Liang 2012 41 60 29 60 2.8% 1.41 [1.03,1.93]

Liu Qiang 2013 31 33 27 33 2.6% 1.15 [0.96,1.38]

LiuXiangling 2009 33 50 23 50 2.2% 1.43 [1.00, 2.06]

Xu Weizhong 2011 23 25 20 25 1.9% 1.15 [0.92,1.44]

Subtotal (95%CI) 228 228 13.0% 1,27 [1.12,1,44]

Total events 171 135

Heterogeneity: Chi= = 2.93, df = 4 (P = 0.57); l: != 0%

Test for overall effect: Z = 3.65 (P = 0.0003)

Total (95% CI) 1645 1623 100.0% 1.32 [1.27,1.38]

Total events 1 391 1 036

Heterogeneity: Chi== 38.30, df= 36 (P = 0.37); l== 6%

Test for overall effect: Z= 13.41 (P = 0.00001)

Test for subgroup differences: Chi== 0.56. df= 2 (P = 0.76). I== 0%

—I-1-1—

0.1 0.2 0.5 1 2 5 1 0 Favours [CT| Favo u rs [SM □ S -<- CT|

Fig. 12 SMDS plus CT versus CT: Rate of improvement of ECG

SMDS + CT CT Risk Ratio

Study or SubarouD Everts Total Everts Total Wei a ht MK Fixed. 95% CI

1.6.1 2D0mg 14d

Chao Shengwu 2009 18 24 15 24 1.9% 1.20 [0.82,1.77]

Chen Chun 2008 25 30 18 30 2.2% 1.39 [1.00,1.94]

Chen Chun 2014 30 36 17 28 2.4% 1.37 [0.98,1.91]

Chen Fei 2009 37 49 32 48 4.0% 1.13 [0.88,1.46]

Dai Dashun 2011 30 37 22 38 2.7% 1.40 [1.02,1.91]

Dou Llhua 2012 38 46 30 46 3.7% 1.27 [0.99,1.63]

Gong Liang 2012 41 60 28 60 3.5% 1.46 [1.06, 2.02]

Kang Shanping 2012 31 35 21 35 2.6% 1.48 [1.10,1.98]

LI Xingho 2005 25 30 22 30 2.7% 1.14 [0.87,1.49]

LI Yan 2012 28 43 16 43 2.0% 1.75 [1.12, 2.73]

LluXincheng 2013 56 60 48 60 5.9% 1.17 [1.01,1.35]

Lun Jia 2011 28 30 20 30 2.5% 1.40 [1.07,1.83]

Ren Yufang 2008 44 50 23 50 2.8% 1.91 [1.39, 2.63]

Wang Jinju 2013 32 40 23 40 2.8% 1.39 [1.02,1.89]

Wang Lljun 2015 85 90 66 90 8.1% 1.29 [1.13,1.47]

Wang Qiang 2013 44 46 37 46 4.6% 1.19 [1.02,1.39]

Xia Jing wen 2016 39 44 32 44 3.9% 1.22 [0.99,1.50]

XieXlaoqin 2011 18 28 12 28 1.5% 1.50 [0.90, 2.50]

Xu Rong 2011 42 45 36 45 4.4% 1.17 [0.99,1.38]

Yin Yuanyuan 2013 39 45 30 45 3.7% 1.30 [1.03,1.65]

Yu Liwel 2013 23 28 16 28 2.0% 1.44 [1.00, 2.07]

Zhai Yanyan 2013 50 56 43 56 5.3% 1.16 [0.98,1.38]

Zhao Fuihong 2012 98 105 63 105 7.8% 1.56 [1.32,1.83]

Zhao Huljun 2011 33 36 27 36 3.3% 1.22 [0.99,1.51]

Subtotal [95% CI) 1093 1085 86.3% 1.33 [1.27,1.40]

Total events 934 697

Heterogeneity: Chi== 26.46, df= 23 (P = 0.28); l= = 13%

Test for overall effect: Z = 11.26 (P = 0.00001)

1.6.2 200m g 10d

DuanXingliang 2010 30 32 18 28 2.4% 1.46 [1.09,1.95]

Jiang Zongpeng 2012 22 30 14 30 1.7% 1.57 [1.01, 2.44]

WanZhi 2013 34 46 23 43 2.9% 1.38 [1.00,1.92]

Wu Zernlng 2012 28 30 20 30 2.5% 1.40 [1.07,1.83]

Subtotal (95%CI) 138 131 9.5% 1,44 [1.22,1.70]

Total events 114 75

Heterogeneity: Chi= = 0.26, df = 3 (P = 0.97); l= = 0%

Test for overall effect: Z = 4.36 (P < 0.0001)

1.6.3 200mg more than 14d

Zhou Kun 2014 45 50 34 50 4.2% 1.32 [1.07,1.64]

Subtotal (95% CI) 50 50 4.2% 1.32 [1.07,1.64]

Total events 45 34

Heterogeneity: Not applicable

Test for overall effect: Z = 2.60 (P = 0.009)

Total (95% CI) 1281 1266 100.0% 1.34 [1.28,1.40]

Risk Ratio M H, Fixed, 95%CI

Total events 1 093 806

Heterogeneity: Chl== 28.49, df= 28 (P = 0.44); l== 2%

Test for overall effect: Z= 12.35 (P < 0.00001)

Test for subgroup differences: Chl= = 0.83. df= 2 (P = 0.66). I== 0%

0.5 1 2 5

Favours[CTl Favours [SMDS■»СП

Fig. 13 SMDS plus CT versus CT: Rate of improvement of ECG, subgroup analysis: according to the treat

atment durai

Study or Subgroup

SKIDS + CT Everts Total

Everts Total Weight

Risk Ratio M-H. Fixed. 95%CI

Risk Ratio M-H. Fixed. 95% CI

1.3.1 unstable angina pectoris

Chen Chun 2008 Chen Chun 2014 Dai Dashun 2011 Gao Wenqian 2010 Li Yan 2012 Subtotal (95%CI) Total events

24 24 29 20 40

30 30 37 32 43 172

16 16 18 12 30

30 30 38 32 43 173

17.4% 17.4% 19.4% 13.1% 32.7% 100.0%

1.50 [1.03, 2.19] 1.50 [1.03, 2.19] 1.65(1.14,2.41] 1.67(0.99,2.81] 1.33(1.08,1.65] 1.50 [1.28, 1.75]

Heterogeneity: Chi== 1.57, df= 4 (P = 0.81); l== 0% Test for overall effect: Z= 5.09 (P < 0.00001)

Test for subgroup differences: Not abblicable

0.01 0.1 1 10 100 Favours [CT] Favours [SMDS + CT]

Fig. 14. SMDS plus CT versus CT: The rate of stopping or reducing the dosage of nitroglycerin

- nitroglyc

Graphic abstract

Salvia miltiorrhiza Bunge

Sulding CT CT Mean Wlmnce

Stuft er Sutufwa Hwn SD Tcttl Hau 58 Totti tttitfU N. fonftm 85% CI

Tan XiaohuB 2015 0.88 0.1 47 1.N All 47 21.7% 4.31(4.37.425]

Rao GucftM 2015 0.89 0.11 SO 1.15 Ol] 50 25.1% 428(4.31-0211

Wen He2C16 0 88 0.12 48 1.13 015 4« 232% 425(430.420|

Xa Jug »w 2016 012 0« 44 033 012 44 29.3% 421(425.4.17]

Rosmarinic acid (RA)

IXX/vM^

Lithospermic acid (LA)

Magnesium

lithospermate B (HLB)

TMIdKR 1H Ol 1«W 4JS|4JMi11

MmgmVTH'*Mftai,*U7.«0(P'Mlt''M TM b M*<fta l = 1231 fl> < 001)

Systematic review

Salvia miltiorrhiza depside salts for infusion