| Objectives:1. To explore the epidemiological trend of chronic hepatitis B, review the research progress of western and traditional Chinese Medicine for treatment of CHB, in order to provide references for further high quality clinical trials of traditional Chinese Medicine for treatment of CHB.2. Try to apply network meta-analysis into the area of traditional Chinese Medicine, and to estimate the potential effect and harms of Chinese proprietary herbal medicines for CHB, and calculate the rank probability of the effect, in order to province evidence-based medicine basis for the generalization and application of Chinese proprietary herbal medicines for the treatment of CHB.Methods:1. Registration of the protocol:The protocol was published in the PROSPERO database (identification number:CRD42016032641).2. Data sources and searches:We conducted literature search in the following databases: Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, SinoMed, CNKI and VIP from their inception through August,2015. Unpublished literatures in the Chinese Conference Papers Database and the Chinese Dissertation Database also have been searched.3. Inclusion and criteria and study selection:We included RCTs of Chinese proprietary herbal medicines in "Chinese National Health Insurance Drug List" which accounted for the top ten literature quantity (i.e. Fuzheng Huayu Capsule/Tablets, Fufang Biejia Ruangan Tablets, Hugan Tablets/Capsule, Dahuang Zhechong Pill, Shuanghu Qinggan Granule, Danshen Injection, Fufang Danshen Tablets/Dripping Pills, Kuhuang Injection, Yigan Qingre Jiedu Tablets, Gansu Granule) for the treatment of CHB. Two authors independently selected relevant trials according to the pre-specified selection criteria. We resolved any disagreement by discussion or by a third party.4. Data extraction and analysis:Data extraction including following items such as details of study design, participants’ characteristics, interventions, outcomes and so on have been performed by two authors independently. The quality of include trials have been assessed for each included RCT independently following the instructions given in the Cochrane Handbook for Systematic Reviews of Intervention and the Cochrane Hepato-Biliary Group Module (Gluud 2015). The assessment have been conducted from following aspects: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 outcome reporting (publication bias), and other bias. The qualities of all the included trials have been evaluated as to be low/unclear/high risk of bias. We judged trials at low risk of bias if assessed with low risk of bias in all above domains. We judged trials at high risk of bias if assessed with unclear risk of bias or high risk of bias in one or more of the above domains.We performed data synthesis through RevMan 5.3 and network meta-analyses by R 3.2.5 software based on the Bayesian statistical model and Markov Chain Monte Carlo method (MCMC). Odds ratio (OR) with 95% confidence intervals (CIs) will be used as effect measure for dichotomous data, and mean difference (MDs) with 95% confidence intervals (CIs) have been used for continuous data. The chi-squared test for heterogeneity has been used to provide an indication of between-trial heterogeneity. In addition, the degree of heterogeneity observed in the results is quantified using the I-squared statistic which can be interpreted as the percentage of variation observed between the trials attributable to between-trial differences rather than sampling error (chance). Node analyses have been performed to test the consistency of direct and indirect comparison evidence by R software. We built node analysis model and calculate the P statistic of inconsistency of each node type which can indicate the potential diversity between the direct comparison results and synthetic indirect comparison results in the evidence loop.Results:Amount of 58 RCTs which involved 6,236 patients have been included. There were 2 three-armed RCTs and 1 four-armed RCT in the included trials. All the included trials were performed and publish in China, and none of them reported sample calculation. All the included trials adopted Chinese diagnostic criteria of CHB, only 5 trials reprrted Chinese differentiation of symptoms and signs for classification of syndrome information.The interventions included Fuzheng Huayu Capsule/Tablets, Fufang Biejia Ruangan Tablets, Hugan Tablets/Capsule, Dahuang Zhechong Pill, Shuanghu Qinggan Granule, Danshen Injection, Fufang Danshen Tablets/Dripping Pills, Kuhuang Injection, Yigan Qingre Jiedu Tablets, Gansu Granule. And the control intervention included conventional western medicine treatment, nucleoside analogues, interferon and other Chinese proprietary herbal medicines, there was no trial used placebo as control.No trials reported All-cause mortality, quality of life, hepatitis B-related mortality, and hepatitis B-related morbidity.25 trials reported TBIL level,33 trials reported ALT level,28 trials reported AST level,11 trials reported ALB level,4 trials reported y-GT level,3 trials reported A/G level,3 trials reported TBIL normalization,5 trials reported ALT normalization, 3 trials reported AST normalization,29 trials reported HA level,26 trials reported LN level, 26 trials reported PCⅢ level,26 trials reported IV-C level,3 trials reported HBV-DNA capacity,17 trials reported HBV-DNA conversion rate,16 trials reported HBeAg conversion rate,7 trials reported HBaAg conversion rate,2 trials reported serious adverse events and 21 trials reported adverse events.Although all included trials mentioned "random allocation," only 7 trials described the method of random sequence generation:random number table. No trial mentioned allocation concealment. Only one trial mentioned "single-blinding", but the detail was unspecified. For incomplete outcome data, one trial provided information on drop-outs such as number of missing cases and the reason for the deletion. No trial reported intention-to-treat (ITT) analysis. With regard to selective reporting,13 RCTs did not report the outcomes in their study design, and we classified other included trials as unclear risk of bias because the study protocols were unattainable. No trial reported sample calculation, and 6 RCTs did not report whether the baseline characteristics of the treatment and the control group were comparable.Meta-analysis results showed that the included Chinese proprietary herbal medicine has good effect on liver function, hepatic fibrosis and HBV marker indexes in the treatment of CHB. As the traditional meta-analysis, NMA results also indicate that the included 10 kinds of Chinese proprietary herbal medicine good effect on ALT level in CHB patients. Furthermore, there was no statistical significance in the inconsistency of global symptom improvement (P>0.05). Among the included 10 interventions, Kuhuang Injection compared with conventional treatment had best effect on ALT level (MD:-54.60 [-85.72,-23.48]) and it had better rank probability (27.21%) of effect on ALT level. Gansu Granule compared with conventional treatment had second best effect on ALT level (MD:-44.54 [-67.48,-21.60]).Adverse events:Only 2 trials mentioned that no serious adverse events happened during the treatment. A total of 21 trials reported non-serious adverse events,6 of them mentioned that no abnormalities existed in the routine blood test, routine urine test, usea nitrogen, creatinine, electrocardiogram or the renal function test of parients; 5 of them did not reported the adverse events in control group. Major included studies reported headache, vertigo, ahypnosis, respiratory infection, flu-like symptoms, sicchasia, emesia, sense of suppression in the chest, cardiopalmus, abdominal distension, diarrhoea, Increased blood pressure, erythra or ttch of skin, and the flu-like symptoms had the highest incidence rate in treatment and control groups (38.1%,69.0%).Conclusion: The results showed that included Chinese proprietary herbal medicine may have benefit on liver function, hepatic fibrosis and HBV marker indexes in DPN patients. However, because of the poor methodology quality of the included trials, and the insufficient number of them, the positive effect should be illustrated cautiously. |
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