Skip to main content
Download PDF

Comparative efficacy of Chinese patent medicines in patients with carotid atherosclerotic plaque: a Bayesian network meta− analysis

Chinese Medicine volume 18, Article number: 152 (2023) Cite this article

Abstract

Background

Traditional Chinese patent medicines (TCPMs) have been widely used to treat carotid atherosclerotic plaque (CAP) in China. However, systematic evaluation of the clinical efficacy of TCPMs for CAP is still unknown, and the comparative efficacy of different TCPMs is unclear.

Objectives

This study aims to compare and rank the effectiveness and safety of different TCPMs in treating CAP using a Bayesian network meta− analysis (NMA).

Methods

This NMA was performed according to the Preferred Reporting Items for Systematic Reviews and Meta− Analyses (PRISMA) Extension Statement. Eight databases were searched from their inception to August 2023 for randomized controlled trials (RCTs). The articles regarding eligibility and extracted data were screened independently by two authors. The Cochrane Risk of Bias tool was used to evaluate quality and bias. The change of carotid artery intimal− medial thickness (IMT), carotid maximal plaque area, carotid atherosclerotic plaque Course score, serum lipid levels, CRP, and adverse events rate (AER) were used as outcomes. Data from each RCTs were first pooled using random− effect pairwise meta− analyses and illustrated as odds ratios (ORs) or standardized mean differences (SMDs) with 95% confidence interval (CI). NMAs were performed using Stata17.0 software and the GeMTC package of R software to evaluate the comparative effectiveness of TCPMs, and displayed as ORs or SMDs with 95% CI. A Bayesian hierarchical random− effects model was used to conduct NMAs using the Markov Chain Monte Carlo algorithm. The GRADE partially contextualised framework was applied for NMA result interpretation.

Results

NMA included 27 RCT trials with 4131 patients and nine types of TCPMs. Pairwise meta− analyses indicated that Conventional Western medicine (CWM) + TCPM was superior to CWM in reducing the IMT (SMD: − 1.26; 95% CI − 1.59 to − 0.93), the carotid maximal plaque area (SMD − 1.27; 95% CI − 1.71, − 0.82) and the carotid atherosclerotic plaque Course score (SMD − 0.72; 95% CI 95% CI − 1.20, − 0.25). NMAs demonstrated that CWM + Jiangzhiling pill (JZL) with SUCRA 70.6% exhibited the highest effective intervention for reducing IMT. CWM + SXBX (Shexiang baoxin pill) was superior to other TCPMs in reducing the carotid maximal plaque area (83.0%), the atherosclerotic plaque Course score (92.5%), TC (95.6%) and LDL (92.6%) levels. CWM + NXT (Naoxintong capsule), CWM + XS (Xiaoshuang granules/enteric capsule), and CWM + ZBT (Zhibitai) were superior to other CPMs in improving TG (90.1%), HDL (86.1%), and CRP (92.6%), respectively. No serious adverse events were reported.

Conclusions

For CAP patients, CWM + XSBX was among the most effective in reducing carotid maximal plaque area, atherosclerotic plaque Course score, TC and LDL levels, and CWM + JZL was the most effective in reducing IMT. Overall, CWM + XSBX may be considered an effective intervention for the treatment of CAP. This study provides reference and evidence for the clinical optimization of TCPM selection in CAP treatment. More adequately powered, well− designed clinical trials to increase the quality of the available evidence are still needed in the future due to several limitations.

Introduction

Carotid atherosclerotic plaque (CAP) is an important cause of carotid artery stenosis and has a high global prevalence. CAP global prevalence was approximately 21.1% in 2020, equivalent to 815.76 million people, and carotid artery stenosis global prevalence was approximately 1.5%, equivalent to 57.79 million people between the ages of 30 and 79 [1]. CAP prevalence between the ages of 30 and 79 was approximately 20.15%, equivalent to 199.83 million people in China [2]. The global burden of CAP is expected to increase as populations age, placing a huge burden on health care. Some guidelines have recommended CAP as a potentially useful predictor of coronary events and stroke [3]. CAP is an independent risk factor for stroke, and 45–50% of ischemic strokes are associated with bilateral CAP [4]. CAP is also detected in up to 80% of ischemic stroke patients [1]. According to a study, every 10% increase in plaque burden leads to a 2.26− fold higher risk of stroke recurrence (95% CI 1.03–4.96) [5]. Additionally, CAP is an effective predictor for coronary event incidence. A study involving 89 papers with 2,783 patients exhibited that CAP outperforms intimal− medial thickness (IMT) in predicting coronary artery disease, with a summary sensitivity of 80% and a summary specificity of 67%, regardless of the diagnostic technique [6]. CAP has become an important global public health concern, increasing the risk of cardiovascular and cerebrovascular disease. CAP increases as the global population ages and is highest among the elderly, significantly increasing the health care burden. However, several studies have discovered that CAP formation can be slowed, stopped, reversed, or even disappear, which has significant implications for improving human health and relieving the medical burden [7].

Currently, carotid endarterectomy (CEA), carotid stent placement (CAS), and optimal drug therapy (OMT) are the primary treatments for CAP and carotid artery stenosis [8]. Although surgical methods may improve stenosis caused by excessive CAP growth, these invasive treatments always carry surgical risks and complications, such as cervical hematoma, craniofacial nerve injury, cardiovascular events, cerebral hyperperfusion syndrome, and infection, and should be reserved for patients with significant syndromes, high stenosis, or vulnerable plaque. Additionally, a study has demonstrated that CEA reduced the risk of bilateral stroke by only 4.1% at five years compared to OMT [9]. Therefore, OMT, as a non− invasive treatment for CAP, is receiving increasing attention [10]. Statin is the central drug in OMT to stabilize and reverse atherosclerotic plaque. A three− dimensional ultrasound study to evaluate CAP has demonstrated regression of 90.25 ± 85.12 mm3 in CAP volume after three months of atorvastatin treatment, compared to a progression of 16.81 ± 74.10 mm3 on placebo (P < 0.0001) [11]. The effect of statin on reversing CAP progression depends on lowering the low− density lipoprotein cholesterol (LDL− C) levels. Expert consensus has recommended long− term intensive statin therapy to reduce LDL− C to 1.8 mmol/L and significantly increase HDL− C, potentially reversing atherosclerotic plaque, but inducing a 12% increased risk of new diabetes, a 5% increased risk of muscle disease and a two—to three− fold increased risk of severe liver damage [12]. An MRI assessment study revealed that statin therapy did not consistently reduce the CAP lipid content. The effect occurred primarily between years one and two, with little further reduction in year three [13]. Long− term intensive statin therapy carries a greater risk, especially for patients who use statins cautiously, such as the elderly, those with low body mass, abnormal liver and kidney function, and those with a history of adverse drug reactions. Therefore, there is an urgent need for complementary and alternative drugs to improve drug regimens of OMT further because the efficacy of statins in reversing CAP is not entirely satisfactory.

Traditional Chinese patent medicines (TCPMs) with reliable pharmaceutical ingredients and manufacturing processes have been widely used to treat chronic diseases as an important part of Traditional Chinese medicine (TCM) in China [14]. In 2018, a meta− analysis of 12 randomized controlled trials (RCT) articles, including 1,052 CAP patients, demonstrated that combined TCM and Western medicine are superior to Western medicine alone for treating CAP regarding clinical efficacy (OR = 3.07 [1.96, 4.81], P < 0.00001), IMT (OR =—0.09 [become an important global public health concern 0.10, − 0.08], P < 0.00001), course score (OR = − 0.96 [− 1.09, − 0.83], P < 0.00001), and plaque area (OR = − 0.20 [− 0.23, − 0.17], P < 0.00001)[15]. Guidelines have recommended that TCPMs combined with conventional Western medicine (CWM) to treat atherosclerotic disease, including coronary arteries, carotid and cerebral arteries [16, 17]. Among them, Tongxinluo capsule (TXL), Xiaoshuang granules/enteric capsule (XS), Naoxintong capsule (NXT), Xuesaitong capsule/soft capsule (XST), Jiangzhiling pill (JZL), Pushen capsule (PS), Shexiang baoxin pill (SXBX), Zhibitai (ZBT), and Dengzhan shengmai capsule (DZSM) were approved by the State Food and Drug Administration of China to treat symptoms of cerebrovascular disease, including dizziness, headache, stroke, aphasia, paralysis and fainting. In the treatment of CPA, TCPMs have the functions of tonifying qi, activating blood, resolving stasis, freeing the collateral vessels, resolving phlegm and resolving turbidity. According to Pharmacopoeia of the people’s Republic of China 2020, Table 1 presents the details of traditional effects of the included TCPMs. A vast number of randomized controlled trials have reported and published TCPMs for treating CAP [18, 19]. However, systematic evaluation of the clinical efficacy of TCPMs for CAP is still unknown, and the comparative effectiveness of different TCPMs is unclear. This study utilizes Bayesian network meta− analysis (NMA) to compare and rank different TCPMs to provide reference and evidence support for the clinical optimization of TCPM selection in CAP treatment.

Table 1 Ingredients and traditional effects of the included TCPMs
Full size table

Methods

Protocol and registration

This NMA was performed per the Preferred Reporting Items for Systematic Reviews and Meta− Analyses (PRISMA) Extension Statement [20]. This study’s protocol was registered in the international prospective register of systematic reviews (PROSPERO) (CRD42022366012).

Eligibility criteria

Study types

RCTs published in Chinese or English, regardless of blinding, publication status, were included.

Participant types

A patient was diagnosed with CAP, including hypertension, coronary atherosclerotic heart disease, and diabetes, using carotid ultrasound [21]. Age, gender, race, disease course, region, and nationality were unrestricted.

Intervention types

The experiment group was administrated TCPMs, regardless of dosage and treatment duration, combined with CWM per guidelines. Patients in the control group received CWM with or without a placebo (PBO) of TCPM or CWM plus another TCPM. Considering that patients with CAP were complicated with hyperlipidemia, hypertension, diabetes, coronary heart disease, cerebral infarction and other underlying diseases, the CWM was primarily used against antihypertensive, hypoglycemic, hypolipidemic, and anti− platelet aggregation.

Outcome types

The primary outcome was the change in indicators of carotid artery IMT at the end of treatment. The additional outcomes were the change in the carotid maximal plaque area, carotid atherosclerotic plaque Course score, serum levels of lipids, CRP, and adverse events rate (AER) at the end of treatment.

Exclusion criteria

Studies that met the following criteria were excluded: (1) animal experiments, reviews, meta− analyses, retrospective studies, or case reports; (2) research data with serious errors or no access to the full text after seeking help online or contacting the corresponding author via email; (3) repeated publication (the first published article was retained); (4) studies with incomparable baseline data between the two groups; (5) studies with a high or unclear risk of bias in sequence generation according to the Cochrane Collaboration’s risk of bias tool; (6) interventions that were combined with other Chinese herbal medicines or common TCM technology, such as acupuncture, moxibustion, and massage; (7) several cases less than 60.

Search strategy

We searched the following databases from their inception to August 2023. Chinese databases include CNKI, WanFang Data, VIP, and CBM, while English databases include PubMed, Embase, the Cochrane Library, and Web of Science. Additionally, other databases include clinical trial registries (WHO ICTRP, Clinical Trials, and ChiCTR) and Allied and Complementary Medicine Database (AMED). The literature search was constructed around search terms for “Chinese patent medicines”, “carotid atherosclerotic plaque”, and “randomized controlled trial” and adapted for each database as necessary. Additional file 1 provides a detailed and specific search strategy.

Literature screening and data extraction

We screened the retrieved articles during the searches and two authors independently conducted a comprehensively assessment of potentially eligible articles according to the inclusion/exclusion criteria. The following data were extracted: author, year of publication, place of conduct, baseline characteristics (sex, age), sample size, intervention(s), comparison(s), course of treatment, and outcome(s). Any disagreement was resolved by discussion until a consensus was reached or by consulting a third author.

Risk of bias assessment

All authors received advanced training and used the Cochrane Risk of Bias tool for quality assessment [22]. Each article was assessed independently by two authors. In case of disagreement between the two authors, a discussion was conducted or a third author was asked for advice. Seven items were used to assess biases covering six different domains for each included study. The bias domains and items were selection bias (random sequence generation and allocation concealment), performance bias (blinding of participants and personnel), detection bias (blinding of outcome assessment), attrition bias (incomplete outcome data), reporting bias (selective reporting), and other biases (other sources of bias). Each domain was assigned a risk of bias judgment within the included study using the labels 'low risk' of bias, 'high risk' of bias, or 'unclear' risk of bias.

Statistical analysis

We conducted a head− to− head comparisons pairwise meta− analyses between CWM combined with TCPM and CWM using Review Manager 5.3. We conducted an NMA analysis using Stata17.0 software and the GeMTC package of R software, applying the Markov Chain Monte Carlo algorithm and a Bayesian hierarchical random− effects model [23]. The results were presented as odds ratios (ORs) with 95% confidence intervals (CIs) for dichotomous variables, and the standardized mean differences (SMDs) with 95% CIs for continuous variables. If the range of 95% CIs of ORs did not cross 1 and 95% CIs of SMDs did not cross 0, then the differences between the groups would be considered statistically significant. The model was used four chains and 50,000 iterations, with the initial 20,000 iterations discarded as the starting point for annealing to eliminate the influence of initial value [24]. Using the surface under the cumulative ranking curve (SUCRA), we sorted the probabilities of different interventions of each outcome [25]. We used the node− splitting analysis to separate mixed evidence into direct and indirect evidence, to evaluate the consistency of the model. We also conducted the multi− dimensional efficacy analysis integrate multiple outcomes, and obtain the optimal intervention. Furthermore, we used a comparison− adjusted funnel plot to detect the publication bias of included RCTs [26]. The interventions were stratified according to the certainty of evidence supporting their relative efficacy which was graded using the GRADE NMA rating system.

Results

Literature screening

Initially, the search strategy yielded 2,159 articles. Duplication resulted in the removal of 1,308 articles. The remaining 851 articles were filtered further and excluded according to the eligibility and exclusion criteria. After rereading the full texts, 27 studies remained for quantitative synthesis [27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53]. Figure 1 presents the details of the literature screening process.

Fig. 1
figure 1

Flowchart of the literature screening process

Full size image

Study characteristics

There were 25 Chinese articles and two English articles involving 11 interventions. All the articles were conducted in China. Overall, 4,131 patients (2,069 in the experimental control group and 2,062 in the control groups). Nine kinds of CPMs were enrolled: Tongxinluo capsule (TXL), Xiaoshuang granules/enteric capsule (XS), Naoxintong capsule (NXT), Xuesaitong capsule/soft capsule (XST), Jiangzhiling pill (JZL), Pushen capsule (PS), Shexiang baoxin pill (SXBX), Zhibitai (ZBT), and Dengzhan shengmai capsule (DZSM). Table 1 presents the details of ingredients of the included TCPMs. Plant names have been checked with www.theplantlist.org.

Most articles were open− label trials except for two double− blind trials. Both groups were based on CWM, with TCPM addition in the treatment group and PBO addition or blank to the control group, including CWM + TXL vs. CWM + PBO (n = 1), CWM + TXL vs. CWM (n = 6), CWM + XS vs. CWM (n = 2), CWM + NXT vs. CWM (n = 3), CWM + XST vs. CWM (n = 2), CWM + JZL vs. CWM (n = 2), CWM + PS vs. CWM (n = 3), CWM + SXBX vs. CWM (n = 3), CWM + ZBT vs. CWM (n = 3), and CWM + DZSM vs. CWM (n = 2). There were no significant differences in gender and age between the study groups with comparable baselines, and most were middle− aged or elderly. Table 2 presents the details of the included study characteristics.

Table 2 Characteristics of the studies included in this network meta− analysis
Full size table

Risk of bias assessment

All the included trials reported ‘randomly allocating’ participants, generating random sequences using random number tables or computer− based or lottery methods, so they were evaluated as "low risk." Two trials reported allocation concealment, evaluated as "low risk," and the other studies did not mention allocation concealment and were evaluated as "uncertain risk." One trial reported double− blind trials were evaluated as "low risk," and the other studies did not mention blinding was evaluated as "high risk" or "uncertain risk". All trials had complete data, no selective reporting or other risk bias, and were all evaluated as "low risk." Fig. 2A depicts the risk bias assessment results. Figure 2B provides the detailed and specific risk of bias assessment.

Fig. 2
figure 2

Risk of bias graph of the included RCT A: the risk of bias graph; B: the risk of bias summary

Full size image

Outcomes

Pairwise meta-analysis

We conducted eight pairwise meta− analyses comparing the effects of CWM and CWM combined with TCPM on improving the IMT, the carotid maximal plaque area, the carotid atherosclerotic plaque Course score, blood lipids, and CRP (Fig. 3). We assessed the certainty of the evidence for each outcome under the GRADE framework. The quality of the evidence for all of these comparisons was rated as low. The detailed GRADE assessment was presented in Table 3.

Fig. 3
figure 3figure 3figure 3figure 3

Forest plot of Pairwise meta-analysis. A: IMT; B: carotid maximal plaque area; C: carotid atherosclerotic plaque course score; D: TC; E: TG; F: LDL; G: HDL; H: CRP; IMT carotid artery intimal- medial thickness, TC total cholesterol, TG Triglyceride, LDL low density lipoprotein, HDL high density lipoprotein, CRP C− reactive protein, AER adverse events rate

Full size image
Table 3 GRADE assessment
Full size table

Compared to CWM, CWM combined with TCPM had a stronger effect in reducing the IMT [26 RCTs; SMD − 1.26 (95% CI − 1.59, − 0.93); p < 0.00001; I2 = 94%; low− quality of evidence] (Fig. 3A), decreasing the carotid maximal plaque area [15 RCTs; SMD − 1.27 (95% CI − 1.71, − 0.82); p < 0.00001; I2 = 94%; low− quality of evidence] (Fig. 3B), lowering the carotid atherosclerotic plaque Course score [8 RCTs; SMD − 0.72 (95% CI − 1.20, − 0.25); p < 0.00001; I2 = 91%; low− quality of evidence] (Fig. 3C), lowering the TC [20 RCTs; SMD − 1.26 (95% CI − 1.66, − 0.86); p < 0.00001; I2 = 95%; low− quality of evidence] (Fig. 3D), lowering the TG [20 RCTs; SMD 1.17 (95% CI − 1.53, − 0.81); p < 0.00001; I2 = 94%; low− quality of evidence] (Fig. 3E), lowering the LDL [20 RCTs; SMD − 1.20 (95% CI − 1.55, − 0.85); p < 0.00001; I2 = 93%; low− quality of evidence] (Fig. 3F), raising the HDL [18 RCTs; SMD 0.80 (95% CI 0.38, 1.22); p < 0.00001; I2 = 95%; low− quality of evidence] (Fig. 3G), and lowering the CRP [10 RCTs; SMD − 0.87 (95% CI − 1.11, − 0.64); p = 0.002; I2 = 66%; low− quality of evidence] (Fig. 3H). Substantial heterogeneity was observed in all results.

We conducted sensitivity analysis comparing pooled results from “ < 6 months of course” and “ ≥ 6 months of course” is illustrated in Fig. 3. There was no significant subgroup difference between the two groups, implying that the difference in length of course did not influence the pooled results on improving the IMT, the carotid maximal plaque area, the carotid atherosclerotic plaque Course score, blood lipids, and CRP.

Network meta− analysis

IMT

A total of 27 RCTs referred to the IMT of nine types of TCPMs and 11 types of interventions, including CWM + TXL vs. CWM + PBO (n = 1), CWM + TXL vs. CWM (n = 6), CWM + XS vs. CWM (n = 2), CWM + NXT vs. CWM (n = 3), CWM + XST vs. CWM (n = 2), CWM + JZL vs. CWM (n = 2), CWM + PS vs. CWM (n = 3), CWM + SXBX vs. CWM (n = 3), CWM + ZBT vs. CWM (n = 3), and CWM + DZSM vs. CWM (n = 2) (Table 2). Figure 4A presents the network evidence plot.

Fig. 4
figure 4

Network diagrams for different outcomes. A: IMT; B: carotid maximal plaque area; C: carotid atherosclerotic plaque course score; D: TC; E: TG; F: LDL; G: HDL; H: CRP; I: AER; CWM conventional western medicine, PBO placebo, TXL Tongxinluo capsule, XS Xiaoshuang granules/enteric capsule, NXT Naoxintong capsule, XST Xuesaitong capsule/soft capsule, JZL Jiangzhiling pill, PS Pushen capsule, SXBX Shexiang baoxin pill, ZBT Zhibitai, DZSM Dengzhan shengmai capsule, IMT carotid artery intimal- medial thickness, TC total cholesterol, TG Triglyceride, LDL low density lipoprotein, HDL high density lipoprotein, CRP C-reactive protein, AER adverse events rate. The width of the lines represents the proportion of the number of trials for each comparison with the total number of trials, and the size of the nodes represents the proportion of the number of randomized patients (sample sizes)

Full size image

Compared to CWM, except for CWM + NXT [MD − 0.18 (95% CI − 0.39, 0.03)], CWM + XST [MD − 0.18 (95% CI − 0.43, 0.08)], CWM + PS [MD − 0.17 (95% CI: − 0.39, 0.04)] and CWM + DZSM [MD − 0.09 (95% CI − 0.34, 0.17)], other five TCPMs demonstrated a statistically significant effect in reducing the IMT. Accordingly, other interventions had no statistically significant difference. The details were shown in Table 4.

Table 4 Pairwise league table of IMT (lower− left quadrant) and carotid maximal plaque area (upper− right quadrant)
Full size table

According to the SUCRA probability results (Fig. 5A), CWM + JZL was likely the best intervention for reducing the IMT. Table 5 illustrates the detailed SUCRA and ranking probability. The interventions were ranked as follows: CWM + JZL (70.6%) > CWM + SXBX (70.5%) > CWM + XS (68.6%) > CWM + TXL (57.8%) > CWM + ZBT (56.5%) > CWM + PBO (51.7%) > CWM + XST (48.0%) > CWM + NXT (46.8%) > CWM + PS (46.8%) > CWM + DZSM (27.2%) >  > CWM (5.4%).

Fig. 5
figure 5

Surface under the cumulative ranking curve (SUCRA) plots for different outcomes. The vertical axis represents cumulative probabilities and the horizontal axis represents rank. A: IMT; B: carotid maximal plaque area; C: carotid atherosclerotic plaque course score; D: TC; E: TG; F: LDL; G: HDL; H: CRP; I: AER; CWM conventional western medicine, PBO placebo; TXL Tongxinluo capsule, XS Xiaoshuang granules/enteric capsule, NXT Naoxintong capsule, XST Xuesaitong capsule/soft capsule, JZL Jiangzhiling pill, PS Pushen capsule, SXBX Shexiang baoxin pill, ZBT Zhibitai, DZSM Dengzhan shengmai capsule, IMT carotid artery intimal-medial thickness, TC total cholesterol, TG Triglyceride, LDL low density lipoprotein, HDL high density lipoprotein, CRP C− reactive protein

Full size image
Table 5 Pairwise league table of TC (lower− left quadrant) and carotid atherosclerotic plaque course score (upper− right quadrant)
Full size table

Carotid maximal plaque area

A total of 16 RCTs referred to the carotid maximal plaque area of eight types of TCPMs and 10 types of interventions, including CWM + TXL vs. CWM + PBO (n = 1), CWM + TXL vs. CWM (n = 4), CWM + NXT vs. CWM (n = 1), CWM + XST vs. CWM (n = 1), CWM + JZL vs. CWM (n = 2), CWM + PS vs. CWM (n = 2), CWM + SXBX vs. CWM (n = 2), CWM + ZBT vs. CWM (n = 2), and CWM + DZSM vs. CWM (n = 1) (Table 2). Figure 4B presents the network evidence plot. All interventions had no statistically significant difference. The details were shown in Table 4.

According to the SUCRA probability results (Fig. 5B), CWM + SXBX was the most likely the best intervention for reducing the carotid maximal plaque area. Table 8 presents the detailed SUCRA and ranking probability. The ranking of interventions was as follows: CWM + SXBX (83.0%) > CWM + JZL (82.7%) > CWM + XST (53.1%) > CWM + ZBT (52.0%) > CWM + TXL (48.4%) > CWM + NXT (45.3%) > CWM + DZSM (44.7%) > CWM + PS (35.0%) > CWM + PBO (31.1%) > CWM (24.8%).

Carotid atherosclerotic plaque course score

Eight RCTs referred to the carotid atherosclerotic plaque Course score of six types of TCPMs and seven types of interventions, including CWM + TXL vs. CWM (n = 2), CWM + XST vs. CWM (n = 1), CWM + PS vs. CWM (n = 1), CWM + SXBX vs. CWM (n = 1), CWM + ZBT vs. CWM (n = 2), and CWM + DZSM vs. CWM (n = 1). (Table 2). Figure 4C presents the network evidence plot. All interventions had no statistically significant differences. The details were shown in Table 5.

According to the SUCRA probability results (Fig. 5C), CWM + XSBX was the most likely the best intervention for lowering the carotid atherosclerotic plaque Course score. Table 8 depicts the detailed SUCRA and ranking probability. The interventions were ranked as follows: CWM + SXBX (92.5%) > CWM + TXL (85.9%) > CWM + ZBT (61.0%) > CWM + PS (55.0%) > CWM (23.2%) > CWM + XST (22.7%) > CWM + DZSM (9.7%).

TC

A total of 21 RCTs referred to the TC of nine types of TCPMs and 11 types of interventions, including CWM + TXL vs. CWM + PBO (n = 1), CWM + TXL vs. CWM (n = 4), CWM + XS vs. CWM (n = 1), CWM + NXT vs. CWM (n = 1), CWM + XST vs. CWM (n = 1), CWM + JZL vs. CWM (n = 2), CWM + PS vs. CWM (n = 3), CWM + SXBX vs. CWM (n = 3), CWM + ZBT vs. CWM (n = 3), and CWM + DZSM vs. CWM (n = 2). (Table 2). Figure 4D presents the network evidence plot.

CWM + TXL [MD − 0.58 (95% CI − 1.14, − 0.03)], CWM + SXBX [MD − 1.33 (95% CI − 1.95, − 0.70)], and CWM + ZBT [MD − 0.69 (95% CI − 1.32, − 0.07)] had a statistically significant effect on lowering TC compared to CWM. CWM + SXBX [MD − 1.30 (95% CI − 2.57, − 0.03)] had a statistically significant effect on lowering TC compared to CWM + XST. Accordingly, other interventions had no statistically significant differences. The details were shown in Table 5.

According to the SUCRA probability results (Fig. 5D), CWM + XSBX was the most likely the best intervention for lowering TC. Table 8 indicates the detailed SUCRA and ranking probability. The 11 types of interventions were ranked as follows: CWM + SXBX (95.6%) > CWM + XS (73.6%) > CWM + ZBT (63.8%) > CWM + JZL (57.1%) > CWM + TXL (57.0%) > CWM + PS (56.3%) > CWM + PBO (46.9%) > CWM + NXT (37.9%) > CWM + DZSM (24.6%) > CWM + XST (23.2%) > CWM (14.0%).

TG

A total of 21 RCTs referred to the TG of nine types of TCPMs and 11 types of interventions, including CWM + TXL vs. CWM + PBO (n = 1), CWM + TXL vs. CWM (n = 4), CWM + XS vs. CWM (n = 1), CWM + NXT vs. CWM (n = 1), CWM + XST vs. CWM (n = 1), CWM + JZL vs. CWM (n = 2), CWM + PS vs. CWM (n = 3), CWM + SXBX vs. CWM (n = 3), CWM + ZBT vs. CWM (n = 3), and CWM + DZSM vs. CWM (n = 2) (Table 2). Figure 4E presents the network evidence plot.

CWM + NXT [MD − 0.76 (95% CI − 1.35, − 0.17)], CWM + JZL [MD − 0.52 (95% CI − 0.94, − 0.10)] and CWM + SXBX [MD − 0.59 (95% CI − 0.95, − 0.23)] had a statistically significant effect on lowering TG compared to CWM. Consequently, other interventions had no statistically significant differences. The details were shown in Table 6.

Table 6 Pairwise league table of LDL (lower− left quadrant) and TG (upper− right quadrant)
Full size table

According to the SUCRA probability results (Fig. 5E), CWM + NXT was the most likely the best intervention for lowering the TG. Table 8 presents the detailed SUCRA and ranking probability. The interventions were ranked as follows: CWM + NXT (90.1%) > CWM + SXBX (81.1%) > CWM + JZL (72.7%) > CWM + XS (66.1%) > CWM + PS (52.5%) > CWM + TXL (47.0%) > CWM + PBO (44.7%) > CWM + ZBT (41.6%) > CWM + DZSM (22.2%) > CWM + XST (21.9%) > CWM (10.0%).

LDL

A total of 21 RCTs referred to the LDL of nine types of TCPMs and 11 types of interventions, including CWM + TXL vs. CWM + PBO (n = 1), CWM + TXL vs. CWM (n = 4), CWM + XS vs. CWM (n = 1), CWM + NXT vs. CWM (n = 1), CWM + XST vs. CWM (n = 1), CWM + JZL vs. CWM (n = 2), CWM + PS vs. CWM (n = 3), CWM + SXBX vs. CWM (n = 3), CWM + ZBT vs. CWM (n = 3), and CWM + DZSM vs. CWM (n = 2). (Table 2). Figure 4F presents the network evidence plot.

CWM + TXL [MD − 0.43 (95% CI − 0.84, − 0.02)], CWM + JZL [MD − 0.63 (95% CI − 1.22, − 0.05)], CWM + SXBX [MD − 0.96 (95% CI − 1.44, − 0.48)], and CWM + ZBT [MD − 0.56 (95% CI − 1.04, − 0.09)] has a statistically significant effect on lowering LDL compared to CWM. CWM + SXBX [MD − 0.86 (95% CI − 1.60, − 0.11)] had a statistically significant effect on lowering LDL compared to CWM + DZSM. Therefore, other interventions had no statistically significant difference. The details were shown in Table 6.

According to the SUCRA probability results (Fig. 5F), CWM + SXBX was the most likely the best intervention for lowering the LDL. Table 8 depicts the detailed SUCRA and ranking probability. The interventions were ranked as follows: CWM + SXBX (92.6%) > CWM + XS (76.9%) > CWM + JZL (69.9%) > CWM + ZBT (64.4%) > CWM + TXL (53.5%) > CWM + PS (49.1%) > CWM + PBO (47.0%) > CWM + NXT (35.9%) > CWM + XST (24.9%) > CWM + DZSM (23.5%) > CWM (12.3%).

HDL

A total of 19 RCTs referred to the HDL of eight types of TCPMs and 10 types of interventions, including CWM + TXL vs. CWM + PBO (n = 1), CWM + TXL vs. CWM (n = 4), CWM + XS vs. CWM (n = 1), CWM + NXT vs. CWM (n = 1), CWM + JZL vs. CWM (n = 2), CWM + PS vs. CWM (n = 3), CWM + SXBX vs. CWM (n = 2), CWM + ZBT vs. CWM (n = 3), and CWM + DZSM vs. CWM (n = 2). (Table 2). Figure 4G presents the network evidence plot.

CWM + TXL [MD 0.34 (95% CI: 0.05, 0.64)] had a statistically significant effect on raising HDL compared to CWM. Thus, no statistically significant difference existed between the other interventions. The details were shown in Table 7.

Table 7 Pairwise league table of HDL (lower-left quadrant) and CRP (upper-right quadrant)
Full size table

According to the SUCRA probability results (Fig. 5G), CWM + XS was the most likely the best intervention for improving HDL. Table 8 illustrates the detailed SUCRA and ranking probability. The interventions were ranked as follows: CWM + XS (86.1%) > CWM + JZL (72.9%) > CWM + TXL (72.9%) > CWM + PBO (62.4%) > CWM + PS (45.6%) > CWM + NXT (45.2%) > CWM + DZSM (43.1%) > CWM + ZBT (28.6%) > CWM + SXBX (26.8%) > CWM (16.4%).

Table 8 Surface under the cumulative ranking curve and ranking probability of different Chinese patent medicines on each outcome
Full size table

CRP

A total of 11 RCTs referred to the CRP of five types of TCPMs and seven types of interventions, including CWM + TXL vs. CWM + PBO (n = 1), CWM + TXL vs. CWM (n = 5), CWM + NXT vs. CWM (n = 2), CWM + PS vs. CWM (n = 2), CWM + SXBX vs. CWM (n = 1), and CWM + ZBT vs. CWM (n = 1). (Table 2). Figure 4H presents the network evidence plot. All interventions had no statistically significant difference. The details were shown in Table 7.

According to the SUCRA probability results (Fig. 5H), CWM + ZBT was the most likely the best intervention for lowering the CRP. Table 8 presents the detailed SUCRA and ranking probability. The interventions were ranked as follows: CWM + ZBT (71.3%) > CWM + PS (67.0%) > CWM + NXT (64.9%) > CWM + TXL (52.3%) > CWM + SXBX (45.7%) > CWM + PBO (42.8%) > CWM (6.0%).

Safety

A total of 18 RCTs reported the number of the AER of eight types of TCPMs and 10 types of interventions, including CWM + TXL vs. CWM + PBO (n = 1), CWM + TXL vs. CWM (n = 5), CWM + XS vs. CWM (n = 1), CWM + XST vs. CWM (n = 1), CWM + JZL vs. CWM (n = 2), CWM + PS vs. CWM (n = 2), CWM + SXBX vs. CWM (n = 2), CWM + ZBT vs. CWM (n = 2), and CWM + DZSM vs. CWM (n = 2) (Table 2). Figure 4I presents the network evidence plot.

Four studies reported no adverse reactions in the experimental and control groups, while the remaining 14 studies reported 204 cases of adverse reactions. Adverse events included gastrointestinal reactions, such as nausea, discomfort, indigestion, abdominal distension, pain, and diarrhea. Autonomic nervous dysfunction symptoms had dizziness, headache, rash, myalgia, mild hepatic or renal insufficiency, bleeding, and delayed PT. However, most resolved spontaneously without special treatment. The detailed list of adverse reactions was shown in Table 9.

Table 9 Occurrence of adverse reactions
Full size table

Inconsistency test

No closed loops were found in the NMA due to the lack of direct comparison of TCPMs. The inconsistency test could not be carried out. Hence, the results were analyzed using a consistency model.

Publication bias

IMT is the leading indicator for publishing the results of the evaluation applications. The comparison− adjusted funnel plots were plotted to test the publication bias of IMT. When the points in the funnel chart are symmetrical based on the position of the centerline, presenting that there is no publication bias. Figure 6 depicts that the points in the funnel chart are asymmetrical along the center line, indicating the potential presence of publication bias favoring CWM + TCPMs in reducing IMT, as compared to CWM and CWM + PBO.

Fig. 6
figure 6

Funnel plot of IMT. CWM conventional western medicine, PBO placebo, TXL Tongxinluo capsule, XS Xiaoshuang granules/enteric capsule, NXT Naoxintong capsule, XST Xuesaitong capsule/soft capsule, JZL Jiangzhiling pill, PS Pushen capsule, SXBX Shexiang baoxin pill, ZBT Zhibitai, Dengzhan shengmai capsule

Full size image

Discussion

OMT, a pharmacotherapy regimen based on statins, is an important non− invasive treatment for CAP. The clinical efficacy of OMT can be improved by adding complementary and alternative medicines [54]. In our study, this NMA was based on 27 RCT trials with 4131 patients with CAP. We compared the efficacy and safety of nine kinds of TCPMs, including JZL, SXBX, TXL, ZBT, XS, XST, NXT, PS, and DZSM, combined with CWM with or without placebo of TCPM for improving IMT, carotid maximal plaque area, carotid atherosclerotic plaque Course score, serum lipid levels, and CRP. Pairwise meta− analyses demonstrated that CWM + TCPM was superior to CWM in the treatment of CAP. This study revealed that CWM + JZL was the most likely the best intervention for reducing IMT, and CWM + SXBX exhibited the highest effective intervention for reducing carotid maximal plaque area, and atherosclerotic plaque Course score. Lipids and inflammatory factors contribute to an increase in CAP volume and vulnerability [55]. The guideline has recommended that LDL− C and CRP are independent risk factors for atherosclerosis and play important roles in the primary and secondary prevention of atherosclerosis [56]. Our study suggested that CWM + XSBX was superior to other TCPMs in decreasing the TC and LDL levels. CWM + NXT and CWM + XS were superior to other TCPMs in reducing TG and increasing HDL, respectively. ​CWM + ZBT was the most likely the best intervention for lowering the CRP. Together, these results implied that CWM + TCPM may be a more effective intervention for patients with CAP than using CWM alone. Of the TCPMs included, SXBX was among the most effective in reducing carotid maxima, atherosclerotic plaque score, TC and LDL levels, and had a more comprehensive advantage. However, the efficacy of XSBX also needs to be evaluated through high− quality, large, double− blind, randomized controlled trials. XSBX still needs to be used with caution. No serious adverse events were reported in the CWM + TCPM and CWM groups. However, adverse events were poorly reported (18/27) in the included studies, and the safety of TCPMs needs further investigation.

Numerous pharmacological studies have also found that TCPMs could improve CAP through multiple targets and signaling pathways. JZL, which traditionally removes dampness and dissolves phlegm, was the best intervention for reducing IMT in this study. Crataegus pinnatifida Bunge, the essential herb of JZL, has anti− atherosclerotic effects by lowering blood lipids, inhibiting oxidative and inflammation, and protecting vascular endothelium [57]. According to TCM theory, XSBX has the traditional functions of resuscitation with aromatics, modifying Qi, and activating circulation. XSBX was the optimal drug for reducing the carotid maximal plaque area compared to the other eight CPMs. A pharmacological study also demonstrated that XSBX could markedly decrease atherosclerotic plaque size by inhibiting the arterial wall's inflammation response and lipid accumulation [58]. XSBX reduced the inflammation pathways by increasing Mfn2 and decreasing the phosphorylation of p38, JNK, and NF− κB levels. XSBX inhibited lipid influx by reducing SR− A and LOX− 1 and increased lipid efflux by promoting LXRα, ABCA1, and ABCG1. Additionally, XSBX could activate macrophages to improve endothelial cell proliferation, migration, and tubule formation and regulate PI3K/Akt and MAPK/Erk1/2 signaling pathways, thereby promoting angiogenesis [59]. Plaque thickness is the principal predictor of carotid stenosis risk. TXL, which traditionally promotes circulation to remove meridional obstructions, was optimal for treating carotid atherosclerotic plaque Course score in nine TCPMs. A study discovered that TXL could inhibit arterial intimal proliferation by reducing the LOX− 1 and improving blood lipids [60]. Moreover, several studies have exposed that TXL could improve plaque stability by inhibiting ROS expression and increasing the relative abundance of Alistipes in the gut microbiome [61].

This NMA study had several strengths. First, this study was the first to evaluate the comparative efficacy and safety of TCPMs for CAP and to guide optimal medication in a clinical setting. Second, this study set strict inclusion criteria and excluded RCTs with incorrect randomization methods, ensuring methodological quality. Finally, the ranking of TCPMs contributed to the formulation of clinical medication plans.

However, this study still has some limitations. First, the overall quality of the studies included was limited because most studies did not report the allocation concealment and blinding in detail. Additionally, clinical heterogeneity may have occurred due to the diversity of CWM and the various TCPMs dosage and duration, and these results should be interpreted with caution. Finally, assuming that the studies included were mainly conducted among Chinese populations, the external adaptability of the results would be restricted when applied for reference in populations of different countries and regions.

Conclusions

This study aims to evaluate the efficacy of TCPMs in treating CAP based on the characteristics of carotid plaque, blood lipids, inflammatory markers, and adverse reactions to guide the clinical medication of CAP more accurately. CWM + JZL was the most effective in reducing IMT. CWM + SXBX was the most effective in reducing carotid maximal plaque area, and atherosclerotic plaque Course score. CWM + XSBX also significantly reduced TC and LDL levels and outperformed other CPMs. CWM + XSBX may be considered an effective intervention for the treatment of CAP. However, further direct comparisons are warranted. This study provides a more accurate selection of TCPMs in CAP therapy, which may help improve drug regimens of OMT by supplementing complementary and alternative drugs. More adequately powered, well− designed clinical trials to increase the quality of the available evidence are still needed in the future due to several limitations.

Availability of data and materials

All data supporting this systematic review and meta− analysis are from previously reported studies and datasets, which have been cited.

Abbreviations

AER:

Adverse events rate

CAP:

Carotid atherosclerotic plaque

CAS:

Carotid stent placement

CEA:

Carotid endarterectomy

CRP:

C− reactive protein

CWM:

Conventional western medicine

DZSM:

Dengzhan shengmai capsule

HDL:

High density lipoprotein

IMT:

Carotid artery intimal-medial thickness

JZL:

Jiangzhiling pill

LDL:

Low density lipoprotein

NMA:

Network meta-analysis

NXT:

Naoxintong capsule

OMT:

Optimal drug therapy

PBO:

Placebo

PS:

Pushen capsule

RCTs:

Randomized controlled trials

SUCRA:

Surface under the cumulative ranking

SXBX:

Shexiang baoxin pill

TC:

Total cholesterol

TCM:

Traditional Chinese medicine

TCPMs:

Traditional Chinese patent medicine

TG:

Triglyceride

TXL:

Tongxinluo capsule

XS:

Xiaoshuang granules/enteric capsule

XST:

Xuesaitong capsule/soft capsule

ZBT:

Zhibitai

References

  1. Song P, Fang Z, Wang H, Cai Y, Rahimi K, Zhu Y, Fowkes FGR, Fowkes FJI, Rudan I. Global and regional prevalence, burden, and risk factors for carotid atherosclerosis: a systematic review, meta− analysis, and modelling study. Lancet Glob Health. 2020;8(5):e721–9.

    Article  PubMed  Google Scholar 

  2. Song P, Xia W, Zhu Y, Wang M, Chang X, Jin S, Wang J, An L. Prevalence of carotid atherosclerosis and carotid plaque in Chinese adults: a systematic review and meta− regression analysis. Atherosclerosis. 2018;276:67–73.

    Article  CAS  PubMed  Google Scholar 

  3. Grubic N, Colledanchise KN, Liblik K, Johri AM. The role of carotid and femoral plaque burden in the diagnosis of coronary artery disease. Curr Cardiol Rep. 2020;22(10):121.

    Article  PubMed  Google Scholar 

  4. Li Z, Jiang Y, Li H, Xian Y, Wang Y. China’s response to the rising stroke burden. BMJ. 2019;364: l879.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Ran Y, Wang Y, Zhu M, Wu X, Malhotra A, Lei X, Zhang F, Wang X, Xie S, Zhou J, et al. Higher plaque burden of middle cerebral artery is associated with recurrent ischemic stroke: a quantitative magnetic resonance imaging study. Stroke. 2020;51(2):659–62.

    Article  PubMed  Google Scholar 

  6. Bytyci I, Shenouda R, Wester P, Henein MY. Carotid atherosclerosis in predicting coronary artery disease: a systematic review and meta− analysis. Arterioscler Thromb Vasc Biol. 2021;41(4):e224–37.

    Article  CAS  PubMed  Google Scholar 

  7. Ibanez B, Vilahur G, Badimon JJ. Plaque progression and regression in atherothrombosis. J Thromb Haemost. 2007;5(Suppl 1):292–9.

    Article  CAS  PubMed  Google Scholar 

  8. Kassaian SE, Goodarzynejad H. Carotid artery stenting, endarterectomy, or medical treatment alone: the debate is not over. J Tehran Heart Cent. 2011;6(1):1–13.

    PubMed  PubMed Central  Google Scholar 

  9. Eckstein HH, Kühnl A, Kallmayer M. Important recommendations of the German− Austrian S3 guidelines on management of extracranial carotid artery stenosis. Chirurg. 2022;93(5):476–84.

    Article  PubMed  Google Scholar 

  10. Zhu Z, Yu W. Update in the treatment of extracranial atherosclerotic disease for stroke prevention. Stroke Vasc Neurol. 2019;5(1):65–70.

    PubMed  PubMed Central  Google Scholar 

  11. Ainsworth CD, Blake CC, Tamayo A, Beletsky V, Fenster A, Spence JD. 3D ultrasound measurement of change in carotid plaque volume: a tool for rapid evaluation of new therapies. Stroke. 2005;36(9):1904–9.

    Article  PubMed  Google Scholar 

  12. Liao YH, Cheng X, Huang K, Zhang Y, Zhang C, Yang YJ, Li JJ, Tang YD, Ge JB, Qian JY. Expert consensus on statin− induced plaque regression in patients with atherosclerotic cardiovascular disease. J Clin Cardiol. 2015;31(01):1–5.

    Google Scholar 

  13. Noyes AM, Thompson PD. A systematic review of the time course of atherosclerotic plaque regression. Atherosclerosis. 2014;234(1):75–84.

    Article  CAS  PubMed  Google Scholar 

  14. Zhai J, Song Z, Wang Y, Han M, Ren Z, Han N, Liu Z, Yin J. Zhixiong Capsule (ZXC), a traditional Chinese patent medicine, prevents atherosclerotic plaque formation in rabbit carotid artery and the related mechanism investigation based on network pharmacology and biological research. Phytomedicine. 2019;59: 152776.

    Article  PubMed  Google Scholar 

  15. Hu N, Zhang W, Yu R, Fu YF. Clinical efficacy of traditional chinese medicine in treatment of carotid atherosclerotic plaques: a meta− analysis. Chin Arch Tradit Chin Med. 2018;36(09):2089–93.

    CAS  Google Scholar 

  16. Ma L, Dai J, Chen J, Cai HW, Li JY, Li XY, Chen SJ, Mao W. Research progress of angiogenesis in atherosclerotic plaque in chinese medicine and western medicine. Chin J Integr Med. 2018;24(12):950–5.

    Article  PubMed  Google Scholar 

  17. Committee CP. Expert consensus on prevention and treatment of atherosclerosis by integrative medicine (2021). Chin J Inte Tradit West Med. 2022;42(3):287–93.

    Google Scholar 

  18. Liang Q, Cai Y, Chen R, Chen W, Chen L, Xiao Y. The effect of naoxintong capsule in the treatment of patients with cerebral infarction and carotid atherosclerosis: a systematic review and meta− analysis of randomized trials. Evid Based Complement Alternat Med. 2018;2018:5892306.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Zhang Z, Leng Y, Chen Z, Fu X, Liang Q, Peng X, Xie H, Gao H, Xie C. The efficacy and safety of Chinese herbal medicine as an add− on therapy for type 2 diabetes mellitus patients with carotid atherosclerosis: an updated meta− analysis of 27 randomized controlled trials. Front Pharmacol. 2023;14:1091718.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Hutton B, Salanti G, Caldwell DM, Chaimani A, Schmid CH, Cameron C, Ioannidis JP, Straus S, Thorlund K, Jansen JP, et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta− analyses of health care interventions: checklist and explanations. Ann Intern Med. 2015;162(11):777–84.

    Article  PubMed  Google Scholar 

  21. Johri AM, Nambi V, Naqvi TZ, Feinstein SB, Kim ESH, Park MM, Becher H, Sillesen H. Recommendations for the assessment of carotid arterial plaque by ultrasound for the characterization of atherosclerosis and evaluation of cardiovascular risk: from the american society of echocardiography. J Am Soc Echocardiogr. 2020;33(8):917–33.

    Article  PubMed  Google Scholar 

  22. Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343: d5928.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Bodnar O, Link A, Arendacka B, Possolo A, Elster C. Bayesian estimation in random effects meta− analysis using a non− informative prior. Stat Med. 2017;36(2):378–99.

    Article  PubMed  Google Scholar 

  24. Crainiceanu CM, Goldsmith AJ. Bayesian functional data analysis using WinBUGS. J Stat Softw. 2010;32(11): i11.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Salanti G, Ades AE, Ioannidis JP. Graphical methods and numerical summaries for presenting results from multiple− treatment meta− analysis: an overview and tutorial. J Clin Epidemiol. 2011;64(2):163–71.

    Article  PubMed  Google Scholar 

  26. Chaimani A, Higgins JP, Mavridis D, Spyridonos P, Salanti G. Graphical tools for network meta− analysis in STATA. PLoS ONE. 2013;8(10): e76654.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wang HF, Zhao YX, Zheng JH, Yong X, Chen JQ, Yin HS, Zhu YB, Chen K. Treatment of senile atherosclerosis with Pushen capsule combined with atorvastatin calcium. J Pract Med. 2019;35(05):809–13.

    Google Scholar 

  28. Wang SY, Li YQ. Effect of Tongxinluo capsule combined with Probucol on ischemic stroke with carotid plague and serum ox− LDL, MMP− 7, IL− 18, carotid intima− media thickness in the patients. Modern J Inte Tradit Chin Western Med. 2016;25(34):3795–7.

    Google Scholar 

  29. Huang P, He XY. Clinical trial of Dengzhan Shengmai capsule in the treatment of patients with acute cerebral infarction. Chin J Clin Pharmacol. 2018;34(05):504–6.

    Google Scholar 

  30. Huang ZJ, He SA, Lei B. Effects of Tongxinluo capsules combined with rosuvastatin calcium on carotid atherosclerosis plaque. China Pharmacy. 2014;25(32):3024–6.

    CAS  Google Scholar 

  31. Chen YJ, Zhang P, Luo Y, Liu GX, Jiang FS, Peng Z. Effect of naoxintong capsule on carotid atherosclerotic plaque and CRP and Hcy in patients with cerebral infarction. Liaoning J Tradit Chin Med. 2017;44(09):1920–1.

    CAS  Google Scholar 

  32. Ji YY, Li G, Li YD, Liu ZY, Zheng XS. Effect of Shexiang Baoxin Pills on atherosclerotic plaque and inflammatory factors of carotid artery in patients with coronary heart disease. Chin J Gerontol. 2015;35(21):6077–9.

    CAS  Google Scholar 

  33. Jia LW, Du YY. Therapeutic effect of Shexiang Baoxin Pills on carotid atherosclerosis. Chin Trad Patent Med. 2004;26(S1):38–41.

    Google Scholar 

  34. Jiang XP, Zeng FP, Liu SM, Lin XY, Feng SL, Shen ZH. Effect of Xuesaitong soft capsules on related indices in patients with hyperlipidemic atherosclerosis. Hunan J Tradit Chin Med. 2021;37(03):11–3.

    Google Scholar 

  35. Zhu D, Zhu LH. Efficacy of TXL combined with atorvastatin in the treatment of H− hypertension carotid atherosclerosis and its influence on plasma L− PGDS and visfatin. Practical Pharm Clin Remedies. 2016;19(07):835–8.

    CAS  Google Scholar 

  36. Liu HJ, Yu WZ, Wang SZ, Xiao JN, Ling W. Efficacy of Xiaoshuan enteric− coated combined with Rosuvastatin calcium tablets on asymptomatic carotid plaque. J Chin Phys. 2018;20(3):453–6.

    Google Scholar 

  37. Liu J, Cui JH, Liu SF. Efficacy of pushen capsule on blood lipid and atherosclerosis in patients with ischemic stroke. Tianjin Med J. 2017;45(07):709–14.

    Google Scholar 

  38. Liu L, Jiang C, Wang YY, Wang YL, Li FF, Wang SY. Effect of Xuesaitong Capsule on carotid atherosclerotic soft plaque and hemorheology in elderly patients with ischemic cerebrovascular disease. Chin J Gerontol. 2017;37(18):4524–6.

    CAS  Google Scholar 

  39. Mei Z, Chen LC. Clinical study on treating of of cerebral infarction and carotid atherosclerosis by atorvastatin combined with naoxin− tong capsule. Chin J Prim Med Pharm. 2013;20(3):391–3.

    Google Scholar 

  40. Mi GQ, Xue MZ, Fu Y, Ma HY, Li L, Wang LH. Effect of Tongxinluo on carotid artery stenosis the hs− CRP and D− Dimer in patients with cerebral infarction. Int J Lab Med. 2017;38(12):1591–3.

    Google Scholar 

  41. Ni ZX, Gao HL, Xie CX, Pei RD. Clinical observation on treatment of hyperlipidemia with carotid atherosclerosis by tongxinluo combined with rosuvastatin calcium and aspirin. World Chin Med. 2017;12(04):807–10.

    CAS  Google Scholar 

  42. Peng L, Jin LL, Ren ZX, Zhu YQ, Li M, Zhang BH. Effect of zhibitai capsule for intensive lipid− lowering on carotid plaque and serum inflammatory factor in patients with recovery phase of cerebral infarction complicated with carotid plaque. Eval Anal Drug− Use Hosp China. 2020;20(06):652–5.

    Google Scholar 

  43. Shen X, Zou S, Jin J, Liu Y, Wu J, Qu L. Dengzhan Shengmai capsule versus Aspirin in the treatment of carotid atherosclerotic plaque: a single− centre, non− inferiority, prospective, randomised controlled trial. Phytomedicine. 2022;106: 154408.

    Article  CAS  PubMed  Google Scholar 

  44. Wang BJ, Wang KQ. Intervention of Shexiang Baoxin Pills combined with Rosuvastatin on vulnerable carotid plaque in elderly patients. Chinese J Pract Med. 2018;45(12):116–9.

    Google Scholar 

  45. Wang H, Huang L, Chen P, Wang J, Lai FJ. Effects of atorvastatin calcium tablets combined with tongxinluo capsules on intima− media thickness of the carotid artery and the levels of plasm inflammation markers. Chinese J New Clin Med. 2011;4(12):1129–31.

    Google Scholar 

  46. Wang J, Cheng SH, Yang XC, Sun GX, Xu GH, Wang YB. The effect of Naoxintong capsule treatment on carotid artery intima− media thickness, serum beta thromboglobulin, P− selectin and plasminogen activator inhibitor− 1 in elderly type 2 diabetic patients with subclinical atherosclerotic vascular diseases. Chin J Geriatr. 2017;36(10):1080–2.

    Google Scholar 

  47. Xia YM, Yu L, Li P, Ye HH. Clinical observation of Zhibitai combined with atorvastatin in the treatment of diabetic cerebral infarction complicated with carotid atherosclerotic plaque. J Chin Phys. 2021;23(6):932–4.

    Google Scholar 

  48. Yang C, Liu T. Effect of Xiaoshuan enteric− coated Capsule on plasma homocysteine and carotid intimal media thickness in patients with coronary heart disease. Heilongjiang Med J. 2017;30(01):93–5.

    Google Scholar 

  49. Yang F, Yang Q. Intervention effect and mechanism of Pushen capsule on unstable CAS plaque. Chin J Exp Tradit Med Formulae. 2016;22(21):177–81.

    Google Scholar 

  50. Yang HY, Han JH. Therapeutic effect of Zhibitai Capsule on carotid atherosclerosis. Chin J Integ Med Cardio− Cerebrovas Dis. 2018;16(18):2696–7.

    Google Scholar 

  51. Zhang J, He B, Zhang X. Clinical study on Jiangzhiling Tablet combined with atorvastatin in the treatment of carotid atherosclerotic plaque in patients with coronary heart disease. Chin Commun Doctors. 2016;32(16):90–1.

    Google Scholar 

  52. Zhang M, Liu Y, Xu M, Zhang L, Liu Y, Liu X, Zhao Y, Zhu F, Xu R, Ou Z, et al. Carotid artery plaque intervention with Tongxinluo capsule (CAPITAL): a multicenter randomized double− blind parallel− group placebo− controlled study. Sci Rep. 2019;9(1):4545.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Zhang XL, Shen Y, Duan XB, Zhang GF, Li H, Chai WJ. Effect of Jiangzhiling Tablet combined with Atorvastatin calcium on carotid artery plaque in patients with hyperlipidemia. Chin J Integ Med Cardio− Cerebrovascular Dis. 2017;15(09):1083–5.

    Google Scholar 

  54. Wang C, Niimi M, Watanabe T, Wang Y, Liang J, Fan J. Treatment of atherosclerosis by traditional Chinese medicine: Questions and quandaries. Atherosclerosis. 2018;277:136–44.

    Article  CAS  PubMed  Google Scholar 

  55. Martinez E, Martorell J, Riambau V. Review of serum biomarkers in carotid atherosclerosis. J Vasc Surg. 2020;71(1):329–41.

    Article  PubMed  Google Scholar 

  56. Ridker PM, Bhatt DL, Pradhan AD, Glynn RJ, MacFadyen JG, Nissen SE. Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials. Lancet. 2023;401(10384):1293–301.

    Article  CAS  PubMed  Google Scholar 

  57. Wu M, Liu L, Xing Y, Yang S, Li H, Cao Y. Roles and mechanisms of hawthorn and its extracts on atherosclerosis: a review. Front Pharmacol. 2020;11:118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lu L, Qin Y, Zhang X, Chen C, Xu X, Yu C, Guo X. Shexiang Baoxin Pill alleviates the atherosclerotic lesions in mice via improving inflammation response and inhibiting lipid accumulation in the arterial wall. Mediators Inflamm. 2019;2019:6710759.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Zhang J, Cui Q, Zhao Y, Guo R, Zhan C, Jiang P, Luan P, Zhang P, Wang F, Yang L, et al. Mechanism of angiogenesis promotion with Shexiang Baoxin Pills by regulating function and signaling pathway of endothelial cells through macrophages. Atherosclerosis. 2020;292:99–111.

    Article  CAS  PubMed  Google Scholar 

  60. Yu YH, Xu XQ, Wang Y, Sun SZ, Chen Y. Intervention of Tongxinluo capsule against vascular lesion of atherosclerosis and its effect on lectin− like oxidized low density lipoprotein receptor− 1 expression in rabbits. Chin J Integr Med. 2006;12(1):32–6.

    Article  PubMed  Google Scholar 

  61. Qi Y, Liu W, Yan X, Zhang C, Zhang C, Liu L, Zheng X, Suo M, Ti Y, Ni M, et al. Tongxinluo may alleviate inflammation and improve the stability of atherosclerotic plaques by changing the intestinal flora. Front Pharmacol. 2022;13: 805266.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This work was supported by the National Natural Science Foundation of China (No. 82174340).

Author information

Author notes

  1. Wenquan Su and Xiaolong Xie contributed equally to this work.

Authors and Affiliations

  1. Dongzhimen Hospital, Beijing University of Chinese Medicine, Beijing, 100700, China

    Wenquan Su, Xiaolong Xie, Jiping Zhao, Qinhua Fan, Naijia Dong, Qingxiao Li, Yawei Du & Shengxian Wu

Authors
  1. Wenquan Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaolong Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiping Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qinhua Fan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Naijia Dong
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Qingxiao Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yawei Du
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shengxian Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

WS: formal analysis, data curation, investigation, and writing− original draft; XX: data curation, formal analysis, validation, and writing− original draft; JZ: methodology, investigation, and formal analysis; QF: formal analysis and data curation; ND: formal analysis and data curation; QL: formal analysis and data curation; YD: supervision, conceptualization, and formal analysis; SW: conceptualization, methodology, funding acquisition, and formal analysis.

Corresponding authors

Correspondence to Yawei Du or Shengxian Wu.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Additional file 1.

Searching strategies.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Su, W., Xie, X., Zhao, J. et al. Comparative efficacy of Chinese patent medicines in patients with carotid atherosclerotic plaque: a Bayesian network meta− analysis. Chin Med 18, 152 (2023). https://doi.org/10.1186/s13020-023-00850-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s13020-023-00850-5

Keywords

Chinese Medicine

ISSN: 1749-8546

Contact us