Qidong Yixin Oral Liquid for Viral Myocarditis: A Systematic Review and Meta-Analysis

Objective This study aimed to evaluate the efficacy and safety of Qidong Yixin (QY) oral liquid in the treatment of viral myocarditis (VMC). Methods We searched seven databases for randomized clinical trials on QY for treating VMC. The retrieval period was from database establishment to December 31, 2019. Cochrane risk of bias tool in the Cochrane Handbook was used to assess the methodological quality. Review Manager (RevMan) 5.3 was used to analyze the results. Results We included 19 studies comprising 2,608 patients, albeit with low methodological quality. Our meta-analysis revealed that combination therapy with QY and western medicine was more effective than western medicine alone (QY vs other Chinese patent medicines: RR = 1.37, 95% Cl: 1.23∼1.52, P < 0.00001; QY + coenzyme Q10 + routine treatment vs coenzyme Q10 + routine treatment: RR = 1.20, 95% Cl: 1.14∼1.27, P < 0.00001; QY + trimetazidine + acyclovir vs trimetazidine + acyclovir: RR = 1.59, 95% Cl: 1.38∼1.83, P < 0.00001; QY + routine treatment vs routine treatment: RR = 1.09, 95% Cl: 1.03∼1.15, P < 0.003). A study on posttreatment myocardial enzyme levels revealed that QY with western medicine downregulated creatine kinase isoenzyme (CK-MB) (QY + antiviral treatment + routine treatment vs antiviral treatment + routine treatment group: MD = −11.28, 95% CI: −13.33∼−9.22, P < 0.00001; QY + routine treatment vs routine treatment: MD = −4.96, 95% CI: −5.56∼−4.32, P < 0.00001), creatine kinase (CK) (MD = −32.10, 95% CI: −35.63∼−28.57, P < 0.00001), and lactate dehydrogenase (LDH) (QY + antiviral treatment + routine treatment vs antiviral treatment + routine treatment: MD = −48.76 95% CI: −58.18∼−39.33, P < 0.00001; QY + routine treatment vs routine treatment: MD = −23.52, 95% CI: −30.10–16.94, P < 0.00001) rather than western medicine alone, with no evidence of aspartate aminotransferase (AST) downregulation on treatment with QY with western medicine (MD = 2.88, 95% CI: −0.95∼6.71, P < 0.00001) in patients. Two studies reported adverse events, indicating that QY is relatively safe. Conclusion Although QY may have potential advantages in treating VMC, they remain unclear owing to the poor methodological quality of most studies. Larger, multicenter, high-quality randomized controlled trials are required to verify the effectiveness of QY.


Introduction
According to the WHO classification of cardiomyopathy, myocarditis is defined as an inflammatory myocardial disease [1]. Viral myocarditis (VMC) is usually caused by viral myocardial infections of coxsackievirus B3, enterovirus, adenovirus, parvovirus B19, and human herpesvirus 6 [2,3]. Myocarditis is significantly associated with mortality and is often a prominent cause of acute heart failure, severe ventricular arrhythmia, or cardiogenic shock. Myocarditis causes sudden cardiac death in up to 12% of young adults and dilated cardiomyopathy in 9% of patients [4][5][6][7][8][9]. Moreover, VMC may cause a series of severe complications and affect the long-term prognosis of patients. However, at present, myocarditis treatment methods are primarily focused on myocardial nutrition, myocardial metabolism improvement, and cardiac failure and arrhythmia treatment, while antiviral therapy and immunotherapy have not significantly benefited patients thus far [10][11][12][13][14][15][16]. e traditional Chinese medicine theory suggests that viral myocarditis presents as palpitations resulting from heat-toxicity invading the heart, consuming qi and injuring yin. erefore, treatment should focus on benefiting qi and nourishing yin, thus clearing heat and eliminating toxicity. Qidong Yixin oral liquid (QY) is composed of Ginseng Radix et Rhizoma, Ophiopogonis Radix, Astragali Radix, Poria, Lonicerae japonicae flos, Epimedii Folium, Fluoritum, Testudinis Carapax et Plastrum, Rehmanniae Radix, Curcumae Radix, Cinnamomi Ramulus, Salviae Miltiorrhizae Radix et Rhizoma, and Fructus Aurantii; most of these components protect damaged cardiomyocytes [17,18]. An animal study reported that QY activates the Nrf2/HO-1 signaling pathway, thereby reducing adriamycin-induced myocardial injury in mice [19]. erefore, treatment of VMC with QY and combination therapy with traditional and western medicine has been common in China over the past few decades. However, most current single-center studies include small cohorts, and the treatment schemes vary greatly; hence, it is difficult to effectively evaluate the clinical efficacy of these treatment strategies. erefore, this meta-analysis aimed to assess the efficacy and safety of combination therapeutic strategies involving QY to treat VMC, providing evidence for clinical practice.

Exclusion Criteria.
Studies were excluded if (1) they were not randomized controlled trials and instead were retrospective studies, case reports, or reviews; (2) they included patients with severe complications; (3) they were not aimed at diagnosing VMC; (4) they contained incomplete or erroneous data; or (5) they were duplicate publications.

Data Extraction.
Based on the PRISMA flowchart, two researchers independently screened the literature, extracted the information, evaluated the methodological quality, and cross-checked the data. Inconsistencies were discussed and negotiated with the third researcher. e data extracted herein were the following: first author, publication time, sample size, age, sex ratio, interventional measures, course of treatment, and outcome indicators.

Quality Assessment.
Based on the criteria of the Cochrane risk of bias assessment tool, two authors independently assessed the methodological quality of the included studies, using RevMan 5.3. Disagreements were settled through discussion with a third author. e following items were evaluated: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), and selective outcome reporting (reporting bias). Other potential sources of bias included sample size estimates and the comparability of baseline characteristics. Each included randomized controlled trial was classified as being of a low, ambiguous, or high risk of bias for quality assessment. Studies that met all criteria were classified as being of a high risk of bias, whereas those that did not meet any criteria were classified as being of a low risk of bias. Others were classified as being of an ambiguous risk of bias.
2.6. Data Synthesis and Analysis. RevMan 5.3 was used for the meta-analysis of multiple studies. Continuous data are expressed as weighted average difference (WMD) values, and dichotomous data are expressed as relative risk (RR), both using a 95% confidence interval (CI). e heterogeneity of the study was qualitatively evaluated by the Q test and quantitatively evaluated by the I 2 test. When there was no significant heterogeneity among multiple studies (P ≥ 0.10, I 2 ≤ 50%), we used the fixed effects model to analyze the data. If there was substantial heterogeneity (P < 0.10, I 2 > 50%), a random effects model was established and the possible sources of heterogeneity were investigated using sensitivity analysis and subgroup analysis. When more than 10 trials were included, funnel plots were generated to detect publication bias.
e filtering process is shown in Figure 1.

CK-MB Levels.
CK-MB levels upon QY treatment among VMC patients were reported in 7 studies including 790 patients. Two subgroups were formed depending on whether antiviral therapy was combined. e meta-analysis revealed that the heterogeneity of each subgroup was small, and the fixed effects model was used for combined analysis. CK-MB levels in the experimental group after treatment were lower than those in the control group on comparing QY + antiviral treatment and antiviral treatment [Chi 2 � 3.32, df � 3 (P � 0.35), I 2 � 10%; MD � -11.28, 95% CI: −13.33∼−9.22, P < 0.00001] (Figure 9) and on comparing QY + routine treatment and routine treatment [Chi 2 � 2.10, df � 2 (P � 0.35), I 2 � 5%; MD � −4.96, 95% CI: −5.56∼−4.32, P < 0.00001] (Figure 10). ese results indicate that QY may reduce CK-MB levels in VMC patients.    . e fixed effects model was adopted for combination analysis, and it was found that the CK level of the experimental group after treatment was lower than that of the control group (MD � −32.10, 95% CI: −35.63∼−28.57, P < 0.00001) ( Figure 11). ese results indicate that QY reduces CK levels in VMC patients.

LDH Levels.
Five RCTs including 416 patients reported changes in LDH levels after QY treatment. Two subgroups were formed depending on whether antiviral therapy was combined. e results show that the heterogeneity of each subgroup was small. e fixed effects model was used for analysis, and it was found that the LDH level of the experimental group after treatment was lower than that of the control group on comparing QY combined with

Random sequence generation (selection bias)
Allocation concealment (selection bias)

Blinding of participants and personnel (performance bias)
Blinding of outcome assessment (detection bias)     (Figure 13), indicating that QY can reduce LDH levels in VMC patients.

AST Levels.
ree RCTs including 270 patients reported changes in AST levels. e heterogeneity test for the included studies revealed that the heterogeneity among the studies was large (P < 0.00001, I 2 � 97%), and sensitivity analysis did not affect the outcomes, probably owing to noncomparability of the baseline AST levels among the included studies. Furthermore, the subjects in Sun's study [29] were adults and those in the other two studies were children. Heterogeneity was reduced upon excluding Sun's study [Chi 2 � 4.56, df � 1 (P � 0.03), I 2 � 78%]. e random effects model was used for combined analysis, and it was found that the AST level in the experimental group after treatment was higher than that in the control group (MD � 2.88, 95% CI: −0.95∼6.71, P < 0.00001) (Figure 14).
ese results indicate that QY may not have the advantage of reducing the AST level in VMC patients, and more highquality studies are needed to increase the credibility of these results.

Favours (control)
Favours (experimental)  Figure 6: Forest plot of the comparison between QY + trimetazidine + acyclovir and trimetazidine + acyclovir for total clinical efficacy.

Favours (control)
Favours (experimental)  Figure 7: Forest plot of the comparison between QY + routine treatment and routine treatment alone for total clinical efficacy.

Discussion
QY is a patented drug approved by the State Food and Drug Administration of China. is study evaluated the efficacy and safety of Qidong Yixin (QY) oral liquid for treating VMC. e present results show that QY may be an effective and safe alternative for treating VMC. e present metaanalysis revealed that combination treatment with QY and western medicine could relieve the symptoms of VMC more effectively than western medicine alone and could reduce the levels of myocardial enzymes. However, QY did not appear to have the advantage of reducing AST levels in VMC patients. Traditional Chinese medicine is a holistic medical system with unique theories and methods with prominent advantages in alleviating symptoms. QY has a high potential to improve clinical symptoms in comparison with other therapeutic methods including myocardial nourishment, improvement of myocardial metabolism, and antiviral treatment. Furthermore, current studies have confirmed the efficacy of QY for treating VMC, and its mechanism may be associated with the improvement of immune function, improvement of serum inflammatory factor levels, reduction of myocardial injury, reduction of myocardial enzyme levels, and improvement of cardiac function. One study reported that Qidong Yixin oral solution significantly reduces myocardial injury in SD rats infected with the coxsackievirus B3, maintains consistency in spontaneous beating of myocardial cells, maintains high pulse frequency, and reduces LDH and AST release [41]. Another animal study using a BALB/c mouse model of VMC intraperitoneally administered coxsackievirus B3, divided into a blank control group, QY-treated group (at different doses), and ribavirin-treated group, reported that serum LDH levels of QY-treated mice were significantly lower than those of control mice, and the viral load decreased and antibodies were detected in this group in comparison with the control group [42].
Furthermore. Some of the included studies reported the immunoregulatory effect of QY. In one study, QY treatment significantly improved cellular immune function and levels of inflammatory factors, significantly increased the levels of cluster of differentiation 4 (CD4) and CD8 in the peripheral blood (P < 0.05), and significantly decreased the levels of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and IL-8 in comparison with basic treatment (P < 0.05) [25]. Another study reported that QY combined with basic treatment significantly improved cardiac function in comparison with basic therapy alone [38]. However, such reports are still rare, and more pharmacological and clinical studies are required to verify the mechanism of action of QY for treating VMC.

Strengths and Limitations
e specific limitations of this study primarily include the following: e diagnostic criteria of this study are not uniform.
e included subjects had a large age range. Baseline levels were not comparable in some studies. No follow-up data are available regarding short-term curative effects. Few, irregular studies reported on the safety of the treatment.
e dosage and usage of drugs in the control group were not clearly described in some studies.

Conclusions
In conclusion, combination therapy with QY and western medicine has higher efficacy and safety against VMC than western medicine alone. However, owing to the high heterogeneity, small sample size, low methodological quality, and low credibility of our results, future, more conclusive, multicenter RCTs with a high methodological quality are required to validate the present results.