Evidence - Based Analysis Of TCM Treatment Of Uterine Leiomyoma And Evidence - Based Evaluation Of Curative Effect Evaluation

BackgroundUterine fibroids are the most common benign tumor of the female reproductive tract. The prevalence rate among women of childbearing age is about 25%, and half of those are always accompanied with symptoms like hypermenorrhea, anemia, pain, pressure symptoms, and infertility. Current treatments include surgical approaches such as hysterectomy, myomectomy, uterine artery embolization (UAE) and magnetic resonance imaging-guided focused ultrasound surgery (MRgFUS), pharmacologic options such as hormonal therapies, and gonadotropin-releasing hormone agonists. However, all the therapies were at risks of complication, recurrence and adverse events. Uterine fibroids has no exactly corresponding disease name in traditional Chinese Medicine (TCM). Based on its clinical manifestation, it belongs to abdominal mass (zheng jia), stony uterine mass (shi jia), lesser abdominal mass in women (chang tan), accumulation-gathering (ji ju). Traditional Chinese herbal medicine is a prevalent treatment for uterine fibroids, and there were many clinical reports about this. However, few bibliometrics studies aimed at pattern, formula, Chinese medicine (CM), and effect in kinds of clinical studies were found. There were lack of high quality and good homogeneity evidence. In practice of TCM, the most important thing for therapeutic effect was correspondence of the symptoms (signs) and CM. The law of symptoms and CM and the common combination of CM were the essence of the clinical experience. We have not retrieved studies aimed at mining the rules of symptoms-CM and CM-CM.AimThis study aims to summarize clinical information of CM for uterine fibroids in pattern, formula, CM, and effect in kinds of clinical studies, as well as to mine and analyse the information and the law of CM for uterine fibroids. Guizhi Fuling Formula was the most common used formula in our study. In order to assess the efficacy and safety of Guizhi Fuling Formula for uterine fibroids, we conducted this study by comprehensively collecting and analysing randomized controlled trials (RCTs) on Guizhi Fuling Formula. In a word, we aim to summarize the experience of CM for uterine fibroids, and provide advices for practice.MethodsBibliometrics study:We retrieved four Chinese and two English databases (CNKI, Sino-Med, VIP, wanfang, PubMed, Cochrane Library) from their inception to July 16th 2014. We included clinical studies according to inclusion and exclusion criteria, and then extracted data of them. Data was imported to Microsoft Excel 2007, and then used to construct control studies (RCT, clinical controlled trial (CCT), cohort study. case control study), case series and case reports databasesfor descriptive statistics.Association rule mining:We extracted information of symptoms, tongue, pulse and CM from case reports database to establish a new database. We normalized terms according to corresponding standards and transformed data to the damand of data mining. The association rule mining was carried out in SAS 8.2.Systematic review:We searched three English electronic databases and four Chinese electronic databases from their inception through May 2013. RCTs were included according to inclusion and exclusion criteria, and then the data was extracted. The methodological quality of included studies was assessed by using the Cochrane risk of bias tool. RevMan 5.2.0 software was applied to analyze data of included randomized trials. We used risk ratios (RR) with 95% confidence intervals (CI) for binary outcomes or mean difference (MD) with 95% CI for continuous outcomes.ResultsIn bibliometrics study of CM for uterine fibroids, we retrieved 11083 citations in 6 electronic databases. After screening,1006 studies were included. Two of them were in English, while the others were all in Chinese. There were 305 RCTs,66 CCTs,410 CSs,142 CRs, and 83 expertise experiences. We extracted 305 items of RCT,66 items of CCT,467 items of CS, and 537 items of CR. In controlled study, CM plus medicine vs medicine was the most frequent study model, and there were only a small number of studies in comparison of CM vs no treatment or CM vs placebo. The most frequent pattern element involving disease’s nature was blood stasis, followed by qi stagnation, qi deficiency, damp and phlegm. The most frequent pattern element of disease’s location was liver, uterus, kidney, chong and ren, and spleen successively. In case reports, heavy menstrual bleeding was the most frequent symptom, and menses with clots, abdominal pain, lack of strength, prolonged menstrual bleeding and lower abdomen pain followed. In terms of CM type, Chinese patent medicine was mostly used in controlled study, while syndrome differentiated herbal treatment in both CS and CR. In all studies included, Guizhi Fuling formula was most frequently used formula. A total of 377 kinds of herbal medicine were used as estimated, of which 81 were high-frequency CMs (with frequency> 20). According to the function classification, the top three ructions of 81 CM were for invigorating blood and dissolving stasis, supplementing deficiency, and clearing heat. The top frequent 10 CM were semen persicae, poria, rhizoma curcumae, radix angelicae sinensis, ramulus cinnamomi, rhizoma sparganii, cortex moutan, radix paeoniae rubra, concha ostreae and radix paeoniae alba. In terms of outcomes, symptoms, volume of fibroids and composite outcomes were mostly used. In controlled studies,92.7% of the studies reported positive contusions, while 1.9% studies were negative.In study exploring mining association rules of CM-symptoms, CM-CM in case report of CM for uterine fibroids, we summarized common combination of CM as rhizoma sparganii-rhizoma curcumae, flos carthami-semen persicae, faeces trogopterori-pollen typhae, thallus laminariae-sargassum, radix codonopsis-radix astragali, rhizoma atractylodis macrocephalae-poria, rhizoma chuanxiong-radix angelicae sinensis, radix paeoniae alba-radix angelicae sinensis, ramulus cinnamomi-radix paeoniae, poria-cortex moutan, ramulus cinnamomi-poria, ramulus cinnamomi-cortex moutan and cortex moutan-radixpaeoniae rubra. We also summarized uncommon combination of CM as pollen typhae-radix paeoniae rubra, flos carthami-radix angelicae sinensis, rhizoma corydalis-radix angelicae sinensis, radix bupleuri-radix angelicae sinensis, rhizoma cyperi-radix angelicae sinensis, squama manitis-radix angelicae sinensis, rhizoma atractylodis macrocephalae-radix angelicae sinensis, radix et rhizoma glycyrrhizae-radix angelicae sinensis, which needs to be verified in further studies. The results of association rules of CM-symptom showed that, prolonged menstruation, purple and dusky menses, rough pulse and macule in tongue were associated with radix angelicae sinensis and semen persicae; deep pulse was associated with radix angelicae sinensis, semen persicae and radix paeoniae rubra; dull-red menses and dusky tongue were associated with rhizoma curcumae; lack of strength, mental fatigue, dizziness, early menstruation, pale tongue, thin white coating, abdominal pain, lower abdominal pain and lumbar pain were associated with radix angelicae sinensis.A total of 38 RCTs involving 3816 participants were identified in systematic reviews of CM for uterine fibroids. The methodological quality of the included trials was generally poor. Meta-analyses demonstrated that Guizhi Fuling Formula plus mifepristone were more effective than mifepristone alone in reducing the volume of fibroids (in total volume of multiple fibroids, MD-19.41 cm3,95%CI-28.68 to-10.14; in average volume of multiple fibroids, MD-1.00 cm3,95% CI-1.23 to-0.76; in average volume of maximum fibroids, MD-3.35 cm3,95% CI-4.84 to-1.87, I2= 93%, random effects model). Guizhi Fuling Formula significantly improved symptoms of dysmenorrhea either when it was used alone (RR 2.27,95% CI 1.04 to 4.97) or in combination with mifepristone (RR 2.35,95%CI 1.15 to 4.82). No serious adverse events were reported.ConclusionThrough multiple databases retrieval and bibliometric analysis, we found many clinical studies of CM for uterine fibroids, including RCT, CCT, CS, CR and expertise experience. We summarized main pattern element and symptom of uterine fibroids, the most frequent formula and CM for treatment. The CM treatments for uterine fibroids were based on pattern, diseases or period differentiation. Through mining the rules of CM and symptoms, we summarized common and uncommon combination of CM, and common symptoms associated with CM. All the information is significant for the treatment of CM for uterine fibroids.Guizhi Fuling Formula appears to have additional benefit based on mifepristone treatment in reducing volume of fibroids. However, due to high risk of bias of the trials, we could not draw confirmative conclusions on its benefit. Future rigorous clinical trials are warranted.