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Chinese herbal medicine Kuntai capsule for treatment of menopausal syndrome: a systematic review of randomized clinical trials
Complementary Therapies in Medicine 29 (2016) 63–71
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Complementary Therapies in Medicine journal homepage: www.elsevierhealth.com/journals/ctim
Chinese herbal medicine Kuntai capsule for treatment of menopausal syndrome: a systematic review of randomized clinical trials Quan Zhou 1 , Jing Tao 1 , Huamei Song 1 , Aihua Chen, Huaijie Yang, Manzhen Zuo ∗ , Hairong Li Department of Gynecology and Obstetrics, The People’s Hospital of Three Gorges University/The First People’s Hospital of Yichang, Yichang 443000, China
a r t i c l e
i n f o
Article history: Received 29 May 2015 Received in revised form 29 April 2016 Accepted 11 September 2016 Available online 13 September 2016 Keywords: Chinese herbal medicine Kuntai capsule Menopausal syndrome Systematic review Randomized clinical trials
a b s t r a c t Objectives: Kuntai capsule has been widely used for the treatment of menopausal syndrome in China for long time. We conducted this review to assess efficacy and safety of Kuntai capsule for the treatment of menopausal syndrome. Methods: We searched studies in PubMed, ClinicalTrials, the Cochrane Library, China National Knowledge Infrastructure Database(CNKI), China Science and Technology Journal Database (VIP), Wan fang Database and Chinese Biomedical Literature Database(CBM) until November 20, 2014. Randomized trials on Kuntai capsule for menopausal syndrome, compared with placebo or hormone replacement therapy (HRT) were included. Two reviewers independently retrieved the randomized controlled trials (RCTs) and extracted the information. The Cochrane risk of bias method was used to assess the quality of the included studies, and a Meta-analysis was conducted with Review Manager 5.2 software. Results: A total of 17 RCTs (1455 participants) were included. The studies were of low methodological quality. Meta-analysis indicated that there was no statistical difference in the Kupperman index (KI) [WMD = 0.51, 95% CI (−0.04, 1.06)], the effective rate of KI [OR = 1.21, 95% CI (0.72, 2.04)], E2 level [WMD = −15.18, 95% CI (−33.93, 3.56)], and FSH level [WMD = −3.46, 95% CI (−7.2, 0.28)] after treatment between Kuntai versus HRT group (P > 0.05). However, Compared with HRT, Kuntai capsule could significantly reduce the total incidence of adverse events [OR = 0.28, 95% CI (0.17, 0.45)]. Conclusions: Kuntai capsule may be effective for treating menopausal syndrome and lower risk of side effects. The studies we analyzed were of low methodological quality. Therefore, more strictly designed large-scale randomized clinical trials are needed to evaluate the efficacy of Kuntai capsule in menopausal syndrome. © 2016 Elsevier Ltd. All rights reserved.
Contents 1. 2.
3.
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 2.1. Study search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 2.2. Study selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 2.3. Data extraction and quality assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 2.4. Data analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 3.1. Description of included trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 3.2. Methodological quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Abbreviations: RCT, randomized clinical trials; CHM, Chinese herbal medicine; KI, Kupperman index; HRT, hormone replacement therapy; E2, 17-estradiol; FSH, follicle-stimulating hormone; PROSPERO, international database of prospectively registered systematic reviews in health and social care. ∗ Corresponding author at: Department of Gynecology and Obstetrics, The People’s Hospital of Three Gorges University/The First People’s Hospital of Yichang, 2 Jiefang Road, Yichang 443000, Hubei Province, China. E-mail addresses: [email protected] (Q. Zhou), [email protected] (J. Tao), [email protected] (H. Song), [email protected] (A. Chen), [email protected] (H. Yang), [email protected] (M. Zuo), [email protected] (H. Li). 1 Contributed equally to this work. http://dx.doi.org/10.1016/j.ctim.2016.09.011 0965-2299/© 2016 Elsevier Ltd. All rights reserved.
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3.3.
Efficacy and safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 3.3.1. Change in Kupperman index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 3.3.2. The effective rate of Kupperman index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 3.3.3. The serum levels of hormone (E2 and FSH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 3.3.4. Adverse events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 3.3.5. Sensitivity analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 3.3.6. Publication bias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 4.1. Main findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 Conflict of interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 Authors’ contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
1. Background Menopause is the phase of life when a woman transitions, both mentally and physically, from sexual maturity to old age. During this phase, the majority of women suffer from a considerable variety of symptoms. These can include hot flashes, night sweats, menstrual irregularities, vaginal dryness, depression, nervous tension, palpitations, memory problem, lack of concentration and others.1,2 Such symptoms are frequently considered part of menopausal syndrome. Menopausal syndrome not only has an impact on women’s quality of life but also is associated with other health problems, for example, immune function, cardiovascular disease and osteoporosis in old age.2–4 These disorders are mainly due to the deficiency of ovarian hormones, especially estrogen.1–5 As such, hormone replacement therapy (HRT) has been thought as the mainstay therapy for over 20 years, but various disadvantages and side effects have been reported since the Women’s Health Initiative’s (WHI) first report of negative findings of HRT in 20026 . It small but significantly increased the risk of breast cancer, ovarian cancer, endometrial hyperplasia, carcinoma, stroke and venous thromboembolism, especially for long-term therapy.7–10 Therefore, the use of HRT in the management of menopausal symptoms is becoming ever more problematic, and not only patients but also physicians are increasingly interested in complementary therapies (CAM) for relief of menopausal syndrome.11,12 In all CAM, traditional Chinese medicine (TCM) has become one of the most popular CAM modality in recent year.11 Chinese herbal medicine has been widely used to disperse menopausal problems and is still currently in use in China and other Asian countries.13,14 Kuntai capsule, a TCM herbal formulation, has been widely used for the treatment of menopausal syndrome for a long time, which is a compound preparation of six Chinese herbs, Prepared rhizome of Adhesive Rehmannia, Coptis chinensis Franch, White Paeony Root, Scutellaria baicalensis, Colla corii Asini and Wolfiporia cocos. Recent clinical trials in China have manifested significant positive effects of Kuntai capsule in alleviating menopausal symptoms in Chinese women.15–31 However, most of the clinical trials were based on small sample size and these findings have not yet been systematically summarized in English. The objective of this review is to critically appraise the existing randomized clinical trials (RCTs) on Kuntai capsule for menopausal symptoms, and provide evidence-based evaluation on the efficacy and safety of Kuntai capsule. 2. Methods 2.1. Study search A comprehensive literature search of electronic databases PubMed, Clinical Trials, the Cochrane Library, China National
Knowledge Infrastructure Database(CNKI), China Science and Technology Journal Database(VIP), Wan fang Database and Chinese Biomedical Literature Database(CBM) until was performed up to November 20, 2014. We also searched reference lists of retrieved papers. The reference lists of relative articles were also screened to further identify potential studies. The following search terms were used: “menopausal syndrome,” “menopause-related symptoms,” “Climacteric syndrome,” “herb,” “herbal medicine,” “Chinese herbal medicine,” “Chinese drug,” “compound prescription,”“traditional Chinese medicine,” “traditional Chinese medical,” “Kuntai capsule,” “Geng Nian Ning Xin,” “Chinese medicine monomer,” “controlled clinical trial,” and “clinical trial.” individually or combined. 2.2. Study selection Titles and abstracts were evaluated to identify relevant publications, and the full text version scanned. The criteria for inclusion were: (1) type of study: randomized clinical trials (RCTs) or quasiRCTs; (2) type of participants: subjects were perimenopausal or postmenopausal women experiencing menopausal symptoms; (3) type of interventions: the study was designed to compare the effectiveness and safety of Kuntai capsule with placebo or traditional Western medicine (HRT); (4) type of outcomes: Kupperman index(KI) and the effective rate of KI (the primary outcome), The serum levels of Hormone level (E2 and FSH) and adverse events(the secondary outcome). The following types of studies were excluded: (1) non-original research, reviews, comments and articles unrelated to our analysis were excluded; (2) lack of basic information on participants or interventions; (3) controlled treatment included other Chinese herbal medicine (CHM) therapies; as in this case, it would be impossible to evaluate the specific effect s of the intervention. There was no limitation on language as well as the minimum patients of every single study. When there were multiple articles by the same group based on similar patients and using same detection methods, only the largest or the most recently article was included. 2.3. Data extraction and quality assessment All data were independently abstracted by two reviewers (Jing Tao and Huamei Song) with standardized data abstraction tool. Differences in the extraction of data were assessed by a third investigator (Quan Zhou). The following information was extracted from the included studies: the name of first author, year of publication, study design, participants’ age and BMI, number of participants in each treatment group, intervention, and length of follow-up, Kupperman index, E2 level, FSH level, and adverse events. When data were not provided in publications, we contacted the authors for information.
Q. Zhou et al. / Complementary Therapies in Medicine 29 (2016) 63–71
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Fig. 1. Flow chart for selection of studies.
We assessed the methodological quality of trials by criteria of the Cochrane Handbook for Systematic Review of Interventions, version 5.1.0.32 The following items were assessed: 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), selective reporting (reporting bias), and other bias. Sample size estimate, comparable baseline characteristic, inclusion and exclusion criteria were considered when we judged the other bias. 2.4. Data analysis Statistical analyses were estimated using Review manager software 5.2 (updated in March 2012 by the Cochrane Collaboration). P values were two-sided, with significance at P < 0.05. A 95% confidence interval (CI) was also calculated from the data using the Cochrane Collaboration’s software. The odd risk (OR) of data was calculated if the variables were dichotomous data. The Mean difference (MD) was calculated if the variables were continuous data. Heterogeneity across studies was evaluated with the Q test and P values. ORs and WMD were calculated by a random-effects model when the P value was less than 0.1. Otherwise, a fixed-effects model was used. Funnel plots was used to assess publication bias. 3. Results
the majority was excluded because of obvious ineligibility, which included irrelevant titles and abstracts. After reading the titles and abstracts, 91 trials were excluded because of duplicated publication. The rest of the 29 trials were case reports, case series, traditional reviews, or not rigorously designed RCTs, 5 trials were animal experiments. After the above selection, only 33 studies were obtained. 10 articles were excluded based on the inclusion criteria. In the rest of the 23 trials, five of them were multiple articles by the same group, and one trial had no data for extraction. Finally, Seventeen RCTs were reviewed.15–31 There were all trials comparing Kuntai capsule with western (conventional HRT pharmaceutical) medicine, the control group of 4 trials was estradiol valerate,16,17,22,26 10 trials was conjugated estrogens,18–20,23–25,27,29–31 and 3 trials was tibolone(a synthetic steroid with estrogenic, progestogenic and androgenic activity).15,22,28 No trial applied placebo or no intervention as control. All of the trials had two arms, except one trial.26 that had four arms. All of the trials were conducted in China and published in Chinese. 17 were all written in Chinese and published between 2005 and 2014. Preparations of Kuntai capsule capsules in all the included trials and were patent medicines approved by the State Food and Drug Administration of China. The characteristics of the 17 RCT are shown in Table 1. 3.2. Methodological quality
3.1. Description of included trials After a primary search of seven databases, 174 trials were screened out from electronic and manual searches (Fig. 1), and
The randomized allocation of participants was mentioned in all trials, but only two trials 20,29 reported method of sequence generation (using random number table). None of the reports described
66
Table 1 Basic information of included studies. Study
Baseline features of participants(TG/CG)
Treatment (Months)
Intervention
Age (years)
BMI (kg/m2 )
Menopause time (Months)
Chen CJ 201415 Chen LH 201416 Chen R 201317 Chen YH 201118
58(30/28)
49.5 ±4.6
NG
Over 6 months
3
100(50/50)
NG
28.8/29.7
3
NG NG
(28.1 ± 33.2) /(29.9 ± 37.7) 0−15
3
129(65/64)
(50.2 ± 4.8) /(50.7 ± 4.6) (50.8 ± 4.4) /(50.4 ± 4.2) 54.8
Li CH 201419
80(40/40)
40–65
NG
NG
3
Kuntai capsule (4# ,tid)
Li WJ 201020
57(28/29)
(48.8 ± 4.2) /(49.2 ± 4.1)
(21.1 ± 1.7) /(21.4 ± 2.4)
11.5/18.0
12
Kuntai capsule (4# ,tid)
Li XH 201421 Luan YQ 200422 Re ZWGL 201423
192(90/92)
(23.3 ± 2.7) /(23.6 ± 2.4) NG NG
(32.2 ± 24.4) /(35.2 ± 21.3) (24.5 ± 42.1) /23.8 ± 27.4) 12–120
2
90(45/45)
(50.6 ± 3.3) /(50.5 ± 3.4) (48.9 ± 3.6) /(50.2 ± 3.1) (58.6 ± 33)
3
Kuntai capsule (4# ,tid) Kuntai capsule (4# ,tid) Kuntai capsule (4# ,tid)
Shen HJ 201124
86(45/41)
54.8
NG
12–132
3
Kuntai capsule (4# ,tid)
Tang LL 201025
57(28/29)
(48.9 ± 4.2) /(49.2 ± 4.1)
(21.1 ± 1.7) /(21.9 ± 2.4)
(16.2 ± 14.4) /(19.5 ± 14.2)
3
Kuntai capsule (4# ,tid)
Wang SH 200726 Yang Y 201027
64(32/34)
(25.1 ± 3.1) /24.2 ± 3.0) NG
(50.4 ± 48.0) /(50.4 ± 50.4) NG
12
70(35/35)
(53.5 ± 3.8) /(52.1 ± 4.2) 40–55
3
Kuntai capsule (4# ,tid) Kuntai capsule (4# ,tid)
Yin BJ 201328 Zhang J 201029
60(30/30)
53
NG
12–108
2
54(27/27)
(51.9 ± 2.3) /(49.8 ± 2.9)
NG
(17.6 ± 12.0) /(16.9 ± 9.9
12
Zhang X. 201330 Zhou J. 201431
98(49/49)
51
NG
NG
3
80(40/40)
(48.7 ± 4.6) /(49.3 ± 3.9)
NG
(17.3 ± 12.7) /(18.4 ± 12.3)
12
147(77/70)
66(33/33)
(1) Kupperman index, (2) Changes in Kupperman index, (3) E2 level, (4) FSH level.
3
3
Treatment
Control
Kuntai capsule (4# ,tid) Kuntai capsule (4# ,tid) Kuntai capsule (4# ,tid) Kuntai capsule (4# ,tid)
Tibolone (2.5 mg 1/3d) Estradiol valerate (0.5 mg, qd) Estradiol valerate (0.5 mg, qd) Conjugated estrogens (1 mg, qd) Conjugated estrogens (0.625 mg, qd) Conjugated estrogens (0.45 mg,qd) Tibolone (NG) Estradiol valerate (0.5 mg, qn) Conjugated estrogens (1 mg,qd) Conjugated estrogens (1 mg,qd) Conjugated estrogens (0.625 mg, qd) Estradiol valerate (0.5 mg, qd) Conjugated estrogens (0.3 g, qd) Tibolone (1.25 mg,qd) Conjugated estrogens (0.45 mg, qd) Conjugated estrogens (1# , qd) Conjugated estrogens (0.45 mg, qd)
Kuntai capsule (4# ,tid) Kuntai capsule (4# ,tid) Kuntai capsule (4# ,tid) Kuntai capsule (4#,tid)
Adverse reactions
(1)(2)
5(0/5)
(1)(3)
NG
(1)(2)
NG
(2)
50(14/36)
(1)(2)(3)(4)
8(3/5)
(1)
36(19/17)
(2)
103(30/73)
(2)(3)(4)
26(11/15)
(1)
29(9/20)
(2)
33(9/24)
(1)
44(19/25)
(1)(3)
40(12/28)
(1)(2)(3)(4)
11(6/5)
(1)
9(2/7)
(3)(4)
18(2/16)
(1)(2)
NG
(1)(3)(4)
53(18/35)
Q. Zhou et al. / Complementary Therapies in Medicine 29 (2016) 63–71
Simple size (n)
Outcome
Q. Zhou et al. / Complementary Therapies in Medicine 29 (2016) 63–71
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Fig. 2. Methodological quality of included trials (summary of risk of bias).
allocation concealment and blinding of outcome assessment. Most of the included trials had a high risk of bias in blinding of the patients and clinicians. Five trials 17,19–21,25 reported dropout of participants, but only 1 study included an adequate intention-totreat analysis.20 For selective reporting, since the protocols of the 17 trials were all not accessible, we made our judgment by comparing the outcome measures mentioned in the method section with the reported outcomes in the results: 5 trials reported all outcome measures described in the methods were evaluated as low risk.15,16,26,27,31 ; one trial19 partially reported the outcomes in the results were evaluated as high risk, and eleven trials17,18,20–25,28–30 were evaluated as unclear risk when no description of outcome measures in the methods. No trial had pretrial sample size estimation. All trials were evaluated as high or unclear risk of bias (Figs. 2 and 3).
3.3. Efficacy and safety 3.3.1. Change in Kupperman index Twelve RCTs provided the change in Kupperman index data after treatment; these studies included 947 patients (476 cases in the experimental group and 471 cases in the control group)15–17,19,20,23,25–28,30,31 Both of these trials showed homogeneity in the consistency of the trial results (chi-square = 15.65, P = 0.14, I2 = 31%).Therefore, a random-effects model should have been used for statistical analysis. The pooled analysis indicated that no significant difference KI between the Kuntai of the experimental group and the Western medicine of the control group [WMD = 0.51; 95% CI, −0.04 to 1.06; P = 0.07]. The analysis was divided into three sub-groups, according to the classification of HRT: estradiol valerate, conjugated estrogens and tibolone. By the subgroup meta-analysis, there were no significant differences in this subgroup analysis compared with the original analysis (Fig. 4).
3.3.2. The effective rate of Kupperman index Nine RCTs provided the effective rate of Kupperman index after treatment; these studies included 884 patients (449 cases in the experimental group and 435 cases in the control group).15,17–19,21,22,24,27,29,31 Both of these trials showed homogeneity in the consistency of the trial results (chi-square = 2.24, P = 0.97, I2 = 0%).Therefore, a fixed-effects model should have been used for statistical analysis. The pooled analysis indicated that no significant difference the effective rate of KI between the Kuntai of the experimental group and the Western medicine of the control group [OR = 1.21; 95% CI, 0.72 to 2.04; P = 0.46]. By the subgroup meta-analysis, there were no significant differences in this subgroup analysis compared with the original analysis (Fig. 5).
Fig. 3. Methodological quality of included trials (each risk of bias item for each included study).
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Fig. 4. Forest plot of comparison of Kuntai with HRT groups on Kupperman index (KI).
Fig. 5. Forest plot of comparison of Kuntai with HRT groups on the effective rate of Kupperman index (KI).
3.3.3. The serum levels of hormone (E2 and FSH) Seven RCTs provided the serum levels of E2 date after treatment; these studies included 499 patients 250 cases in the experimental group and 249 cases in the control group) 16,19,22,26,27,30,31 . Both of these trials showed homogeneity in the consistency of the trial results (chi-square = 120.28, P < 0.001, I2 = 95%).Therefore, a random-effects model should have been used for statistical analysis. The pooled analysis indicated that no significant difference
the serum levels of E2 level between the Kuntai of the experimental group and the Western medicine of the control group [WMD = −15.18; 95% CI, −33.93 to 3.56; P = 0.11]. By the subgroup meta-analysis, the serum levels of E2 in Kuntai groups was significant lower than that of Estradiol valerate groups [WMD = −31.55; 95% CI, −55.98 to −7.13; P = 0.01], but no significant differences between the Kuntai and Conjugated estrogens groups compared with the original analysis (Fig. 6).
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Fig. 6. Forest plot of comparison of Kuntai with HRT groups on the serum levels of E2.
Fig. 7. Forest plot of comparison of Kuntai with HRT groups on the serum levels of TSH.
Five RCTs provided the serum levels of TSH date after treatment; these studies included 326 patients (165 cases in the experimental group and 161 cases in the control group).19,22,27,29,31 Both of these trials showed homogeneity in the consistency of the trial results (chi-square = 4.49, P = 0.34, I2 = 11%). Therefore, a fixedeffects model should have been used for statistical analysis. The pooled analysis indicated that no significant difference between the effects of the Kuntai of the experimental group and the Western medicine of the control group [WMD = −3.46; 95% CI, −7.20 to 0.28; P = 0.07]. By the subgroup meta-analysis, there were no significant differences in this subgroup analysis compared with the original analysis (Fig. 7).
3.3.4. Adverse events Fourteen RCTs provided the adverse events date after treatment; these studies included 1132 patients (566 cases in the experimental group and 566 cases in the control group).15,18–29,31 Both of these trials showed homogeneity in the consistency of the trial results (chi-square = 31.66, P = 0.003, I2 = 59%).Therefore, a random-effects model should have been used for statistical analysis. The pooled analysis indicated that the total incidence of adverse events significant lower in the Kuntai of the experimental group compared to the Western medicine (HRT) of the control group [OR = 0.28; 95% CI, 0.17 to 0.45; P < 0.00001]. By the subgroup meta-analysis, there were no significant differences in remainder subgroup analysis compared with the original analysis (Fig. 8).
3.3.5. Sensitivity analysis To confirm the stability of the results, were moved the most and the least weighted of every subgroup, and changed from fixed mode to random mode. There was no clear difference compared with the previous results, so the degree of sensitivity of the study was not high. 3.3.6. Publication bias Begg’s funnel plots were used to evaluate the publication bias of all the relevant literature. The shapes of Begg’s funnel plots of the KI (A) and the total incidence of adverse events seemed to have no evidence of obviously asymmetrical in results of meta-analyses (Fig. 9). As less than ten studies were included, we failed to perform funnel plot of the serum levels of hormone level (E2 and FSH) and the effective rate of KI to detect publication bias. 4. Discussion 4.1. Main findings HRT is the primary management of menopausal symptoms in Western medicine. However, the potential adverse effects drive the clinicians to actively seeking alternative therapies.33 Among the alternative treatments, Chinese medicine, such as Kuntai capsule, may give them a better solution and fruitful area, but the efficacy and safety of Kuntai capsule on menopausal symptoms remains under explored due to language barrier of many studies reported in Chinese language. In the present study, we conducted this review to assess efficacy and safety of Kuntai capsule for
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Fig. 8. Forest plot of comparison of Kuntai with HRT groups on the total incidence of adverse events.
Fig. 9. Funnel plots was assessed for KI (A) and the total rate of adverse events (B).
the treatment of menopausal syndromes in 4 main Chinese language databases and 3 main English language databases. To the best of our knowledge, this is the first English language systematic review and meta-analysis of RCTs for Kuntai capsule in treating menopausal syndrome. Compared with some previous meta-analyses,34,35 strengths of our meta-analysis include the large sample size and increasing the statistical power of the analysis based on substantial number of cases and controls from differential studies, which minimized selection bias and led to relatively stable risk estimation. In our systematic review, we found no significant differences between the Kuntai capsule and traditional Western medicine (HRT) for the treatment of menopausal syndromes in terms of KI, the effective rate of KI, the serum levels of E2 and FSH, and the results showed that Kuntai capsule have lower risk of adverse events than HRT. Moreover, there were no significant differences in this subgroup analysis compared with the original analysis in KI, the effective rate of KI, the serum levels of FSH and total incidence of adverse reactions. Except three studies including 332 participants
showed that Kuntai capsule group had a lower E2 level than Estradiol group [WMD = −31.55; 95% CI, −55.98 to −7.13; P = 0.01]. This result is not surprising because estradiol valerate can direct supplement the levels of E2. The pooled results indicate that Kuntai capsule may be effective for treating menopausal syndrome and lower risk of side effects. There are several strengths in this study. This meta-analysis on an important topic of women health, and was conducted at an appropriate time because despite several RCTs having been reported most are of a small sample size with conflicting results. We applied multiple strategies to identify the studies, strict criteria to include and evaluate the methodological quality of the studies, and subgroup and sensitivity analysis to minimize the heterogeneity. Moreover, we had a standard protocol registration in PROSPERO, an international prospective register of systematic reviews and published the protocol. The systematic review in our study has its own limitations. First, in terms of the current evaluative standards, the methodological quality of included studies was generally low. The majority of tri-
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als did not report randomization procedures and all trials lacked information on blinding. Additionally, intention-to-treat analysis and pre-trial sample size estimate were not applied. Second, In terms of adverse reactions, we only analyzed the statistical data of patients with the total rate of adverse reactions, due to the lack of descriptions of the concrete data. Third, none of the included trials described the economic index. Fourth, we tried to compare Kuntai capsule with other Chinese patent medicines, but failed to draw any conclusions due to no relevant randomized controlled trials. 5. Conclusions The findings of the current trials suggest that Kuntai capsule may be effective for treating menopausal syndromes and lower risk of side effects. However, due to the poor methodology quality, the confirmative conclusions on the beneficial effect of Kuntai capsule for the menopausal syndromes could not be drawn. More rigorously designed, large-sample, randomized controlled trials are warranted to confirm and update the findings of this analysis in the future. Conflict of interests No competing financial interests exist. Authors’ contributions ZQ, SHM and ZMZ developed the idea and designed the research. TJ developed the search strategy, ran the search strategy with CAH, selected which studies to include and extracted data from studies with CAH, interpreted the analysis and drafted the final review. ZQ and SHM obtained copies of studies and revised the writing. ZQ carried out the analysis. All authors read and approved the final manuscript. Acknowledgment This study was supported by National Natural Science Foundation of China (no, 81401187). References 1. Nelson HD. Menopause. Lancet. 2008;371(9614):760–770. 2. Ghosh M, Rodriguez-Garcia M, Wira CR. The immune system in menopause: pros and cons of hormone therapy. J Steroid Biochem Mol Biol. 2014;142:171–175. 3. Main C, Knight B, Moxham T, et al. Hormone therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database Syst Rev. 2013;4. CD002229. 4. Christenson ES, Jiang X, Kagan R, Schnatz P. Osteoporosis management in post-menopausal women. Minerva Ginecol. 2012;64(3):181–194. 5. Shifren JL, Schiff I. Role of hormone therapy in the management of menopause. Obstet Gynecol. 2010;115(4):839–855. 6. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321–333. 7. Vandenbroucke JP. The HRT controversy: observational studies and RCTs fall in line. Lancet. 2009;373(9671):1233–1235. 8. Shapiro S. Recent epidemiological evidence relevant to the clinical management of the menopause. Climacteric: J Int Menopause Soc. 2007;10(Suppl (2)):2–15.
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9. Canonico M, Plu-Bureau G, Lowe GD, Scarabin PY. Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis. BMJ. 2008;336(7655):1227–1231. 10. Marjoribanks J, Farquhar C, Roberts H, Lethaby A. Long term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database Syst Rev. 2012;7. CD004143. 11. Posadzki P, Lee MS, Moon TW, Choi TY, Park TY, Ernst E. Prevalence of complementary and alternative medicine (CAM) use by menopausal women: a systematic review of surveys. Maturitas. 2013;75(1):34–43. 12. Peng W, Adams J, Sibbritt DW, Frawley JE. Critical review of complementary and alternative medicine use in menopause: focus on prevalence, motivation, decision-making, and communication. Menopause. 2014;21(5):536–548. 13. Wang XY, Nie GN, Yang HY, Zong LL. Chinese medicine for menopausal syndrome: current status, problems and strategies. Chin J Integr Med. 2011;17(12):889–892. 14. Xu LW, Jia M, Salchow R, et al. Efficacy and side effects of chinese herbal medicine for menopausal symptoms: a critical review. Evid Based Complement Altern Med. 2012;2012:568106. 15. Chen CJ. Clinical observation on treating menopausal syndrome with Kuntai capsule. Clin J Chin Med. 2014;6(7):48–49. 16. Chen LH. Kuntai capsule for treatment of menopausal syndrome: a retrospective analysis of 56 cases. China Pharm. 2014;23(14):108–109. 17. Chen R, Lin SQ, Yang X, Luan YQ, Chen JY, Li DM. Effects of Kuntai capsule and estradiol valerate on different symptoms of climacteric syndrome. Med Recapitulate. 2013;19(10):1869–1872. 18. Chen YH. Clinical experience on Kuntai capsules for the treatment of menopausal syndrome. Tradit Chin Med. 2011;18(29):113–114. 19. Li CH, Li XL, Zheng JH, Wang YF. Clinical observation of Kuntai capsule on perimenopausal syndrome. World Latest Med Inf. 2014;14(5):119–120. 20. Li WJ, Xu LZ, Liu HW, et al. Effects of Kuntai Capsule and hormone replacement therapy on cognitive function and mental symptoms of early postmenopausal women: a randomized controlled trial. Zhong Xi Yi Jie He Xue Bao = J Chin Integr Med. 2010;8(4):321–327. 21. Li XH, Wen QF, Zhang LZ, Zou HH. Clinical efficacy of Kuntai capsule for early menopausal syndrome. China Health Care Nutr. 2014;6(6):3600. 22. Luan YQ, Yang X, Peng XL, Fu C, Meng ZX, Zhang J. Double-blind double–dummy randomized parallel clinical trial of Kun-tai capsul in the treatment of perimenopausal symptoms. Chin J Clin Pharmacol. 2004;20(6):452–455. 23. Re ZWGL. Efficacy and safety of Kuntai capsule and estradiol valerate for menopausal syndrome. Chin Foreign Women’s Health. 2014;N(3), 17,88. 24. Shen HJ. Kuntai capsule for treatment of menopausal syndrome: a retrospective analysis of 86 cases. Med Inf. 2011;24(9):6091–6092. 25. Tang LL, Xu LZ, Liu HW, et al. The impact on Kuntai capsule and premarin on improving early menopause symptoms and cardiovascular risk factors. J Sichuan Univ (Med Sci). 2010;41(2):366–369. 26. Wang SH, Lin SQ, Jin MJ, Gui QF, Chen FL. Efficacies of different low-dose regimens of hormone therapy in postmenopausal women. Chin J Pract Gynecol Obstet. 2007;23(3):184–188. 27. Yang Y. Clinical efficacy of Kuntai capsule for menopausal syndrome. Tanjin Pharm. 2010;22(3):34–35. 28. Yin BJ, Niu HJ, Jin RL. The impact on Kuntai capsule and tibolone on improving quality of life in postmenopausal women. World Health Dig. 2013;N(52):33. 29. Zhang J, Gong LL, Zhang SF. Effects of kuntai capsule on quality of life, breast distending pain and vaginal bleeding in women at early stage of menopause. Zhongguo Zhong Xi Yi Jie He Za Zhi = Chin J Integr Tradit Western Med. 2008;28(11):972–976. 30. Zhang X. Clinical efficacy of Kuntai capsule on improving autonomic dysfunction symptoms in postmenopausal women. Chin J Pract Nerv Dis. 2014;17(14):103–104. 31. Zhou J. Clinical efficacy of Kuntai capsule on improving menopause symptoms. Shaanxi J Tradit Chin Med. 2013;34(11):1456–1457. 32. Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions, Version 5.1.0. The Cochrane Collaboration; 2009. 33. Al-Safi ZA, Santoro N. Menopausal hormone therapy and menopausal symptoms. Fertil Steril. 2014;101(4):905–915. 34. Zhang QY, Wang JW, Yu JM. Efficacy and safety of Kuntai capsule and estrogen for menopausal syndrome: a meta-analysis. Zhonghua Yi Xue Za Zhi. 2013;93(43):3445–3449. 35. Li CC, Wang JJ, Chen C, et al. Treating menopause syndrome by kuntal capsule and hormone replacement therapy: a meta-analysis of efficacy and safety comparison. Zhongguo Zhong Xi Yi Jie He Za Zhi = Chin J Integr Tradit Western Med. 2013;33(9):1183–1190.
Contents lists available at ScienceDirect
Complementary Therapies in Medicine journal homepage: www.elsevierhealth.com/journals/ctim
Chinese herbal medicine Kuntai capsule for treatment of menopausal syndrome: a systematic review of randomized clinical trials Quan Zhou 1 , Jing Tao 1 , Huamei Song 1 , Aihua Chen, Huaijie Yang, Manzhen Zuo ∗ , Hairong Li Department of Gynecology and Obstetrics, The People’s Hospital of Three Gorges University/The First People’s Hospital of Yichang, Yichang 443000, China
a r t i c l e
i n f o
Article history: Received 29 May 2015 Received in revised form 29 April 2016 Accepted 11 September 2016 Available online 13 September 2016 Keywords: Chinese herbal medicine Kuntai capsule Menopausal syndrome Systematic review Randomized clinical trials
a b s t r a c t Objectives: Kuntai capsule has been widely used for the treatment of menopausal syndrome in China for long time. We conducted this review to assess efficacy and safety of Kuntai capsule for the treatment of menopausal syndrome. Methods: We searched studies in PubMed, ClinicalTrials, the Cochrane Library, China National Knowledge Infrastructure Database(CNKI), China Science and Technology Journal Database (VIP), Wan fang Database and Chinese Biomedical Literature Database(CBM) until November 20, 2014. Randomized trials on Kuntai capsule for menopausal syndrome, compared with placebo or hormone replacement therapy (HRT) were included. Two reviewers independently retrieved the randomized controlled trials (RCTs) and extracted the information. The Cochrane risk of bias method was used to assess the quality of the included studies, and a Meta-analysis was conducted with Review Manager 5.2 software. Results: A total of 17 RCTs (1455 participants) were included. The studies were of low methodological quality. Meta-analysis indicated that there was no statistical difference in the Kupperman index (KI) [WMD = 0.51, 95% CI (−0.04, 1.06)], the effective rate of KI [OR = 1.21, 95% CI (0.72, 2.04)], E2 level [WMD = −15.18, 95% CI (−33.93, 3.56)], and FSH level [WMD = −3.46, 95% CI (−7.2, 0.28)] after treatment between Kuntai versus HRT group (P > 0.05). However, Compared with HRT, Kuntai capsule could significantly reduce the total incidence of adverse events [OR = 0.28, 95% CI (0.17, 0.45)]. Conclusions: Kuntai capsule may be effective for treating menopausal syndrome and lower risk of side effects. The studies we analyzed were of low methodological quality. Therefore, more strictly designed large-scale randomized clinical trials are needed to evaluate the efficacy of Kuntai capsule in menopausal syndrome. © 2016 Elsevier Ltd. All rights reserved.
Contents 1. 2.
3.
Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 2.1. Study search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 2.2. Study selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 2.3. Data extraction and quality assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 64 2.4. Data analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 3.1. Description of included trials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65 3.2. Methodological quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65
Abbreviations: RCT, randomized clinical trials; CHM, Chinese herbal medicine; KI, Kupperman index; HRT, hormone replacement therapy; E2, 17-estradiol; FSH, follicle-stimulating hormone; PROSPERO, international database of prospectively registered systematic reviews in health and social care. ∗ Corresponding author at: Department of Gynecology and Obstetrics, The People’s Hospital of Three Gorges University/The First People’s Hospital of Yichang, 2 Jiefang Road, Yichang 443000, Hubei Province, China. E-mail addresses: [email protected] (Q. Zhou), [email protected] (J. Tao), [email protected] (H. Song), [email protected] (A. Chen), [email protected] (H. Yang), [email protected] (M. Zuo), [email protected] (H. Li). 1 Contributed equally to this work. http://dx.doi.org/10.1016/j.ctim.2016.09.011 0965-2299/© 2016 Elsevier Ltd. All rights reserved.
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3.3.
Efficacy and safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 3.3.1. Change in Kupperman index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 3.3.2. The effective rate of Kupperman index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 3.3.3. The serum levels of hormone (E2 and FSH) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67 3.3.4. Adverse events . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 3.3.5. Sensitivity analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 3.3.6. Publication bias . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 4. Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 4.1. Main findings . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 69 5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 Conflict of interests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 Authors’ contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71
1. Background Menopause is the phase of life when a woman transitions, both mentally and physically, from sexual maturity to old age. During this phase, the majority of women suffer from a considerable variety of symptoms. These can include hot flashes, night sweats, menstrual irregularities, vaginal dryness, depression, nervous tension, palpitations, memory problem, lack of concentration and others.1,2 Such symptoms are frequently considered part of menopausal syndrome. Menopausal syndrome not only has an impact on women’s quality of life but also is associated with other health problems, for example, immune function, cardiovascular disease and osteoporosis in old age.2–4 These disorders are mainly due to the deficiency of ovarian hormones, especially estrogen.1–5 As such, hormone replacement therapy (HRT) has been thought as the mainstay therapy for over 20 years, but various disadvantages and side effects have been reported since the Women’s Health Initiative’s (WHI) first report of negative findings of HRT in 20026 . It small but significantly increased the risk of breast cancer, ovarian cancer, endometrial hyperplasia, carcinoma, stroke and venous thromboembolism, especially for long-term therapy.7–10 Therefore, the use of HRT in the management of menopausal symptoms is becoming ever more problematic, and not only patients but also physicians are increasingly interested in complementary therapies (CAM) for relief of menopausal syndrome.11,12 In all CAM, traditional Chinese medicine (TCM) has become one of the most popular CAM modality in recent year.11 Chinese herbal medicine has been widely used to disperse menopausal problems and is still currently in use in China and other Asian countries.13,14 Kuntai capsule, a TCM herbal formulation, has been widely used for the treatment of menopausal syndrome for a long time, which is a compound preparation of six Chinese herbs, Prepared rhizome of Adhesive Rehmannia, Coptis chinensis Franch, White Paeony Root, Scutellaria baicalensis, Colla corii Asini and Wolfiporia cocos. Recent clinical trials in China have manifested significant positive effects of Kuntai capsule in alleviating menopausal symptoms in Chinese women.15–31 However, most of the clinical trials were based on small sample size and these findings have not yet been systematically summarized in English. The objective of this review is to critically appraise the existing randomized clinical trials (RCTs) on Kuntai capsule for menopausal symptoms, and provide evidence-based evaluation on the efficacy and safety of Kuntai capsule. 2. Methods 2.1. Study search A comprehensive literature search of electronic databases PubMed, Clinical Trials, the Cochrane Library, China National
Knowledge Infrastructure Database(CNKI), China Science and Technology Journal Database(VIP), Wan fang Database and Chinese Biomedical Literature Database(CBM) until was performed up to November 20, 2014. We also searched reference lists of retrieved papers. The reference lists of relative articles were also screened to further identify potential studies. The following search terms were used: “menopausal syndrome,” “menopause-related symptoms,” “Climacteric syndrome,” “herb,” “herbal medicine,” “Chinese herbal medicine,” “Chinese drug,” “compound prescription,”“traditional Chinese medicine,” “traditional Chinese medical,” “Kuntai capsule,” “Geng Nian Ning Xin,” “Chinese medicine monomer,” “controlled clinical trial,” and “clinical trial.” individually or combined. 2.2. Study selection Titles and abstracts were evaluated to identify relevant publications, and the full text version scanned. The criteria for inclusion were: (1) type of study: randomized clinical trials (RCTs) or quasiRCTs; (2) type of participants: subjects were perimenopausal or postmenopausal women experiencing menopausal symptoms; (3) type of interventions: the study was designed to compare the effectiveness and safety of Kuntai capsule with placebo or traditional Western medicine (HRT); (4) type of outcomes: Kupperman index(KI) and the effective rate of KI (the primary outcome), The serum levels of Hormone level (E2 and FSH) and adverse events(the secondary outcome). The following types of studies were excluded: (1) non-original research, reviews, comments and articles unrelated to our analysis were excluded; (2) lack of basic information on participants or interventions; (3) controlled treatment included other Chinese herbal medicine (CHM) therapies; as in this case, it would be impossible to evaluate the specific effect s of the intervention. There was no limitation on language as well as the minimum patients of every single study. When there were multiple articles by the same group based on similar patients and using same detection methods, only the largest or the most recently article was included. 2.3. Data extraction and quality assessment All data were independently abstracted by two reviewers (Jing Tao and Huamei Song) with standardized data abstraction tool. Differences in the extraction of data were assessed by a third investigator (Quan Zhou). The following information was extracted from the included studies: the name of first author, year of publication, study design, participants’ age and BMI, number of participants in each treatment group, intervention, and length of follow-up, Kupperman index, E2 level, FSH level, and adverse events. When data were not provided in publications, we contacted the authors for information.
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Fig. 1. Flow chart for selection of studies.
We assessed the methodological quality of trials by criteria of the Cochrane Handbook for Systematic Review of Interventions, version 5.1.0.32 The following items were assessed: 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), selective reporting (reporting bias), and other bias. Sample size estimate, comparable baseline characteristic, inclusion and exclusion criteria were considered when we judged the other bias. 2.4. Data analysis Statistical analyses were estimated using Review manager software 5.2 (updated in March 2012 by the Cochrane Collaboration). P values were two-sided, with significance at P < 0.05. A 95% confidence interval (CI) was also calculated from the data using the Cochrane Collaboration’s software. The odd risk (OR) of data was calculated if the variables were dichotomous data. The Mean difference (MD) was calculated if the variables were continuous data. Heterogeneity across studies was evaluated with the Q test and P values. ORs and WMD were calculated by a random-effects model when the P value was less than 0.1. Otherwise, a fixed-effects model was used. Funnel plots was used to assess publication bias. 3. Results
the majority was excluded because of obvious ineligibility, which included irrelevant titles and abstracts. After reading the titles and abstracts, 91 trials were excluded because of duplicated publication. The rest of the 29 trials were case reports, case series, traditional reviews, or not rigorously designed RCTs, 5 trials were animal experiments. After the above selection, only 33 studies were obtained. 10 articles were excluded based on the inclusion criteria. In the rest of the 23 trials, five of them were multiple articles by the same group, and one trial had no data for extraction. Finally, Seventeen RCTs were reviewed.15–31 There were all trials comparing Kuntai capsule with western (conventional HRT pharmaceutical) medicine, the control group of 4 trials was estradiol valerate,16,17,22,26 10 trials was conjugated estrogens,18–20,23–25,27,29–31 and 3 trials was tibolone(a synthetic steroid with estrogenic, progestogenic and androgenic activity).15,22,28 No trial applied placebo or no intervention as control. All of the trials had two arms, except one trial.26 that had four arms. All of the trials were conducted in China and published in Chinese. 17 were all written in Chinese and published between 2005 and 2014. Preparations of Kuntai capsule capsules in all the included trials and were patent medicines approved by the State Food and Drug Administration of China. The characteristics of the 17 RCT are shown in Table 1. 3.2. Methodological quality
3.1. Description of included trials After a primary search of seven databases, 174 trials were screened out from electronic and manual searches (Fig. 1), and
The randomized allocation of participants was mentioned in all trials, but only two trials 20,29 reported method of sequence generation (using random number table). None of the reports described
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Table 1 Basic information of included studies. Study
Baseline features of participants(TG/CG)
Treatment (Months)
Intervention
Age (years)
BMI (kg/m2 )
Menopause time (Months)
Chen CJ 201415 Chen LH 201416 Chen R 201317 Chen YH 201118
58(30/28)
49.5 ±4.6
NG
Over 6 months
3
100(50/50)
NG
28.8/29.7
3
NG NG
(28.1 ± 33.2) /(29.9 ± 37.7) 0−15
3
129(65/64)
(50.2 ± 4.8) /(50.7 ± 4.6) (50.8 ± 4.4) /(50.4 ± 4.2) 54.8
Li CH 201419
80(40/40)
40–65
NG
NG
3
Kuntai capsule (4# ,tid)
Li WJ 201020
57(28/29)
(48.8 ± 4.2) /(49.2 ± 4.1)
(21.1 ± 1.7) /(21.4 ± 2.4)
11.5/18.0
12
Kuntai capsule (4# ,tid)
Li XH 201421 Luan YQ 200422 Re ZWGL 201423
192(90/92)
(23.3 ± 2.7) /(23.6 ± 2.4) NG NG
(32.2 ± 24.4) /(35.2 ± 21.3) (24.5 ± 42.1) /23.8 ± 27.4) 12–120
2
90(45/45)
(50.6 ± 3.3) /(50.5 ± 3.4) (48.9 ± 3.6) /(50.2 ± 3.1) (58.6 ± 33)
3
Kuntai capsule (4# ,tid) Kuntai capsule (4# ,tid) Kuntai capsule (4# ,tid)
Shen HJ 201124
86(45/41)
54.8
NG
12–132
3
Kuntai capsule (4# ,tid)
Tang LL 201025
57(28/29)
(48.9 ± 4.2) /(49.2 ± 4.1)
(21.1 ± 1.7) /(21.9 ± 2.4)
(16.2 ± 14.4) /(19.5 ± 14.2)
3
Kuntai capsule (4# ,tid)
Wang SH 200726 Yang Y 201027
64(32/34)
(25.1 ± 3.1) /24.2 ± 3.0) NG
(50.4 ± 48.0) /(50.4 ± 50.4) NG
12
70(35/35)
(53.5 ± 3.8) /(52.1 ± 4.2) 40–55
3
Kuntai capsule (4# ,tid) Kuntai capsule (4# ,tid)
Yin BJ 201328 Zhang J 201029
60(30/30)
53
NG
12–108
2
54(27/27)
(51.9 ± 2.3) /(49.8 ± 2.9)
NG
(17.6 ± 12.0) /(16.9 ± 9.9
12
Zhang X. 201330 Zhou J. 201431
98(49/49)
51
NG
NG
3
80(40/40)
(48.7 ± 4.6) /(49.3 ± 3.9)
NG
(17.3 ± 12.7) /(18.4 ± 12.3)
12
147(77/70)
66(33/33)
(1) Kupperman index, (2) Changes in Kupperman index, (3) E2 level, (4) FSH level.
3
3
Treatment
Control
Kuntai capsule (4# ,tid) Kuntai capsule (4# ,tid) Kuntai capsule (4# ,tid) Kuntai capsule (4# ,tid)
Tibolone (2.5 mg 1/3d) Estradiol valerate (0.5 mg, qd) Estradiol valerate (0.5 mg, qd) Conjugated estrogens (1 mg, qd) Conjugated estrogens (0.625 mg, qd) Conjugated estrogens (0.45 mg,qd) Tibolone (NG) Estradiol valerate (0.5 mg, qn) Conjugated estrogens (1 mg,qd) Conjugated estrogens (1 mg,qd) Conjugated estrogens (0.625 mg, qd) Estradiol valerate (0.5 mg, qd) Conjugated estrogens (0.3 g, qd) Tibolone (1.25 mg,qd) Conjugated estrogens (0.45 mg, qd) Conjugated estrogens (1# , qd) Conjugated estrogens (0.45 mg, qd)
Kuntai capsule (4# ,tid) Kuntai capsule (4# ,tid) Kuntai capsule (4# ,tid) Kuntai capsule (4#,tid)
Adverse reactions
(1)(2)
5(0/5)
(1)(3)
NG
(1)(2)
NG
(2)
50(14/36)
(1)(2)(3)(4)
8(3/5)
(1)
36(19/17)
(2)
103(30/73)
(2)(3)(4)
26(11/15)
(1)
29(9/20)
(2)
33(9/24)
(1)
44(19/25)
(1)(3)
40(12/28)
(1)(2)(3)(4)
11(6/5)
(1)
9(2/7)
(3)(4)
18(2/16)
(1)(2)
NG
(1)(3)(4)
53(18/35)
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Simple size (n)
Outcome
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Fig. 2. Methodological quality of included trials (summary of risk of bias).
allocation concealment and blinding of outcome assessment. Most of the included trials had a high risk of bias in blinding of the patients and clinicians. Five trials 17,19–21,25 reported dropout of participants, but only 1 study included an adequate intention-totreat analysis.20 For selective reporting, since the protocols of the 17 trials were all not accessible, we made our judgment by comparing the outcome measures mentioned in the method section with the reported outcomes in the results: 5 trials reported all outcome measures described in the methods were evaluated as low risk.15,16,26,27,31 ; one trial19 partially reported the outcomes in the results were evaluated as high risk, and eleven trials17,18,20–25,28–30 were evaluated as unclear risk when no description of outcome measures in the methods. No trial had pretrial sample size estimation. All trials were evaluated as high or unclear risk of bias (Figs. 2 and 3).
3.3. Efficacy and safety 3.3.1. Change in Kupperman index Twelve RCTs provided the change in Kupperman index data after treatment; these studies included 947 patients (476 cases in the experimental group and 471 cases in the control group)15–17,19,20,23,25–28,30,31 Both of these trials showed homogeneity in the consistency of the trial results (chi-square = 15.65, P = 0.14, I2 = 31%).Therefore, a random-effects model should have been used for statistical analysis. The pooled analysis indicated that no significant difference KI between the Kuntai of the experimental group and the Western medicine of the control group [WMD = 0.51; 95% CI, −0.04 to 1.06; P = 0.07]. The analysis was divided into three sub-groups, according to the classification of HRT: estradiol valerate, conjugated estrogens and tibolone. By the subgroup meta-analysis, there were no significant differences in this subgroup analysis compared with the original analysis (Fig. 4).
3.3.2. The effective rate of Kupperman index Nine RCTs provided the effective rate of Kupperman index after treatment; these studies included 884 patients (449 cases in the experimental group and 435 cases in the control group).15,17–19,21,22,24,27,29,31 Both of these trials showed homogeneity in the consistency of the trial results (chi-square = 2.24, P = 0.97, I2 = 0%).Therefore, a fixed-effects model should have been used for statistical analysis. The pooled analysis indicated that no significant difference the effective rate of KI between the Kuntai of the experimental group and the Western medicine of the control group [OR = 1.21; 95% CI, 0.72 to 2.04; P = 0.46]. By the subgroup meta-analysis, there were no significant differences in this subgroup analysis compared with the original analysis (Fig. 5).
Fig. 3. Methodological quality of included trials (each risk of bias item for each included study).
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Fig. 4. Forest plot of comparison of Kuntai with HRT groups on Kupperman index (KI).
Fig. 5. Forest plot of comparison of Kuntai with HRT groups on the effective rate of Kupperman index (KI).
3.3.3. The serum levels of hormone (E2 and FSH) Seven RCTs provided the serum levels of E2 date after treatment; these studies included 499 patients 250 cases in the experimental group and 249 cases in the control group) 16,19,22,26,27,30,31 . Both of these trials showed homogeneity in the consistency of the trial results (chi-square = 120.28, P < 0.001, I2 = 95%).Therefore, a random-effects model should have been used for statistical analysis. The pooled analysis indicated that no significant difference
the serum levels of E2 level between the Kuntai of the experimental group and the Western medicine of the control group [WMD = −15.18; 95% CI, −33.93 to 3.56; P = 0.11]. By the subgroup meta-analysis, the serum levels of E2 in Kuntai groups was significant lower than that of Estradiol valerate groups [WMD = −31.55; 95% CI, −55.98 to −7.13; P = 0.01], but no significant differences between the Kuntai and Conjugated estrogens groups compared with the original analysis (Fig. 6).
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Fig. 6. Forest plot of comparison of Kuntai with HRT groups on the serum levels of E2.
Fig. 7. Forest plot of comparison of Kuntai with HRT groups on the serum levels of TSH.
Five RCTs provided the serum levels of TSH date after treatment; these studies included 326 patients (165 cases in the experimental group and 161 cases in the control group).19,22,27,29,31 Both of these trials showed homogeneity in the consistency of the trial results (chi-square = 4.49, P = 0.34, I2 = 11%). Therefore, a fixedeffects model should have been used for statistical analysis. The pooled analysis indicated that no significant difference between the effects of the Kuntai of the experimental group and the Western medicine of the control group [WMD = −3.46; 95% CI, −7.20 to 0.28; P = 0.07]. By the subgroup meta-analysis, there were no significant differences in this subgroup analysis compared with the original analysis (Fig. 7).
3.3.4. Adverse events Fourteen RCTs provided the adverse events date after treatment; these studies included 1132 patients (566 cases in the experimental group and 566 cases in the control group).15,18–29,31 Both of these trials showed homogeneity in the consistency of the trial results (chi-square = 31.66, P = 0.003, I2 = 59%).Therefore, a random-effects model should have been used for statistical analysis. The pooled analysis indicated that the total incidence of adverse events significant lower in the Kuntai of the experimental group compared to the Western medicine (HRT) of the control group [OR = 0.28; 95% CI, 0.17 to 0.45; P < 0.00001]. By the subgroup meta-analysis, there were no significant differences in remainder subgroup analysis compared with the original analysis (Fig. 8).
3.3.5. Sensitivity analysis To confirm the stability of the results, were moved the most and the least weighted of every subgroup, and changed from fixed mode to random mode. There was no clear difference compared with the previous results, so the degree of sensitivity of the study was not high. 3.3.6. Publication bias Begg’s funnel plots were used to evaluate the publication bias of all the relevant literature. The shapes of Begg’s funnel plots of the KI (A) and the total incidence of adverse events seemed to have no evidence of obviously asymmetrical in results of meta-analyses (Fig. 9). As less than ten studies were included, we failed to perform funnel plot of the serum levels of hormone level (E2 and FSH) and the effective rate of KI to detect publication bias. 4. Discussion 4.1. Main findings HRT is the primary management of menopausal symptoms in Western medicine. However, the potential adverse effects drive the clinicians to actively seeking alternative therapies.33 Among the alternative treatments, Chinese medicine, such as Kuntai capsule, may give them a better solution and fruitful area, but the efficacy and safety of Kuntai capsule on menopausal symptoms remains under explored due to language barrier of many studies reported in Chinese language. In the present study, we conducted this review to assess efficacy and safety of Kuntai capsule for
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Fig. 8. Forest plot of comparison of Kuntai with HRT groups on the total incidence of adverse events.
Fig. 9. Funnel plots was assessed for KI (A) and the total rate of adverse events (B).
the treatment of menopausal syndromes in 4 main Chinese language databases and 3 main English language databases. To the best of our knowledge, this is the first English language systematic review and meta-analysis of RCTs for Kuntai capsule in treating menopausal syndrome. Compared with some previous meta-analyses,34,35 strengths of our meta-analysis include the large sample size and increasing the statistical power of the analysis based on substantial number of cases and controls from differential studies, which minimized selection bias and led to relatively stable risk estimation. In our systematic review, we found no significant differences between the Kuntai capsule and traditional Western medicine (HRT) for the treatment of menopausal syndromes in terms of KI, the effective rate of KI, the serum levels of E2 and FSH, and the results showed that Kuntai capsule have lower risk of adverse events than HRT. Moreover, there were no significant differences in this subgroup analysis compared with the original analysis in KI, the effective rate of KI, the serum levels of FSH and total incidence of adverse reactions. Except three studies including 332 participants
showed that Kuntai capsule group had a lower E2 level than Estradiol group [WMD = −31.55; 95% CI, −55.98 to −7.13; P = 0.01]. This result is not surprising because estradiol valerate can direct supplement the levels of E2. The pooled results indicate that Kuntai capsule may be effective for treating menopausal syndrome and lower risk of side effects. There are several strengths in this study. This meta-analysis on an important topic of women health, and was conducted at an appropriate time because despite several RCTs having been reported most are of a small sample size with conflicting results. We applied multiple strategies to identify the studies, strict criteria to include and evaluate the methodological quality of the studies, and subgroup and sensitivity analysis to minimize the heterogeneity. Moreover, we had a standard protocol registration in PROSPERO, an international prospective register of systematic reviews and published the protocol. The systematic review in our study has its own limitations. First, in terms of the current evaluative standards, the methodological quality of included studies was generally low. The majority of tri-
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als did not report randomization procedures and all trials lacked information on blinding. Additionally, intention-to-treat analysis and pre-trial sample size estimate were not applied. Second, In terms of adverse reactions, we only analyzed the statistical data of patients with the total rate of adverse reactions, due to the lack of descriptions of the concrete data. Third, none of the included trials described the economic index. Fourth, we tried to compare Kuntai capsule with other Chinese patent medicines, but failed to draw any conclusions due to no relevant randomized controlled trials. 5. Conclusions The findings of the current trials suggest that Kuntai capsule may be effective for treating menopausal syndromes and lower risk of side effects. However, due to the poor methodology quality, the confirmative conclusions on the beneficial effect of Kuntai capsule for the menopausal syndromes could not be drawn. More rigorously designed, large-sample, randomized controlled trials are warranted to confirm and update the findings of this analysis in the future. Conflict of interests No competing financial interests exist. Authors’ contributions ZQ, SHM and ZMZ developed the idea and designed the research. TJ developed the search strategy, ran the search strategy with CAH, selected which studies to include and extracted data from studies with CAH, interpreted the analysis and drafted the final review. ZQ and SHM obtained copies of studies and revised the writing. ZQ carried out the analysis. All authors read and approved the final manuscript. Acknowledgment This study was supported by National Natural Science Foundation of China (no, 81401187). References 1. Nelson HD. Menopause. Lancet. 2008;371(9614):760–770. 2. Ghosh M, Rodriguez-Garcia M, Wira CR. The immune system in menopause: pros and cons of hormone therapy. J Steroid Biochem Mol Biol. 2014;142:171–175. 3. Main C, Knight B, Moxham T, et al. Hormone therapy for preventing cardiovascular disease in post-menopausal women. Cochrane Database Syst Rev. 2013;4. CD002229. 4. Christenson ES, Jiang X, Kagan R, Schnatz P. Osteoporosis management in post-menopausal women. Minerva Ginecol. 2012;64(3):181–194. 5. Shifren JL, Schiff I. Role of hormone therapy in the management of menopause. Obstet Gynecol. 2010;115(4):839–855. 6. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321–333. 7. Vandenbroucke JP. The HRT controversy: observational studies and RCTs fall in line. Lancet. 2009;373(9671):1233–1235. 8. Shapiro S. Recent epidemiological evidence relevant to the clinical management of the menopause. Climacteric: J Int Menopause Soc. 2007;10(Suppl (2)):2–15.
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