Chinese medicinal herbs for cholelithiasis

  • Review
  • Intervention

Authors


Abstract

Background

Cholelithiasis is a common disease of the biliary tract. Chinese medicinal herbs are being used widely as an alternative treatment in people with cholelithiasis, but their beneficial or harmful effects have not been assessed systematically.

Objectives

To assess the beneficial and harmful effects of Chinese medicinal herbs in people with cholelithiasis.

Search methods

We conducted searches in the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, Chinese Medicine Conference Disc, and Chinese Bio-Medicine Disc to January 2013. We handsearched four Chinese journals. No language or year of publication restrictions were applied.

Selection criteria

Randomised clinical trials studying Chinese medicinal herbs for treatment of cholelithiasis.

Data collection and analysis

Two review authors (SJ, TG) independently extracted data. For dichotomous data, we estimated the risk ratio (RR), and for continuous data, we calculated the mean difference. We also calculated 95% confidence intervals (CI).

Main results

Eleven randomised trials with 1205 participants with asymptomatic or mild-to-moderate cholelithiasis were included. None of the randomised clinical trials compared a single Chinese medicinal herb with a Western medicine or with surgery. No placebo-controlled trials were identified. In the trials comparing one Chinese herbal medicine (Gandanxiaoshi tablet) versus another (Aihuodantong tablet), there was no significant difference in the improvement of upper abdominal pain after the end of treatment (RR 1.21; 95% CI 0.71 to 2.05), and the heterogeneity among trials was not substantial. No other outcomes could be assessed. The remaining trials of Chinese medicinal herbs (Qingdan capsule, Danshu capsule, Paishi capsule, Rongdanpaishi capsule), did not offer specific data on symptoms, signs, or change in gallstones that would permit assessment of significant differences in curative effects between the treatment and control groups. No serious adverse events were reported.

Authors' conclusions

This review reveals no strong evidence that the analysed Chinese medicinal herbs have any beneficial effects on asymptomatic or mild-to-moderate cholelithiasis. Definitive conclusions will require much better designed randomised trials to reduce risk of bias and allow detailed assessment of clinical outcomes.

Résumé scientifique

Les herbes médicinales chinoises contre la cholélithiase

Contexte

La cholélithiase est une maladie courante des voies biliaires. Les herbes médicinales chinoises sont largement utilisées comme traitement alternatif chez les personnes souffrant de cholélithiase, mais leurs effets bénéfiques ou nocifs n'ont pas été systématiquement évalués.

Objectifs

Evaluer les effets bénéfiques et nocifs des herbes médicinales chinoises chez les personnes atteintes de cholélithiase.

Stratégie de recherche documentaire

Nous avons réalisé des recherches dans le registre d'essais du groupe Cochrane sur les maladies hépato-biliaires, le registre Cochrane sur les essais contrôlés (CENTRAL) dans The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, Chinese Medicine Conference Disc et Chinese Bio-Medicine Disc jusqu'en janvier 2013. Nous avons effectué des recherches manuelles dans quatre journaux chinois. Aucune restriction concernant la langue ou l'année de publication n'a été appliquée.

Critères de sélection

Les essais cliniques randomisés étudiant les herbes médicinales chinoises pour traiter la cholélithiase.

Recueil et analyse des données

Deux auteurs (SJ, TG) ont indépendamment extrait les données. Pour les données dichotomiques, nous avons estimé le rapport de risque (RR) et pour les données continues, nous avons calculé la différence moyenne. Nous avons également calculé des intervalles de confiance (IC) à 95 %.

Résultats principaux

Onze essais randomisés totalisant 1205 participants avec une cholélithiase asymptomatique ou légère à modérée ont été inclus. Aucun essai randomisé ne comparait une herbe médicinale chinoise à un médicament occidental ou à la chirurgie. Aucun essai contrôlé par placebo n'a été identifié. Dans les essais comparant une herbe médicinale chinoise (comprimé Gandanxiaoshi) à un autre (comprimé Aihuodantong), il n'a pas été constaté de différence significative dans l'amélioration des douleurs dans la partie supérieure de l'abdomen après le fin du traitement (RR 1,21 ; IC à 95 % 0,71 à 2,05), et l'hétérogénéité entre les essais n'était pas substantielle. Aucun autre résultat n'a pu être évalué. Les autres essais sur les herbes médicinales chinoises (capsule de Qingdan, capsule de Danshu, capsule de Paishi, capsule de Rongdanpaishi) ne mentionnaient pas de données spécifiques sur les symptômes, les signes ou le changement dans les calculs biliaires qui permettraient une évaluation des différences significatives dans les effets curatifs entre les groupes avec traitement et les groupes témoins. Aucun effet indésirable grave n'a été signalé.

Conclusions des auteurs

Cette revue ne révèle aucune preuve solide que les herbes médicinales chinoises analysées ont des effets bénéfiques sur la cholélithiase asymptomatique ou légère à modérée. Pour établir des conclusions définitives, il faudra réaliser des essais randomisés mieux conçus afin de diminuer le risque de biais et permettre une évaluation détaillée des résultats cliniques.

アブストラクト

胆石症に対する漢方薬

背景

胆石症は、胆道系の一般的な疾患である。胆石症患者の代替治療として漢方薬は広く用いられている。ただし、漢方薬の有益性や有害性はシステマティックに評価されていない。

目的

胆石症患者に対する漢方薬の有益性および有害性を評価すること。

検索戦略

Cochrane Hepato-Biliary Group Controlled Trials Register、Cochrane Central Register of Controlled Trials (CENTRAL、コクラン・ライブラリ)、MEDLINE、EMBASE、Science Citation Index Expanded、Chinese Medicine Conference Disc、およびChinese Bio-Medicine Discを2013年1月まで検索した。 中国の雑誌をハンドサーチした。言語および出版年による制限は設けなかった。

選択基準

胆石症治療に対する漢方薬を対象としたランダム化臨床試験。

データ収集と分析

2名のレビュー著者(SJ, TG)が独立してデータを抽出した。二分法データについてはリスク比(RR)、連続データについては平均差を評価した。95%信頼区間(CI)も算出した。

主な結果

無症候性または軽度から中等度の胆石症の参加者1205例を対象とした11件のランダム化試験を選択した。漢方薬単剤と西洋薬または手術とを比較したランダム化臨床試験はなかった。プラセボ比較試験も同定されなかった。ある漢方薬(Gandanxiaoshi錠剤)と別の漢方薬(Aihuodantong錠剤)を比較した試験では、治療後に上腹部痛の改善に有意差は認められず(RR 1.21、95%CI 0.71~2.05)、試験間の異質性は大きくなかった。他に評価できたアウトカムはなかった。他の漢方薬(Qingdanカプセル、Danshuカプセル、Paishiカプセル、Rongdanpaishiカプセル)試験では、治療群とコントロール群間で治療効果の有意差の評価ができる症状、徴候または胆石の変化に関する特定のデータを得られなかった。重篤な有害作用は報告されなかった。

著者の結論

本レビューでは、無症候性または軽度から中等度の胆石症に解析対象の漢方薬が有益な効果を及ぼす強固なエビデンスは認められない。確定的な結論を得るには、バイアスのリスクを低下させ、臨床アウトカムを詳細に評価できるような、さらに優れたデザインのランダム化試験が必要となる。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2015.12.30]
《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。

Plain language summary

Chinese medicinal herbs for cholelithiasis

Cholelithiasis (gallstone disease) causes significant morbidity, severe complications, and economic burden worldwide. Though current surgical therapies are effective for gallstones, some types of gallstones (e.g., calcium bilirubinate calculi) cannot easily be eradicated by surgery and they often recur in the bile duct system, putting people at high risk of severe complications. The objective of this review was to evaluate the benefits and harms of Chinese medicinal herbs for people with cholelithiasis. Though some Chinese medicinal herbs appear to be safe for people with asymptomatic, mild, or moderate disease, they have not been conclusively shown to have curative effects on gallstones due to the low methodological quality (high risk of bias) of the included trials. Thus, randomised clinical trials with low risk of bias should be conducted to assess the effects of Chinese medicinal herbs before they can be used widely in the clinic.

Résumé simplifié

Les herbes médicinales chinoises contre la cholélithiase

La cholélithiase (maladie biliaire) entraîne une morbidité significative, des complications graves et représente un fardeau économique à l'échelle mondiale. Bien que les thérapies chirurgicales actuelles soient efficaces pour les calculs biliaires, certains types de calculs (par ex. les calculs de bilirubinate de calcium) ne peuvent pas être facilement éradiqués par la chirurgie et récidivent souvent dans le système biliaire, mettant les individus face à des risques élevés de complications graves. L'objectif de cette revue était d'évaluer les avantages et les inconvénients des herbes médicinales chinoises pour les personnes souffrant de cholélithiase. Même si certaines herbes médicinales chinoises semblent sans danger pour les personnes avec une maladie asymptomatique, légère ou modérée, elles n'ont pas montré de manière concluante qu'elles avaient des effets curatifs sur les calculs biliaires en raison de la qualité méthodologique faible (risque de biais élevé) des essais inclus. Par conséquent, des essais cliniques randomisés avec un risque de biais faible devront être réalisés pour évaluer les effets des herbes médicinales chinoises avant qu'elles ne puissent être utilisées à grande échelle dans la pratique clinique.

Notes de traduction

Traduit par: French Cochrane Centre 7th August, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

平易な要約

胆石症に対する漢方薬

胆石症は、世界的に著しい病的状態、重症合併症および経済的負担を引き起こしている。現在の外科的治療法は胆石に有効である。しかし、一部のタイプの胆石(例えば、ビリルビン酸カルシウム結石)は手術で簡単に除去できず、胆管系で再発することが多く、重症合併症のリスクを高める。本レビューの目的は、胆石症患者に対する漢方薬の有益性および有害性を評価することとした。一部の漢方薬は、無症候性や軽度、中等度の胆石症患者には安全のように思われるが、選択した試験は方法論の質が低い(バイアスのリスクが高い)ため、胆石に対する治療効果がはっきりとは示されていない。したがって、漢方薬を診療の場で広く用いる前に、バイアスのリスクが低いランダム化臨床試験を実施してその効果を評価するべきである。

訳注

《実施組織》厚生労働省「「統合医療」に係る情報発信等推進事業」(eJIM:http://www.ejim.ncgg.go.jp/)[2015.12.30]
《注意》この日本語訳は、臨床医、疫学研究者などによる翻訳のチェックを受けて公開していますが、訳語の間違いなどお気づきの点がございましたら、eJIM事務局までご連絡ください。なお、2013年6月からコクラン・ライブラリーのNew review, Updated reviewとも日単位で更新されています。eJIMでは最新版の日本語訳を掲載するよう努めておりますが、タイム・ラグが生じている場合もあります。ご利用に際しては、最新版(英語版)の内容をご確認ください。

Background

Cholelithiasis, which refers to the presence of gallstones in the biliary tract, is a relatively common disease, with an incidence mean rate of 9% to 15% in adults worldwide (Shipeng 2000). The frequency of gallstone occurrence differs greatly across continents and countries, varying from 6% to 70% (Jorgensen 2000). The disease is caused by multiple risk factors, including increasing age, ethnic and hereditary factors, female sex, multiple pregnancies, obesity, diabetes, liver cirrhosis, long-term intravenous nutrition (total parenteral nutrition), and certain types of operations for peptic ulcers (Mendez-Sanchez 1991). In people with a mild form of the disease, no symptoms can be observed (silent stones), but gallstones may be found in the biliary system using such imaging methods as abdominal ultrasound, cholecystography, and computed tomography (Yirong 1994). In symptomatic patients, cholelithiasis can induce biliary colic, bile duct infection, cholecystitis, or even suppurative cholangitis and pancreatitis (Wu 2000). Severe complications of gallstone disease, such as suppurative cholangitis or pancreatitis, always occur due to migration of the gallstone into the common bile duct from the gallbladder. These stones may enter the common bile duct and cause occlusion of the lumen, causing obstructive jaundice; pancreatitis due to obstruction of the pancreatic ducts; or ascending cholangitis as a result of diminished bile flow (Veedfald 2011). These complications are the main causes of death related to cholelithiasis (Jieping 2000). Gallstone disease is usually chronic, and symptomatic gallstone disease adversely affects quality of life. Furthermore, gallstone disease is associated with high medical costs, and causes an economic burden in the form of healthcare expenses.

Currently cholecystectomy, predominantly performed via laparoscopy, is the standard treatment for symptomatic cholecystolithiasis (Keus 2010). It is estimated that more than 500,000 cholecystectomies are carried out annually for symptomatic gallstone disease in the USA (Fischer 2004). If the gallstone in the biliary system must be cleared, choledochoscopy and endoscopic papillotomy are invasive therapeutic options (Ronglai 2001). However, some types of gallstone recur easily and are quite difficult to eradicate in a single surgical or non-surgical procedure (Nakavama 1980; Ha 2011); one such type of gallstone is calcium bilirubinate calculus, a sandy or massive stone in the bile duct caused by biliary tract infection or parasite infestation (Xiaosi 1994; Sackmann 1997). People with these types of gallstones can be a challenge to treat because the people are reluctant to undergo surgery, or because the presence of comorbidities can preclude the multiple surgeries needed to resolve the condition.

Several non-invasive and pharmacological treatment options have been used as an alternative to surgery. These include lithotripsy (Neuhaus 1998), bile acid administration (chenodeoxycholic acid, ursodeoxycholic acid) (Veedfald 2011), disodium edetate, or methyl tert-butyl ether (Patino 1998).

Chinese medicinal herbs are commonly defined as a series of therapeutic plants that are compatible with one another, which means that some are used as the main therapeutic ingredients for the disease, some are used as accessorial intensifiers for therapeutic ingredients, and others are used as neutral ingredients to control side effects. When an environmental factor is involved in the occurrence of a disease, that factor can interact with an underlying imbalance in the body and thereby lead to the disease. Thus, a physician will treat the underlying imbalance, not only the disease itself. Herbal medicines are abundant tools for re-establishing the underlying balance, thereby restoring health to the body. Several medicinal herbs have been commonly held to be effective against cholelithiasis (Ziliang 2001). These herbs include Lysimachia christinae Hance, Scutellaria baicalensis Georgi, Citrus aurantium L, Artemisia capillaris Thunb, Forsythia suspensa (Thunb) Vahl, Lonicera japonica Thunb, and Crataegus pinnatifida Bge.var.major N.E.Br.

Chinese medicinal herbs are used to treat cholelithiasis in China (Hong 1997). Some clinical trials have been performed to assess the benefits or harms of these herbs on people with gallstones (Zhang 2001b; Binghui 2002). However, we did not find any Chinese systematic reviews until 2010 (Chen 2010); the review provided only an incomplete appraisal of methodological quality in the included trials, preventing definitive conclusions.

Objectives

To assess the beneficial and harmful effects of Chinese medicinal herbs for cholelithiasis when compared with placebo, no intervention, another therapeutic agent (e.g., ursodeoxycholic acid), or surgical treatment.

Methods

Criteria for considering studies for this review

Types of studies

All parallel-group randomised clinical trials and the first phase of randomised cross-over trials testing Chinese medicinal herbs for treatment of cholelithiasis. The trials could be published in any language.

Types of participants

People with cholelithiasis, confirmed by cholecystic or biliary operation, or clinically diagnosed by radiological imaging, including abdominal ultrasound, cholecystography, computed tomography, or other techniques. Cholelithiasis could be defined based on the presence of any cholecystic symptoms according to the criteria in the books Practical Internal Medicine (Lin 1993), Chinese Traditional Medicine Trial and Instruction Principle in Clinic (Wang 1993), and Chinese Traditional Sign and Diagnosis (Deng 1987). Diagnostic standards included the following definitions: 1) plus 2), or 1) plus 3), or 1) plus 2) plus 3):

  1. A typical history of cholelithiasis, with or without positive physical signs.

  2. Positive results of certain auxiliary examinations that can confirm the presence of gallstones in the biliary system (Downs 1996). These examinations include B-mode ultrasonography (B-ultrasound), computed tomography, magnetic resonance imaging, percutaneous transhepatic cholangiography, and endoscopic retrograde cholangiopancreatography/magnetic resonance cholangiopancreatography (Downs 1996).

  3. Gallstones in the gallbladder or the biliary ducts, or both as confirmed by a surgical procedure.

Types of interventions

Chinese medicinal herbs (a single medicinal herb, i.e., patent herbal medicines or a medicinal herbal compound, i.e., self-made herbal compounds) were compared with placebo or no treatment, ursodeoxycholic acid, or another Western medicine (a product made by chemical synthesis or extraction in a pharmaceutical factory), and surgery.

Trials with Chinese medicinal herbs combined with other Western medicine (the commonly used medicines included in Cecil Textbook of Medicine (Cecil 1996) andSabiston Textbook of Surgery (Sabiston 2012)) versus the same type of Western medicine in the intervention group were also considered for the review.

Types of outcome measures

We planned to evaluate the following outcomes.

Primary outcomes

1. Mortality.
2. Number of people without relief of symptoms (i.e., upper abdominal pain, biliary colic, nausea, and vomiting or icterus).
3. Number of people without reduction, excretion, or dissolution of gallstones.
4. Adverse events defined as any untoward medical occurrence not necessarily having a causal relationship with the treatment but resulting in a dose reduction or discontinuation of treatment (ICH-GCP 1997).

Severe adverse events are defined as any event that would increase mortality; is life-threatening; requires inpatient hospitalisation; results in a persistent or significant disability; or any important medical event that may jeopardise the person or require intervention to prevent it. All other adverse events are considered non-serious.

Non-serious adverse events are defined as symptoms or abnormality of biochemical results caused by Chinese medicinal herbs at any dose:

  • Vertigo or nausea.

  • Abdominal pain/biliary colic.

  • Diarrhoea.

  • Other symptoms, such as rash, bitter taste, abdominal distension, constipation, etc.

  • Abnormality of liver function or kidney function, or other biochemical results.

These adverse effects could disappear by the expectant treatment, or discontinuation of the therapies, or by reduction in the dosage of the Chinese medicinal herbs.

Secondary outcomes

5. The number of people undergoing biliary surgical interventions.
6. Quality of life.
7. Patients' expenditures for hospitalisation, medication, and medical examination. (In China, people may be responsible for paying some or all treatment costs depending on the type of hospitalisation, medication, and medical examination.)

Search methods for identification of studies

Electronic searches

We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (Gluud 2013), the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, MEDLINE, EMBASE, Science Citation Index Expanded, Chinese Medicine Conference Disc (CMCD), and Chinese Bio-Medicine Disc (CBMD) (Royle 2003). The search strategies with the time spans of the searches are given in Appendix 1.

Searching other resources

We also searched the following journals for the relevant trials from the first publication date onwards: Chinese Journal of Integrated Traditional and Western Medicine of Zhejiang (1991 to November 2012), Chinese Journal of Beijing University of Traditional Chinese Medicine (1980 to November 2012), Chinese Surgical Journal of Integrated Traditional and Western Medicine (1994 to November 2012), and Chinese Journal of Integrated Traditional, and Western Medicine (1980 to November 2012). Conference proceedings not published in journals, such as Chinese hepatobiliary conference proceedings, were also searched.

Further trials were sought by scanning of the reference lists of the relevant articles. In addition, the authors of the trials and the pharmaceutical companies producing the drugs involved in the review were contacted for information on additional published or unpublished randomised clinical trials, but no responses were received.

Data collection and analysis

We performed the review and meta-analyses following the recommendations of The Cochrane Collaboration (Higgins 2011) and The Cochrane Hepato-Biliary Group Module (Gluud 2013). The analyses were performed using Review Manager 5.2 (RevMan 2012).

Selection of studies

Two review authors (SJ, TG) independently selected the trials to be included in the review according to the above-mentioned eligibility criteria. Disagreements were resolved by discussion. In case of disagreement, a third review author (YW) was consulted. Decisions on included trials or excluded studies were based on the entire text of the publication whenever available.

Data extraction and management

Data extraction was conducted up to and including November 2012 by two review authors (SJ, JC). Data were extracted from the included trials using standardised extraction sheets: study type and methodology; number and description of participants; details of type, dosage, and time schedule/duration of intervention; and type and measurement method of outcomes.

The authors of the trials were queried to specify any data not sufficiently reported in the publication. The contents of data extraction included information on participants, study design, characteristics of intervention formulae (CMS) and comparators, any adverse effects, and baseline data (Characteristics of included studies).

Assessment of risk of bias in included studies

Methodological quality is defined as the confidence that the trial design and report will restrict bias in the intervention comparison (Moher 1998). According to empirical evidence (Schulz 1995; Moher 1998; Kjaergard 2001; Wood 2008; Lundh 2012; Savovic 2012a; Savovic 2012b), bias risk assessment was achieved through the following domains:

Allocation sequence generation 

  • Low risk of bias: sequence generation was achieved using computer random number generation or a random number table. Drawing lots, tossing a coin, shuffling cards, and throwing dice were adequate if performed by an independent adjudicator.

  • Uncertain risk of bias: the trial was described as randomised, but the method of sequence generation was not specified.

  • High risk of bias: the sequence generation method was not, or may not have been, random. Quasi-randomised studies, those using dates, names, or admission numbers in order to allocate patients, are inadequate and were excluded for the assessment of benefits but not for assessing harms.

Allocation concealment

  • Low risk of bias: allocation was controlled by a central and independent randomisation unit; sequentially numbered, opaque and sealed envelopes; or similar so that intervention allocations could not have been foreseen in advance of or during enrolment.

  • Uncertain risk of bias: the trial was described as randomised, but the method used to conceal the allocation was not described so that intervention allocations may have been foreseen in advance of or during enrolment.

  • High risk of bias: if the allocation sequence was known to the investigators who assigned participants or if the study was quasi-randomised. Quasi-randomised studies were excluded for the assessment of benefits but not for assessing harms.

Blinding of participants, personnel, and outcome assessors

  • Low risk of bias: blinding was performed adequately, or the outcome measurement was not likely to be influenced by lack of blinding.

  • Uncertain risk of bias: there was insufficient information to assess whether the type of blinding used was likely to induce bias on the estimate of effect.

  • High risk of bias: no blinding or incomplete blinding, and the outcome or the outcome measurement was likely to be influenced by lack of blinding.

Incomplete outcome data

  • Low risk of bias: the underlying reasons for missing data were unlikely to make treatment effects depart from plausible values, or proper methods were employed to handle missing data.

  • Uncertain risk of bias: there was insufficient information to assess whether the missing data mechanism in combination with the method used to handle missing data were likely to introduce bias in the estimate of effect.

  • High risk of bias: the crude estimate of effects (e.g., complete case estimate) was clearly biased due to the underlying reasons for missing data, and the methods used to handle missing data were unsatisfactory.

Selective outcome reporting

  • Low risk of bias: pre-defined or clinically relevant and reasonably expected outcomes were reported on.

  • Uncertain risk of bias: not all pre-defined or clinically relevant and reasonably expected outcomes were reported on, or were not reported fully, or it was unclear whether data on these outcomes were recorded or not.

  • High risk of bias: one or more clinically relevant and reasonably expected outcomes were not reported on; data on these outcomes were likely to have been recorded.

The clinically relevant and reasonably expected outcomes include the data of mortality and morbidity, symptoms, physical signs, and image results of reduction, excretion, or dissolution of gallstones, or other results which the original investigators intended to assess.

Other bias

  • Low risk of bias: the trial appeared to be free of other factors that could put it at risk of bias. 

  • Uncertain risk of bias: the trial might or might not have been free of other factors that could put it at risk of bias.

  • High risk of bias: there were other factors in the trial that could put it at risk of bias.

Other bias include profit involvement, or academic bias (i.e., authors have conducted trials on the same topic, etc.).

Trials assessed as having 'low risk of bias' in all of the specified individual domains were considered trials with 'low risk of bias'. Trials assessed as having 'uncertain risk of bias' or 'high risk of bias' in one or more of the specified domains were considered trials with 'high risk of bias'.

Measures of treatment effect

For binary outcomes, such as the presence or absence of symptoms, the impact of the intervention was expressed as a risk ratio (RR) together with 95% confidence intervals (CI). For continuous outcomes, means and standard deviations (SD) were used to summarise the values in each group. The mean differences or the standardised mean differences for continuous outcomes were used, depending on whether the continuous data used the same scale or not.

Unit of analysis issues

Participants in the randomised trials. We planned to use participants' data from the first period of the randomised cross-over trial if such trials were identified.

Dealing with missing data

The intention-to-treat analysis was performed for dichotomous and continuous outcomes if complete data were available. If complete data were not available at the end of the trial, for dichotomous data, a 'worst-case' scenario was employed in which participants with missing or incomplete data were considered to be treatment failures in both groups; for continuous data, a similar scenario was also employed in which the baseline data at the time of group allocation were used as the final data for analysis.

Assessment of heterogeneity

We tested statistical heterogeneity using the Chi2 test with a P value < 0.1 set as the cut-off (Higgins 2002), if these existed.

Assessment of reporting biases

Whenever possible (i.e., if there were more than 10 included trials), we used a regression analysis to assess funnel plot asymmetry (Egger 1997).

Data synthesis

We used the Cochrane Review Manager 5.2 software (RevMan 2012) for meta-analyses. All meta-analyses were performed using both the random-effects and fixed-effect models. If the two models gave different results, both sets of results were reported; if the two models gave similar results, only the results of the fixed-effect model were reported.

We planned not to carry out meta-analysis of trials involving completely different types of interventions. The trials comparing herbs versus herbs were to be analysed separately from trials comparing herbs versus no treatment (with or without placebo). We planned to perform descriptive analysis using the Chi2 test (P value < 0.05) to compare dichotomous outcomes between two treatment groups. If the theoretical frequency was < 1 or if fewer than 40 participants were involved in the comparison during the Chi2 test, Fisher's exact test would then be used for further evaluation (Cochran 1954). Under theoretical frequency, it is to be understood a distributional frequency that would result if the data followed a theoretical distribution law rather than the actual observed frequencies. If we had only one trial for each comparison, Students' t-test (P value < 0.05), as implemented in SPSS version 13.0, would be applied to continuous data in order to assess the efficacy of Chinese medicinal herbs to treat cholelithiasis.

Subgroup analysis and investigation of heterogeneity

We planned to compare the trials with low risk of bias versus those with high risk of bias for the primary outcome measures. We had also planned to perform further subgroup analyses (if P value < 0.1) to explore the association between dose and duration of experimental interventions and effect as well as the association between disease severity at entry and effect.

Results

Description of studies

Our search in January 2013 identified 336 articles. Seven publications came from the search in The Cochrane Hepato-Biliary Group Controlled Trials Register, 48 from the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library, 26 from MEDLINE, 55 from EMBASE, 25 from Science Citation Index Expanded, 133 from CBMD, 29 from CMCD, and 13 from handsearching. Duplicate publications were excluded, leaving 133 publications. Of the 133 publications, we excluded 122 after reading the abstracts or full text, because they were not focused on people with cholelithiasis or on the objectives of this review. The reasons for exclusion are listed in the Characteristics of excluded studies table. The remaining 11 publications of randomised controlled trials (RCTs) were chosen for further assessment.

Trial design

All 11 publications described randomised trials with parallel design, involving 1205 people with asymptomatic, mild, or moderate cholelithiasis. No quasi-randomised trials and cohort studies were identified for detailed assessment of harm. Trials comparing herbs versus placebo or no treatment were not identified, and no cross-over trials were found. All 11 trials were performed in China. Five trials compared Chinese medicinal herbs versus other Chinese medicinal herbs (Dai 2000; Zhang 2001a; Zhang 2001b; Deng 2005; Su 2012), and the others compared Chinese medicinal herbs (or Chinese medicinal herbs plus Western medicines) versus Western medicines.

Sample size

Thirty-four participants took part in the trial of herbs plus one antibiotic versus the same antibiotic (She 1981), while 60 to 200 participants (mean 110) took part in the other trials comparing Chinese medicinal herbs versus different types of herbs or Western medicines.

Setting

Four trials included outpatients (Zhao 2004; Xing 2009; Shi 2012; Su 2012). Although another six trials did not define the status of the patients (Zhu 1997; Dai 2000; Zhang 2001a; Zhang 2001b; Deng 2005; Huang 2005), we assume that they were outpatients based on the patient's condition and treatment duration of at least eight weeks. The last trial (She 1981), which compared Chinese medicinal herbs plus one antibiotic versus the same antibiotic alone, did not specify clearly the status of the patients, but we assume them to be inpatients since patients with cholecystitis requiring intravenous infusion are usually admitted as inpatients in Chinese hospitals.

Participants

Ten trials included adults only (She 1981; Zhu 1997; Dai 2000; Zhang 2001a; Zhang 2001b; Deng 2005; Huang 2005; Xing 2009; Shi 2012; Su 2012), and one trial included adult, children (the youngest was eight years old), and teenagers (Zhao 2004), but the ratio of the children and teenage patients in the two groups was not reported. The male to female ratio was approximately 1:2 in eight trials (275 men/520 women) (She 1981; Dai 2000; Zhang 2001a; Zhao 2004; Deng 2005; Huang 2005; Xing 2009; Shi 2012), 1.6:1 in one trial (Su 2012), and undefined in the remaining two trials (Zhu 1997; Zhang 2001b). The age of the participants in ten of the trials ranged from 8 to 91 years old (She 1981; Zhu 1997; Dai 2000; Zhang 2001a; Zhang 2001b; Zhao 2004; Deng 2005; Xing 2009; Shi 2012; Su 2012). The trial by Huang 2005 did not explicitly report age. The average age range in seven trials varied between 42 and 51 (Zhang 2001a; Zhao 2004; Deng 2005; Huang 2005; Xing 2009; Shi 2012; Su 2012). The trials of She 1981; Zhu 1997; Dai 2000; and Zhang 2001b did not provide the mean age of the participants.

Interventions

The Chinese medicinal herbs used in the intervention group of the 11 trials were either patent herbal medicines (i.e., proprietary formulations made by a pharmaceutical company) or herbal compounds prepared in a pharmacy at the discretion of the pharmacist. As a primary supportive treatment for symptoms, such as upper abdominal pain, biliary colic, nausea, and vomiting, trial participants in three trials received an antibiotic, spasmolytics, or analgesics. An antibiotic was given in the trial comparing herbs plus antibiotic versus the same antibiotic alone (She 1981), and the spasmolytics as well as analgesics were given in two trials (She 1981; Xing 2009). From the publication of the She 1981 trial, it is clear that the same antibiotic was administered to the control and intervention groups, but the identity and dosage were not provided (Table 1).

Table 1. Administration of Chinese medical herbs (herbs plus Western medicine (an antibiotic) versus the same Western medicine (an antibiotic)
Number of trialsHerbs with Western medicine in the intervention groupRoute of administration in the intervention groupPeriod of administration in the intervention group Other herbs with Western medicine in the control group Route of administration in the control group Period of administration in the control groupRandomised trial and method of blinding Observation of follow-up
She 1981Cai hu cheng qi decoction without specific dosages (Radix Bupleuri, Natrii Sulphas, Radix Et Rhizoma Rhei, Sterculis euosma W.W.Smith, Herba Lysimachiae, Herba Artemisiae Capillaris, Fructus Aurantii, Radix Aucklandiae, Radix Linderae, Radix Paeoniae Alba, Herba Taraxaci, Fructus Meliae Toosendan, Endothelium Corneum Gigeriae Galli, Radix Curcumae)
(self-produced herbal compounds) + transfusion and antibiotics without specific dosages and medicine
Taken orallyThe period of treatment was unclearTransfusion and antibiotics without specific dosages and medicine (same with the intervention group)Intravenous dripThe period of treatment is unclearRandomised trial without blindingNo follow-up

Five trials compared Chinese medicinal herbs (538 people) with three types of Chinese medicines: Chinese medicinal herbs (Tongfupaishizhitong decoction) versus medicinal herbs (Anetholi trithionum) in one trial (Deng 2005); Chinese medicinal herbs (Paishi capsule) versus Chinese medicinal herbs (Lidanpaishi capsule) in one trial (Su 2012); and Chinese medicinal herbs (Gandanxiaoshi tablet) versus medicinal herbs (Aihuodantong capsule) in three trials (Dai 2000; Zhang 2001a; Zhang 2001b). Five trials compared Chinese medicinal herbs (633 people) versus two types of Western medicines: Chinese medicinal herbs versus ursodeoxycholic acid in four trials (Zhu 1997; Zhao 2004; Huang 2005; Shi 2012); and Chinese medicinal herbs versus chenodeoxycholic acid in one trial (Xing 2009) (Table 2; Table 3). One trial compared Chinese medicinal herbs plus Western medicine (antibiotic) (34 people) versus the same Western medicine (antibiotic) (She 1981) (Table 1). None of the included trials compared a single Chinese medicinal herb versus Western medicine or versus surgery.

Table 2. Administration of Chinese medical herbs (herbs versus other herbs or Western medicine)
  1. b.i.d.: twice a day; t.i.d.: three times a day.

Number of trialsHerbs in regimen in the intervention groupRoute of administration in the intervention groupPeriod of administration in the intervention group Western medicine in the control group Route of administration in the control group Period of administration in the control groupRandomised clinical trial and method of blinding Observation of follow-up
Huang 2005Danshu capsule without specific dosages and herbs
(patent herbal medicine)
Oral3 monthsUrsodesoxycholic acid0.2 g t.i.d.3 monthsRandomised without blindingNo follow-up
Zhao 2004Rongpaidanshi capsule (Pericarpium Citri Reticulatae Viride 10 g, Pericarpium Citri Reticulatae 10 g, Radix Aucklandiae 5 g, Fructus Aurantii Immaturus 5 g, Radix Curcumae 12 g, Radix Paeoniae Alba 10 g, Endothelium Corneum Gigeriae Galli 20 g, Alumen 10 g, Nitrum 21 g, Radix Et Rhizoma Rhei 10 g, Fructus Crataegi 5 g, Radix Scrophulariae 10 g, Radix Glycyrrhizae 5 g, Herba Artemisiae Capillaris 10 g, Flos Lonicerae 10 g, Herba Lysimachiae 10 g, Radix Codonopsis Pilosulae 10 g, Radix Angelicae Sinensis 10 g, Evodia rutaecarpa (Juss.) Benth 3 g, Radix Scutellariae 6 g)
(self produced herbal compounds)
Oral6 monthsUrsodesoxycholic acid500 mg q.n.6 monthsRandomised without blinding6 months to 1 year
Zhu 1997Qingdan capsule (No specific ingredients reported)
(patent herbal medicine)
Oral3 monthsUrsodesoxycholic acid10 mg/kg/day Q.n.3 monthsRandomised without blindingNo follow-up
Xing 2009Jinzhihuang capsule (Fructus Aurantii, Endothelium Corneum Gigeriae Galli, Rheum Officinale Baill, Radix Paeoniae Alba, Herba Lysimachiae, Rhizoma Corydalis, Radix Glycyrrhizae)Oral12 weeksChenodeoxycholic acid0.5 g t.i.d.12 weeksRandomised without blinding6 months
Shi 2012

Jinjidanshi decoction (Herba Lysimachiae 10 g, Endothelium Corneum Gigeriae Galli 15 g, Rhizoma Polygoni Cuspidati 30 g, Radix Bupleuri 10 g, Fructus Aurantii 10 g, Vaticamangachapoi Blauco 10 g, Rhizoma Cyperi 15 g, Herba Artemisiae Capillaris 15 g, Taraxacum officinale 15 g, Radix Curcumae 10 g, Rhizoma Corydalis Fructus 10 g)

(self-produced herbal compounds)

Oral6 monthsUrsodesoxycholic acid0.3 g b.i.d.6 monthsRandomised without blindingNo follow-up
Table 3. Western medicine or herbs used in the control group
  1. b.i.d.: twice a day; H: herbs; t.i.d.: three times a day; W: Western medicine.

Number of trialsWestern medicine by venous transfusionWestern medicine or herbs by oral administration
She 1981Type of antibiotic without specific dosages and name-
Dai 2000-(H) Aihuodantong capsule 0.1 g t.i.d. for 90 days
Deng 2005-(H) Anetholi trithionum 25 mg t.i.d. for 8 weeks
Huang 2005-(W) Ursodesoxycholic acid 0.2 g t.i.d. for 3 months
Zhang 2001a-(H) Aihuodantong capsule 0.1 g t.i.d. for 3 months
Zhang 2001b-(H) *Aihuodantong capsule 0.1 g t.i.d. for 3 months
Zhao 2004-(W) Ursodesoxycholic acid 500 mg q.n. for 6 months
Zhu 1997-(W) Ursodesoxycholic acid 10 mg/kg/dayq.n. for 3 months
Xing 2009-(W) Chenodeoxycholic acid 0.5 g t.i.d. for 12 weeks
Shi 2012-(W) Ursodesoxycholic acid 300 mg b.i.d. for 6 months
Su 2012-(H) Lidanpaishi Capsule 3 # t.i.d. for 20 days

All of the participants in the included trials were asymptomatic or had mild-to-moderate symptoms, including mild upper abdominal pain, biliary colic, nausea, vomiting, or icterus. In one trial, an antibiotic was administered for three to five days due to complications of mild acute cholecystitis, and the acute cholecystitis symptoms disappeared in less than one week (She 1981).

In most trials, herbs were given orally in dosages of 10 to 50 g for periods ranging from 20 days to six months (median, one to three months). Herb dosage was not reported in some trials to protect commercial or proprietary interests. Across all 11 trials, more than 30 individual Chinese medicinal herbs were used, with the most frequent being the 7 to 15 herbs listed in Table 2. The following herbs were used most frequently: Herba Lysimachiae, 54.5% (6 trials); Fructus Aurantii, 54.5% (6 trials); Radix Paeonia Alba, 45.5% (5 trials); Radix Aucklandiae, 45.5% (5 trials); Rheum Offcinale Baillon, 36.4% (4 trials); Rhizoma Corydalis Fructus, 36.4% (4 trials); Radix Curcumae, 36.4% (4 trials); Herba Artemisiae Capillaris, 36.4% (4 trials), and Radix Glycyrrhizae, 27.3% (3 trials). Each trial used different formulations and dosages of Chinese medicinal herbs. The constituents and the dosage of the Chinese medicinal herbs were different in all the trials except for the three trials by Dai 2000; Zhang 2001a; and Zhang 2001b.

Outcomes

The trial authors did not report some specific results anticipated by our protocol; instead, most trials reported general clinical effects based on a general clinical curative index that aggregates changes in symptoms and signs, as well as reduction, excretion, or dissolution of gallstones. In this index, complete curative effects were defined as disappearance of all symptoms and signs, and complete disappearance of gallstones based on imaging tests. Partial curative effects were defined as the disappearance of some symptoms, signs, and gallstones, and reduction (but not total disappearance) of gallstones based on imaging tests. No curative effects were defined as the disappearance of some or all symptoms, and an increase or no change in gallstones based on imaging tests. Some trials did not report symptoms and signs of interest to this review (see Types of outcome measures), but they did provide data on other symptoms, such as anorexia, belching, dry throat with bitter taste, and constipation. Some trials recorded some symptoms of adverse events, such as diarrhoea.

Risk of bias in included studies

The risk of bias of the included trials was high (Figure 1; Figure 2).

Figure 1.

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

Figure 2.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

The number of people at follow-up and the reasons for the failures at follow-up were not reported in any of the trials. All participants completed their respective treatment courses in all included studies. However, only three trials (27.3%) reported complete clinical outcome data (Zhang 2001a; Zhao 2004; Xing 2009); the other eight had incomplete results or incomplete follow-up. Among the trials comparing Chinese medicinal herbs versus Western medicine, only two trials (40.0%) reported follow-up lasting from six months to one year (Zhao 2004; Xing 2009; see Table 2); among the trials comparing certain Chinese medicinal herbs versus other herbs, only one trial (20.0%) reported follow-up lasting from six months to one year (Zhang 2001a; see Table 4).

Table 4. Administration of Chinese medical herbs (herbs versus other herbs)
  1. t.i.d.: three times a day.

Number of trials Herbs in regimen in the intervention group Route of administration in the intervention group Period of administration in the intervention group Herbs in the control group Route of administration in the control group Period of administration in the control group Randomised clinical trial and method of blinding Observation of follow-up
Dai 2000Gandanxiaoshi tablet (OX bile Infusion, Nitrum, Endothelium Corneum Gigeriae Galli, Fructus Crataegi, Rhizoma Cyperi, Pericarpium Citri Reticulatae Viride, Flos Inulae, Rhizoma Coptidis, Baked Rhizoma Atractylodis Macrocephalae, Fructus Aurantii, Rhizoma Galangae, Radix Aucklandiae, Massa Fermentata Medicinalis) without specific dosages
(patent herbal medicine)
Oral90 daysAihuodantong capsule (extractive of Glechoma hederacea + Sunflower oil without specific dosages)
(patent herbal medicine)
0.1 g t.i.d.90 daysRandomised without blindingNo follow-up
Deng 2005Tongfupaishizhitong decoction (Herba Lysimachiae 30 g, Herba Artemisiae Capillaris 30 g, Spora Lygodii 20 g, Radix Codonopsis Pilosulae 20 g, Radix Atragali seu Hedysari 20 g, Radix Paeoniae Alba 15 g, Endothelium Corneum Gigeriae Galli 10 g, Radix Et Rhizoma Rhei 10 g, Fructus Aurantii 10 g, Radix Glycyrrhizae 10 g, Radix Pittospori 10 g, Fructus Meliae Toosendan 10 g, Rhizoma Corydalis 10 g, Radix Aucklandiae 5 g)
(self produced herbal compounds)
Oral8 weeksAnetholi trithionum (2-dithiole-3-thione)1# t.i.d.8 weeksRandomised without blindingNo follow-up
Zhang 2001aGandanxiaoshi tablet (OX bile Infusion, Nitrum, Endothelium Corneum Gigeriae Galli, Fructus Crataegi, Rhizoma Cyperi, Pericarpium Citri Reticulatae Viride, Flos Inulae, Rhizoma Coptidis, Baked Rhizoma Atractylodis Macrocephalae, Fructus Aurantii, Rhizoma Galangae, Radix Aucklandiae, Massa Fermentata Medicinalis) without specific dosages
(patent herbal medicine)
Oral3 monthsAihuodantong capsule (extractive of Glechoma hederacea + Sunflower oil without specific dosages)
(patent herbal medicine)
0.1 g t.i.d.3 monthsRandomised without blinding6 months to 1 year
Zhang 2001bGandanxiaoshi tablet (OX bile Infusion, Nitrum, Endothelium Corneum Gigeriae Galli, Fructus Crataegi, Rhizoma Cyperi, Pericarpium Citri Reticulatae Viride, Flos Inulae, Rhizoma Coptidis, Baked Rhizoma Atractylodis Macrocephalae, Fructus Aurantii, Rhizoma Galangae, Radix Aucklandiae, Massa Fermentata Medicinalis) without specific dosages
(patent herbal medicine)
Oral3 monthsAihuodantong capsule (extractive of Glechoma hederacea + Sunflower oil without specific dosages)
(patent herbal medicine)
0.1 g t.i.d.3 monthsRandomised without blindingNo follow-up
Su 2012Paishi Capsule (Rhizoma Phei, Fructus Aurantii Immaturus, Natrii Sulfas Exsiccatus) without specific dosagesOral20 daysLidanpaishi capsule (Herba Lysimachiae 25 g, Herba Artemisiae Capillaris 25 g, Radix Scutellariae 7.5 g, Radix Aucklandiae 7.5 g, Radix Curcumae 7.5 g, Rhizoma Phei 7.5 g, Semen Arecae 12.5 g, Fructus Aurantii Immaturus 12.5 g, sodium sulfate decahydrate 2.5 g, Magnoliaofficinalis Rehd.EtWils 5.0 g )3 # t.i.d.20 daysRandomised without blindingNo follow-up

No randomised clinical trials reported using an intention-to-treat analysis to evaluate their data. Information on baseline differences between the control and intervention groups was not reported sufficiently clearly in two of the trials (22.2%) (Zhu 1997; Dai 2000). The other trials reported no baseline differences between the two groups. See information in Table 2 and Table 4 (Chinese medicinal herbs versus Western medicine).

Allocation

All included trials were described as randomised clinical trials. Only one trial described the method used to generate the allocation sequence (random number table) (Zhang 2001a), and another trial described the method of allocation concealment (Zhu 1997).

Blinding

None of the study authors described that blinding was used in their trials.

Incomplete outcome data

Information on adverse events and follow-up was incomplete, despite the fact that all participants completed the study and there were no treatment withdrawals and no changes within the trial groups.

Selective reporting

Trial protocols were not available. The trial publications left the impression that all outcomes that the investigators aimed to study were reported. However, outcomes important to participants and practitioners alike, such as mortality, biliary operation, quality of life, and medical costs, were not reported.

Other potential sources of bias

Unclear or not found in the trials.

Effects of interventions

Primary outcomes

Mortality

No mortality data were reported in any of the 11 trials.

Number of participants without relief of symptoms (i.e., upper abdominal pain, biliary colic, nausea, vomiting, and icterus)

Three trials comparing one Chinese herbal medicine versus another Chinese herbal medicine could be included in a meta-analysis (Dai 2000; Zhang 2001a; Zhang 2001b). In these trials, Gandaoxiaoshi tablet, a compound of Chinese medicinal herbs, was given to the intervention group (200 people) at a dose of 3.0 g three times per day for three months, and Aihuodantong capsule at 0.1 g three times per day was given to the control group (90 people) for three months. The specific symptom of upper abdominal pain was mentioned in only two trials (Dai 2000; Zhang 2001a), and statistical analysis of the outcomes of the two trials are presented in Analysis 1.1. Authors of these trials did not report data for other symptoms and signs listed in the protocol, such as biliary colic, nausea, vomiting, and icterus, so they could not be assessed.

Upper abdominal pain

Of the three trials, only two presented specific data (Dai 2000; Zhang 2001a). The results of these trials showed no significant improvement on hypochondriac pain between the intervention group of 120 people (106 of whom reported upper abdominal pain before treatment) and the control group of 60 people (47 of whom reported upper abdominal pain before treatment) (RR 1.21; 95% CI 0.71 to 2.05) (Analysis 1.1).

In the trial of She 1981, the intervention group (16 people) received Cai hu cheng qi decoction, a compound of Chinese medicinal herbs, plus an antibiotic at an unspecific dose and for an unspecified treatment period. The control group (18 people) received the same antibiotic at an unspecific dose and for an unspecified treatment period. Detailed results about upper abdominal pain, biliary colic, nausea, vomiting, and icterus were not specified; the authors simply mentioned that there was no significant difference between the intervention and control groups in the disappearance time of upper abdominal pain and in the rate with which fever resolved. Therefore, outcomes related to symptoms, signs, and the underlying gallstone syndrome could not be assessed.

In the trial of Zhao 2004, the intervention group (100 people) was given Rongdanpaishi capsule, a compound of Chinese medicinal herbs, at a dose of 5 # three times per day for six months, and the control group (100 people) received ursodesoxycholic acid at 0.5 g every night for six months. In addition to the significant difference in general clinical curative effects, the authors reported improvement in upper abdominal pain, bitter taste, anorexia, and abdominal fullness in the intervention group. However, the authors did not report specific quantitative data for these outcomes, so the results could not be assessed in detail. Similarly, the other seven trials did not report detailed results on upper abdominal pain, biliary colic, nausea, vomiting, or icterus (Zhu 1997; Zhang 2001b; Deng 2005; Huang 2005; Xing 2009; Shi 2012; Su 2012); the trial authors mentioned only that there was a significant difference between the intervention and control groups in general clinical curative effects. Therefore, symptoms and signs could not be assessed.

Number of participants without reduction, excretion, or dissolution of gallstones

The effects of Chinese medicinal herbs on reduction, excretion, or dissolution of gallstones were assessed by B-ultrasound at the end of the treatment period (Table 5). 'Excretion' refers to the disappearance of the stone in follow-up ultrasound, presumably due to migration of the stone from the bile system to the intestine, while 'dissolution' refers to detectable reduction in stone size (e.g., from 2 cm to 1 cm), with the residual stone still detectable by ultrasound. The results show a significant difference in the effect on reduction, excretion, or dissolution of the gallstones between the intervention and control groups in two trials (She 1981; Dai 2000). In the study of She 1981, gallstones were excreted in 10 of 16 participants in the intervention group, while excretion did not occur in any of the 18 participants in the control group (P value = 0.000); this trial did not report the numbers of participants in whom the gallstones partially dissolved or reduced. Of the three trials pooled for meta-analysis (Dai 2000; Zhang 2001a; Zhang 2001b), only Dai 2000 presented data on the numbers of participants not showing reduction, excretion, or dissolution of gallstones; however, these numbers, determined by B-ultrasound, did not differ significantly between the intervention group (54/60 people) and the control group (25/30 people) (P value = 0.496).

Table 5. The statistical results of symptoms and signs in two trials (Chi2 test or Fischer's exact test)
  1. Chi2 = value of Chi2 tests; P = value of Fisher's exact test.

The statistical results of trials (Chi2(P))Upper abdominal painNausea and vomitingAbdominal distensionAnorexiaBelchingIcterusMurphy's signTenderness in right upper abdomen Without reductionof gallstones Without increase or change of gallstonesWithout excretion or dissolution of gallstones
She 1981----------Chi2=15.9 (P value = 0.000)
Dai 2000--------Chi2= 0.26 (P value > 0.10)

Chi2= 0.02

(P value > 0.10)

Chi2= 0.83 (P value = 0.496)

The other trials did not present specific data on numbers of participants not showing reduction, excretion, or dissolution of gallstones.

Participants with serious adverse events

No serious adverse events were reported in the included trials.

Participants with non-serious adverse events

Number and type of adverse effects

Adverse effects were mentioned in six of the 11 included trials (54.5%) (Table 6). Three of these six trials compared one Chinese herbal medicine (Gandanxiaoshi tablet) versus another Chinese herbal medicine, which was either Aihuodantong capsule (Dai 2000; Zhang 2001a) or Lidanpaishi capsule (Su 2012). The other three trials compared the Western medicine, ursodesoxycholic acid, versus different Chinese medicinal herbs, which were either Rongpaidanshi capsule (Zhao 2004), Danshu capsule (Huang 2005), or Paishi capsule (Shi 2012). Shi 2012 reported no adverse events in either the intervention or control group, whereas the numbers of participants experiencing adverse effects varied from 2 to 25 in the other five trials (Dai 2000; Zhang 2001a; Zhao 2004; Huang 2005; Su 2012). The following adverse effects were reported: vertigo, nausea, abdominal pain, and diarrhoea. The trial authors did not indicate whether the adverse effects were ascertained by standardised monitoring or voluntary self report, neither did they attempt to isolate the specific Chinese medicinal herbs that might be inducing those adverse effects. Fortunately, all adverse effects were mild and disappeared upon discontinuation of herbal therapy or reduction in herbal dosage.

Table 6. The statistical results of adverse effects in one trial (Chi2 test or Fischer's exact test)
  1. Chi2 = value of Chi2 tests; P = value of Fisher's exact test.

The statistical results of trials (Chi2(P))DiarrhoeaAbdominal pain with vertigoAbdominal painObstructive cholangitis
Huang 2005--

Chi2= 1.03

(P value = 0.548)

-
Zhao 2004

Chi2= 65.91

(P value < 0.001)

---
Diarrhoea

Of the 11 trials, three trials presented specific data on occurrence of diarrhoea as an adverse effect (Table 6). In the trial of Zhao 2004, diarrhoea occurred in 11 of 100 participants in the intervention group (Rongpaidanshi capsule) compared to 67 of 100 participants in the control group (ursodesoxycholic acid) (P value < 0.001). In the trials of Dai 2000 and Zhang 2001a, diarrhoea occurred in 7 of 120 participants in the intervention group (Gandanxiaoshi tablet) and in none of the 60 participants in the control group (Aihuodantong capsule) (RR 4.07; 95% CI 0.52 to 31.78) (Analysis 1.2).

Abdominal pain

In this systematic review, we assessed the occurrence of abdominal pain as a side effect of treatment; this was different from the upper abdominal pain caused by cholelithiasis. Of the 11 trials, only one presented data on abdominal pain as an adverse effect (Huang 2005) (Table 6). That study found no significant difference between the frequency of occurrence in the intervention group (2 of 40 participants), which received Danshu capsule, and the control group (0 of 20 participants), which received ursodesoxycholic acid (P value = 0.548).

Secondary outcomes

The number of participants undergoing biliary surgical interventions

No participant in any of the included trials underwent biliary surgical intervention.

Quality of life

No study reported data on participant quality of life.

Participant's economic condition for medical costs during hospitalisation, medication, and medical examination

No trials reported data on participants' medical costs during hospitalisation, medication, or medical examination.

Subgroup analysis and investigation of heterogeneity

We could not perform subgroup analyses because we could not include a sufficient number of comparable and homogeneous clinical trials in this review.

Discussion

Summary of main results

The results of the systematic review suggest that Gandanxiaoshi tablet, a patent Chinese medicinal herb, has equivalent clinical effects on cholelithiasis as compared to another herbal medicine, Aihuodnatong capsule; however, the absolute efficacy of either Gandanxiaoshi tablet or Aihuodantong capsule is unknown because we did not find any trials comparing these herbal medicines to placebo or no treatment. The result from the meta-analyses in this review showed that Gandanxiaoshi tablet showed no significant difference from Aihuodantong capsule in the improvement of cholelithiasis symptoms. The other studied Chinese medicinal herbs in the included studies, while traditionally believed to reduce upper abdominal pain, biliary colic, nausea, vomiting, and icterus, did not show any significant difference from control groups for the majority of outcome measures. The therapeutic effects on reduction, excretion, or dissolution of gallstones in the bile duct or the gallbladder, or both were unclear in comparisons of Gandanxiaoshi tablet and Aihuodantong capsule.

Overall completeness and applicability of evidence

The long-term goal of cholelithiasis treatment is to prevent recurrence of gallstones and onset of severe complications. The investigators of the included trials relied on a general clinical curative index that aggregated changes in certain specific symptoms and signs, as well as reduction, excretion, or dissolution of gallstones, but that did not take into account changes in other symptoms, such as upper abdominal pain, biliary colic, nausea, vomiting, and icterus. However, all the included participants in the trials are asymptomatic or just mild-to-moderate symptoms, participants with severe symptoms were excluded from the research because Chinese medicine practitioners believe medicinal herbs to play only an accessory role in treating cholelithiasis, therefore, people with severe cholelithiasis are usually treated with Western approaches. Furthermore, most trials did not report specific data on the reduction, excretion, or dissolution of gallstones, so we could not evaluate these outcomes. None of the trials reported how many participants had undergone biliary operations after treatment, so the proportion of participants who had undergone these operations could not be determined. In fact, most trials did not report other important outcomes, such as mortality, patient quality of life, medical costs, incidence of complications, or follow-up. As a result, we could not draw any definite conclusions about the outcomes of interest to our review.

No serious adverse effects of the Chinese medicinal herbs for cholelithiasis were reported. However, definitive conclusions about adverse effects could not be drawn from this review as the sample size of the included trials was not large, and the period of treatment and follow-up seemed insufficient. Though some slight symptoms, such as diarrhoea, were observed both in the Chinese medicinal herbs group (Dai 2000; Zhang 2001a), and Western medicine control group (Zhao 2004), reporting of adverse effects was poor and unsystematic, so we could not draw any conclusion about which medicine had more frequent or serious adverse effects. In fact, most Chinese clinical trials on Chinese medicinal herbs do not report adverse effects of the herbs or simply do not mention adverse effects, consistent with our previous observations that harm reporting is unreliable in studies on Chinese medicinal herbs (Chen 2010).

A plausible explanation for this lack of reporting is that Chinese clinical practitioners traditionally believe that Chinese medicinal herbs have few or no adverse effects since the herbs are natural products that have been used in China for many years. However, a growing number of studies show that Chinese medicinal herbs do cause adverse effects (Singh 2012). Therefore, medical researchers as well as clinical practitioners should pay more attention to such adverse effects and should consider them during clinical trial design and therapy planning. 

Quality of the evidence

All randomised clinical trials included in this review were of poor methodological quality, which led to a relatively high risk of bias. Trial reports provided only a limited description of study design and randomisation, and not all trials used allocation concealment. All trials stated only that random assignment was used, which we confirmed with the trial authors by telephone, but the reported outcomes data were incomplete, preventing us from drawing appropriate conclusions about the curative effects of the Chinese medicinal herbs on cholelithiasis. Most trials provided only general statements about the effects of the herbs; specific outcomes data, such as the numbers of participants experiencing reduction, excretion, or dissolution of gallstones, were not presented. We could not obtain this missing information, even after contacting the trial authors.

As a result of the different medicinal herbs used in the included trials and the high risk of bias, the therapeutic effects of several commonly used Chinese medicinal herbs, such as Herba Lysimachiae, Radix Paeonia Alba, Fructus Aurantii, Rheum Offcinale Baillon, Rhizoma Corydalis Fructus, and Radix Curcumae, remain uncertain. The trials also presented different clinical prescriptions in the diversity of Chinese medicinal herbs applied, as well as in baseline patient parameters such as age, sex ratio, and cholelithiasis aetiology and severity, preventing us from performing meta-analyses.

The evidence we collected for our analyses is weak and we can neither recommend nor argue against the use of the Chinese medicinal herbs studied in our review for treatment of cholelithiasis.

Potential biases in the review process

We found the design, execution, and reporting of the included clinical trials to be inadequate: important outcomes, such as mortality, biliary operations, quality of life, and medical costs, were not reported. There were no treatment withdrawals in the included trials, but information on adverse events, participant follow-up, and outcomes was incomplete. Participant characteristics at baseline were not clearly described in some of the trials. All these factors led us to estimate the trials to be at high risk of bias.

Agreements and disagreements with other studies or reviews

The results of one systematic review are in agreement with our review (Chen 2010), that is, that Chinese medicines do affect clinical symptoms of cholelithiasis. However, the long-term therapeutic effects have rarely been reported. The conclusions of the present review require verification due to the low methodological quality, heterogeneity, and inherent risk of bias in the included trials.

Authors' conclusions

Implications for practice

According to this systematic review, Chinese medicinal herbs should not be claimed to have strong positive therapeutic effects on the reduction, excretion, or dissolution of gallstones in the bile duct or the gallbladder even for people with asymptomatic or mild-to-moderate cholelithiasis. The risk of bias of the included randomised trials is high, and the available clinical data remain scanty. There is no strong evidence for the routine application of Chinese medicinal herbs in treatment of cholelithiasis.

Implications for research

The methodological quality of future randomised clinical trials for treatment of cholelithiasis with Chinese medicinal herbs should be improved. In particular, the trials should present how allocation sequences were generated and how allocation was concealed in detail. Trials should use blinding and should be placebo-controlled. Withdrawals and dropouts during the trial should be clearly reported. In fact, trials should report on all clinically important outcomes over a sufficiently long follow-up period.

Future studies of medicinal herbs to treat cholelithiasis should be well-designed, multicentre, large-scaled randomised trials that compare Chinese medicinal herbs versus no treatment/placebo and versus a standard treatment for which we have data (e.g., ursodeoxycholic acid and the dissolution of gallstones). Trials should present in detail how allocation sequences were generated and how allocation was concealed. Specific outcomes should be assessed, including reduction, excretion, or dissolution of gallstones; recurrence of gallstones; quality of life; mortality; adverse effects; symptoms; signs; complications; and cost-effectiveness, in addition to general clinical curative effects. Adverse effects should be critically assessed by standardised monitoring or by an effective self report system, or both. More attention should be paid to the long-term adverse effects caused by Chinese medicinal herbs.

Acknowledgements

We thank Dimitrinka Nikolova, Kate Whitfield, Sarah Louise Klingenberg, Jianping Liu, Edwin David McIntosh, and Luit Penninga for their help in the preparation of this review.

We also thank the peer reviewers and contact editors for their good suggestions (names given below).

Peer reviewers: Edwin David McIntosh, UK; Luit Penninga, Denmark.
Contact editors: Jian Ping Liu, China; Ronald L Koretz, USA.

Data and analyses

Download statistical data

Comparison 1. Trials of Gandanxiaoshi tablet (herbs) versus Aihuodantong capsule (herbs)
Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size
1 Upper abdominal pain2153Risk Ratio (M-H, Fixed, 95% CI)1.21 [0.71, 2.05]
2 Adverse effects: diarrhoea2180Risk Ratio (M-H, Fixed, 95% CI)4.07 [0.52, 31.78]
Analysis 1.1.

Comparison 1 Trials of Gandanxiaoshi tablet (herbs) versus Aihuodantong capsule (herbs), Outcome 1 Upper abdominal pain.

Analysis 1.2.

Comparison 1 Trials of Gandanxiaoshi tablet (herbs) versus Aihuodantong capsule (herbs), Outcome 2 Adverse effects: diarrhoea.

Appendices

Appendix 1. Search strategies

DatabaseTime of searchSearch strategy
The Cochrane Hepato-Biliary Group Controlled Trials RegisterJanuary 2013.(((traditional OR Chinese OR oriental OR alternative OR complementary) AND medicine*) OR herb* OR plant*) AND cholelithiasis
The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane LibraryIssue 12 of 12, 2012.#1 MeSH descriptor Phytotherapy explode all trees in MeSH
#2 MeSH descriptor Drugs, Chinese Herbal explode all trees in MeSH
#3 MeSH descriptor Medicine, Herbal explode all trees in MeSH
#4 MeSH descriptor Plants, Medicinal explode all trees in MeSH
#5 MeSH descriptor Medicine, Traditional explode all trees
#6 ((traditional or Chinese or oriental or alternative or complementary) and medicine*) or herb* or plant* ?
#7 (#1 OR #2 OR #3 OR #4 OR #5 OR #6)
#8 MeSH descriptor Cholelithiasis explode all trees
#9 cholelithiasis
#10 (#8 OR #9)
#11 (#7 AND #10)
MEDLINE (Ovid SP)1946 to January 2013.1. exp Medicine, Traditional/
2. exp Drugs, Chinese Herbal/
3. exp Medicine, Herbal/
4. exp Phytotherapy/
5. exp Plants, Medicinal/
6. (((traditional or Chinese or oriental or alternative or complementary) and medicine*) or herb* or plant*).mp. [mp=title, original title, abstract, name of substance word, subject heading word]
7. 1 or 2 or 3 or 4 or 5 or 6
8. exp Cholelithiasis/
9. cholelithiasis.mp. [mp=title, original title, abstract, name of substance word, subject heading word]
10. 8 or 9
11. 7 and 10
12. (random* or blind* or placebo* or meta-analysis).mp. [mp=title, original title, abstract, name of substance word, subject heading word]
13. 11 and 12
EMBASE (Ovid SP)1974 to January 2013.1. exp Traditional Medicine/
2. exp Medicinal Plant/
3. Plant Medicinal Product/
4. exp Phytotherapy/
5. (((traditional or Chinese or oriental or alternative or complementary) and medicine*) or herb* or plant*).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name]
6. 1 or 2 or 3 or 4 or 5
7. exp Cholelithiasis/
8. Cholelithiasis.mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name]
9. 8 or 7
10. 6 and 9
11. (random* or blind* or placebo* or meta-analysis).mp. [mp=title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name]
12. 11 and 10
Science Citation Index Expanded
(apps.webofknowledge.com)
1900 to January 2013.# 3 #2 AND #1
# 2 TS=cholelithiasis
# 1 TS=(((traditional or Chinese or oriental or alternative or complementary) and medicine*) or herb* or plant*)
Chinese Medicine Conference Disc1979 to January 2013.(((traditional OR Chinese OR oriental OR alternative OR complementary) AND medicine*) OR herb* OR plant*) AND (cholelithiasis OR cholelith OR stone of bile duct)
Chinese Bio-Medicine Disc1974 to January 2013.(((traditional OR Chinese OR oriental OR alternative OR complementary) AND medicine*) OR herb* OR plant*) AND (cholelithiasis OR cholelith OR stone of bile duct)

Contributions of authors

Tao Gan designed and revised the review, and controlled the overall quality of the review.
Tao Gan wrote the first draft of the review.
Jun Chen and Shuli Jin performed handsearches, retrieved the papers, and extracted the data.
Yiping Wang conceived the idea for the review and gave some suggestions to the review.

Declarations of interest

None known.

Sources of support

Internal sources

  • Chinese Cochrane Center, China.

  • Chinese Center of Evidence-based Medicine, China.

  • Huaxi Hospital of Sichuan University, China.

External sources

  • China Medical Board of New York, China.

Differences between protocol and review

We also included people with gallstones in the gallbladder or the biliary ducts, or both as confirmed by a surgical procedure.

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Dai 2000

MethodsRandomised clinical trial.
Sample size: estimation not reported.
Diagnostic criteria: B-ultrasound.
Baseline was comparable among the intervention and control groups.
ParticipantsIntervention group: 60 participants; M 20, F 40.
Control group: 30 participants; M 11, F 19.
InterventionsIntervention group: Gandanxiaoshi tablet 3.0 g t.i.d. for 90 days.
Control group 1: Aihuodantong capsule 100 mg t.i.d. for 90 days.
Outcomes

General clinical curative effects, a comprehensive index including clinical symptoms; signs; and the reduction, dissolution, or excretion of gallstones were reported.

Clinical symptoms, including upper abdominal pain, abdominal distension, bitter taste, constipation, and anorexia were reported.

Adverse events were reported.

NotesWe contacted the primary author by telephone regarding the unclear information in the trial in March 2009, but they could not remember the details.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
High riskNot used.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLosses to follow-up were not addressed.
Selective reporting (reporting bias)High risk

General clinical curative effects, a comprehensive index including clinical symptoms, signs, and the reduction, dissolution, or excretion of gallstones were reported.

The clinical symptoms, including upper abdominal pain, abdominal distension, bitter taste, constipation, anorexia were reported.

The adverse events were reported.

The specific results of symptoms, including biliary colic, nausea, vomiting, icterus, and signs were not reported.

Mortality, biliary operation, quality of life, medical costs during hospitalisation, medication and medical examination were not reported.

Other biasUnclear riskNot stated.

Deng 2005

MethodsRandomised clinical trial.
Sample size: estimation not reported.
Diagnostic criteria: B-ultrasound.
Baseline was comparable among the intervention and control groups.
ParticipantsIntervention group: 60 participants; M 25, F 35
Control group: 60 participants; M 20, F 40
InterventionsIntervention group: TCMHs 250 mL b.i.d. for 8 weeks.
Control group: Danweita 1# t.i.d. for 8 weeks.
OutcomesGeneral clinical curative effects, a comprehensive index including clinical symptoms; signs; and the reduction, dissolution, or excretion of gallstones.
NotesWe could not contact the primary author by letter and telephone regarding the unclear information in the trial.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
High riskNot used.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLosses to follow-up were not addressed.
Selective reporting (reporting bias)High risk

General clinical curative effects, a comprehensive index including clinical symptoms; signs; and the reduction, dissolution, or excretion of gallstones were reported.

Specific results of symptoms, including upper abdominal pain, biliary colic, nausea, vomiting, icterus, and signs were not reported.

Mortality, biliary operation, quality of life, medical costs during hospitalisation, medication, medical examination, and adverse events were not reported.

Other biasUnclear riskNot stated.

Huang 2005

MethodsRandomised clinical trial.
Sample size: estimation not reported.
Diagnostic criteria: B-ultrasound.
Baseline was comparable among the intervention and control groups.
ParticipantsIntervention group: 40 participants; M 22, F 18.
Control group: 20 participants; M 12, F 8.
InterventionsIntervention group: Danshu capsule 2# t.i.d. for 3 months.
Control group: ursodeoxycholic acid 0.2 g t.i.d. for 3 months.
OutcomesGeneral clinical curative effects, a comprehensive index including clinical symptoms; signs; and the reduction, dissolution, or excretion of gallstones.
NotesWe contacted the primary author regarding the unclear information in the trial in March 2009, but the authors of the publication could not remember the details.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskSequence generation was not offered by the authors.
Allocation concealment (selection bias)Unclear riskAllocation concealment was not offered by the authors.
Blinding (performance bias and detection bias)
All outcomes
High riskNot used.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLosses to follow-up were not addressed.
Selective reporting (reporting bias)High risk

General clinical curative effects, a comprehensive index including clinical symptoms; signs; and the reduction, dissolution, or excretion of gallstones were reported.

Adverse events were reported.

Specific results on symptoms, including upper abdominal pain, biliary colic, nausea, vomiting, icterus, and signs were not reported.

Mortality, biliary operation, quality of life, medical costs during hospitalisation, medication, and medical examination were not reported.

Other biasUnclear riskNot stated.

She 1981

MethodsRandomised clinical trial.
Sample size: estimation not reported.
Diagnostic criteria: B-ultrasound.
Baseline was comparable among the intervention and control groups.
ParticipantsIntervention group: 16 participants; M 6, F 10.
Control group: 18 participants; M 8, F 10.
InterventionsIntervention group: TCMHs.
Control group: Western medicine (antibiotic) (the period of treatment is unclear).
OutcomesClinical manifestation: the TCMHs led to excretion of gallstones, from the bile system, time to disappearance of upper abdominal pain, fever.
NotesWe could not contact the primary author by letter and telephone regarding the unclear information in the trial.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
High riskNot used.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLosses to follow-up were not addressed.
Selective reporting (reporting bias)High risk

Excretion of gallstones from the bile system was reported.

Dissolution or excretion of gallstones from the bile system were not reported.

Time for disappearance of upper abdominal pain and fever was mentioned without complete data.

Specific results of symptoms, including upper abdominal pain, biliary colic, nausea, vomiting, icterus, and signs were not reported.

Mortality, biliary operation, quality of life, medical costs during hospitalisation, medication, medical examination, and adverse events were not reported.

Other biasUnclear riskNot stated.

Shi 2012

MethodsRandomised clinical trial.
Sample size: estimation not reported.
Diagnostic criteria: B-ultrasound, ERCP or PTC.
Baseline was comparable among the intervention and control groups.
ParticipantsIntervention group: 44 participants; M 15, F 29.
Control group: 38 participants; M 13, F 25.
InterventionsIntervention group: Jinjidanshi decoction 1 dose b.i.d. for 6 months.
Control group: ursodeoxycholic acid 0.3 g b.i.d. for 6 months.
OutcomesThe general clinical curative effects, a comprehensive index including clinical symptoms; signs; and the reduction, dissolution, or excretion of gallstones.
Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
High riskNot used.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLosses to follow-up were not addressed.
Selective reporting (reporting bias)High risk

General clinical curative effects, a comprehensive index including clinical symptoms; signs; and the reduction, dissolution, or excretion of gallstones were reported.

Adverse events were reported.

Specific results on symptoms, including upper abdominal pain, biliary colic, nausea, vomiting, icterus, and signs were not reported.

Mortality, biliary operation, quality of life, medical costs during hospitalisation, medication, and medical examination were not reported.

Other biasUnclear riskNot stated.

Su 2012

MethodsRandomised clinical trial.
Sample size: estimation not reported.
Diagnostic criteria: B-ultrasound, or CT.
Baseline was comparable among the intervention and control groups.
ParticipantsIntervention group: 64 participants; M 42, F 22.
Control group: 64 participants; M 37, F 27.
InterventionsIntervention group: Paishi capsule 2˜4 # t.i.d. for 20 days.
Control group: Lidanpaishi tablet 3 # t.i.d. for 20 days.
OutcomesThe general clinical curative effects, a comprehensive index including clinical symptoms; signs; and the reduction, dissolution, or excretion of gallstones.
Notes-
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
High riskNot used.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThe losses to follow-up were not addressed.
Selective reporting (reporting bias)High risk

General clinical curative effects, a comprehensive index including clinical symptoms; signs; and the reduction, dissolution, or excretion of gallstones were reported.

Adverse events were reported.

Specific results on symptoms, including upper abdominal pain, biliary colic, nausea, vomiting, icterus, and signs were not reported.

Mortality, biliary operation, quality of life, medical costs during hospitalisation, medication, and medical examination were not reported.

Other biasUnclear riskNot stated.

Xing 2009

MethodsRandomised clinical trial.
Sample size: estimation not reported.
Diagnostic criteria: B-ultrasound.
Baseline was comparable among the intervention and control groups.
ParticipantsIntervention group: 100 participants; M 25, F 75.
Control group: 101 participants; M 25, F 76.
InterventionsIntervention group: Jinzhihuang capsule 6# t.i.d. for 12 weeks.
Control group: chenodeoxycholic acid 0.5 g t.i.d. for 12 weeks.
OutcomesGeneral clinical curative effects, a comprehensive index including clinical symptoms; signs; and the reduction, dissolution, or excretion of gallstones.
NotesWe contacted the primary author regarding the unclear information in the trial in October 2009, but the author could not remember the requested information.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
High riskNot used.
Incomplete outcome data (attrition bias)
All outcomes
Low riskSame number of participants randomised and analysed.
Selective reporting (reporting bias)High risk

General clinical curative effects, a comprehensive index including clinical symptoms; signs; and the reduction, dissolution, or excretion of gallstones were reported.

Specific results of symptoms, including upper abdominal pain, biliary colic, nausea, vomiting, icterus, and signs were not reported.

Mortality, biliary operation, quality of life, medical costs during hospitalisation, medication, medical examination, and adverse events were not reported.

Other biasUnclear riskNot stated.

Zhang 2001a

MethodsRandomised clinical trial.
Sample size: estimation not reported.
Diagnostic criteria: B-ultrasound.
Baseline was comparable among the intervention and control groups.
ParticipantsIntervention group: 60 participants; M 23, F 37.
Control group: 30 participants; M 14, F 16.
InterventionsIntervention group: Gandanxiaoshi tablet 3.0 g t.i.d. for 3 months.
Control group: Aihuodantong capsule 0.1 g t.i.d. for 3 months.
Outcomes

General clinical curative effects, a comprehensive index including clinical symptoms; signs; and the reduction, dissolution, or excretion of gallstones were reported.

Clinical symptoms, including upper abdominal pain, abdominal distension, bitter taste, constipation, and anorexia were reported.

Adverse events were reported.

NotesWe contacted the primary author by telephone regarding the unclear information in the trial in March 2009, but the authors of the publication could not remember the trial in detail.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Low riskRandom number table was used.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
High riskNot used.
Incomplete outcome data (attrition bias)
All outcomes
Low riskSame number of participants randomised and analysed.
Selective reporting (reporting bias)High risk

General clinical curative effects, a comprehensive index including clinical symptoms; signs; and the reduction, dissolution, or excretion of gallstones were reported.

Clinical symptoms, including upper abdominal pain, abdominal distension, bitter taste, constipation, anorexia were reported.

Adverse events were reported.

Specific results of symptoms, including biliary colic, nausea, vomiting, icterus, and signs were not reported.

Mortality, biliary operation, quality of life, medical costs during hospitalisation, medication, and medical examination were not reported.

Other biasUnclear riskNot stated.

Zhang 2001b

MethodsRandomised clinical trial.
Sample size: estimation not reported.
Diagnostic criteria: B-ultrasound.
Baseline was comparable among the intervention and control groups.
ParticipantsIntervention group: 80 participants.
Control group: 30 participants; the ratio of M/F is unclear.
InterventionsIntervention group: Gandanxiaoshi tablet 3.0 g t.i.d. for 3 months.
Control group 1: Aihuodantong capsule 1# t.i.d. for 3 months.
OutcomesGeneral clinical curative effects, a comprehensive index including clinical symptoms; signs; and the reduction, dissolution, or excretion of gallstones.
NotesWe contacted the primary author by telephone regarding the unclear information in the trial in March 2009, but the authors of the publication could not remember the trial in detail.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
High riskNot used.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskLosses to follow-up were not addressed.
Selective reporting (reporting bias)High risk

General clinical curative effects, a comprehensive index including clinical symptoms; signs; and the reduction, dissolution, or excretion of gallstones were reported.

Specific results of symptoms, including upper abdominal pain, biliary colic, nausea, vomiting, icterus, and signs were not reported.

Mortality, biliary operation, quality of life, medical costs during hospitalisation, medication, medical examination, and adverse events were not reported.

Other biasUnclear riskNot stated.

Zhao 2004

MethodsRandomised clinical trial.
Sample size: estimation not reported.
Diagnostic criteria: B-ultrasound.
Baseline was comparable among the intervention and control groups.
ParticipantsIntervention group: 100 participants; M 31, F 69.
Control group: 100 participants; M 33, F 67.
InterventionsIntervention group: Rongpaidanshi capsule 5# t.i.d. for 6 months;
Control group: UDCA 500 mg q.n. for 6 months.
OutcomesGeneral clinical curative effects, a comprehensive index including clinical symptoms; signs; and the reduction, dissolution, or excretion of gallstones.
NotesWe contacted the primary author by telephone regarding the unclear information in the trial in March 2009, but the authors of the publication could not remember the trial in detail.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated.
Allocation concealment (selection bias)Unclear riskNot stated.
Blinding (performance bias and detection bias)
All outcomes
High riskNot used.
Incomplete outcome data (attrition bias)
All outcomes
Low riskSame number of participants randomised and analysed.
Selective reporting (reporting bias)High risk

General clinical curative effects, a comprehensive index including clinical symptoms; signs; and the reduction, dissolution, or excretion of gallstones were reported.

Time for disappearance of upper abdominal pain and fever were mentioned without complete data.

Adverse events were reported.

Specific results of symptoms, including upper abdominal pain, biliary colic, nausea, vomiting, icterus, and signs were not reported.

Mortality, biliary operation, quality of life, medical costs during hospitalisation, medication, and medical examination were not reported.

Other biasUnclear riskNot stated.

Zhu 1997

  1. a

    b.i.d.: twice daily; CT: computer tomography; ERCP: endoscopic retrograde cholangiopancreatography; F: female; M: male; PTC: percutaneous transhepatic cholangiography; q.n.: every night; TCMH: traditional Chinese medicinal herb; t.i.d.: three times a day; UDCA: ursodeoxycholic acid.

MethodsRandomised clinical trial.
Sample size: estimation not reported.
Diagnostic criteria: B-ultrasound or X-ray cholecystography
Baseline was comparable among the intervention and control groups.
Participants

Intervention group I: 30 participants.

Intervention group II: 30 participants.
Control group: 30 participants.
Ratio of M/F unclear.

InterventionsIntervention group I: Qingdan capsule 3# t.i.d. for 3 months.
Intervention group II: danning tablet 5# t.i.d. for 3 months.
Control group: UDCA 10 mg/kg/day q.n. for 3 months.
OutcomesThe general clinical curative effects, a comprehensive index including clinical symptoms; signs; and the reduction, dissolution, or excretion of gallstones.
NotesWe contacted the primary author by telephone regarding the unclear information in the trial in April 2009, but the authors of the publication could not remember the trial in detail.
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNot stated.
Allocation concealment (selection bias)Unclear riskQuote: ''Concealed envelops''.
Blinding (performance bias and detection bias)
All outcomes
High riskNot used.
Incomplete outcome data (attrition bias)
All outcomes
Unclear riskThe losses to follow-up were not addressed.
Selective reporting (reporting bias)High risk

General clinical curative effects, a comprehensive index including clinical symptoms; signs; and the reduction, dissolution, or excretion of gallstones were reported.

Specific results of symptoms, including upper abdominal pain, biliary colic, nausea, vomiting, icterus, and signs were not reported.

Mortality, biliary operation, quality of life, medical costs during hospitalisation, medication, medical examination, and adverse events were not reported.

Other biasUnclear riskNot stated.

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    TCMHs: Traditional Chinese Medicinal Herb; RCT: randomised controlled trial.

Bie 1992The article was not an RCT; information confirmed over the telephone by the author.
Binghui 2002The article was not an RCT according to the author's description of random principle.
Bu 2008The article was not an RCT; information confirmed over the telephone by the author.
Chen 1991The article was not an RCT; information confirmed over the telephone by the author.
Chen 1993The article was not an RCT; information confirmed over the telephone by the author.
Chen 1997The article was not an RCT; information confirmed over the telephone by the author.
Chen 2000The article was not an RCT; information confirmed over the telephone by the author.
Chen 2001The article was not an RCT; information confirmed over the telephone by the author.
Chen 2003aThe article was not an RCT; information confirmed over the telephone by the author.
Chen 2003bThe article was not an RCT; information confirmed over the telephone by the author.
Chen 2003cThe article was not an RCT; information confirmed over the telephone by the author.
Chen 2006The article was not an RCT; information confirmed over the telephone by the author.
Cheng 2005The article was not an RCT; information confirmed over the telephone by the author.
Cui 1995The article was not an RCT; information confirmed over the telephone by the author.
Dai 2009The article was not an RCT; information confirmed over the telephone by the author.
Du 2004The article was not an RCT; information confirmed over the telephone by the author.
Fan 2009The article was not an RCT; information confirmed over the telephone by the author.
Gao 2004The article was not an RCT; information confirmed over the telephone by the author.
Gao 2007The article was not an RCT; information confirmed over the telephone by the author.
Guan 2001The article was not an RCT; information confirmed over the telephone by the author.
Guo 2003The article was not an RCT; information confirmed over the telephone by the author.
He 2004The aim of this RCT was to appraise the effect of TCMHs for acupoint-massage in ears.
Hou 1995The article was not an RCT; information confirmed over the telephone by the author.
Huang 1998The article was not an RCT; information confirmed over the telephone by the author.
Huang 2002The article was not an RCT; information confirmed over the telephone by the author.
Huang 2004The article was not an RCT; information confirmed over the telephone by the author.
Huang 2007The article was not an RCT; information confirmed over the telephone by the author.
Jia 2003The article was not an RCT; information confirmed over the telephone by the author.
Jin 2004The article was not an RCT; information confirmed over the telephone by the author.
Jin 2007The article was not an RCT; information confirmed over the telephone by the author.
Kang 2004The article was not an RCT; information confirmed over the telephone by the author.
Kui 1996The article was not an RCT; information confirmed over the telephone by the author.
Li 1998aThe article was not an RCT; information confirmed over the telephone by the author.
Li 2001The article was not an RCT; information confirmed over the telephone by the author.
Li 2003The article was not an RCT; information confirmed over the telephone by the author.
Li 2005aThe article was not an RCT; information confirmed over the telephone by the author.
Li 2005bThe article was not an RCT; information confirmed over the telephone by the author.
Li 2005cThe article was not an RCT; information confirmed over the telephone by the author.
Li 2007The article was not an RCT; information confirmed over the telephone by the author.
Li 2009aThe article was not an RCT; information confirmed over the telephone by the author.
Li 2012aThe article was not an RCT.
Li 2012bThe article was not an RCT.
Li 2012cThe article was not an RCT.
Lian 2006The article was not an RCT; information confirmed over the telephone by the author.
Liang 2000The article was not an RCT; information confirmed over the telephone by the author.
Lin 1989The article was not an RCT; information confirmed over the telephone by the author.
Lin 1999The article was not an RCT; information confirmed over the telephone by the author.
Lin 2003The article was not an RCT; information confirmed over the telephone by the author.
Liu 1997The article was not an RCT; information confirmed over the telephone by the author.
Liu 1999The article was not an RCT; information confirmed over the telephone by the author.
Liu 2000The article was not an RCT; information confirmed over the telephone by the author.
Liu 2002aThe article was not an RCT; information confirmed over the telephone by the author.
Liu 2002bThe article was not an RCT; information confirmed over the telephone by the author.
Liu 2003The article was not an RCT; information confirmed over the telephone by the author.
Liu 2008The article was not an RCT; information confirmed over the telephone by the author.
Liu 2012The article was not an RCT.
Long 1998The article was not an RCT; information confirmed over the telephone by the author.
Long 2002aThe article was not an RCT; information confirmed over the telephone by the author.
Long 2002bThe article was not an RCT; information confirmed over the telephone by the author.
Lu 2003The article was not an RCT; information confirmed over the telephone by the author.
Lv 1989The article was not an RCT; information confirmed over the telephone by the author.
Ma 2002The article was not an RCT; information confirmed over the telephone by the author.
Ma 2003The article was not an RCT; information confirmed over the telephone by the author.
Mu 1992The article was not an RCT; information confirmed over the telephone by the author.
Qing 2000The article was not an RCT; information confirmed over the telephone by the author.
Qiu 2006The article was not an RCT; information confirmed over the telephone by the author.
Shang 2006aThe article was not an RCT; information confirmed over the telephone by the author.
Shang 2006bThe article was not an RCT; information confirmed over the telephone by the author.
Shao 2010The article was not an RCT according to the author's description of random principle.
Shen 1991The article was not an RCT; information confirmed over the telephone by the author.
Shi 1999The article was not an RCT; information confirmed over the telephone by the author.
Shi 2002The article was not an RCT; information confirmed over the telephone by the author.
Shi 2003The article was not an RCT; information confirmed over the telephone by the author.
Song 1992The article was not an RCT.
Song 2005The article was not an RCT; information confirmed over the telephone by the author.
Song 2006The article was not an RCT; information confirmed over the telephone by the author.
Sun 2005The article was not an RCT; information confirmed over the telephone by the author.
Tan 2005The article was not an RCT; information confirmed over the telephone by the author.
Tang 1997The article was not an RCT; information confirmed over the telephone by the author.
Tang 2002The article was not an RCT; information confirmed over the telephone by the author.
Tao 2006The article was not an RCT; information confirmed over the telephone by the author.
Tian 2005The article was not an RCT; information confirmed over the telephone by the author.
Wan 2006The article was not an RCT; information confirmed over the telephone by the author.
Wang 1995aThe article was not an RCT; information confirmed over the telephone by the author.
Wang 1995bThe article was not an RCT; information confirmed over the telephone by the author.
Wang 2000The article was not an RCT; information confirmed over the telephone by the author.
Wang 2003aThe article was not an RCT; information confirmed over the telephone by the author.
Wang 2003bThe article was not an RCT; information confirmed over the telephone by the author.
Wang 2003cThe article was not an RCT; information confirmed over the telephone by the author.
Wang 2005The article was not an RCT; information confirmed over the telephone by the author.
Wang 2007aThe article was not an RCT; information confirmed over the telephone by the author.
Wang 2009The article was not an RCT; information confirmed over the telephone by the author.
Wang 2012The article was not an RCT, but a retrospective study.
Wei 1995The article was not an RCT; information confirmed over the telephone by the author.
Wu 2011The article was not an RCT, but a retrospective study
Xie 1992The article was not an RCT; information confirmed over the telephone by the author.
Xie 1997The article was not an RCT; information confirmed over the telephone by the author.
Xu 1996The article was not an RCT; information confirmed over the telephone by the author.
Xu 2006The article was not an RCT; information confirmed over the telephone by the author.
Yang 1998The article was not an RCT; information confirmed over the telephone by the author.
Yang 2002The article was not an RCT; information confirmed over the telephone by the author.
Yang 2012The article was not an RCT.
Yao 2001The article was not an RCT; information confirmed over the telephone by the author.
Yu 2005The article was not an RCT; information confirmed over the telephone by the author.
Yuan 1989The article was not an RCT; information confirmed over the telephone by the author.
Yuan 1999The article was not an RCT; information confirmed over the telephone by the author.
Zang 2009The article was not an RCT; information confirmed over the telephone by the author.
Zeng 1994The article was not an RCT; information confirmed over the telephone by the author.
Zeng 2004aThe article was not an RCT; information confirmed over the telephone by the author.
Zeng 2004bThe article was not an RCT; information confirmed over the telephone by the author.
Zhang 1999The article was not an RCT; information confirmed over the telephone by the author.
Zhang 2000aThe article was not an RCT; information confirmed over the telephone by the author.
Zhang 2000bThe article was not an RCT; information confirmed over the telephone by the author.
Zhang 2001The article was not an RCT; information confirmed over the telephone by the author.
Zhang 2003The article was not an RCT; information confirmed over the telephone by the author.
Zhang 2005The article was not an RCT; information confirmed over the telephone by the author.
Zhao 1993The article was not an RCT; information confirmed over the telephone by the author.
Zheng 2006The article was not an RCT; information confirmed over the telephone by the author.
Zhou 2004The article was not an RCT; information confirmed over the telephone by the author.
Zhu 2007The article was not an RCT; information confirmed over the telephone by the author.
Zhu 2009The article was not an RCT; information confirmed over the telephone by the author.
Zhuang 2002The article was not a RCT; information confirmed over the phone by the author.

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