Efficacy Evaluation of the Mahuang-Fuzi-Xixin Decoction in Combination with Shenmai Injection for Bradyarrhythmia Treatment: A Systematic Review and Meta-Analysis

Background Bradyarrhythmia treatment is often not timely enough, posing a potential threat to health. It is necessary to find a strategy with stable curative effects and high safety. Mahuang-Fuzi-Xixin (MFX) decoction and Shenmai injection (SMI) are compound Chinese Patent Medicines. Recent evidence has shown that the combined use of these two drugs can effectively treat bradyarrhythmia. Purpose To evaluate the effect of MFX decoction combined with SMI on bradyarrhythmia. Methods PRISMA was followed as the guideline for this systematic review. RevMan 5.4 software was applied for meta-analysis. Results Eight studies were included in the analysis, with a total of 340 patients in the intervention and control groups. The results of the meta-analysis showed that the effective rate of MFX combined with SMI treatment was higher than that of SMI alone (OR = 3.27, 95% CI (2.18, 4.89), P < 0.01); after treatment, MFX combined with SMI treatment and SMI alone had no significant difference in heart rate. In the subgroup of patients with an age less than 60, the effect of MFX combined with SMI treatment on the 24-hour mean heart rate was better than that of SMI alone (MD = 3.68, 95% CI (3.14, 4.22), P < 0.01), as did the 24-hour minimal heart rate (MD = 3.48, 95% CI (3.03, 3.93), P < 0.01). In addition, the effect of MFX combined with SMI treatment on the Traditional Chinese Medicine syndrome score (TCMSS) was significantly better than that of SMI alone (MD = −2.69, 95% CI (−3.10, −2.28), P < 0.01). In terms of safety, two adverse events were reported in the SMI combined with MFX group compared to 12 in the SMI alone group. Conclusions MFX combined with SMI treatment is effective in treating bradyarrhythmia. However, the results were heterogeneous. The safety of MFX combined with SMI treatment should be verified and treated with caution.


Introduction
Bradyarrhythmia is a common cardiovascular disease (CVD), and every year one million people have pacemakers installed worldwide [1,2]. Bradyarrhythmias are heartbeats fewer than 60 times per minute [2]. Generally, a slower heart rate at rest means health, which is normal among adolescents [3], but it may indicate abnormalities in the elderly [4]. Severe patients often need to install a pacemaker or use drugs such as atropine or isoproterenol to increase the heart rate [5]. In the acute phase, although these drugs can quickly restore the heart rate, they are simultaneously violent and may bring greater adverse reactions [6]. Tere is an urgent need to fnd treatment strategies with good efcacy and low toxicity.
Traditional Chinese medicine injection (TCMI) is a proprietary Chinese medicine with a long history of development [7]. People mainly use traditional Chinese medicine (TCM) orally or externally, but the emergence of TCMI can assist many clinical drugs in the treatment of severe and chronic diseases [8,9]. Shenmai injection (SMI) is composed of red ginseng and Ophiopogon japonicus, which have been used clinically to treat bradyarrhythmia [10,11]. Mahuang-Fuzi-Xixin (MFX) decoction, a TCM prescription, is mainly composed of ephedra, asarum, and aconite [12]. It is used to treat physical weakness and chills [13]. MFX decoction has been widely used to treat bradyarrhythmia and is often used in combination with other drugs [12]. For example, in the case of MFX plus atropine for treating bradyarrhythmia versus the control group using atropine alone, the efcacy after the treatment was signifcantly better than using atropine alone [14]. Other studies comparing the efcacy of MFX and Erxian decoction (another TCM) in the treatment of bradyarrhythmia found that compared to the control group, they can better improve the slow heart rate [15]. MFX combined with SMI has been clinically used for the treatment of bradyarrhythmias, and it has shown better efcacy than single drug. However, there is no basic research and large-scale RCT research and evaluation of the mechanism and efcacy of this strategy. Besides, the results of several RCTs are inconsistent, and the clinical evidence is insufcient. Terefore, a systematic review and meta-analysis is needed to provide clinical evidence.
Tis study included clinical studies in recent years, with the efective rate, 24-hour mean heart rate, 24-hour minimal heart, rate and TCM syndrome score (TCMSS) as outcome indicators, aiming to evaluate the efectiveness of the combination of MFX with SMI for treating bradyarrhythmia.

Databases and Search
Methodology. Tis research method strictly adhered to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). As of November 2021, we searched the following 6 databases: the Chinese Biomedical Database (CBM), Web of Science, EMBASE, PubMed, the China National Knowledge Infrastructure Database (CNKI), and the Cochrane Library. Te language of the references was limited to Chinese and English. Search terms included "Shenmai injection," "Mahuang-Fuzi-Xixin decoction," "bradyarrhythmia," "bradyarrhythmias," "bradycardia," "Bradycardias," "slow arrhythmia," and "arrhythmia." A search methodology that combined subject terms and free word lines was utilized. In addition, to avoid omissions, related references were manually searched.

Inclusion and Exclusion
Criteria. Endnote X9 was applied to import the search results, followed by removing duplicate literature. Te inclusion criteria met the following criteria: (1) compared the clinical trials of bradyarrhythmia between the SMI alone treatment group and the MFX decoction combined with SMI treatment group, (2) the control group received SMI alone, (3) the intervention group received MFX decoction combined with SMI treatment, and (4) at least one of the following results were reported: (1) efcacy, (2) 24-hour mean heart rate, (3) 24-hour minimal heart rate, and (4) Traditional Chinese Medicine Syndrome Score (TCMSS). Exclusion criteria met the following criteria: (1) incomplete data, (2) diferent baseline levels of patients, and (3) animal experiments, meeting reports, review comments, repeated published studies, and other nonconforming studies.

Data Extraction.
Two experienced researchers searched and selected studies based on inclusion and exclusion criteria. If there was a disagreement in the data extraction step, the third researcher discussed and resolved the disagreement. Tese data were extracted: the name of the frst author, the year of publication, the sample size, gender distribution, intervention measures, duration of treatment, comorbidity, outcome, and adverse events.

Quality Evaluation.
Te methodological quality of the included studies was evaluated according to the Cochrane Collaboration's tool. Te risk of bias assessment mainly included fve aspects: (1) the bias generated by the randomization process; (2) the deviation caused by the deviation from the expected intervention; (3) the deviation caused by the missing result data; (4) the deviation of the measurement result; and (5) the bias in the selection of the reported result. Finally, a judgment of the overall risk of bias was generated. Te risk of bias was categorized into three levels: "low," "high," and "unclear."

Data Analysis.
For binary variables, the odds ratio (OR) was used to assess the efect; for continuous variables, the mean diference (MD) was used. For the above variables, the 95% confdence interval (CI) was calculated. Te heterogeneity among diferent studies was assessed by the χ 2 test and I 2 statistic. If there was heterogeneity (I 2 > 50% or P < 0.05), the random efects model was used for data analysis; otherwise, a fxed efects model was adopted. At the same time, sensitivity analysis or subgroup analysis was used to determine the source of heterogeneity. Our study did not perform a funnel plot analysis because only 8 (less than 10) studies were included. RevMan 5.4 software was employed for statistical analysis.

Search Results.
We retrieved a total of 488 studies from 6 databases. First, 120 duplicate studies were removed. Ten, the title and abstract were read by experienced researchers, and 282 studies were removed because they were case reports, conference papers, or other nonconforming study types. Next, the full text was carefully checked, and 78 studies were not included in this step because their interventions or results did not meet the inclusion criteria. In the fnal stage, 8 studies were included [11,[16][17][18][19][20][21][22]. Te complete screening process is shown in Figure 1.

Study Characteristics.
Eight studies were included in the analysis, with a total of 340 patients in the intervention and control groups (170 in the intervention group and 170 in the control group). Te detailed characteristics of these studies are shown in Table 1.

Quality Assessment of Included Studies.
All studies randomly grouped patients but did not report the allocation concealment method and blinding. Two studies did not report predetermined results, nor did they report other biases. Te Cochrane risk of bias results is shown in Figure 2.

Bias Risk Assessment.
After evaluating the bias risk of included RCTs, the risk of random sequence generation and allocation concealment was found to be low. However, the blinding of participants and blinded reporting of outcome assessments remained unclear in these studies. But it was found that there were three studies with biased reporting of primary outcome and incomplete outcome data [17,18,20], causing high risk, while the risk of others was low ( Figure 2).

24-Hour Mean Heart
Rate. Four studies [11,16,21,22] reported the 24-hour mean heart rate. Before treatment, the 24-hour mean heart rate of patients was less than 60, and there was no diference between the intervention group and the control group (Table 1). After treatment, the 24-hour mean heart rate of patients was improved, but the heterogeneity was high (I 2 � 99%) (Figure 4). Terefore, we conducted a subgroup analysis based on age and divided them into two subgroups, aged ≤60 and >60, to investigate the source of heterogeneity. Te subgroup heterogeneity of the aged ≤60 subgroup was signifcantly reduced (I 2 � 0). Although the heterogeneity of the aged >60 subgroup was reduced, it still had high heterogeneity (I 2 � 53%) ( Figure 5). It was indicated that age might be part of the sources of heterogeneity, but other sources of heterogeneity still existed. Te results showed that compared to SMI treatment alone, MFX decoction combined with SMI treatment increased the 24-hour mean heart rate in patients aged less than 60 years.

24-Hour Minimal Heart
Rate. Heart rate, a measure of bradyarrhythmia, is often measured with a 24-hour mean heart rate and a 24-hour minimal heart rate to assess the extent of improvement of disease. Four studies [11,16,21,22] reported a 24-hour minimal heart rate. Before treatment, there was no diference between the intervention group and the control group (Table 1). After treatment, the patients' 24-hour minimal heart rate was improved, but the heterogeneity was high (I 2 � 98%) ( Figure 6). Terefore, a subgroup analysis was conducted according to age and divided into two groups, aged ≤60 and >60 subgroups, to investigate the source of heterogeneity. Te heterogeneity of the two subgroups was signifcantly reduced (aged ≤ 60 subgroup, I 2 � 0; aged > 60 subgroup, I 2 � 21%) (Figure 7). Tis indicated that age was the main source of heterogeneity, but there may be other sources of heterogeneity that have an efect on the results. Te results showed that MFX combined with SMI treatment further increased the 24-hour minimal heart rate (MD � 3.48, 95% CI (3.03, 3.93), P < 0.00001) in patients aged less than 60 years. Evidence-Based Complementary and Alternative Medicine It could be applied to determine the condition from the perspective of TCM. Two studies [11,22] reported TCMSS.
Tere was no diference in the TCMSS of patients before treatment (Table 1). After treatment, the patients' TCMSS decreased, and compared with SMI treatment alone, SMI combined with MFX treatment more efectively reduced the symptoms of bradyarrhythmia (MD � −2.69, 95% CI (−3.10, −2.28), P < 0.00001) (Figure 8). However, it should be noted that there were few studies using TCMSS as an outcome, and this conclusion needs to be treated with caution.

Safety.
Tree studies [16,19,21] listed the occurrence of adverse events (the total sample size was 190, and the sample size of the intervention group (MFX combined with SMI) and the control group (SMI alone) were 95 each). Tere were 2 cases of vomiting in the intervention group and 12 cases of adverse events in the control group (4 cases of vomiting, 2 cases of dizziness, and 6 cases of anorexia) ( Table 2). One of the studies [19] did not report the specifc number of adverse events. Te other 5 studies [11,17,18,20,22] did not report adverse reactions. From the results, the SMI combined with MFX treatment group seemed to have higher safety, but this result needed to be treated with caution because in the studies we included, there were too few studies reporting adverse reactions.

Discussion
Trough our analysis, it was found that, compared with SMI treatment alone, MFX decoction combined with SMI treatment could further improve the efective rate, 24-hour mean heart rate, and 24-hour minimal heart rate in patients less than 60 years of age and reduce the TCMSS. In terms of safety, our results showed that there were no serious adverse reactions in the included studies, and the adverse reaction rate of the intervention group was lower than that of the control group. Among the included studies, 6 studies reported treatment duration (4 weeks or 1 month), and the variety in treatment duration was small. Te electrocardiogram (ECG) is an important way to continuously record heart rhythm [23]. However, the sources of these studies were quite diferent, and the professional level of ECG data analysts varied. Tis was mainly refected in the high heterogeneity of the 24-hour mean heart rate and the 24-hour minimal heart rate after treatment. Ten, we performed subgroup analysis according to age, which indicated that age may be a source of heterogeneity, and the additive efect of SMI combined with MFX on heart rate reduction exists in patients aged less than 60 years. Indeed, studies have shown that the absorption and metabolism of antiarrhythmic drugs may be diferent in aged patients, and thus, the administration of these drugs needs to be individualized for elderly adults [24]. For TCMSS, there was no heterogeneity, and SMI combined with MFX further decreased TCMSS compared to SMI alone. However, the number of included studies was relatively small. Te accuracy of the conclusion remains to be demonstrated. Bradyarrhythmia is a common disease [25] with symptoms of syncope, transient dizziness, fatigue, etc. [26], which cause many inconveniences to patients' lives. Te clinical diagnosis of bradyarrhythmia is no longer limited to the measurement of heart rate but also includes assessment and management of the degree of bradyarrhythmia [27]. For example, after the initial medical history and physical examination, the doctor will perform a 12-lead ECG or even a Holter test on patients or laboratory tests, including thyroid function tests and electrolyte tests [5]. Bradyarrhythmia requires long-term treatment and nursing measures, which increase the fnancial burden on both patients and the medical system. At present, clinicians recommend alternative therapies to patients, and TCM has played an important role [12]. Indeed, the efect of MFX decoction in the treatment of bradyarrhythmia has been demonstrated [12]. Furthermore, nonrandomized clinical trials proved that MFX decoction combined with SMI can treat bradyarrhythmia. However, there are still no RCTs on the adjuvant treatment of bradyarrhythmia. Considering the efcacy of TCM treatment and the large number of nonsevere bradyarrhythmia patients, it is necessary to carry out RCT research on TCM. To provide stronger clinical evidence for   MFX decoction combined with SMI treatment of bradyarrhythmia, we performed the current meta-analysis to show the efcacy of this treatment. Blood rheology is the main factor afecting the development of arrhythmia. Te increase in blood viscosity and vascular resistance in patients will cause ischemia and hypoxia in local tissues and organs [28]. Relevant pharmacological studies have shown that the mechanism of MFX in the treatment of bradyarrhythmias may involve its ability to excite β receptors, increase heart rate, and increase myocardial contractility. Its active ingredient, ephedra fruit polysaccharide, can improve the blood rheology of model rats and resist the formation of blood stasis [29]. Tere have been studies showing that SMI has a protective efect on the heart. For example, SMI can reduce mitochondrial oxidative stress and mitochondrial rupture during myocardial injury [30]. Tis was demonstrated in a randomized controlled study-compared with trimetazidine (TMZ) and the control group, the comprehensive treatment of SMI can improve energy metabolism in heart failure [31]. It has been reported that SMI can be combined with standard treatment to treat ischemia-reperfusion (I/R) injuries. In this process, SMI mainly alleviates the reduction of key enzymes and transporters after I/R and the utilization of metabolic substrates. Cell apoptosis was reduced, and the depletion of ATP caused by I/R was also restored [32]. Te molecular mechanism of the combination treatment is not clear, but it could be evidenced from current studies on the ingredients of MFX and SMI. Te active components of MFX include ephedrine and aconitine, which have been reported to increase heart rate [33]. Red ginseng, the main component of SMI, has also been reported to raise heart rate [34]. Te mechanisms by which all of these components elevate heart rate involve modulation of adrenergic beta receptors (β-AR) and electrophysiological properties and ionic cardiomyocyte membrane channels [35]. Tese active ingredients jointly activate these receptors or ion channels to achieve their cumulative therapeutic efect.

Limitation.
Our research had certain limitations. First, from the included studies, both the intervention and control groups showed high safety. However, only 3 studies reported the occurrence of adverse reactions, and the evidence was not very reliable. Terefore, we believe that the safety of the intervention cannot be fully shown. In the future, more studies need to be included to prove this hypothesis. Second, these studies had small sample sizes, and no detailed randomization or blocking strategy was provided, leading to a poor evaluation methodology. Tird, the mechanism of the

Data Availability
Te data used to support the fndings of this study are included within the article.

Conflicts of Interest
All authors report no conficts of interest.