Meta-analysis of efficacy and safety of Qianliexin capsule combined with western medicine in benign prostatic hyperplasia treatment

Sheng-Nan Wang,Yi-Hua Fan,Shan Lin,Jin-Rui Wei,Sheng-Xuan Zhao,Qiao Liu,Kai Zhong*

1School of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China; 2First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, China; 3National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin 300381, China; 4School of Acupuncture and Massage, Tianjin University of Traditional Chinese Medicine,Tianjin 301617,China.

Abstract Objective: To systematically evaluate the efficacy and safety of Qianliexin capsule combined with western medicine in benign prostatic hyperplasia treatment. Methods: Randomized controlled trials of Qianliexin capsule combined with western medicine in the treatment of benign prostatic hyperplasia were searched from PubMed, the Cochrane Library,EMBASE, Web of Science, China National Knowledge Infrastructure,VIP,Wanfang and China Biomedical Literature Databases from establishment of the database to February 2021.Meta-analysis was performed using RevMan5.4 software after two researchers independently screened the literatures, extracted the data and evaluated the bias risks in the included studies according to the Cochrane Collaboration System Evaluator Manual. Results: 6 randomized controlled trials involving 1060 patients were included.Meta-analysis results showed that the treatment group was better than the control group in total effective rate(Relative Risk=1.19,95%Confidence Interval (1.10, 1.28), P < 0.00001), International Prostate Symptom Score (Mean Difference = -2.99,95%confidence interval(-4.00,-1.99),P<0.00001),prostate volume (Mean Difference=-3.77,95%Confidence Interval (-4.67, -2.86), P < 0.00001), postvoid residual urine volume (Mean Difference = -5.96, 95% Confidence Interval (-8.15, -3.77), P < 0.00001) and maximum urine flow rate (Mean Difference = 3.45, 95% Confidence Interval (2.53, 4.37), P < 0.00001).While there was no significant difference in the adverse effects rate (Relative Risk = 0.71, 95% Confidence Interval (0.33, 1.56), P = 0.40) between the treatment group and the control group.Conclusion: Qianliexin capsule combined with western medicine in the treatment of benign prostatic hyperplasia showed good efficacy and high safety.However,more high-quality and large-sample studies are needed to confirm the above conclusions.

Key words:Qianliexin capsule,Benign prostatic hyperplasia,Meta-analysis,Randomized controlled trial

Background

Benign prostatic hyperplasia (BPH) is the most common disease that causes micturition dysfunction in middle-aged and elderly men [1].It is mainly manifested as frequent urination, urgency of urination,difficulty in urination and dripping after urination [2,3], which may cause acute urinary retention, urinary tract infection, bladder stones, and even renal damage[4, 5].The prevalence of BPH increases with age, and the prevalence of 40~45 years old is about 60%,while that of 80 years old reaches 80% [6].Modern medical treatment of BPH mainly includes drug therapy,traditional surgery, minimally invasive treatment and so on [7].Drug therapy can be divided into α-receptor blockers and 5 α reductase inhibitors.However, there are certain side effects in drug therapy, for example,orthostatic hypotension, dizziness, headache, nasal obstruction, fatigue and ejaculation dysfunction for the α-receptor blockers, and erectile dysfunction,ejaculation dysfunction, decreased sexual desire,dizziness and upper respiratory tract infection for the 5 α reductase inhibitors.Therefore,it is necessary to find therapeutic materials for BPH [8].Traditional Chinese medicine has advantages in the prevention and treatment of BPH, especially in the improvement of symptoms,such as stable curative effect,small adverse reaction and low recurrence rate [9].The use of Chinese herbal medicine in the treatment of BPH has been a long time in various countries [10, 11].There have been more studies on the treatment of BPH with Qianliexin capsule.Qianliexin capsule is a Chinese patent medicine for the treatment of BPH caused by Qi stagnation and blood stasis [12].Studies have pointed out that the single use of Qianliexin capsule in the treatment of BPH has a certain efficacy with good safety, but the efficacy is not ideal.However, the combination of Qianliexin capsule and western medicine has a better efficacy than the single use of Qianliexin capsule [13].This study aims to evaluate the efficacy and safety of Qiaoliexin capsule combined with western medicine in the treatment of BPH through a meta-analysis system to provide a more sufficient evidence-based basis for the clinical application of Qiaoliexin capsule.

Information and methodology

Inclusion and exclusion criteria

Study type.Randomized controlled trials reported with Chinese and English,not limited to blind.

Study objects.patients with BPH.In this meta-analysis, the included studies adopted different diagnostic criteria.The following were referenced:Wu Jieping Urology (2004),Guidelines for Diagnosis and Treatment of Urological Diseases in China(2007),Diagnosis and Curative Effect Standard of TCM Disease Tyndrome,Guidelines for the Diagnosis and Treatment of BPH by Integrated Traditional Chinese and Western Medicine(Trial Version),Guidelines for the Clinical Diagnosis and Treatment of BPH,The Chinese Guidelines for the Diagnosis and Treatment of Urological Diseases(2014 Edition).Medical history collection, physical examination, routine urine, urinary flow rate, intravenous urography, urethral dynamics,etc were collected.The diagnostic criteria of each study were shown in Table 2.

Interventions.Treatment group: treatment of Qianliexin capsule combined with western medicine;Control group: western medicine routine treatment,such as fenasteride,tansorosin,etc.

Outcome indicators.Main outcome indicators: total effective rate, International Prostate Symptom Score(IPSS); Secondary outcome indicators: ①prostate volume (PV); ②postvoid residual urine volume(PVR); ③maximum urine flow rate (Qmax); ④adverse effects rate.

Exclusion criteria.①repeated publications; ②non-clinical studies, such as animal experiments; ③literatures that cannot obtain full text or extract data;④literatures in which other traditional Chinese medicine treatments, such as acupuncture, were used as interventions.

Search strategy

Searching related studies of Qianliexin capsule in the treatment of BPH from China National Knowledge Infrastructure, VIP, Wanfang, China Biomedical Literature Database, PubMed, the Cochrane Library,EMBASE and Web of Science, and the retrieval time was from establishment of the database to February 2021.The retrieval method was the combination of theme words and free words.The Chinese search words included: qian lie xian zeng sheng (prostatic hyperplasia), qian lie xian fei da (prostatic hypertrophy), qian lie xin jiao nang (Qianliexin capsule) and so on; English key words included:prostatic hyperplasia, enlargement of the prostate, qian lie xin capsule, etc.Take PubMed as an example, the specific retrieval strategies are shown in Table 1.

Literature Screening and Data Extraction

Two researchers were selected to independently screen the literature, extract the data and cross-check according to the inclusion and exclusion criteria.When the two sides had different opinions, the third researcher was involved in the discussion and negotiation to solve the problem.Firstly,the literatures that obviously did not meet the inclusion criteria were excluded by reading the title and summary.Then, the final inclusion literatures were determined by downloading and reading the full text.Data extraction included: first author, publication time, sample size of each group, course of disease, diagnostic criteria,intervention measures, outcome indicators, allocation methods,whether blind method was used,etc.

Risk assessment of bias in the included studies

This study used the randomized controlled trial bias risk assessment tool recommended in Cochrane manual 5.1.0 to evaluate the bias risk of the included studies, including generation of random methods,allocation concealment, blind methods, data integrity,selective reporting and other bias.The included studies were independently evaluated by two investigators and cross-checked.When the evaluation opinions were inconsistent, a third researcher was invited to discuss and solve the problem.Finally, the included literatures were evaluated as "high risk", "low risk" and"uncertain".

Statistical analysis

Revman 5.4 software provided by the Cochrane Collaboration was used for meta-analysis of the included literatures.For continuous variables, if the measurement tool and measurement unit were the same,mean difference (MD) was used as the statistic of effect analysis.When the measurement tools and measurement units were inconsistent, standardified mean difference was used as the statistic for effect analysis.Relative risk (RR) and 95% confidence interval (95% CI) were used as statistics for effect analysis.

Chi-square test combined withI2quantitative analysis was used to determine the heterogeneity and magnitude of the results.IfP≥0.1 andI2≤50%, there was no significant heterogeneity between studies, and a fixed effects model was used for meta-analysis.IfP< 0.1 andI2> 50%, significant heterogeneity existed between studies.The sources of heterogeneity were analyzed.Subgroup analysis was performed on the data that might cause high heterogeneity, and the random effects model was used for meta-analysis.The level of meta-analysis was set at α = 0.05.When the number of included studies was ≥10,funnel plots were used to determine whether there was publication bias.P<0.05 was considered statistically significant.

Table 1 PubMed Retrieval strategy.

Results

Literature screening process and results

A total of 98 articles were retrieved from the database,and 49 articles were obtained after excluding repetitive studies.36 articles were excluded after preliminary screening of reading topics and abstracts,and 7 articles were excluded after reading the full text of the remaining 13 articles.Finally, 6 articles related to research were included.The literature screening process is shown in Figure 1.

Basic characteristics of the included studies

The literatures included were all reported with Chinese,including 1060 patients.The treatment group was Qianliexin capsule combined with routine treatment of western medicine, and the control group was routine treatment of western medicine.The treatment period of each study was 1~3 months.Four studies [15−17, 19]reported total effective rate; six studies [14−19]reported IPSS; six studies [14−19] reported PV; six studies [14−19] reported PVR; six studies [14−19]reported Qmax; four studies [16−19] reported the adverse effects rate.The basic characteristics of included literatures in the study are shown in table 2.

Risk of bias assessment results of included studies

Among the 6 included literatures, 3 [16−18] correctly used the method of random sequence generation,1[15]assigned according to the odd-even number of admission and was evaluated as high risk of bias,and 2[14,19]did not mention the specific allocation method and was evaluated as unclear.No allocation concealment scheme or blind method was mentioned in any literature [14−19].One study [18] reported missing data, including 3 cases in the treatment group and 2 cases in the control group; and the study were evaluated as low risk of bias due to the missing data of the two groups were comparable.While, the other studies [14−17, 19] were evaluated as low risk.In terms of selective reporting and other biases, all literatures[14−19]were evaluated as having a low risk of bias.The evaluation results of bias risk are shown in Figure 2.

Figure 1 Literature screening process and results

Table 2 Basic characteristics of included studies

Figure 2 Bias risk assessment of included studies

Figure 3 The total effective rate for benign prostatic hyperplasia

Meta analysis results

Total effective rate.Four studies [15−17, 19]involving 419 patients reported total effective rate.The analysis results showed that there was no heterogeneity between the studies (P= 0.64,I2= 0%) and the fixed-effect model was used.The results showed that RR = 1.19, 95% CI (1.10, 1.28),P< 0.00001,indicating that the difference in total effective rate between the treatment group and the control group was statistically significant.As shown in figure 3.

IPSS.Six studies [14−19] involving 1055 patients reported IPSS.The analysis showed that there was significant heterogeneity among the studies (P<0.00001,I2= 93%), and the random effects model was used for analysis.Meta analysis results showed that the difference of IPSS between the treatment group and the control group was statistically significant (MD =-2.99, 95% CI (-4.00, -1.99),P< 0.00001).According to the course of medication,they were divided into two subgroups: 1-month group, 3-month group.In the 1-month group,the results of heterogeneity test wereP=0.001,I2=91%.The average course of disease in the study of Gao Zhan[18]was 20 months and the average age was 70 years, while the average course of disease in the study of Zhao Xiaoshun[19]was 5 years and the average age was 65 years,which may be the reason for the large heterogeneity of the studies.However, as there were only two studies in the 1-month group,subgroup analysis could not be performed, and the results showed that there was no statistically significant difference in IPSS between the treatment group and the control group (MD = -2.06, 95% CI(-4.26, 0.14),P= 0.07).In the 3-month group, the results of heterogeneity test wereP< 0.00001,I2=94%.The average course of disease of the patients studied by Cheng Jun [14] and Wang Chunxian [15]was 3 years, and the average course of disease of the patients studied by Xu Mengkang [17] was 4 years,which may be the reason for the large heterogeneity of the studies.However, since the average course of disease of the patients was not mentioned in the study of Wu Huajun [16], subgroup analysis could not be carried out.The results showed that the difference of IPSS between the treatment group and the control group was statistically significant (MD = -3.41, 95%CI(-4.71,-2.11),P<0.00001).As shown in figure 4.PV.Six studies [14−19] involving 1055 patients reported PV.The analysis showed that there was significant heterogeneity among the studies (P= 0.01,I2= 67%), and the random effects model was used for analysis.Meta analysis results showed that the difference of PV between the treatment group and the control group was statistically significant(MD=-3.77,95% CI (-4.67, -2.86),P< 0.00001).They were divided into two subgroups according to the duration of medication: 1-month group, 3-month group.In the 1-month group,the results of heterogeneity test wereP= 0.04,I2= 76%.The average course of disease in the study of Gao Zhan[18]was 20 months and the average age was 70 years, while the average course of disease in the study of Zhao Xiaoshun[19]was 5 years and the average age was 65 years,which may be the reason for the large heterogeneity of the study.However, as there were only two studies in the 1-month group, subgroup analysis could not be performed.The results showed no statistically significant difference in PV between the treatment group and the control group (MD = -2.98,95%CI(-8.44,2.48),P=0.28).In the 3-month group,the results of heterogeneity test wereP=0.38,I2=2%,and the difference of PV between treatment group and control group was statistically significant(MD=-3.27,95% CI (-3.63, -2.91),P< 0.00001).As shown in figure 5.

Figure 4 The international prostate symptom score for benign prostatic hyperplasia

Figure 5 Prostate volume for benign prostatic hyperplasia

Figure 6 The postvoid residual urine volume between the treatment group and the control group for benign prostatic hyperplasia

PVR.Six studies [14−19] involving 1055 patients reported PVR.The analysis showed that there was significant heterogeneity among the studies (P<0.00001,I2= 94%), and the random effects model was used for analysis.Meta analysis results showed that the difference of PVR between the treatment group and the control group was statistically significant(MD =-5.96,95% CI (-8.15, -3.77),P< 0.00001).They were divided into two subgroups according to the duration of medication: 1-month group, 3-month group.In the 1-month group,the results of heterogeneity test wereP= 0.03,I2= 79%.The average course of disease in the study of Gao Zhan[18]was 20 months and the average age was 70 years, while the average course of disease in the study of Zhao Xiaoshun[19]was 5 years and the average age was 65 years, which may cause the large heterogeneity of the studies.However, as there were only two studies in the 1-month group, subgroup analysis could not be performed.The results showed that the difference in PVR between the treatment group and the control group was not statistically significant(MD = -4.86, 95% CI (-11.30, 1.57),P= 0.14).In the 3-month group,the results of heterogeneity test wereP< 0.00001,I2= 96%.The average course of disease of the patients studied by Cheng Jun [14] and Wang Chunxian [15] was 3 years, and the average course of disease of the patients studied by Xu Mengkang [17]was 4 years, which may be the reason for the large heterogeneity of the studies.However, since the average course of disease of the patients was not mentioned in the study of Wu Huajun [16], the subgroup analysis could not be carried out.The results showed that the difference of PVR between the treatment group and the control group was statistically significant (MD = -6.13, 95% CI (-8.65, -3.61),P<0.00001).As shown in figure 6.

Qmax.Six studies [14−19] involving 1055 patients reported Qmax.The analysis showed that there was significant heterogeneity among the studies (P<0.00001,I2= 91%), and the random effects model was used for analysis.Meta analysis results showed that the difference of Qmax between the treatment group and the control group was statistically significant (MD =3.45, 95% CI (2.53, 4.37),P< 0.00001).They were divided into two subgroups according to the duration of medication: 1-month group, 3-month group.In the 1-month group,the results of heterogeneity test wereP= 0.08,I2= 68%.The average course of disease in the study of Gao Zhan[18]was 20 months and the average age was 70 years, while the average course of disease in the study of Zhao Xiaoshun[19]was 5 years and the average age was 65 years, which may lead to the large heterogeneity of the studies.However, as there were only two studies in the 1-month group, subgroup analysis could not be performed, and the results showed that the difference in Qmax between the treatment group and the control group was not statistically significant (MD = 2.24, 95% CI (0.64,3.84),P= 0.006).In the 3-month group, the results of heterogeneity test wereP< 0.00001,I2= 93%.The average course of disease of the patients studied by Cheng Jun [14] and Wang Chunxian [15] was 3 years,and the average course of disease of the patients studied by Xu Mengkang [17]was 4 years, which may be the reason for the large heterogeneity of the studies.However, since the average course of disease of the patients was not mentioned in the study of Wu Huajun[16], the subgroup analysis could not be carried out.The results showed that the difference of Qmax between the treatment group and the control group was statistically significant (MD = 3.93, 95% CI (2.87,4.98),P<0.00001).As shown in figure 7.

Figure 7 The maximum urine flow rate for benign prostatic hyperplasia

Figure 8 The adverse effects rate of the treatment group and the control group for benign prostatic hyperplasia

Sensitivity analysis.To evaluate the stability of the results of this study, a one-by-one elimination method was used to analyze the sensitivity of the above outcome indicators.When the PV was analyzed, it was found that when Zhao Xiaoshun's study was excluded[19],the heterogeneity changed fromP=0.01,I2=67%toP= 0.29,I2= 19%.When analyzing the Qmax, it was found that when Wu Huajun's study was excluded[16], the heterogeneity changed fromP< 0.00001,I2=91% toP= 0.03,I2= 61%.In the 3-month group, the heterogeneity changed fromP< 0.00001,I2= 93% toP= 0.21,I2= 37%, butPvalues of all outcome indicators did not fluctuate significantly (P< 0.05),and the direction of the combined results did not change, suggesting that the meta-analysis results were stable despite the significant heterogeneity of these outcome indicators in the process of merger.

Publication bias.The Begg's test and Egger's test were used to evaluate the publication bias of the total effective rate and IPSS,and the results showed that the total effective rate had publication bias (Begg's test =0.042, Egger's test = 0.006), while IPSS had no publication bias (Begg's test = 0.188, Egger's test =0.482).

Discussion

Benign prostatic hyperplasia is the benign growth of the prostate, characterized by the proliferation of smooth muscle, epithelium and connective tissue [20].There are many etiology and pathogenesis, but no unified conclusion has been reached, among which there are more researches on hormone endocrine theory,growth factor theory, epithelial-mesenchymal cell interaction theory,apoptosis and gene regulation theory,inflammation theory and so on[21].In a 2012 analysis of 12.2 million patients with BPH, more than half of them chose Western drugs [22].According to different etiological theories, commonly used therapeutic drugs include 5α reductase inhibitors, androgen receptor antagonists, α receptor blockers, etc.However,long-term medication is needed, the cost is high, and there are certain adverse drug reactions [23−25].Traditional Chinese medicine (TCM) is one of the important methods for clinical treatment of BPH [26],and TCM believes that BPH is closely related to dampness, heat and blood stasis [27−30].Qianliexin Capsule was collected in theChinese Pharmacopoeiain 2010.It is mainly composed of Danshen (Radix Salviae Miltiorrhiae), Honghua (Flos Carthami),Wangbuliuxing (Semen Vaccariae), Zaojiaoci (Spina Gleditsiae), Gouqizi(Fructus Lycii)and other drugs.It has the effect of promoting blood circulation and removing blood stasis, clearing heat and removing dampness, and is clinically used to treat BPH caused by blood stasis and dampness-heat [31].Among them,the flavonoid glycosides extracted fromSemen Vaccariaeand salvianolic acid B extracted fromRadix Salviae Miltiorrhiaecould inhibit the synthesis of prostatic DNA and reduce the contents of prostate-specific antigen, acid phosphatase and testosterone in serum of rats [31];Flos Carthamiextract treated BPH by inhibiting type I and Ⅱ 5α reductase [32]; Saponins extracted fromSpina Gleditsiaecan reduce the expression of proliferating nuclear antigen and basic fibroblast growth factor in prostate tissue, and thus inhibit the proliferation of prostate cells in the process of prostate hyperplasia[33]; The extract ofFructus Lyciican treat BPH by inhibiting the proliferative activity of human prostate cancer PC3 cells[34].

A total of 6 randomized controlled trials [14−19]were included in this study to evaluate the efficacy and safety of Qianliexin capsule in the treatment of BPH from six aspects, including total effective rate, IPSS,PV, PVR, Qmax, and adverse effects rate.Meta analysis results showed that:(1)The total effective rate,IPSS, PV, PVR, and Qmax were all superior to the routine treatment with western medicine; (2) There was significant heterogeneity in IPSS, PV, PVR, and Qmax.The 1-month group, the average course of disease of the patients studied by Gao Zhan [18] was 20 months with an average age of 70 years, while the average course of disease of the patients studied by Zhao Xiaoshun [19] was 5 years with an average age of 65 years, which may be the reason for the large heterogeneity of the study.However, since there were only two studies in the 1-month group, subgroup analysis could not be carried out, so random effects model was adopted for analysis.In the 3-month group of IPSS, PVR, and Qmax, the average course of disease of the patients studied by Cheng Jun [14] and Wang Chunxian [15] was 3 years, and the average course of disease of the patients studied by Xu Mengkang [17] was 4 years, which may be the reason for the large heterogeneity of the study.However,since the study of Wu Huajun [16] did not mention the average course of disease of patients, subgroup analysis could not be carried out, so random effect model was adopted for analysis.(3) The sensitivity analysis using the one-by-one elimination method showed that although there was significant heterogeneity in IPSS, PV, PVR and Qmax, thePvalues of each outcome index did not fluctuate significantly (P< 0.05) during the analysis process,and the direction of the combined results did not change.These results suggested that although there was significant heterogeneity in these outcome indicators during the merger process, the results of the meta-analysis were relatively stable.(4) According to the course of medication, they were divided into two subgroups: In the 1-month group and the 3-month group, the analysis showed that there was no statistical difference in IPSS, PV and PVR after 1-month of routine treatment, but it was superior to the control group in terms of Qmax.After 3 months of treatment,it was superior to the control group in terms of IPSS,PV, PVR and Qmax.The results showed that Qianliexin capsule combined with western medicine had a better effect after 3 months.(5) There was no statistical difference in the adverse effects rate, and the adverse effects rate in both groups was low,mostly due to gastrointestinal reactions such as dizziness,headache, nausea and acid reflux, and no serious adverse reactions such as liver and kidney injury,suggesting that both traditional Chinese medicine and western medicine have high safety in the short-term use.

There are some limitations in this paper, as follows:(1) the methodological quality of the included studies was generally poor.Among the 6 included studies, 2[14, 19] did not specify the specific random allocation method,1[15]used the wrong random method,and all the studies [14−19] did not mention the hiding of allocation scheme and the implementation of blind method, which reduced the quality of the included literatures.It had a certain influence on the credibility of outcome indicators;(2)the included studies were all from China, with certain regional limitations; (3)problems such as inconsistency in sample size, course of disease and duration of medication exist in different studies, which increased clinical heterogeneity among studies and had a certain influence on the results; (4)there were less than 10 literatures included in the outcome indicators observed in this study, and no funnel plot was drawn to analyze their publication bias;(5)follow-up after treatment was not reported in all the studies, making it difficult to judge the long-term efficacy and safety of the drugs.

In summary, Qianliexin capsule combined with western medicine in the treatment of BPH has good curative effect in terms of total effective rate,IPSS,PV,PVR and Qmax, and has high safety.However, due to the small sample size and low methodological quality,large sample and high quality randomized controlled trials are still needed to confirm the above conclusions in the future.