Acupuncture combined with Buyang Huanwu decoction in the treatment of sequelae of cerebrovascular accident:a systematic review and meta-analysis

Shao-Fu Yu, Yun-Yun Wang, Qi-Yuan He, Lei Zhang, Ying-Hui Jin, Bo-Xuan Liu, Jian-Ping Gong, Li-Ming Tan

1Department of Clinical Pharmacy, the Second People's Hospital of Huaihua, Huaihua 418000, China.2Center for Evidence-Based and Translational Medicine, Zhongnan Hospital of Wuhan University, Wuhan 430071, China.3Key Laboratory of Ministry of Education for Medicinal Plant Resource and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an 710119, China.4Precision Medicine Center, the Second People's Hospital of Huaihua, Huaihua 418000, China.5The Second People's Hospital of Huaihua, Huaihua 418000, China.

Abstract

Keywords:Acupuncture, Buyang Huanwu decoction, Sequelae of cerebrovascular accident, Randomized controlled trials, Clinical efficacy, Nerve function

Background

Cerebrovascular accident (CVA) is a neurologic syndrome caused by abnormal cerebral circulation that lasts more than 24 hours, which can be divided into two types (ischemic or hemorrhagic) [1], with high morbidity, high disability, high mortality, and high recurrence rate, with multiple sequelae [2].Sequelae of cerebrovascular accident (SCVA) mainly include cognitive, language, motor, and neurologic dysfunctions [3], bringing a heavy burden to the patient, the family, and the society [4].

Buyang Huanwu decoction (BYHWD) is a classic prescription of traditional Chinese medicine (TCM) for treating SCVA, such as language, motor, and neurologic dysfunctions, pharmacologically improving blood rheology, exhibiting anti-thrombotic effects,dilating blood vessels, and promoting nerve regeneration; along with the basic prescription of Radix astragali, R.angelicae sinensis, R.paeoniae rubra, Lumbricus, Rhizoma chuanxiong, Flos carthami,Semen persicae [5, 6].As an essence of TCM in treating SCVA, such as cognitive, language, and motor dysfunctions, acupuncture therapy has the mechanism of action of improving cerebral blood supply,alleviating cerebral edema and inflammation reaction,reducing cell apoptosis, and improving neurologic function [7].

Clinical studies on the combination of acupuncture and BYHWD in treating SCVA have been reported.The purpose of this study is to evaluate the efficacy and safety of acupuncture combined with BYHWD in treating SCVA through systematic review and meta-analysis.

Methods

Inclusion criteria

Study design.Randomized controlled trials (RCTs).

Participants.Patients diagnosed as having SCVA through the “Diagnostic Criteria of Integrated Traditional Chinese and Western Medicine for Cerebral Infarction and Cerebral Hemorrhage (Trial)”[8] issued by the Professional Board of the Neurology Department of Chinese Association of Integrative Medicine.

Interventions.The treatment group was treated with acupuncture combined with BYHWD, and there was no restriction on acupuncture methods (including special acupuncture methods, such as electro-acupuncture and fire acupuncture), and the basic BYHWD prescription can be modified according to the patient's condition of` illness.The control group was treated with acupuncture alone in the same manner as the treatment group.

Outcomes.(1) Clinical efficacy (the effectivity rate =effective cases/total cases × 100%) was divided into effective (cured, significantly effective, SCVA improvement) and ineffective levels.The evaluation criteria [9] for clinical efficacy are shown in Supplementary Table 1.(2) The degree of nerve function impairment was evaluated using the National Institutes of Health Stroke Scale (NIHSS) for patients with SCVA.(3) Daily self-care capacity was evaluated using the Barthel scoring method for patients with SCVA.(4) Fugl-Meyer locomotor function score was used to evaluate the locomotor function of patients with SCVA.(5) Life quality score was determined using the Short Form Health Survey Scale (SF-36 scale)for patients with SCVA.The researchers also examined the occurrence of adverse reactions after the indicated treatment methods.

Exclusion criteria

(1) Trials wherein the interventions included routine Western medicine treatment or acupoint injection,acupoint catgut embedding, acupoint application,moxibustion, and other non-acupuncture treatments; (2)trials with missing or incomplete data, or were not available when the original author was contacted; (3)trials that are repeatly published, and only the latest trials were included; and (4) trials that were published in non-Chinese and non-English publications were excluded from the study.

Search strategy

Relevant RCTs involving the use of acupuncture combined with BYHWD to treat patients with SCVA were comprehensively retrieved from electronic databases from inception to May 8, 2020, including PubMed, Embase, The Cochrane Library, China National Knowledge Infrastructure, WanFang Data,and China Science and Technology Journal Database.The following search terms were used to combine searches:(stroke OR apoplexy OR apoplexia OR apoplectic OR cerebral infarction OR cerebral hemorrhage OR intracranial thrombosis OR cerebral thrombosis OR cerebrovascular accident OR cerebrovascular disease) AND (acupuncture OR acupuncture therapy OR acupuncture point OR acupoint OR acutherapy OR acutreatment) AND(Buyang Huanwu decoction OR Jiawei Buyang Huanwu decoction OR modified Buyang Huanwu decoction).The Boolean indicator “OR” was repeatedly used between the search terms of each set of keywords, and the Boolean indicator “AND” was used to connect the three sets of keywords.Additionally, we also searched the reference lists of all eligible studies,previous systematic reviews, and meta-analyses for additional relevant studies.The search strategy on PubMed is presented as an example in Supplementary Table 2.

Study selection and data extraction

Two researchers (Shao-Fu Yu and Yun-Yun Wang)independently selected all articles using the PRISMA flow diagram according to the inclusion and exclusion criteria, and we resolved disagreements through a consensus meeting with a third researcher (Ying-Hui Jin).Data extraction was independently conducted by two investigators (Shao-Fu Yu and Bo-Xuan Liu),extracted information on the first author, year of publication, sample size, gender, age, disease course,SCVA, interventions, and outcomes were recorded in an electronic data extraction form, and disagreements were resolved through a consensus meeting with a third investigator (Li-Ming Tan).

Risk of bias assessment

Two authors (Shao-Fu Yu and Jian-Ping Gong)independently assessed the methodological quality of the included RCTs using the criteria described in the Cochrane Handbook for Systematic Reviews of Interventions (Version 5.2.0)(https://training.cochrane.org/handbook/PDF/v5.2/chap ter-08), and the risks of bias were classified as low,high, or unclear risks of bias.Disagreements were resolved through a consensus meeting with a third author (Lei Zhang).

Statistical analysis

Meta-analysis was performed using the Stata/SE 12.0 software.Descriptive analysis was conducted when quantitative integration among studies was impossible.Binary data and continuous data were estimated through relative risk (RR) assessment with 95%confidence interval (CI) and weighted mean difference(WMD) with 95% CI, respectively.Chi-square andI2tests were used to evaluate the heterogeneity among the included trials.The fixed-effect model was applied to pool the data when high homogeneity among the included trials existed withP> 0 andI2≤ 50%.Otherwise, the random-effect model was used [10].Z-test was performed to evaluate the significance of the pooled effects, and statistical differences were determined at aP< 0.05 level of significance.When more than 20 trials were included for one outcome,Begg’s funnel plot was drawn to analyze if there was publication bias.

Figure 1 PRISMA flow diagram of the selection process of the studies included in the systematic review and meta-analysis

Results

Selection of studies

After systematically searching electronic databases from inception to May 8, 2020, including PubMed,Embase, The Cochrane Library, China National Knowledge Infrastructure, WanFang Data, and China Science and Technology Journal Database, a total of 2,653 records were retrieved, and a total of 28 RCTs[11–38] (N = 2,341 patients with SCVA) met the eligibility criteria and were included.The PRISMA flow diagram is shown in Figure 1.

Study characteristics and quality assessment

The baseline characteristics of all included trials are described in Table 1.The included studies had different degrees of bias as determined through methodological quality assessment.A total of 22 studies [12, 14–22,25–27, 29–34, 36–38] did not specify the method of random sequence generation and were judged as“unclear risk”.Three studies [11, 13, 28] were judged as “l(fā)ow risk” with “random number method”, and another three studies were judged as “high risk” of“false random” with “hospitalized single and double number random method” [23], “consultation sequence numbering method” [24], and “random selection method” [35], respectively.All included studies did not mention allocation concealment and blinding and were judged as “unclear risk”.In terms of incomplete outcome data, two studies [18, 27] did not report complete data and were judged as “high risk”, and the remaining studies were judged as “l(fā)ow risk”.All included studies did not describe selective outcome reporting and other sources of bias and were wholly judged as “unclear risk”.The methodology quality assessment of the included studies is shown in Table 2.

Meta-analysis

Clinical efficacy.A total of 26 studies [11–16, 18–25,27–38] (N = 2,231 patients with SCVA) reported the comparison of the clinical efficacy of the treatment group (acupuncture combined with BYHWD) with the control group (acupuncture).There was a significant statistical difference between the clinical efficacy of the treatment group and the control group in the studies(RR = 1.19, 95% CI (1.14, 1.23),P< 0.001),indicating that patients with SCVA receiving acupuncture treatment plus BYHWD performed better in terms of clinical efficacy than those who only received acupuncture treatment (Figure 2).

The degree of nerve function impairment according to the National Institutes of Health Stroke Scale(NIHSS).Eight RCTs [14, 17–20, 27, 34, 38] (N = 499 patients with SCVA) reported the comparison of the improvement of nerve function impairment in the treatment group and the control group.In one RCT[18], the scoring method of the outcome was contrary to other studies; and in another RCT [34], the evaluation tool of the outcome was different from other studies; whereas in a third study [27], the specific score of the degree of nerve function impairment was not described; hence, they could not be pooled for meta-analysis.The results of the quantitative analysis for the remaining five studies [14, 17, 19, 20, 38]showed that acupuncture treatment plus BYHWD was more beneficial for improving the nerve function impairment of patients with SCVA than acupuncture treatment alone (WMD = -4.89, 95% CI (-8.25,-1.53),P= 0.004) (Figure 3).

Daily self-care capacity according to the Barthel score.There were 11 trials [14, 17–20, 23, 29, 33, 34,37, 38] (N = 900 patients with SCVA) that described the data of improved daily self-care capacity in the treatment group and the control group.The results suggested that, compared with acupuncture alone,acupuncture plus BYHWD had more advantages in improving daily self-care capacity of patients with SCVA (WMD = 15.87, 95% CI (11.22, 20.51),P<0.001) (Figure 4).

Fugl-Meyer locomotor function score.Five RCTs[19, 23, 29, 37, 38] (N = 495 patients with SCVA)concentrated on the improved Fugl–Meyer locomotor function in both treatment and control groups.The results of the meta-analysis indicated that acupuncture treatment plus BYHWD can significantly enhance the Fugl–Meyer locomotor function score in patients with SCVA more than acupuncture treatment alone (WMD= 20.89, 95% CI (13.79, 27.98),P< 0.001) (Figure 5).

Life quality score according to the SF-36 scale.Five trials [13, 14, 26, 35, 38] (N = 485 patients with SCVA)compared the improvement of the life quality score of both treatment and control groups.Among them, two trials [13, 38] only described the total score of the SF-36 scale using the opposite scoring method, and the result of life quality score in another trial [26] did not match the description in the text; hence, they cannot be quantitatively pooled for meta-analysis.The remaining two studies [14, 35] had different scoring dimensions on the SF-36 scale with only two identical dimensions,physical functioning (PF) and mental health (MH),were analyzed in the subgroups.The result of the subgroup analysis manifested that acupuncture treatment plus BYHWD had considerably more advantages in improving the PF and MH dimensions in the life quality score of patients with SCVA, compared with acupuncture treatment alone (WMD = 16.99, 95%CI (6.01, 27.96),P< 0.001; WMD = 16.91, 95% CI(9.14, 24.69),P< 0.001) (Figure 6).

Occurrence of adverse reactions.One study [21]investigated adverse reactions, and its result prompted that the occurrence of adverse reactions in the control group was 32% among seven patients with SCVA involving gastrointestinal reactions, and nine patients with SCVA involving edema; and that of the treatment group was 12% among four patients with SCVA involving gastrointestinal reactions, and two patients with SCVA involving edema.Two studies [13, 24]pointed that no serious adverse reactions occurred in both groups.The remaining studies did not describe any occurrence of adverse reactions.

Table 1 Summary of baseline characteristics of included studies

Table 1 Summary of baseline characteristics of included studies (continued)

Table 1 Summary of baseline characteristics of included studies (continued)

Table 1 Summary of baseline characteristics of included studies (continued)

Table 1 Summary of baseline characteristics of included studies (continued)

Table 1 Summary of baseline characteristics of included studies (continued)

Table 1 Summary of baseline characteristics of included studies (continued)

Table 1 Summary of baseline characteristics of included studies (continued)

Table 1 Summary of baseline characteristics of included studies (continued)

Table 1 Summary of baseline characteristics of included studies (continued)

Table 1 Summary of baseline characteristics of included studies (continued)

Table 1 Summary of baseline characteristics of included studies (continued)

Table 1 Summary of baseline characteristics of included studies (continued)

Publication bias

There was evidence of publication bias with regard to relevant studies [11-16, 18-25, 27-38] involving clinical efficacy.Begg’s funnel plot was asymmetric,and one study was distributed outside 95% CI,indicating that there was a certain publication bias (Z>1.96,P< 0.05) (Figure 7).

Discussion

Summary of evidence

A total of 28 RCTs were included in this study,including 2,341 patients with SCVA.The results of the systematic review and meta-analysis indicated that,compared with acupuncture treatment alone,acupuncture treatment plus BYHWD can significantly increase the clinical efficacy, improve nerve function impairment, promote daily self-care capacity,strengthen Fugl-Meyer locomotor function, and enhance the life quality of patients with SCVA.Since only a few [21] of the included studies reported adverse reactions, the safety of acupuncture treatment plus BYHWD for patients with SCVA needs further confirmation.

Table 2 Methodology quality assessment of included studies

In the included studies, several outcomes were only reported by a single study; hence, the study cannot be pooled for quantitative analysis.However, it paved the way for further exploration of the outcomes.

One study [22] researched the effect of acupuncture treatment plus BYHWD on blood lipid profile and rheology before and after treatment in patients with SCVA of multiple lacunar infarction, with main outcomes such as cholesterol, triglycerides, whole blood high shear viscosity, low shear viscosity, and plasma viscosity; and the results showed that acupuncture treatment plus BYHWD can improve the blood lipid profile and rheology of patients with SCVA better than acupuncture treatment alone.

Several studies have shown the involvement of acute inflammation in the pathophysiology of cerebrovascular disease [39], and cerebrovascular diseases may induce the expression of various cytokines, such as TNF-α, IL-1, IL-6, IL-8, IL-10,fractalkine, and taurine upregulated gene 1, and may trigger inflammation and immune responses in patients with SCVA [40, 41].One [36] of the included trials detected the levels of inflammatory factors IL-1β and IL-6 in the serum of patients with SCVA of both treatment and control groups before and after treatment,and the results showed that serum IL-1 and IL-6 levels in the treatment group were significantly lower than those in the control group after 2 weeks and 4 weeks of treatment, indicating that the effects of electro-acupuncture treatment plus BYHWD on cytokine regulation was stronger than that of electro-acupuncture treatment alone, thereby providing strong evidence for further research on the cytokine mechanism of cerebrovascular disease.

Figure 2 Forest plot of the clinical efficacy of acupuncture treatment plus BYHWD vs.acupuncture alone

Figure 3 Forest plot of the degree of improvement of nerve function impairment of acupuncture treatment plus BYHWD vs.acupuncture alone

Figure 4 Forest plot of the daily self-care capacity of acupuncture treatment plus BYHWD vs.acupuncture alone

Figure 5 Forest plot of Fugl-Meyer locomotor function score of acupuncture treatment plus BYHWD vs.acupuncture alone

Figure 6 Forest plot of life quality score of acupuncture treatment plus BYHWD vs.acupuncture alone (PF,Physical Functioning; MH, Mental Health)

Figure 7 Begg's funnel plot for the publication bias test

Limitations

This study has the following limitations:(1) the sample sizes of all included trials were small, and there were few original studies that included certain outcomes,such as the degree of nerve function impairment,Fugl-Meyer locomotor function score, and life quality score, thereby reducing the accuracy of related outcomes; (2) most trials did not specify the random sequence generation method, and all included trials did not mention allocation concealment and blinding,indicating possible selection bias or performance bias;(3) most of the included trials did not describe the withdrawal or loss of patients with SCVA and follow-up sessions, and the studies did not perform any evaluation of long-term efficacy, suggesting possible attrition bias; and (4) finally, a high level of heterogeneity existed among the trials, with main reasons, such as (i) the inclusion criteria and exclusion criteria of cases among trials were not completely consistent; (ii) the disease severity, average course, and average age of patients with SCVA were different, and the possible interference of other basic diseases was unknown; (iii) there were differences in the specific procedure of acupuncture treatment methods,acupuncture manipulation, acupuncture points,acupuncture amount, needle retention time, interval time, and treatment course, as well as in BYHWD composition, TCM quality, decocting method,medication method, medication time, medication dosage, medication frequency, and medication course.

Implications

Although the results of this study indicated that acupuncture treatment plus BYHWD had a significantly more comprehensive effect on the condition of patients with SCVA than acupuncture alone, there were still several limitations (as mentioned in the previous text), which provided the following implications for future research:(1) the methodology section should be thoroughly optimized to reduce bias;(2) the effects of acupuncture manipulation,acupuncture points, needle retention time, BYHWD prescription, intake method, and course of treatment on the condition of patients with SCVA should be further explored; (3) additional research of TCM symptoms,hemorheology, and inflammatory mechanism of SCVA are necessary; (4) more attention should be given to the occurrence of adverse reactions during treatment and to further analysis of the safety of these treatment methods; (5) focus on the follow-up of patients with SCVA after treatment is necessary, as well as on the observation and evaluation of long-term efficacy; and(6) finally, it will be suitable to make the best treatment decision based on the specific conditions of patients with SCVA, such as age, disease course, disease severity, and the presence of other basic diseases.These implications will further provide better clinical guidance for TCM treatment of patients with SCVA.

Conclusion

In summary, the results of this study indicated that acupuncture treatment plus BYHWD had a better comprehensive effect on the condition of patients with SCVA than acupuncture treatment alone, and no obvious adverse reactions were reported.However, due to the small sample size and the limitation of quality of the included RCTs, as well as the high heterogeneity among several studies, the above conclusions need to be further confirmed by conducting a study with higher quality and larger sample size involving multi-center RCTs, which may provide strong evidence-based medical evidence for TCM diagnosis and treatment of patients with SCVA.