1 Introduction
Coronary heart disease (CHD) often stems from abnormal lipid metabolism, leading to the deposition of intravascular lipids in the endothelium of the coronary arteries. This deposition results in luminal narrowing and obstruction, thereby causing an imbalance between coronary blood flow and myocardial demand (Fan et al., 2021). Among non-communicable diseases (NCDs), cardiovascular diseases (CVDs) are the primary contributors to the global disease burden and the leading cause of death worldwide (2020). The Global Burden of Ischemic Heart Disease report indicates that approximately 9.14 million individuals succumbed to CVDs in 2019 globally, with about 197 million people living with these diseases (Safiri et al., 2022). The most common medications for CVDs include atorvastatin tablets, isosorbide mononitrate extended-release tablets, metoprolol tablets, and aspirin tablets; however, the clinical effect is not ensured when used only as a routine medicine (Feng et al., 2021). Percutaneous coronary intervention (PCI) is also a major treatment option, and in recent years, the application of this therapy has become widespread with the rising incidence of CVD (Safiri et al., 2022). It is now considered the primary treatment method for CHD (Shen et al., 2023). While it effectively improves perfusion and eases angina symptoms in patients, PCI is accompanied by postoperative complications such as thrombosis, myocardial infarction, heart failure, cognitive dysfunction, and cranial nerve injury (Shi et al., 2019). Moreover, insufficient postoperative rehabilitation care often results in repeated coronary angiography and revascularization. This hampers patients’ return to daily activities and significantly diminishes their quality of life (Tanaka et al., 2015). Therefore, exploring potential medications that can effectively prevent and treat these complications is imperative.
The primary pharmacological agents currently used for secondary prevention after PCI include antiplatelet drugs, statins, angiotensin-converting enzyme inhibitors (ACEIs), beta-blockers, and sodium-glucose cotransporter-2 (SGLT2) inhibitors (Desta et al., 2021; Virani et al., 2023). These drugs are chemically synthesized and are not derived from natural plants; hence, they are often referred to as Western medicine (WM). However, these WM treatments have certain drawbacks. For instance, antiplatelet drugs may cause severe bleeding and gastrointestinal adverse effects (Fras et al., 2021; Du et al., 2023). Statins can cause side effects such as hepatotoxicity, myotoxicity, hypotension, and newly developed diabetes (Gao et al., 2022). ACEIs may lead to hyperkalemia, renal dysfunction, and hepatotoxicity (Mustafa et al., 2022). Beta-blockers are associated with bradycardia and atrioventricular blocks (Li, 2019). SGLT2 inhibitors, which have been used in recent years as one of the drugs to reduce cardiovascular risk in nondiabetic patients, have also been associated with adverse drug reactions (ADRs) such as ketoacidosis and Fanconi syndrome (Zhang and Ji, 2021). Moreover, studies have shown that despite patients’ adherence to the recommended post-PCI pharmacological interventions, there remains a significant prevalence of adverse cardiovascular events, including stent thrombosis, myocardial infarction, and repeated revascularization procedures (Madhavan et al., 2020). Therefore, developing new adjunctive medications is crucial to improve the quality of life and survival rates of individuals receiving PCI.
The Naoxintong capsule (NXT) — a Chinese patent medicine—demonstrates a range of therapeutic effects, such as blood circulation activation, lipid regulation, and blood pressure reduction (Han et al., 2019). This capsule is composed of 16 distinct traditional Chinese medicines (TCMs), including Astragalus mongholicus Bunge [Fabaceae, astragali radix], Paeonia lactiflora Pall. [Paeoniaceae, paeoniae radix rubra], Salvia miltiorrhiza Bunge [Lamiaceae, salviae miltiorrhizae radix et rhizoma], Angelica sinensis (Oliv.) Diels [Apiaceae, angelicae sinensis radix], Conioselinum anthriscoides ‘Chuanxiong’ [Apiaceae, chuanxiong rhizoma], Prunus persica (L.) Batsch [Rosaceae, persicae ramulus], Carthamus tinctorius L. [Asteraceae, carthami flos], Boswellia sacra Flück. [Burseraceae, olibanum], Commiphora myrrha (T. Nees) Engl. [Burseraceae, Myrrha], Spatholobus suberectus Dunn [Fabaceae, spatholobi caulis], Achyranthes bidentata Blume [Amaranthaceae, achyranthis bidentatae radix], Neolitsea cassia (L.) Kosterm. [Lauraceae, cinnamomi cortex], and Morus alba L. [Moraceae, cortex mori]. In the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP, http://tcmspw.com/tcmsp.php), the screening criteria were established as Dyslipidemia (DL) ≥0.18, Obesity (OB)≥40%, Cancer Colon 2 (Caco-2) ≥−0.4, and Hyperlipidemia (HL) ≥4 (Zhang W. et al., 2020), and the botanical drug ingredients of NXT were queried. The composition is detailed in Supplementary File S1.
Previous research has indicated that NXT exhibits cardioprotective effects and may decrease the likelihood of major adverse cardiovascular events (MACEs) post-PCI (Feng et al., 2014). The combination of NXT and WM has shown potential in enhancing clinical outcomes post-PCI, reducing myocardial injury, augmenting cardiac function, and alleviating symptoms (Fu, 2012; Li and Wei, 2016). Meanwhile, a previous meta-analysis demonstrated that the NXT and WM combination can amplify the antithrombotic effect in patients with coronary artery disease post-PCI (Liu et al., 2022). However, there is a deficiency in systematic evaluation and safety analysis concerning the comprehensive efficacy of this combination therapy, including clinical rate effectiveness, MACE rate, improvement of clinical symptoms, enhancement of cardiac function, laboratory indices, and TCM symptom scores. Herein, we performed a systematic meta-analysis of existing studies and comprehensively evaluated the combined efficacy of NXT and WM therapy in CHD patients post-PCI, which may inform clinical practice and future research.
2 Materials and methods
This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Extension Statement and was registered with the International Prospective Register of Systematic Reviews (PROSPERO, https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=369174, registration number CRD42022369174).
2.1 Search strategy
Randomized controlled trials (RCTs) of NXT for patients with CHD after PCI were thoroughly searched from seven databases, including PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wan Fang Database, Chinese Science and Technology Journal Database (VIP), and Chinese Biomedical Literature, from inception until 31 January 2023. The English search terms included “Naoxintong Capsule,” “Naoxintong,” and “percutaneous coronary intervention,” The detailed search strategy employed for each database can be found in Supplementary File S2.
2.2 Inclusion and exclusion criteria
The inclusion criteria were as follows:
(1) Study subjects: Patients who underwent PCI.
(2) Control group treatment: The control group received WM treatments, including aspirin, statins, β-blockers, and calcium channel blockers.
(3) Experimental group treatment: The experimental group received a combination of NXT intervention and the same WM treatments as the control group.
(4) Study Design: RCTs.
(5) Selected study outcomes: Studies were considered if any of the following outcomes occurred.
Primary outcomes:
1) Effective clinical rate: This was defined as the percentage of patients who showed improvement after treatment. The effective clinical rate was calculated by subtracting the number of ineffective cases from the total number of cases and dividing the result by the total number of cases. The effectiveness of the treatment was assessed based on symptoms such as chest tightness, palpitation, shortness of breath, and weakness. Significant efficacy was defined as a substantial improvement in patients’ symptoms and signs after therapy. An effective outcome was defined as an improvement in symptoms and signs following treatment, while an ineffective outcome was defined as no significant change or a worsening of symptoms and signs after treatment (Wang et al., 2021).
2) MACE rate: This included acute coronary syndrome, heart failure, and cardiovascular death.
Secondary outcomes:
1) Effective rate in electrocardiogram (ECG): This was defined as the percentage of patients who showed improved myocardial ischemia as indicated by changes in their ECG, such as the normalization of T-wave inversion.
2) Effective rate in angina: Angina symptoms disappeared, without the need for nitroglycerin as effective; the number of angina episodes and the dosage of nitroglycerin halved as effective; angina not reduced to half or aggravated as ineffective. The effective rate in angina was calculated by subtracting the number of ineffective cases from the total number of cases and dividing the result by the total number of cases (Du et al., 2018).
3) Changes in left ventricular ejection fraction (LVEF), brain natriuretic peptide (BNP), creatine kinase-MB (CK-MB), cardiac troponin I (CTnI), and maximum platelet aggregation rate before and after treatment.
4) Chinese Medicine Evidence Score: The points of TCM symptoms were calculated according to the Guidelines for Clinical Research of New Chinese Medicines (GCRNCM). Chest tightness, shortness of breath, palpitation, and chest pain were observed in the two groups and scored according to the GCRNCM as 2 (mild), 4 (moderate), and 6 (severe). A significant effect was defined as the disappearance of symptoms before treatment, and the total score was reduced by >80%; effective was defined as the relief of symptoms before treatment, and the total score was reduced by about 40%–79%; ineffective was defined as insignificant relief of symptoms before treatment, and the total score was reduced by <40% (Qin, 2020; Gong, 2021).
5) ADRs.
The exclusion criteria were as follows:
(1) the original data is incomplete.
(2) Patients exhibit severe conditions post-PCI, including heart and renal failure.
(3) Studies exhibited either failed randomization or significant disparities in baseline data across groups.
(4) The experimental or control group received treatment with other TCMs or herbal medicines.
2.3 Data extraction
A blend of software and manual methods were utilized to pinpoint pertinent studies. First, all duplicate studies were removed. Next, the initial screening of titles and abstracts was independently conducted by two researchers, adhering to pre-set inclusion and exclusion criteria. A secondary screening and data extraction were then conducted by thoroughly reviewing the full text of the selected papers. The data extracted from eligible studies included the first author, year of publication, sample size, age, disease progression, treatment duration, and dosage. It also covered outcome indicators and relevant information for assessing the quality of the literature. The results were then cross-checked to ensure accuracy. Any disagreements were resolved through consensus discussions between the two reviewers or with a third party.
2.4 Analysis of study quality
The bias risk for the RCTs included in this meta-analysis was assessed using the Cochrane recommended risk-of-bias tool, Version 2 (RoB 2) (Sterne et al., 2019). This tool evaluated five crucial elements: the randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and the selection of the reported result. Each element was categorized as either “low risk,” “high risk,” or “some concerns” of bias. A trial was deemed to have an overall “low risk” of bias only if all elements were classified as “low risk.” Two reviewers worked together to address and resolve disagreements to ensure accuracy and consistency. If a consensus was not achieved, a third reviewer was consulted.
2.5 Data analysis
All statistical analyses were performed using R statistical software (version 4.2.2) and its Meta package (version 6.5.0). Continuous and categorical variables were evaluated using the mean difference (MD) and odds ratio (OR), respectively, along with a 95% confidence interval (95% CI). The statistical significance was set at p < 0.05. Heterogeneity within each study was assessed using the Q statistic and I2 test. Forest and Labbé plots were employed to visually inspect heterogeneity and identify variation sources. The I2 test was also applied to evaluate heterogeneity during data integration. When I2 was less than 50%, indicating low heterogeneity, a fixed-effects model was applied. Conversely, a random-effects model was applied when I2 exceeded 50%, suggesting high heterogeneity. To address potential heterogeneity and ensure the robustness of the results, meta-regression and sensitivity analyses were performed using the “metareg” and “metainf” commands for all outcome indicators with I2 values ≥ 50%. In addition, subgroup analyses were conducted based on positive covariates identified in the meta-regression. Sensitivity analyses were performed by excluding each literature individually. For outcomes involving more than five studies, potential publication bias was explored using adjusted funnel plots and Egger’s and Begg’s tests, implemented via the “metabias” command.
4 Discussion
To the best of our knowledge, this is the first meta-analysis to explore the collective efficacy of NXT and WM combination therapy in CHD patients post-PCI. The results highlighted that the NXT and WM combination significantly enhances clinical effectiveness and reduces the incidence of MACEs. This dual therapy also substantially improves LVEF—a crucial determinant of cardiac function and prognosis in patients receiving PCI. The findings also demonstrated a significant increase in LVEF in the dual therapy group compared with the WM monotherapy group. Additionally, the combined therapy markedly enhances ECG and angina improvement rates. The NXT and WM combination therapy also significantly decreases BNP, CK-MB, and the maximum platelet aggregation rate but does not significantly benefit CTnI level reduction. Furthermore, the NXT and WM combination alleviates symptoms such as chest discomfort, palpitations, breathlessness, and fatigue, thereby improving the Chinese medicine evidence score. However, subgroup analyses of BNP based on treatment duration and subject age were inconclusive due to a lack of sufficient studies (<2) within subgroups. Notably, no significant difference was found between the combined and single WM treatments in reducing ADRs (Liu et al., 2022).
According to the principles of TCM, CHD belongs to “chest paralysis” and “heart pain” (Diseases, 2021). The pathogenesis of CHD in TCM is characterized by a deficiency at the root and excess at the branch. The root deficiency mainly being a deficiency of Qi and Yin and the excess at the branch includes blood stasis, phlegm turbidity, and Qi stagnation (Xia et al., 2022). Clinical practice has shown that CHD PCI, as a traumatic surgery, can easily damage the body’s meridians, leading to a depletion of vital energy (Wang et al., 2019). Therefore, Qi deficiency and blood stasis are the main symptoms after CHD PCI. NXT is the first Chinese patent medicine that combines plant and animal medicines to treat cardiovascular and cerebrovascular diseases. In the prescription, Astragalus is the sovereign, mainly for replenishing Qi, while animal medicines mainly clear the meridians and expel pathogenic factors. Angelica, Chuanxiong, Danshen, Baishao, Frankincense, Myrrh, Safflower, and Peach Kernel mainly invigorate the blood. The mechanism of NXT in treating CHD with Qi deficiency and blood stasis mainly includes anti-atherosclerosis, reducing inflammatory response, inhibiting platelet aggregation, enhancing endothelial function, and reducing myocardial ischemia/reperfusion (I/R) injury.
The quercetin in Astragalus, S. miltiorrhiza, and Safflower is the main active ingredient of NXT. It plays a role in anti-atherosclerosis by acting on signaling pathways such as tumor necrosis factor (TNF), interleukin-17 (IL-17), hypoxia-inducible factor-1, and vascular endothelial growth factor (Boutet et al., 2018; Xing et al., 2018; Yang et al., 2020; Singh et al., 2021). It can improve myocardial ischemia, coronary blood flow, and lipid levels, which are essential in the prevention and treatment of CVDs. Polysaccharides, primary compounds in Astragalus, have been shown to enhance macrophage capacity for oxidized low-density lipoprotein phagocytosis. This process promotes cholesterol efflux, thereby exerting anti-atherosclerosis effects (Duan et al., 2020; Ge et al., 2022). Additionally, these polysaccharides improve endothelial function and stabilize plaques by inducing macrophages to produce nitric oxide, nitric oxide synthase, and TNF-α via nuclear factor kappa B. The underlying mechanism appears to involve the promotion of the expression of α messenger RNA (mRNA) in aortic smooth muscle 22α, while simultaneously inhibiting the expression of matrix metalloproteinase-2 and TNF-α mRNA (Yang et al., 2016). Coronary artery obstruction is often caused by the activation of the coagulation system, platelet aggregation, and thrombosis. Certain substances, including hirudin, earth dragon, total paeoniflorin, Angelica volatile oil, and components containing ferulic acid, have been found to inhibit adenosine diphosphate-induced platelet aggregation. These substances also prolong prothrombin time (PT), activate partial thromboplastin time (APTT), and reduce blood viscosity (Martin et al., 2019; Ma et al., 2022; Wei, 2022; Li et al., 2023). Furthermore, the purified liquid from the whole scorpion has been shown to inhibit thrombosis by extending rat APTT and PT, inhibiting tissue-type plasminogen activator (tPA), and enhancing the activity of plasminogen activator inhibitor-1 (PAI-1) (Wali et al., 2019). Notably, oxidative stress reaction represents the key pathological mechanism underlying CHD, facilitating the development of atherosclerosis (D'Oria et al., 2020). Lactoperoxidase (LPO) and myeloperoxidase (MPO) serve as reliable markers for lipid peroxidation; elevated LPO levels can exacerbate myocardial injury (Chen et al., 2021), whereas MPO contributes to the generation of reactive oxygen species (Yang et al., 2023). NXT effectively inhibits adhesion molecules and delays the progression of atherosclerosis by reducing MPO and LPO levels and enhancing oxidative stress conditions (Yang et al., 2023). This may be related to our findings suggesting that NXT improves clinical efficacy and increases the rate of ECG and angina improvement.
Dyslipidemia is an independent risk factor for CHD. Studies have proposed that flavonoids and triterpenoids found in S. miltiorrhiza can potentially decrease the expression of scavenger receptor A on the surface of macrophages, ultimately inhibiting the formation of foam cells and effectively reducing blood lipid levels (Ren et al., 2019). Furthermore, pharmacological studies have substantiated that S. miltiorrhiza and Rhizoma Ligustici Chuanxiong exhibit notable protective effects against myocardial I/R injury (liu et al., 2020). It has been previously demonstrated that inflammatory responses are pivotal in precipitating cardiovascular events in patients diagnosed with CHD (Haybar et al., 2019). NXT can suppress intra-arterial inflammatory responses, thereby reducing serum levels of inflammatory markers such as TNF-α, IL-6, IL-18, monocyte chemoattractant protein 1 (MCP-1) (Luo and Liao, 2019), and metalloproteinase 9 (Lv et al., 2021). This reduction in inflammatory indicators contributes to a decrease in the incidence of adverse cardiovascular events in patients, thereby enhancing their prognosis. Our data suggest that these effects are associated with further improvements in patient prognosis, as evidenced by a reduction in MACEs.
A meta-analysis (Liu et al., 2022) evaluating the efficacy of combining NXT with WM in patients with coronary artery disease after PCI found that this combination therapy inhibited platelet activation and aggregation in patients with coronary artery disease after PCI, improved the body’s coagulation function, and increased the antithrombotic efficacy. However, this meta-analysis had limitations, as it focused solely on antithrombotic efficacy and safety, resulting in a relatively narrow scope of findings. Additionally, the study lacked sensitivity or meta-regression analysis and failed to systematically analyze sources of heterogeneity, reducing the reliability and validity of the results. Hence, the present study evaluated the comprehensive effect and safety of NXT and WM combination therapy based on clinical effectiveness, MACEs, LVEF, CK-MB, Chinese medicine evidence score, and adverse effects in CHD patients post-PCI. Moreover, meta-regression and sensitivity subgroup analyses were performed to identify and analyze sources of heterogeneity and ensure the robustness of the results.
Nonetheless, while our study yielded encouraging results, it also has some limitations. Firstly, all 15 RCTs included in this meta-analysis were conducted in China, with relatively small sample sizes. Some of these studies were characterized by inadequate sample sizes and unidentified risks, while others exhibited a pronounced risk of bias. These factors could potentially compromise the statistical power. Secondly, we observed significant heterogeneity in some outcome indicators such as BNP, CK-MB, and CTnI across the reviewed articles. This variability could be ascribed to differences in clinical trial methodologies and the diverse characteristics of the study participants. Finally, the evaluation criteria for the outcome indicators varied across studies, particularly the Chinese medicine evidence score, which lacks globally recognized outcome indicators. Thus, the current findings should be interpreted cautiously. We believe that future large-scale RCTs with standardized intervention protocols would contribute to more reliable evidence. Additionally, ensuring methodological rigor such as proper blinding and allocation concealment and the use of validated outcome measures would also enhance the quality of future studies.