Efficacy and safety of Guipi Decoction combined with conventional Western medicine in the treatment of insomnia with deficiency of heart and spleen: a meta-analysis

Objective: To systematically evaluate the efficacy and safety of Guipi Decoction combined with Western medicine in the treatment of insomnia with deficiency of heart and spleen. Methods: English databases (PubMed, Web of Science, The Cochrane Library, EMBASE) and Chinese databases (CNKI, Wanfang database, China Biomedical Literature Service System, VIP database) were searched by computer. Randomized controlled trials of Guipi Decoction on insomnia with deficiency of heart and spleen were searched from the database construction to November 2021.After the first and second authors independently screened the literature, extracted the data and evaluated the risk of bias in the included studies, meta-analysis was performed using RevMan5.3 software. Results: A total of 9 RCTS were included after screening, including 914 patients.Meta-analysis results showed that: Total effective rate [RR=1.22,95%CI (1.16,1.30), P < 0.00001], total PSQI score [MD=-3.05,95%CI (-3.96, -2.14), P =0.008], number of night awakening times [[MD=-1.18, 95%CI(-1.42, -0.94), P < 0.00001], adverse reaction rate [RR=0.32, 95%CI (0.21,0.51), P < 0.00001] were better than the control group, and the differences were statistically significant. Conclusion: The current evidence shows that, compared with pure using conventional western medicine, belongs to the spleen decoction combined western medicine therapy, cases both deficiency type of insomnia in the total effective rate, reducing the total PSQI score (improve sleep quality, sleep efficiency, sleep disorder, daytime function, etc.), reducing frequency of nighttime awakening, security, have more advantages. However, due to the limitation of the quality and quantity of articles included in the study, more randomized, double-blind, large-sample clinical studies are needed to confirm the above conclusions.


Introduction
Insomnia is very common in modern society, the definition is in good sleep environment, under the condition of patients with at least three times a week or more sleep disorder, sleep to start or maintain disorder patients, and more than a month, and because of insufficient sleep and sleep quality and cause severe pain or damage of the daily activities [1].Epidemiological studies show that in western countries, one-third of adults experience difficulty in initiating or maintaining sleep at least once a week, the annual incidence of insomnia is 30.7%, and the incidence of insomnia syndrome is 7.4%, and the incidence of women is higher than that of men [2].At present, the specific factors that cause insomnia to persist are not fully determined, but include anxiety about sleep, poor sleep habits and other possibilities [2].
For primary insomnia, western medicine is mainly through hormone replacement therapy, with anti-anxiety and sedative hypnotic maintenance, which has a good effect on the treatment of the disease [3].Western drugs such as estazolam, zopicone, diazepam, etc are commonly used.However it often makes patients dependent on the drug.Withdrawal is very likely to relapse or even more serious, and after long-term use, prone to headache, dizziness, nausea, gastrointestinal discomfort, weakness and other side effects [4].The understanding of insomnia in TRADITIONAL Chinese medicine began in Huangdi Neijing, which also called insomnia "sleepless" and "eye not sleep".Huangdi Neijing attaches importance to the significance of sleep in human life activities, which believes that sleep is a physiological adjustment of human body to adapt to the changes of day and night in nature, and that the reason for insomnia is that Yang does not enter Yin [5].In clinical most patients due to spleen deficiency qi weak, or fatigue injury spleen, or excessive thinking, fatigue and spleen, will cause the lack of biochemical source of qi and blood, camp blood deficiency deficiency, resulting in restlessness, insomnia [6].Traditional Chinese medicine for insomnia patients with deficiency of heart and spleen, on the basis of a variety of prescriptions, plus or minus or combined, has also achieved good therapeutic effects, such as guipi decoction, baizi heart-nourishing pill, ciwujia injection, etc [7].Clinical trials show that when we use Traditional Chinese medicine to treat insomnia of deficiency of heart and spleen, the side effects and adverse reactions are much smaller , so it is a very effective complementary treatment [8].
Guipi decoction is one of the first choice for the treatment of insomnia with deficiency of heart and spleen, and the research shows that [9], guipi decoction combined with conventional Western medicine in the treatment of insomnia with deficiency of heart and spleen is better than the simple use of western medicine, which can stabilize the patient's condition faster and improve the sleep quality of patients.In recent years, there have been more and more studies on guipi decoction in the treatment of insomnia with deficiency of heart and spleen, but the sample size is relatively small, and the literature quality and efficacy have not been systematically evaluated.Therefore, this paper conducted a meta-analysis on the randomized controlled trial of Guipi decoction combined with conventional Western medicine to provide a reliable evidence-based basis for clinical work and scientific research.

Inclusion Criteria
Study Types Only RCTs were included in this study, regardless of whether blind method was used, and the languages were limited to Chinese and English.

Research object
The subjects of the study had diagnostic criteria of TCM or Western medicine for insomnia and TCM syndrome type of deficiency of heart and spleen, and patients with serious primary diseases such as cardiovascular, lung, liver, kidney and hematopoietic system were excluded.Interventions Test group: Guipi decoction combined with conventional western medicine was used for treatment.The dosage form was traditional Chinese medicine decoction, and the quantity, dosage and course of medicine were not limited; Control group: conventional western medicine treatment, medication frequency and dosage and use course were not limited.Outcome Indicators Main outcome indicators: total effective rate which was evaluated according to the guiding principles for clinical research of new Chinese medicine released by the ministry of health in 2002 [10]; Secondary outcome measures: total PSQI score, number of nocturnal awakenings, and adverse drug reactions.Exclusion criteria ① For repeated publications, only the earliest publications were included; ②Literature without relevant outcome indicators; ③The type of published articles is abstract or the relevant data in the article is incomplete, but the relevant data cannot be obtained by contacting the author; ④Studies with a high-risk Random method; ⑤Studies with unclear diagnostic criteria; ⑥The dosage forms of Traditional Chinese medicine are pill, granule, etc.

Retrieval Strategy
PubMed, Web of Science, The Cochrane Library, EMBASE, CNKI, Wanfang Database, China Biomedical Literature Service System and VIP database were searched by computer, and the retrieval time was established until November 2021.Keywords and free words are combined in the retrieval.Chinese keywords include: gui pi tang, shimian, shuimian zhang'ai, etc. English keywords include: guipi decoction、decoction for invigorating the spleen、 Guipi soup 、 spleen-invigorating soup 、 insomnia 、 agrypnia 、 insomnia、featuring bobby、hyposomnia etc. Taking PubMed as an example, the specific retrieval strategy is shown in Table 1.

Bias risk assessment of included studies.
The risk of bias for included RCTs was assessed independently by the first and second authors and the results were cross-checked.If there is any discrepancy in the evaluation, discuss and resolve it with a third party.The RCT bias risk assessment tool recommended by Cochrane Manual 5.1.0was used to evaluate the risk of bias [9].

Statistical Analysis.
Meta-analysis was performed using RevMan5.3software provided by the Cochrane collaboration.For continuous variables, if the units of measurement indicators or tools are the same, mean difference (MD) is used for analysis; If measurement tools or units are inconsistent, standardized mean difference (SMD) is used for analysis.If the research data are dichotomous variables, relative risk (RR) is used as the statistic χ2 test was used to test heterogeneity and was combined I2 Quantitative determination of heterogeneity.If P ＞ 0.10, I2 ＜ 50%, there was no significant heterogeneity between studies, and a fixed-effect model was used for meta-analysis.If P ＜ 0.10, I2 ＞ 50%, indicating significant heterogeneity between studies, the cause of heterogeneity needs to a further analyzed.After excluding the influence of obvious clinical and methodological heterogeneity, the random-effect model is used for Meta analysis.Sensitivity analysis was used to observe the influence of single study on the combined effect size and judge the stability of meta-analysis results.When the number of outcome indicators included exceeded 10 studies, publication bias was evaluated by using RevMan5.3software to make funnel plots.

Literature screening process and results
After searching PubMed, Web of Science, The Cochrane Library, EMBASE, CNKI, Wanfang Database, China Biomedical Literature Service System and VIP database, 479 relevant literatures were obtained, and 300 literatures were obtained after picking out.270 reading titles and abstracts were initially screened out, 21 of the 30 articles were read in full and excluded, and 9 articles were finally included [11][12][13][14][15][16][17][18][19].Literature screening process is shown in Figure 1.

Meta-analysis results.
Total effective rate.[20].Each component score assesses a specific feature of sleep, and finally, the scores for each component are added to obtain an overall score, also known as the global score, with a higher PSQI score indicating poorer sleep quality [21].Six RCT [9][10][11][12]14,16]reported total PSQI scores, including 700 patients.There was statistical heterogeneity among studies [P < 0.00001, I2=92%].In order to analyze the source of heterogeneity, the characteristics of included RCTS were analyzed, and it was found that the western drugs used in included RCTS were different.Therefore, according to the name of western drugs, they were divided into three subgroups: ezolam tablet group, diazepam group and lorazepam group, and a random effect model was adopted.The results of Meta-analys is showed that the experimental group was superior to the control group in PSQI total score [MD=-3.05,95%CI (-3.96, -2.14), P=0.008].In the estazolam group, there was statistical heterogeneity in PSQI total score between the experimental group and the control group [P=0.0003,I2=88%],and there was significant difference in PSQI total score between experimental group and control group Submit a manuscript: https://www.tmrjournals.com/atr[MD=-4.34,95%CI(-6.07,-2.60),P < 0.00001]; In diazepam group, PSQI total scores of test group and control group showed statistical heterogeneity [P=0.09,I2=66%], and there was significant difference in PSQI total score between experimental group and control group [MD=-2.14,95%CI(-2.76,-1.52),P < 0.00001] ;In lorazepam group, there was statistical significance between experimental group and control group [MD=-3.05,95%CI(-2.03,-1.35),P<0.00001].Subgroup analysis showed that no matter which western medicine was used, the therapeutic effect of experimental group was better than that of control group (As shown in figure 4).

Incidence of adverse reactions
Adverse reactions were mentioned in 7 of the 8 studies [12][13][14][15][16]18,19].No adverse reactions occurred in the experimental group and the control group in Yang Yanhong's paper [19].The incidence of adverse reactions included dizziness, headache, drowsiness and fatigue, gait instability, nausea and vomiting, etc.With no significant heterogeneity among studies [P=0.20,I2=31%], using the fixed effect model,Meta-analysis showed that there was statistically significant difference in the incidence of adverse reactions between the experimental group and the control group [RR=0.32,95%CI(0.21,0.51),P< 0.00001] (Figure 6).It was shown thant the safety of experimental group is better than that of control group.

Sensitivity analysis
The sensitivity analysis of the above indicators was carried out by using the one-by-one elimination method, and the effect size and p-value changes were observed after the exclusion.For example, the total response rate, PSQI score, night awakening times, etc, excluding any literature, the effect size and P value of outcome indicators did not change significantly (P<0.05).So it was suggested that the results of Meta-analysis had good stability and reliability in these indicators.

Publication bias
The outcome index of total effective rate was included in only 8 of the 9 articles, so funnel plot could not be used to evaluate publication bias.

Discussion
From Chinese medical theory analysis, insomnia is due to deficiency of Yin blood mostly, and maladjusted heart, liver, spleen, kidney function can bring about mind to be disturbed and not sleep [20].The main and most common syndrome differentiation type of this disease is the deficiency of heart and spleen [21,22].For insomnia with deficiency syndrome, most need to supplement the source of biochemistry and regulate the mind, and guipi decoction is one of the common clinical drugs [23].
Guipi secoction originated from Jisheng Fang, which treated insomnia from the heart and spleen.In guipi soup, raw astragalus membranaceus can nourish qi, promote jin and nourish blood, and longan meat can nourish blood, calm the heart and strengthen the spleen, which are the king's medicine.Dangshen and stir-fried atractylodes macrocephala can warm and nourish qi, and the compatibility with raw astragalus membranaceus can strengthen the effect of invigorating spleen and supplementing qi.Angelica is known as "the first blood tonic medicine", and the compatibility of longan meat can give full play to the effect of nourishing qi and blood.Above three kinds of medicine for the minister.On this basis, adding and subtracting can make qi and blood biochemical active, heart and spleen treatment, then god can be safe, night can sleep [22].Guipi decoction mainly affects the digestive system, immune system and blood system through the coordination of active components such as astragaloside IV, longan polysaccharide, ginsenoside, Atractylodes atractylodes polysaccharide, ferulic acid, jujube rensaponin, Poria cocos polysaccharide, radix saponin, cocolactone, glycyrrhizic acid and so on, so as to play the role of invigorating spleen and invigorating qi [24].
This paper systematically evaluated 8 randomized controlled trials of guipi decoction combined with conventional Western medicine in the treatment of insomnia with deficiency of heart and spleen.The results of Meta-analysis showed that: (1) Compared with conventional western medicine alone, Guipi decoction combined with conventional western medicine could improve the total clinical effective rate, and the sensitivity analysis was stable.The subgroup analysis showed that: regardless of the course of treatment, after treatment, the efficacy of the experimental group was better than the control group.(2) In terms of PSQI score, the efficacy of the experimental group was better than that of the control group, indicating that the sleep quality of the patients was improved.Subgroup analysis showed that the efficacy of the esazolam group was the best, followed by the diazepam and lorazepam groups.After sensitivity analysis, the analyzed indicators had good stability and reliability.(3) In terms of reducing the number of night awakenings, the efficacy of the experimental group was superior to that of the control group, indicating that the patients' sleep at night was stable and their sleep quality was improved to some extent, and the sensitivity analysis was stable, indicating that the efficacy was reliable.(4) In terms of the incidence of adverse reactions, both groups had symptoms such as dizziness, headache, drowsiness and fatigue, gait instability, nausea and vomiting.But compared with the control group, the experimental group had higher safety, relatively low incidence of adverse reactions, and stable sensitivity analysis, indicating the reliability of the analysis results.
At the same time, this study has some limitations :(1) the quality of the included studies is low, and there are few descriptions of allocation hiding schemes and blind methods, which may have bias and influence on the reliability of the results.(2) The accuracy of the results was affected by the small sample size of the included studies and the insufficient test efficiency.(3) The included studies were all from China, with regional limitations and poor universality.(4) Follow-up after treatment was not reported in all studies, which is insufficient to judge the long-term efficacy and safety of drugs.(5) Due to the differences in dosage of Guipi Decoction among different studies, the heterogeneity among the studies was increased.
Current evidence proves that Guipi decoction combined with conventional western medicine in the treatment of insomnia patients with deficiency of heart and spleen can improve the total effective rate, reduce the total score of PSQI, reduce the number of night awakenings, and reduce the rate of adverse reactions.However, due to the limitations of the quality and quantity of included studies, more high-quality studies are needed to confirm the above conclusions.

Figure 2 Figure 3
Figure 2Bias risk assessment of included studies

Figure 4
Figure 4 Meta-analysis of PSQI total score comparison between experimental group and control group in the treatment of insomnia with deficiency of heart and spleen.number of night awakenings The number of night awakenings reflects the patient's sleep to a certain extent.The less the number of night awakenings, the better the sleep quality.3RCTS[11-13]reported the number of night awakenings,including 305 patients.There was no statistical

Figure 5
Figure 5 Meta-analysis of treatment of insomnia with deficiency of heart and spleen in experimental group and control group to reduce the number of nocturnal awakening

Table 2 ,
including authors, course of disease, course of treatment, age of patients, ratio of male to female, outcome indicators and diagnostic criteria of diseases, etc.The intervention characteristics and guipi decoction composition of the Submit a manuscript: https://www.tmrjournals.com/atrexperimentalgroupwere different as shown in Table3.In Zhu Xianzhou and Wang Yanqing's articles

Table 2 Basic characteristics of included studies
Total effective rate ② total PSQI scores.③number of night awakening times.④ Incidence of adverse reactions.a. Clinical diagnostic criteria of Psychiatric Classification Scheme and Diagnostic Criteria compiled in 1995.b.Diagnostic standards for insomnia of Psychiatry Society of Chinese Medical Association.c. Relevant diagnostic standards for insomnia of TCM Diagnosis and Efficacy Standards.d.Relevant diagnostic standards for Insomnia of Chinese Insomnia Diagnosis and Treatment Guidelines.e. Relevant diagnostic standards for Insomnia of TCM Clinical Practice Guidelines.f.Related diagnostic criteria in Internal Medicine of Traditional Chinese Medicine (edited by Zhou Zhongying).g.Syndrome differentiation criteria in Guiding Principles for Clinical Research of New Chinese Medicine (2002 edition) on syndrome differentiation of deficiency of heart and spleen h.Refer to Guiding Principles of Clinical Research on TCM New Drugs for Insomnia.i. Refer to The Chinese Classification and Diagnostic Criteria for Note: T: test group; C: control group;NA: Not mentioned; ① Mental Disorders Submit a manuscript: https://www.tmrjournals.com/atr