Efficacy and Safety of Salvia miltiorrhiza for Treating Chronic Kidney Diseases: A Systematic Review and Meta-Analysis.

Objective: This meta-analysis evaluated the effects and potential harms of Salvia miltiorrhiza or its extracts Salvianolate and Tanshinone for the treatment of population with a chronic kidney disease (CKD).
Methods: We searched for the randomized clinical trials (RCTs) through databases including the Cochrane Library, PubMed, Embase, Web of Science, Current Controlled Trials, China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform (Wanfang Data), China Biology Medicine Disc (SinoMed), and Chinese Clinical Trial Registry (ChiCTR). Meta-analysis was performed with STATA 16 software after data extraction. The risk of bias was assessed with the Cochrane risk-of-bias tool (RoB 2.0), and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework was employed to evaluate the quality of evidence. Result: A total of 32 studies were included involving 2264 participants. Compared to the control group, the treatment group significantly decreased serum creatinine (SCr) (SMD -0.60, 95% CI -0.79 to -0.41, P < 0.0001), blood urea nitrogen (BUN) (SMD -0.66, 95% CI -0.81 to -0.50, P < 0.0001), Cystatin C (CysC) (SMD -5.16, 95% CI -14.84 to 4.53, P=0.297), 24 hour urine protein (24 h UPE) (SMD -0.70, 95% CI -1.21 to -0.19, P=0.008), time to initiation of dialysis (Log RR 0.43, 95% CI 0.23 to 0.81, P=0.0089), serum total cholesterol (TC) (SMD -0.53, 95% CI -0.88 to -0.17, P=0.0042, P=0.0035), plasma fibrinogen (FIB) (SMD -0.79, 95% CI -1.12 to -0.46, P < 0.0001), C-reactive protein (CRP) (SMD -0.56, 95% CI -0.93 to -0.19, P=0.0029); increased creatinine clearance (Ccr) (SMD 0.92, 95% CI 0.43 to 1.41, P=0.0002), glomerular filtration rate (GFR) (SMD 0.56, 95% CI 0.30 to 0.83, P < 0.001), effective rate (Log RR 0.30, 95% CI 0.23 to 0.37, P < 0.0001), and hemoglobin (Hb) (SMD 0.42, 95% CI 0.13 to 0.71, P=0.0042). Moreover, the incidences of adverse effects were similar between the two groups. Conclusions: Salvia miltiorrhiza or its extracts Salvianolate and Tanshinone, as a complementary therapy to conventional medicine, presents potential impacts to improve kidney functions and delay the progression of CKD without obvious adverse effects. However, the certainty of the evidence and the risk of bias are suboptimal and further clinical studies are still required to determine the underlying effects.

1. Introduction

A chronic kidney disease (CKD) arises from various heterogeneous diseases. The diagnosis of CKD rests on establishing a chronic reduction in the kidney function and structural damage.

The prevalence of CKD for stages 1–5 is 13.4% and 10.6% for stages 3–5 [1]. Contrary to diabetes or other metabolic diseases as prevalent as CKD, renal function impairment is often asymptomatic until very late stages [2]. According to the National Kidney Foundation, 30 million adults in the United States had CKD in 2017, and only 10 percent knew they had it, at a medical cost of $103 billion. In addition, CKD ranks fourteenth in the list of leading causes of death, which accounts for 12.2 deaths per 1,00,000 people, and the death rate of CKD will continue to increase to reach 14 per 1,00,000 people by 2030 [3]. In short, CKD has the characteristics of high incidence, high cost, high mortality, and low recognition rate.

Patients with CKD need efficient treatments to delay disease progression and improve the quality of life and the survival rate. In China, Chinese herbal medicines (CHMs) are widely used for the treatment of CKD. There are many prescriptions containing varieties or single CHM for CKD. It could also be said that every doctor's prescription may be different and is constantly modified during patients' followup. Hence, comparing the efficacy of diverse prescriptions is inherently heterogeneous and is not conducive to promotion outside China. Furthermore, according to the traditional Chinese medicine (TCM) theory, promoting blood circulation and removing blood stasis should be adopted throughout the treatment of CKD. Salvia miltiorrhiza (Danshen) is one of the most commonly used CHMs. Studies have demonstrated that Salvia miltiorrhiza is the top single CHM prescribed for CKD in China [4]. Medicinal parts of Salvia miltiorrhiza (Danshen) is the dried root and rhizomes of Salvia miltiorrhiza Bge. Salvia miltiorrhiza has specific preparations for clinical applications, such as Salvia miltiorrhiza tablet or injection and its extracts Salvianolate injection as well as Tanshinone injection, which all have strict quality control standards and the procedures are fully reproducible. Salvia miltiorrhiza and its extracts Salvianolate and Tanshinone are extensively used for CKD.

Clinically, a number of studies have displayed that Salvia miltiorrhiza can improve kidney function in CKD patients by increasing the glomerular filtration rate (GFR) and creatinine clearance (Ccr) and reducing serum creatinine (SCr) and proteinuria, but this conclusion is yet to be verified [5]. Research studies also reveal that Salvia miltiorrhiza could alleviate kidney injury via inhibiting oxidative stress and apoptosis [6] and exerting prominent renal protective effects in iron-overloaded mice by decreasing of iron deposition and suppression of lipid peroxidation and apoptosis in the kidney [7]. Tanshinone IIA significantly attenuates kidney fibrosis by inhibiting the recruitment of fibrocytes into the kidney [8] and decreases renal damage in diabetic rats via inhibiting oxidative stress and inflammation [9]. Salvianolate might alleviate the renal damage in chronic renal failure rats through antioxidant stress [10], accordingly attenuating glomerular injury, including albuminuria secretion, mesangial matrix expansion, foot process effacement in the kidneys of db/db mice, and ameliorated oxidative podocyte injury [11].

There is one previous meta-analysis that evaluated the efficacy and safety of Tanshinone for CKD [12], which includes 21 studies published before June 1, 2019. In our meta-analysis, we include Salvia miltiorrhiza and its extracts Salvianolate besides Tanshinone because they have a strong connection with each other and they are all widely used in China for CKD. All of the studies we included were published before November 9th, 2021. The subjects in the previous meta-analysis were diagnosed with diabetic nephropathy (3 studies), hypertensive renal damage (4 studies), renal vascular hypertension (1 study), and cardiorenal syndrome (1 study) rather than CKD (12 studies). Whereas, we focused on the subjects of patients diagnosed with CKD. The inclusion of subjects was more rigorous, whereas we may miss some patients with CKD who were diagnosed with hypertensive nephropathy or other diagnoses.

The current meta-analysis was performed to comprehensively evaluate the efficacy and safety of Salvia miltiorrhiza and its extracts Salvianolate and Tanshinone for the treatment of patients with CKD, with a view to provide substantial evidence for supporting its clinical application in CKD patients.

2. Methods

2.1. Protocol and Registration

This meta-analysis had been registered in PROSPEPO with registration number CRD42021291786.

2.2. Eligibility Criteria

2.2.1. Types of Studies

All randomized controlled trials (RCTs) evaluating the efficacy of Salvia miltiorrhiza for CKD were included.

2.2.2. Types of Participants

(1) Inclusion Criteria. Adults and children with CKD at all stages.

(2) Exclusion Criteria. Studies stating that participants had renal damage, but without baseline GFR, Ccr, or SCr; participants with diabetic nephropathy. These issues had been investigated in a previous study [13]; studies involving Salvia miltiorrhiza as one of several active components in a compound recipe were not included.

2.2.3. Types of Interventions

Treatment group received Salvia miltiorrhiza or its extracts Salvianolate and Tanshinone. The control group received placebo, no treatment, or conventional treatment.

2.2.4. Outcomes

(1) Primary outcomes. Kidney function measured by SCr, Ccr, GFR, blood urea nitrogen (BUN) cystatin C (CySC), or effective rate, proteinuria measured by 24 hour urinary protein excretion (24 h UPE), time to initiation of dialysis, and adverse effects.

(2) Secondary outcomes. Nutritional status assessed by serum albumin (ALB) and serum total cholesterol (TC), anemia measured by hemoglobin (Hb), hemorheology index measured by plasma fibrinogen (FIB), and inflammatory factor measured by C-reactive protein (CRP).

2.3. Search Methods

This meta-analysis was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA 2020 [14,15]) (Supplementary Table S1). We searched the Cochrane Library, PubMed, Embase, Web of Science, Current Controlled Trials, and Chinese databases including China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform (Wanfang Data), China Biology Medicine Disc (SinoMed), and Chinese Clinical Trial Registry (ChiCTR) from inception until November 9th, 2021 (Supplementary Table S2).

2.4. Study Selection

The search strategy described was used to obtain titles and abstracts of studies that may be relevant to this review. Titles, abstracts, and full texts were screened independently by two authors who determined which met the inclusion criteria and excluded studies that were not appropriate.

2.5. Data Collection Process

Data extraction was carried out independently by the same two authors using a pre-tested data extraction form. If more than one publication of one study existed, the publication with the most complete data was used. Any discrepancy between published versions was to be highlighted. Disagreements between authors were resolved by consensus and with a third author.

2.6. Quality Assessment and Statistical Methods

The publications included in this meta-analysis were subject to quality assessment according to the Cochrane criteria [15]. The risk of bias was assessed using the Cochrane risk-of-bias tool (RoB. 2.0) [16]. In addition, the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework was employed to evaluate the quality of evidence contributing to each estimate [15].

The STATA 16 software was used for data analysis. For dichotomous outcomes, results were expressed as Log risk ratio (Log RR) with 95% confidence intervals (CI). For continuous outcomes, the standard mean difference (SMD) was presented with 95% confidence intervals (CI).

Heterogeneity was analyzed using a Chi2 test on N − 1 degrees of freedom, with an alpha of 0.1 used for statistical significance and with the I2-test [15]. I2 > 50% corresponds to high levels of heterogeneity, respectively. A subgroup or sensitivity analysis was conducted to explore the underlying causes of heterogeneity in treatment outcomes.

To assess small-study effects, we generated Egger's test or funnel plots [15] including at least 10 trials of varying size. If asymmetry was detected in the funnel plot, a contour-enhanced funnel plot was generated to assess whether the asymmetry was likely due to publication bias or other factors of the trials.

2.7. Additional Analyses

We conducted subgroup analyses to explore the impact of Salvia miltiorrhiza and its extracts Salvianolate and Tanshinone preparations.

3. Results

3.1. Study Selection

Our initial search found 332 records. After excluding 47 duplicate reports and 232 irrelevant records based on identification of titles and abstracts, we reviewed 53 full-text studies for inclusion and then 21 studies were further excluded. Finally, a total of 32 studies were included in the meta-analysis (Figure 1).

Figure 1

Flow of information through the different phases of the meta-analysis.

3.2. Study Characteristics

32 included studies involved 2264 participants and were conducted in hospitals of China and published in Chinese. All studies were parallel arm. Participants' age ranged from 18–96 years. Authors, year of publication, treatment plan, sample size, duration of treatment, and index of evaluation of each study are presented in Table 1.

Table 1

Characteristics of included studies.

Study Year	Treatment	Control	Number (T/C)	Duration	Results report
Bao et al. 2002 [17]	Salvia miltiorrhiza injection (6–10 ml ivgtt qd) + conventional steroid treatment	Conventional steroid treatment	24/20	2 weeks	Scr, BUN, 24 h UPE, ALB
Huang 2009 [18]	Salvia miltiorrhiza injection (20 ml ivgtt qd) + conventional treatment	Conventional treatment	46/46	2 weeks	Effective rate
Wang et al. 2015 [19]	Salvia miltiorrhiza Injection (1 ml ivgtt qd) + Huang qi injection (2.5 ml) + conventional treatment	Conventional treatment	30/29	2 months	Scr, BUN, Ccr
Wang and Zhao [20]	Salvia miltiorrhiza injection (400 mg ivgtt qd) + conventional treatment	Conventional treatment	53/45	35 days	Effective rate, SCr
Wang et al. 2008 [21]	Salvianolate injection (200 mg ivgtt qd) + alprostadil Injection (30 μg ivgtt qd) + reduced glutathione injection (2.4 g ivgtt qd) conventional treatment	Conventional treatment	42/42	7 days	BUN SCr, BUN, GFR
Liu 2017 [22]	Salvianolate injection (200 mg ivgtt qd) + conventional treatment	Conventional treatment	30/30	2 weeks	CySC, adverse effect
Fu et al. 2012 [23]	Salvianolate Injection (200 mg ivgtt qd) + alprostadil Injection (20 μg ivgtt qd) + reduced glutathione Injection (2.4 g ivgtt qd) + conventional treatment	Conventional treatment	15/15	12 to 64 months	Effect time to initiation of
Liu 2015 [24]	Salvianolate injection (100 mg ivgtt qd) + conventional treatment	Conventional treatment	16/16	2 weeks	Dialysis, adverse effect of SCr, BUN
Hu et al. 2011 [25]	Salvianolate injection (200 mg ivgtt qd) + conventional treatment	Conventional treatment	27/27	4 weeks	SCr, 24 h UPE
Sun and Luo 2012 [26]	Salvianolate injection (200 mg ivgtt qd) + conventional treatment	Conventional treatment	40/38	2 weeks	Effective rate, SCr
Xiong et al. 2007 [27]	Salvia miltiorrhiza injection (80 mg ivgtt qd) + TCM decoction ((Rhubarb 20 g, calcined keel 20 g, calcined oyster 20 g, dandelion 20 g, Ligusticum chuanxiong 20 g) 300 ml retention enema for 1-2 h, qd) + conventional treatment	Conventional treatment	40/40	30 days	BUN, Ccr, adverse effect effective rate, SCr
Wang et al. 2007 [28]	Salvia miltiorrhiza injection (800 mg ivgtt qd) + conventional treatment	Xueshuantong Injection (450 mg ivgtt qd) + conventional treatment	24/23	15 days	BUN, GFR, Hb, ALB, adverse effect effective rate
Xu et al. 2011 [29]	Salvia miltiorrhiza injection (20 ml ivgtt qd) + Huang qi injection (40 g ivgtt qd) + conventional treatment	Conventional treatment	39/36	2 weeks	Effective rate, SCr
Guohua et al. 2009 [30]	Salvia miltiorrhiza tablet (4 pills tid p.o.) + irbesartan (150 mg qd p.o.) + conventional treatment	Irbesartan (150 mg qd pop.o.) + conventional treatment	32/31	6 months	BUN, CysC, Hb, ALB, CRP effective rate, SCr
Wang 2012 [31]	Salvia miltiorrhiza injection (800 mg ivgtt qd) + Valsartan (80 mg p. o. qd) + conventional treatment	Valsartan (80 mg p.o. qd) + conventional treatment	30/30	4 weeks	BUN, 24 h UPE, TC SCr, 24 h UPE, TC
Xiang and Mo 2011 [32]	Sodium Tanshinone II A sulfonate injection (40 mg ivgtt qd) + TCM decoction ((Rhubarb 10 g, Calcined oyster 20 g, Dandelion 30 g) 400 ml retention enema for 20–30 m, bid) + conventional treatment	TCM decoction [(Rhubarb 10 g, Calcined oyster 20 g, Dandelion 30 g) 400 ml retention enema for 20–30 m, bid] + conventional treatment	31/30	8 weeks	SCr, BUN, Ccr
Wang and Xian-Qin 2007 [33]	Sodium Tanshinone II A sulfonate Injection (20 ml ivgtt qd) + conventional treatment	Conventional treatment	31/28	2 months	FIB effective rate, SCr
Gao and Gao 2011 [34]	Sodium Tanshinone II A sulfonate injection (50 mgivgtt qd) + conventional treatment	Conventional treatment	48/42	4 weeks	BUN, Ccr SCr, BUN, 24 h
Wang 2014 [35]	Sodium Tanshinone II A sulfonate injection (40 mg ivgtt qd) + Alprostadil injection (10 μg ivgtt qd) + conventional treatment	Conventional treatment	32/32	28 days	UPE, CySC, CRP, FIB SCr, BUN, GFR
Tian et al. 2005 [36]	Salvia miltiorrhiza injection (60 ml ivgtt qd) + conventional treatment	Conventional treatment	106/96	10 days	Adverse effect SCr, Ccr
Peng et al. 2010 [37]	Sodium tanshinone II A sulfonate injection (50 mg ivgtt qd) + Haikunshenxi capsule (2 pills p.o. tid) + conventional treatment	Conventional treatment	30/28	3 weeks	SCr, BUN, Ccr
Xu et al. 2012 [38]	Salvia miltiorrhiza injection (1200 mg ivgtt qd) + Haikunshenxi capsule (2 pills p.o. tid) + conventional treatment	Conventional treatment	30/30	15 days	Effective rate, SCr,BUN, 24 h, UPE, ALB, Ccr, Hb
Peng et al. 2010 [39]	Salvianolate injection (200 mg ivgtt qd) + Alprostadil	Conventional treatment	29/28	2 weeks	SCr, BUN, Ccr
Liu et al. [40]	Salvianolate injection (100 mg ivgtt qd) + alprostadil injection (20 μg ivgtt qd) + conventional treatment	Alprostadil injection (20 μgivgtt qd) + conventional treatment	63/63	4 weeks	Effective rate, SCr,BUN, Ccr
Lv et al. 2006 [41]	Salvia miltiorrhiza tablet (4 pills tid p.o.) + Jieduxiezhuo II decoction 150 ml retention enema qd + conventional treatment	Jieduxiezhuo II decoction 150 ml retention enema qd + conventional treatment	30/30	1 month	Effective rate, SCr, BUN, Hb
Guowei et al. 2016 [42]	Sodium Tanshinone II A sulfonate injection (40 mg ivgtt qd) + alprostadil injection (10 μg ivgtt qd) + conventional treatment	Conventional treatment	27/15	2 weeks	Effective rate, SCr
Pang 2004 [43]	Salvia miltiorrhiza injection (30 ml ivgtt qd) + TCM decoction 200 ml retention enema bid + low molecular levo-anhydride injection (250 ml ivgtt qd) + conventional treatment	Conventional treatment	20/20	12	BUN, effective rate, SCr
Chen 2016 [44]	Salvianolate Injection (150 mg ivgtt qd + conventional treatment	Conventional treatment	32/32	14 days	SCr, BUN, Ccr
Wang 2015 [45]	Salvianolate injection (100 mg ivgtt qd) + Valsartan (80 mg p.o. qd) + conventional treatment	Valsartan (80 mg p.o. qd) + conventional treatment	45/45	2 weeks	SCr, BUN, 24 h UPE, CySC
Zhi et al. 2016 [46]	Salvianolate injection (200 mg ivgtt qd) + Shenshuaining granules (1 bag p.o. 3–4 times/day) + conventional treatment	Conventional treatment	31/31	2 weeks	SCr, BUN, Ccr, adverse effect
Chen and Lu 2012 [47]	Salvia miltiorrhiza injection (0.8 g ivgtt qd) + sodium ferulate injection (0.3 g ivgtt qd) + conventional treatment	Conventional treatment	36/32	5 weeks	Effective rate, SCr, BUN, Ccr, Hb
Xie et al. 2020 [48]	Sodium tanshinone II A sulfonate injection (50 mg ivgtt qd) + Corbrin capsule (2 g p.o. tid) + conventional treatment	Corbrin capsule (2 g p.o.tid) + conventional	53/52	2 months	Effective rate, SCr, BUN, 24 h UPE

T. treatment group; C. control group; p.o.: per os; qd: quaque die; tid: ter in die; ivgtt: injectio intiavenosus gutta; 24 h UPE: 24 hour urine protein excretion; GFR: glomerular filtration rate; Ccr. creatinine clearance; SCr: serum creatinine; BUN: Blood urea nitrogen; CysC. cystatin C; ALB: serum albumin; TC: serum total cholesterol; Hb: haemoglobin; FIB: plasma fibrinogen; and CRP: C-reactive protein.

3.3. Risk of Bias

The 32 studies included were all RCTs, yet only 9 had detailed descriptions of the methods. In one study, computer-generated random numbers were used in the sequence generation process, and in 6 studies, random number tables were adopted. Nevertheless, in another 2 studies, patient record numbers were used. Only one study specified the method of blinding, and that was single-blind. All studies were assessed according to the RoB. 2.0 tool, of which 8 (25%) were assessed as “low risk of bias,” 22 (68.75%) as “some concerns,” and 2 (6.25%) as “high risk” (Figure 2).

Figure 2

Risk of bias.

3.4. Results of Included Studies

3.4.1. Kidney Function

(1) SCr. A total of 29 studies compared Scr levels between the treatment and control group. We classified these studies into following subgroups based on the different preparations: Salvia miltiorrhiza, Salvianolate, and Tanshinone. As indicated in Figure 3, the random-effect model was used due to the high heterogeneity. Scr levels in the treatment group were significantly reduced compared with the control group (SMD −0.60, 95% CI −0.79 to −0.41, P < 0.0001, I2 = 77.82%). Subgroup analysis revealed that all of the 3 subgroups notably decreased SCr compared with control group (Salvia miltiorrhiza group: SMD −0.41, 95% CI −0.59 to −0.22, P < 0.0001, I2 = 38.4%. Salvianolate group: SMD −0.97, 95% CI −1.42 to −0.52, P < 0.0001, I2 = 80.49%. Tanshinone group: SMD −0.48, 95% CI −0.68 to −0.29, P < 0.0001, I2 = 32.90%). The Salvianolate group was the main source of heterogeneity. Then, we divided the studies of the Salvianolate group into various subgroups based on bias, when we removed the RCT of Wang et al. [21] which had the highest Scr and the Liu [24] with the smallest sample size, both low risk group and some concerns group had low heterogeneity (I2 = 0 and I2 = 6.03%).

Figure 3

Forest plot of meta-analysis of SCr.

Egger's test exhibited that there was no publication bias P < 0.001.

(2) Ccr. A total of 13 studies compared Ccr levels between the treatment group and control group. We classified studies into different subgroups based on the preparations: Salvia miltiorrhiza, Salvianolate and Tanshinone. As demonstrated in Figure 4, the random-effect model was used because of the high heterogeneity. Ccr levels in the treatment group were significantly increased compared to the control group (SMD 0.92, 95% CI 0.43 to 1.41, P=0.0002, I2 = 92.51%). Subgroup analysis indicated that Ccr levels in the Salvianolate subgroups was distinctly increased compared with control group (SMD 1.55, 95% CI 0.56 to 2.53, P=0.002, I2 = 94.30%). Ccr levels in the Salvia miltiorrhiza and Tanshinone groups were increased but not significant compared with control group (SMD 0.46, 95% CI 0.06 to 0.87, P < 0.0249, I2 = 58.82%; SMD 0.61, 95% CI −0.02 to 1.20, P=0.0426, I2 = 85.39%).

Figure 4

Forest plot of meta-analysis of Ccr.

Egger's test displayed that there was no publication bias (P=0.2624).

(3) GFR. A total of 3 studies compared GFR levels between the treatment group and control group. As shown in Figure 5, the heterogeneity was low (I2 = 0%) and the fixed-effect model was employed to analyze the data. GFR levels in the treatment group were significantly increased compared with the control group (SMD 0.56, 95% CI 0.30 to 0.83, P < 0.001, I2 = 0%).

Figure 5

Forest plot of meta-analysis of GFR.

(4) BUN. A total of 26 studies reported BUN levels between the two groups. As presented in Figure 6, the random-effect model was used due to the high heterogeneity. BUN levels in the treatment group were significantly reduced compared with the control group (SMD −0.66, 95% CI −0.81 to −0.50, P < 0.0001, I2 = 60.89%). Subgroup analysis indicated that all of the 3 subgroups had decreased BUN compared with the control group (Salvia miltiorrhiza group: SMD −0.52, 95% CI −0.70 to −0.34, P < 0.0001, I2 = 30.29%; Salvianolate group: SMD −0.90, 95% CI −1.28 to −0.52, P < 0.0001, I = 79.72%; Tanshinone group: SMD −0.63, 95% CI −0.81 to −0.45, P < 0.0001, I = 0%). The Salvianolate group was the main cause of heterogeneity.

Figure 6

Forest plot of meta-analysis of BUN.

Egger's test reflected that no publication bias existed (P=0.9602).

(5) CysC. A total of 4 studies recorded CysC levels between the treatment group and control group. As presented in Figure 7, CysC levels in the treatment group were decreased but without significance compared with the control group (SMD −5.16, 95% CI −14.84 to 4.53, P=0.297, I2 = 99.93%).

Figure 7

Forest plot of meta-analysis of CysC.

(6) Effective Rate. A total of 15 studies compared the effective rate between the two groups. As listed in Figure 8(a), the effective rate in the treatment group was significantly higher compared with the control group (Log RR 0.30, 95% CI 0.23 to 0.37, P < 0.0001, I2 = 0%), and the heterogeneity was low. Subgroup analysis indicated that the effective rates were remarkably higher in Salvia miltiorrhiza and Tanshinone groups compared to the control group (Log RR 0.40, 95% CI 0.30 to 0.50, P < 0.0001, I2 = 0%; Log RR 0.28 95% CI 0.11 to 0.44, P < 0.001, I2 = 0%), the effective rate was higher in the Salvianolate group compared with the control group (Log RR 0.30, 95% CI -0.07 to 0.68, P=0.113, I2 = 76.77%). Liu et al. [40] used alprostadil injection combined Salvianolate injection in the treatment group, which might bias the heterogeneity. Furthermore, removal of this study resulted in a considerable reduced I2 (I2 = 0%).

Figure 8

(a) Forest plot of meta-analysis of effective rate. (b) Contour-enhanced funnel plot of meta-analysis of the effective rate.

Egger's test revealed that there was publication bias (P < 0.05). As shown in Figure 8(b), 7 studies were imputed and 2 studies were in the area of 5%