Mifepristone for uterine fibroids

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Mifepristone for uterine fibroids (Review)

Tristan M, Orozco LJ, Steed A, Ramírez-Morera A, Stone P

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library2012, Issue 8

http://www.thecochranelibrary.com

Mifepristone for uterine fibroids (Review)

Copyright © 2012 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

http://www.thecochranelibrary.com

T A B L E O F C O N T E N T S

1HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . .5BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8

10RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

15ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . .22DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .22AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . .35DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Analysis 1.1. Comparison 1 Mifepristone compared with placebo, Outcome 1 Relief of bleeding. . . . . . . . 35Analysis 1.2. Comparison 1 Mifepristone compared with placebo, Outcome 2 Relief of pain. . . . . . . . . . 36Analysis 1.4. Comparison 1 Mifepristone compared with placebo, Outcome 4 Uterine Fibroid Symptom Quality of Life. 36Analysis 1.5. Comparison 1 Mifepristone compared with placebo, Outcome 5 Reduction in average fibroid volume. . 37Analysis 1.6. Comparison 1 Mifepristone compared with placebo, Outcome 6 Reduction in uterine volume. . . . 37Analysis 1.7. Comparison 1 Mifepristone compared with placebo, Outcome 7 Adverse events. . . . . . . . . 38

38APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .43WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .44HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .44CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . .44DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .44SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .45DIFFERENCES BETWEEN PROTOCOL AND REVIEW . . . . . . . . . . . . . . . . . . . . .

iMifepristone for uterine fibroids (Review)


[Intervention Review]

Mifepristone for uterine fibroids

Mario Tristan1, Leonardo J Orozco2, Antonia Steed3, Anggie Ramírez-Morera4, Peter Stone3

1Board of Directors, International Health Central American Institute, San José, Costa Rica. 2OBGYN Women’s Hospital San José,Costa Rica, Caja Costarricense Seguro Social (CCSS) & Central American Cochrane Center, San José, Costa Rica. 3Department ofObstetrics and Gynaecology, University of Auckland, Auckland, New Zealand. 4Caja Costarricense de Seguro Social, Area de Atencióna las Personas, IHCAI Foundation, San José, Costa Rica

Contact address: Leonardo J Orozco, OBGYN Women’s Hospital San José, Costa Rica, Caja Costarricense Seguro Social (CCSS) &Central American Cochrane Center, Bo Carit, San José, San Jose, 11619-1000, Costa Rica. [email protected]. [email protected].

Editorial group: Cochrane Menstrual Disorders and Subfertility Group.Publication status and date: New, published in Issue 8, 2012.Review content assessed as up-to-date: 18 November 2011.

Citation: Tristan M, Orozco LJ, Steed A, Ramírez-Morera A, Stone P. Mifepristone for uterine fibroids. Cochrane Database of SystematicReviews 2012, Issue 8. Art. No.: CD007687. DOI: 10.1002/14651858.CD007687.pub2.


A B S T R A C T

Background

Uterine fibroids are the most common benign uterine tumours present in women of reproductive age. Mifepristone (RU-486) competi-tively binds and inhibits progesterone receptors. Studies have suggested that fibroid growth depends on the sexual steroids. Mifepristonehas been shown to decrease fibroid size. This review summarises the effects of mifepristone treatment on fibroids and the associatedadverse effects as described in randomised controlled trials.

Objectives

To determine the efficacy and safety of mifepristone for the management of uterine fibroids in pre-menopausal women.

Search methods

We searched the specialised register of the Cochrane Menstrual Disorders and Subfertility (Cochrane Menstrual Disorders and subfertilityReview Group), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 4), MEDLINE,EMBASE, PsycINFO, and CINAHL (to November 2011). We handsearched a number of journals, and searched reference lists,databases of ongoing trials and the Internet. There were no language restrictions.

Selection criteria

Only truly randomised controlled trials of mifepristone versus other forms of medical therapy or placebo in pre-menopausal womenwith confirmed uterine fibroids were included.

Data collection and analysis

Four authors independently extracted data and assessed trial quality. Data were analysed using the Peto odds ratios (OR) for dichotomousdata and the weighted mean differences for continuous data, with 95% confidence intervals (CI). Meta-analyses were performed usingthe fixed-effect model.

1Mifepristone for uterine fibroids (Review)


mailto:[email protected]

mailto:[email protected]

Main results

Three studies involving 112 participants were included. Comparison interventions included different dosages of mifepristone, placeboand vitamin B tablets. There is evidence that treatment with mifepristone relieves heavy menstrual bleeding compared with placebo(Peto OR 17.84; 95% CI 6.72 to 47.38; 2 RCTs, 77 women, I2 = 0%). Three studies (Bagaria 2009; Engman 2009; Fiscella 2006) wereincluded in the meta-analysis of this comparison. There was no evidence of an effect of mifepristone on the fibroid volume (standardisedmean difference (SMD) -0.02; 95% CI -0.38 to 0.41; 99 women). Two studies (Bagaria 2009; Fiscella 2006) were included in themeta-analysis of this comparison. There was no evidence of an effect of mifepristone on uterine volume (mean difference (MD) -77.24;95% CI -240.62 to 86.14; 72 women). The pooled data suggest an increased adverse event (abnormal endometrial histology) in themifepristone group compared to placebo (OR 31.65; 95% CI 4.83 to 207.35; 2 RCTs; 54 women; I2 = 0%). Only one study (Bagaria2009) reported endometrial hyperplasia at the end of the therapy (12/19 women in the mifepristone group versus 0/16 in the placebogroup; OR 55.0; 95% CI 2.86 to 105.67). Engman 2009 found a significantly higher rate of cystic glandular dilatation in women inthe mifepristone group (5/8 women biopsied) compared with the placebo group (1/11 women biopsied) (OR 16.67; 95% CI 1.36 to204.03). One study (Fiscella 2006) suggested significant improvements (P < 0.001) for specific quality of life outcomes.

Authors’ conclusions

Mifepristone reduced heavy menstrual bleeding and improved fibroid-specific quality of life. However, it was not found to reducefibroid volume. Further well-designed, adequately powered RCTs are needed before a recommendation can be made on the use ofmifepristone for the treatment of uterine fibroids.

P L A I N L A N G U A G E S U M M A R Y

Mifepristone for uterine fibroids

Uterine fibroids are also known as uterine leiomyoma, myoma or fibromyoma and are non-cancerous benign growths in the uterus.Fibroids are the most common benign tumours in females and are typically found during the middle and later reproductive years.Common symptoms include heavy bleeding, menstrual pain, pressure in lower abdomen, infertility or miscarriage. Fibroids can betreated with surgery using either myomectomy (removal of fibroids leaving the uterus in place) or hysterectomy (removal of uterus).Drugs such as mifepristone have been suggested as a therapeutic option. This review includes three trials and 112 women with uterinefibroids under mifepristone treatment. These clinical trials included a small number of participants and show limited methodologicalquality. The studies included in this review show that mifepristone had a moderate effect in relief of bleeding and showed an improvementin fibroid-specific quality of life. Determination of the effects of mifepristone on uterine fibroid volume requires much larger trials todraw a confident conclusion for mifepristone in clinical use.



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Patientorpopulation:patientswithuterinefibroids

Settings:trialswereconductedintheUS( Fiscella2006),Sweden(Engman2009)andIndia(Bagaria2009)

Intervention:mefepristone

Outcomes

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Highquality:Furtherresearchisveryunlikelytochangeourconfidenceintheestimateofeffect.

Moderatequality:Furtherresearchislikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandmaychangetheestimate.

Lowquality:Furtherresearchisverylikelytohaveanimportantimpactonourconfidenceintheestimateofeffectandislikelytochangetheestimate.

Verylowquality:Weareveryuncertainabouttheestimate.

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B A C K G R O U N D

Description of the condition

Uterine fibroids, also known as uterine leiomyomas or myomas,are almost always benign growths of smooth muscle layer of theuterus (Meniru 2001). Fibroids may grow as a single tumour orin clusters. A single fibroid can range in size from one to 20 cm ormore (Marshall 1997).Fibroids are the most common benign uterine tumours present inwomen of reproductive age. The incidence varies from 5.4% to77% in women of reproductive age, depending on the method ofdiagnosis (Drinville 2007; Lethaby 2002).The aetiology of uterine fibroids is unknown. However they arethought to be oestrogen and progesterone dependant because fi-broids are known to shrink after either menopause or treatmentwith gonadotrophin-releasing hormone agonists (GnRH) (whichreduce oestrogen and progesterone levels) (Rein 1995; West 1993).Most women with fibroids are asymptomatic. Notwithstandingthis, women may complain of a lump or “pelvic fullness”, causedby the size of the fibroids. The most common symptom is ab-normal uterine bleeding, usually long and heavy menstrual peri-ods. Fibroids may interfere with fertility because they can causedistortion of the uterus. Apart from the mass effect, the primarymechanism by which fibroids may cause subfertility is unknown(Hart 2001).The type of treatment approach should consider medical and socialfactors, age, parity, childbearing expectancies, extent and severityof symptoms, size and number of myomas, location of myomas,associated medical conditions, proximity to menopause and desirefor uterine preservation (Wallach 2004).Hysterectomy is the most common treatment when fibroids aresymptomatic. Based on data from 1990 to 1997, the presence ofuterine fibroids was the main indication for hysterectomy in theUS (Farquhar 2002). Myomectomy, the removal of fibroids surgi-cally without hysterectomy, is the second most common surgicaltreatment (Guarnaccia 2001).The management of uterine myomas may involve the follow-ing approaches (or a combination of them): expectant man-agement, medical management (GnRH analogues, progestationalcompounds, anti-progestins), uterine artery embolisation, andother approaches (e.g. high-frequency focused ultrasound, lasertreatment, cryotherapy, or thermoablation) (Wallach 2004).Even although fibroids are often diagnosed and treated, there re-mains considerable uncertainty and controversy among cliniciansand women regarding their best management (Myers 2002).

Description of the intervention

Observational data suggested that treatment with mifepristone isassociated with a reduction in uterine and fibroid size, pain, andbleeding.

This could be based on the fact that mifepristone competitivelybinds and antagonises progesterone receptors. A number of short-term investigations have suggested that mifepristone is effectivein inhibiting ovulation, inducing luteolysis and disrupting en-dometrial integrity when administered to normally cycling women(Garzo 1988; Liu 1987; Luukkainen 1988; Roseff 1990). Thelong-term administration of 100 mg/day of mifepristone may in-duce absence of ovarian cycles and relief of pelvic pain in womenwith endometriosis (Kettel 1991). Mifepristone is thought to havean inhibitory effect on the growth of fibroids. Transient eleva-tions in transaminases occurred in 4% of women, and endometrialhyperplasia was detected in 10 (28%) of 36 women screened byendometrial biopsy (Steinauer 2004). A spectrum of endometrialpathology induced by progesterone receptor modulators has beenreported (Mutter 2008). Currently, mifepristone is approved onlyfor medical abortion.

How the intervention might work

Progestogens alone have been reported to influence fibroid growth.These compounds were thought to produce a hypo-oestrogenic ef-fect by inhibiting gonadotrophin secretion and suppressing ovar-ian function (Istre 2007; Tiltman 1985; Vikhliaeva 1990).Mifepristone may represent a viable alternative to GnRH ana-logues for pre-operative application. Also, it could have an indica-tion in peri-menopausal women with large, symptomatic fibroids,who could be able to take this medication until menopause, whenthe fibroids typically decrease. Consequently, it would yield ma-jor savings in cost and morbidity in view of the large numberof hysterectomies done for fibroids in peri-menopausal women(Drinville 2007). Another possible application is in youngerwomen with large fibroids who wish to retain their fertility. Theymay also benefit from continuous low-dose mifepristone, until thetime that they wish to conceive (Eisinger 2003).

Why it is important to do this review

Studies have suggested that fibroid growth depends on sex hor-mone steroids (Kawaguchi 1989). Studies have provided furtherbiochemical, histological and clinical evidence that progesteronehas a critical role in leiomyoma growth (Kim 2012). Mifepris-tone, a progesterone receptor modulator with primarily antago-nistic properties, has been shown to decrease leiomyoma size innon-RCTs (Murphy 1995; Yang 1996).We have systematically reviewed the literature in an attempt tosummarise the effects of mifepristone treatment on fibroids andthe associated adverse effects as described in RCTs.

O B J E C T I V E S



To determine the efficacy and safety of mifepristone for the man-agement of uterine fibroids in pre-menopausal women.

M E T H O D S

Criteria for considering studies for this review

Types of studies

RCTs were included. We excluded quasi RCTs. We would haveincluded cross-over studies if they had pre-cross-over data avail-able; however, no cross-over studies were found.

Types of participants

Pre-menopausal women with confirmed uterine fibroid diagnosedby clinical manifestation and physical signs, and confirmed byultrasound scanning, computerised tomography (CT), magneticresonance imaging (MRI), or a combination of at least two of theprocedures. The diagnostic criteria produced by The InternationalFederation of Gynecology and Obstetrics (FIGO 2001) or theInternational Gynecology and Obstetrics Association were used.Women with an intrauterine device (IUD), ectopic pregnancy,adrenal failure, haemorrhagic disorders, inherited porphyria, andanticoagulant or long-term corticosteroid therapy were excluded.

Types of interventions

• Mifepristone compared to placebo.• Mifepristone compared to no treatment.• Mifepristone compared to other medical intervention (e.g.

GnRH analogues, progestational compounds, anti-progestins).• Mifepristone compared to a surgical intervention (e.g.

hysterectomy, myomectomy hysteroscopic or laparoscopic, high-frequency focused ultrasound, laser treatment, cryotherapy, orthermoablation).

Types of outcome measures

Primary outcomes

• Relief of symptoms: abnormal uterine bleeding, pain andpressure measured by patient self reports or scales.

Secondary outcomes

• Reduction in fibroid size: measured by ultrasonography orMRI.

• Reduction in uterine volume measured by ultrasonographyor MRI.

• Live birth.• Pregnancy rate.• Recurrence rate with the possibility of necessitating further

additional therapy.• Occurrence of adverse events.• Cost-effectiveness.• Uterine Fibroid Symptoms - Quality of Life.

Search methods for identification of studies

See the Menstrual Disorders and Subfertility Group methodsused in reviews as stated in their module.All reports that describe (or might describe) RCTs of mifepristonefor uterine fibroids were sought.

1. The MDSG Specialised Register of controlled trials wassearched by the Group’s trial search co-ordinator using the keywords:Keywords CONTAINS “Leiomyoma”or“leiomyomata”or“fibroids”or “myoma”or“myomas”or “my-omata”or “Leiomyoma”or “leiomyomata”or “uterine fibroids”or“uterine leiomyomas”or“uterine myoma”or“uterine myomas” orTitle CONTAINS “Leiomyoma”or “leiomyomata”or“fibroids”or“myoma”or“myomas”or “myomata”or “Leiomyoma”or “leiomy-omata”or “uterine fibroids”or “uterine leiomyomas”or“uterine my-oma”or“uterine myomas”ANDKeywords CONTAINS “mifepristone” or “RU486” or TitleCONTAINS “mifepristone” or “RU486”This register also contains unpublished trial abstracts. These arefound through the handsearching of 20 relevant journals and con-ference proceedings.External referees who are experts in this field were asked to checkthe completeness of the search strategy, and to identify any addi-tional, ongoing and planned trials.No language restrictions were applied.

Electronic searches

We searched electronic databases using key words and the appro-priate Cochrane highly sensitive search strategies for identifyingrandomised trials. The last search was conducted in November2011 (Higgins 2011). The databases searched were: MEDLINE,EMBASE, CENTRAL and CINAHL. The full search strings foreach database are available in the following appendices: Appendix1; Appendix 2; Appendix 3; Appendix 4.

Searching other resources

Other strategies for locating studies included:• contacting organisations and individuals working in the

field,• screening conference proceedings and reference list of

review articles,



http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD005287/bibliography.html#CD005287-bbs2-0018

http://www.mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD005287/bibliography.html#CD005287-bbs2-0018

• searching clinical trial registers.

Data collection and analysis

Data was analysed using Review Manager 5.1 software (RevMan2011).

Selection of studies

We used the criteria for study eligibility as described by theCochrane MDSG entity (see Appendix 5).The titles and abstracts of articles found in the search were screenedby LO, who discarded clearly ineligible studies. The aim was tobe overly inclusive to minimise the risk of losing relevant studies.MT, AS and AR obtained copies of the full-text articles and madecopies for LO, in which details of the authors and institutions werestruck out and the results sections removed.At least two out of three review authors (LO, AS, MT), includingtwo content experts, screened the studies for inclusion.Both review authors independently assessed whether the studiesmet inclusion criteria. No disagreement needed to be resolved bydiscussion.Further information was asked of the study authors when the in-formation contained in papers was insufficient to make a decision

about eligibility.

Data extraction and management

LO provided MT, AR, PS and AS with the results sections ofthe included studies and the four review authors independentlyextracted information using a prepared form (see Appendix 6).Discrepancies were resolved by discussion.For each included trial, information was collected regarding thelocation of the study, methods of the study (as per ’Risk of bias’assessment checklist), participants (age range, eligibility criteria),nature of the interventions and data relating to the outcomes spec-ified above.

Assessment of risk of bias in included studies

The risk of bias of all studies deemed eligible for the reviewwas assessed independently by four review authors (MT, AR, LOand PS), and discrepancies were resolved by discussion. A sum-mary of the ’Risk of bias’ assessment was presented as part of theCharacteristics of included studies table.Risk of bias was assessed using six domains (see below) and a judge-ment of either ’high’, ’low’ and ’unclear’ was made. All judgementswere fully described and presented as Figure 1 and 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 qualityitem for each included study.



1. Sequence generation

Was the allocation sequence adequately generated?

2. Allocation concealment

Was allocation adequately concealed?

3. Blinding of participants, personnel and outcome assessors

Was knowledge of the allocated intervention adequately preventedduring the study?

4. Incomplete outcome data

Were incomplete outcome data adequately addressed?

5. Selective outcome reporting

Are reports of the study free of suggestion of selective outcomereporting?

6. Other sources of bias

Was the study apparently free of other problems that could put itat a high risk of bias?

Measures of treatment effect

The data from the primary studies was entered into RevMan 5.1software (RevMan 2011).For binary (or dichotomous) outcomes, results for each study wasexpressed as Peto odds ratios (OR) with 95% confidence intervals(CI) and combined for meta-analysis where appropriate.For continuous outcome data, results from each study were ex-pressed as a mean difference (MD) with 95% CI and combinedfor meta-analysis using the weighted mean difference (WMD).

Unit of analysis issues

As clusters RCTs were not included, individuals were consideredas the unit of analysis.

Dealing with missing data

The review authors contacted the lead authors of the trials wheredata clarification was required. This contact was made by email,telephone, or both.

Assessment of heterogeneity

Assessment of heterogeneity was possible when two or more pri-mary studies were available for inclusion in a meta-analysis.Statistical analysis was performed in accordance with the guidelinesdeveloped by The Cochrane Collaboration (Higgins 2011).Heterogeneity (variability) between the results of different studieswas examined by:

• visual inspection of the CIs. A poor overlap indicatesheterogeneity,

• low P value (< 5%) or a large Chi2 statistic relative to thedegree of freedom indicates heterogeneity,

• I2 statistic > 50% suggests substantial heterogeneity.

Assessment of reporting biases

This review sought to expose the publication and related bi-ases (PRB) by using alternative, robust search strategies includinghandsearching (Hopewell 2007a) and the Internet (e.g. Googleand other search engines), comprehensive search of the grey liter-ature (Hopewell 2007b), alternative sources of data or synthesisedevidence, and by contacting experts and the research community.Graphical, descriptive and analytical methods were used to detect,and mitigate, the problem. If sufficient trials were available, fun-nel plots were to be constructed to illustrate the effect size versusmeasure of precision. A visual inspection of the plot(s) would havebeen used to confirm the presence and magnitude of PRB (Song2002). Further, complex statistical methods were not used to ex-plore for PRB by plotting estimates against corresponding preci-sion for each meta-analysis as follows: Begg & Mazumdar’s rankcorrelation test (Begg 1994), Egger’s regression test (Egger 1997)and the Trim and Fill method (Duval 2000). These alternativemethods are necessary because we anticipate that, as in most re-views, our meta-analysis may include a small numbers of studies.Further, the asymmetry observed in the funnel plot may be dueeither to serious methodological flaws (Stuck 1998) or to the factthat the intervention is highly effective.

Data synthesis

The included studies were combined when appropriate usingfixed-effect models.Where combining primary studies was not appropriate, they weresummarised in a narrative form. This review shall be updated everytwo years or earlier if any new RCT evidence becomes available.

Subgroup analysis and investigation of heterogeneity

The presence or absence of heterogeneity was considered beforepooling data from two or more trials.



The pre-specified potential sources of heterogeneity were used toexplore possible explanations of variation in effect between trials,and to guide interpretation of the findings.If substantial heterogeneity was present, then the potential sourcesof heterogeneity that would have been explored were individualstudy risk of bias, dosage of mifepristone and differences betweenpatient populations such as age or size of fibroid.Steps to assess this would have included:

• considering if a meta-analysis was appropriate,• considering completing a subgroup analysis (age, dose),• considering completing a meta-regression analysis,• considering ignoring the heterogeneity.

Where heterogeneity has been identified, we are aware of the lim-ited value of an interpretation of the causes of it.

Sensitivity analysis

A sensitivity analysis was considered to explore the presence of anysubstantial heterogeneity and to confirm the results seen.Sensitivity analyses would have been conducted for the primaryreview outcomes to determine whether the results were robust todecisions made during the review process. These analyses wouldexclude the following studies:

1. studies that do not clearly describe adequate procedures forallocation concealment and blinding,

2. studies with more than 10% of data missing or imputed forthe primary outcomes.Other sensitivity or subgroup analyses may have been conductedto investigate significant heterogeneity found during the reviewprocess. These would be interpreted with caution as they were notpre-specified.

R E S U L T S

Description of studies

See: Characteristics of included studies; Characteristics of excludedstudies.

Studies identified

The initial electronic searches identified 135 citations. After read-ing the titles and abstracts 126 were excluded because they wereduplicates, non-clinical studies, review articles, case reports, caseseries or had study objectives different from those of this review.Nine studies appeared to meet inclusion criteria but six studieswere excluded after three review authors (LO, MT and AR) inde-pendently assessed the full articles. We identified three studies thatmet the inclusion criteria. We have shown the flow of referenceretrieval in Figure 3.



Figure 3. Study flow diagram.



Results of the search

The initial electronic search identified 135 citations. Search cur-rent date November 2011.

Included studies

Three RCTs were included in this review (Bagaria 2009; Engman2009; Fiscella 2006). These RCTs reported random assignmentof participants with uterine fibroids to mifepristone or placebo(Bagaria 2009; Fiscella 2006), or vitamin-B tablets (Engman 2009)(see Characteristics of included studies). The trials were conductedin the US (Fiscella 2006), Sweden (Engman 2009) and India (Bagaria 2009). All trials were published in English.

Participants

The total number of participants was 112. Trials included pre-menopausal women with symptomatic uterine fibroids diagnosedby vaginal and abdominal uterine ultrasonography. One trial re-ported baseline comparability between groups (Bagaria 2009),while there was a slight difference in free testosterone levels at base-line in one study (Engman 2009). In Fiscella 2006, the medianbody mass index and uterine volume differed between the controland intervention groups at baseline.

Interventions

One study (Engman 2009) compared mifepristone at a dose of50 mg every other day with vitamin B tablets as placebo, whileanother (Bagaria 2009) compared mifepristone at a dose of 10mg/day with placebo. Another study (Fiscella 2006) comparedmifepristone at a dose of 5 mg/day with placebo tablets. Treatmentduration was six months in one trial (Fiscella 2006) and threemonths in the other two trials (Bagaria 2009; Engman 2009).

Outcomes measured

See Characteristics of included studies.All three studies assessed the effect of mifepristone on leiomyoma-related symptoms such as menorrhagia, dysmenorrhoea, pelvicpressure, pelvic pain, low backache, rectal pressure, urinary fre-quency and dyspareunia. These symptoms were measured accord-ing to a visual analogue scale in one study (Bagaria 2009) and a 5-point Likert scale was used in two trials (Engman 2009; Fiscella2006).Only one study (Fiscella 2006) assessed specific overall quality oflife (QoL) using a Uterine Fibroid Symptom Quality of Life scale(Spies 2002). This study also included global health status (mea-sured by the Medical Outcomes 36-item Short Form (SF- 36)

survey) and global pain (measured by the McGill Pain Question-naire).Fibroid volume and uterine volume were assessed by ultrasoundevaluation (transvaginal or transabdominal) in all studies. Eachstudy used different calculation methods. See Characteristics ofincluded studies.Blood loss was quantified using a pictorial blood loss assessmentchart and calculating a menstrual blood loss (MBL) index in twotrials (Bagaria 2009; Fiscella 2006) while a daily record of bleedingreported on a 5-point Likert scale in one trial (Engman 2009).All the included studies assessed haemoglobin levels and liver func-tion tests, and all studies investigated side effects such as nausea,vomiting, diarrhoea, headache, fatigue, hot flushes and decreasedlibido.Endometrial biopsy was done at baseline and after completion ofthe therapy in all included studies (Bagaria 2009; Engman 2009;Fiscella 2006).None of the studies assessed live birth, pregnancy rate, recurrencerate with the possibility of necessitating further additional therapy,or cost-effectiveness of treatment.The bibliographic search did not identify studies comparingmifepristone with no treatment, other medical intervention (ex-cept for leuprolide acetate, which was excluded (Reinsch 1994))or surgical intervention.

Excluded studies

Of the nine studies initially identified, six were excluded. Detailsare included in the Characteristics of excluded studies table.

Risk of bias in included studies

See Figure 1; Figure 2

Allocation

Bagaria 2009, Engman 2009 and Fiscella 2006 all had a low risk ofbias with regard to method of allocation concealment (see risk ofbias in Characteristics of included studies). In one study (Bagaria2009) packets were randomised to contain either the drugs or theplacebo, then participants as they were enrolled in the trial wereassigned to receive a previously sequentially numbered packet ofidentical appearance. Fiscella 2006 used sequentially numbered,opaque, sealed envelopes and a pharmacy-controlled randomisa-tion, and Engman 2009 also used a central allocation and codedpackets.Sequence generation was by computer-generated random tables/lists (Bagaria 2009; Engman 2009; Fiscella 2006).



Blinding

All the included studies stated that patients and study personnelwere blinded to the treatment groups. However, the importantchanges in symptoms such as bleeding patterns or flushes couldhave affected the blinding. One study (Fiscella 2006) reported atthe end of the trial that 19 of 20 (95%) women in the treatmentgroup correctly guessed that they had been receiving mifepristone.Although no other study stated this information, it is possible thata similar situation may have been present in these studies becauseof the marked effect of the intervention on bleeding patterns. Al-though there is no risk of bias in the outcome measurements (fi-broid volume and related symptoms: bleeding patterns) this state-ment is unclear for performance bias.No study reported outcome assessor blinding.

Incomplete outcome data

Bagaria 2009 reported five women lost to follow-up; however,no reasons for missing data were provided. Engman 2009 ex-cluded two participants after randomisation owing to uncontrol-lable bleeding in one case and elevated serum follicle-stimulatinghormone (FSH) in the other. Neither case had a clinically relevantimpact on the intervention effect estimate. Fiscella 2006 statedthat all participants, including the three who provided only base-line measures and two more who withdrew later, were included inthe analysis, but the method of imputation was not described.

Selective reporting

Protocols were available online for two of the three included studies(Engman 2009; Fiscella 2006). Engman 2009 reported all dataas stated in the protocol; however Fiscella 2006 failed to report

non-significant symptom data. Bagaria 2009 had an unclear riskof reporting bias because the protocol was not available.

Other potential sources of bias

No other potential sources of bias were identified.

Effects of interventions

See: Summary of findings for the main comparisonMifepristone for uterine fibroids; Summary of findings 2Mifepristone (10 mg/day/3 months) compared to placebo foruterine fibroids; Summary of findings 3 Mifepristone (50 mg/1day after/3 months) compared to placebo for uterine fibroids;Summary of findings 4 Mifepristone (5 mg/day/6 months) versusplacebo for uterine fibroidsThe studies identified used different doses of mifepristone andwere not easily comparable. Meta-analyses for relief of bleeding,fibroid volume, uterine volume and adverse events were possible;however, the small number of participants limits the generalisabil-ity of the results.

Comparison of mifepristone versus placebo

The three included studies compared mifepristone with placebo(Bagaria 2009, Fiscella 2006) or vitamin B (Engman 2009).

1.1 Relief of bleeding (Analysis 1.1)

Data from two studies were included in the meta-analysis (Bagaria2009; Fiscella 2006). There is evidence that treatment withmifepristone relieved bleeding compared with placebo (Peto OR17.84; 95% CI 6.72 to 47.38; two RCTs, 77 women, I2 = 0%)(Analysis 1.1; Figure 4).

Figure 4. Forest plot of comparison: 1 Mifepristone compared with placebo, outcome: 1.1 Relief of bleeding.



Engman 2009 presented the data as median and ranges, so thestudy was not included in the meta-analysis. The authors reportedthat, during weeks 9 to 12 of treatment, women in the mifepristonegroup had one bleeding day (median, no range provided), whilein the placebo group, women had three bleeding days (range 0 to27 days; P < 0.001).

1.2 Relief of pain (Analysis 1.2)

We have subgrouped this outcome into two as set out below (Analysis 1.2; Figure 5).

Figure 5. Forest plot of comparison: 1 Mifepristone compared with placebo, outcome: 1.2 Relief of pain.

1.2.1 Relief of dysmenorrhoea

Only Bagaria 2009 reported on this outcome. There was no ev-idence of an effect of treatment with mifepristone on dysmenor-rhoea compared with placebo (Peto OR 2.10; 95% CI 0.38 to11.71; one RCT, 26 women).

1.2.2 Relief of pelvic pain

Only Bagaria 2009 reported on this outcome in a form suitablefor analysis. There was no evidence of an effect when comparingmifepristone with placebo (Peto OR 0.89; 95% CI 0.27 to 2.95;one RCT, 26 women).Fiscella 2006 provided data on change in bleeding patterns andchange in pain, but only as graphics; therefore, it was not possibleto use numerical data.

1.3 Relief of pressure symptoms

Only Engman 2009 reported on bladder pressure, but not in aformat suitable for analysis. Bagaria 2009 reported on a reductionin urinary complaints, which is not an outcome pre-specified inthis protocol.

1.4 Uterine Fibroid Symptom Quality of Life (Analysis 1.4)

One study (Fiscella 2006) used the UFS-QoL, a new disease-spe-cific symptom and health-related QoL questionnaire for fibroids(Spies 2002). The scale is 1 to 100, with higher scores indicat-ing better QoL. The author has provided raw data for individualindicators of the Uterine Fibroid Symptoms UFS-QoL measures.There is evidence of an effect of mifepristone on fibroid-specificquality of life (MD 33.05, 95% CI 18.27, 47.83, 37 women,Analysis 1.4). By 6 months, the mean fibroid-specific quality oflife measures had improved by 135% in the mifepristone group,compared with a 41% improvement in the placebo arm of thetrial. The study suggests significant improvements (P < 0.001) forspecific fibroid-related QoL, with aspects including concern, ac-tivities, energy and mood, control, self-consciousness and sexualfunctioning.

1.5 Reduction in fibroid volume (Analysis 1.5)

Three studies (Bagaria 2009; Engman 2009; Fiscella 2006) wereincluded in the meta-analysis of this comparison. There was noevidence of an effect of mifepristone on the fibroid volume (SMD-0.02; 95% CI -0.38 to 0.41; 99 women) (Analysis 1.5).



1.6 Reduction in uterine volume (Analysis 1.6)

Two studies (Bagaria 2009; Fiscella 2006) were included in themeta-analysis of this comparison. There was no evidence of aneffect of mifepristone on uterine volume (MD -77.24; 95% CI -240.62 to 86.14; 72 women) (Analysis 1.6).

1.7 Live birth rate

None of the identified studies reported live birth rate.

1.8 Pregnancy rate

None of the identified studies reported pregnancy rate.

1.9 Recurrence rate

None of the studies identified reported recurrence rate necessitat-ing additional therapy.

1.10 Adverse events (Analysis 1.7)

The pooled data show more women with endometrial change inthe mifepristone group compared with placebo (OR 31.65; 95%

CI 4.83 to 207.35; two RCTs, 54 women, I2 = 0%) (Analysis1.7). Only one study (Bagaria 2009) reported endometrial hyper-plasia at the end of the therapy, 12/19 women in the mifepris-tone group compared with 0/16 in the placebo group (OR 55.0;95% CI 2.86 to 105.67). There was no demonstrated atypia. Trialauthors reported that all the patients with endometrial hyperpla-sia (12 patients) showed normal endometrium on histopathologyspecimens when they underwent surgical intervention. Engman2009 also collected endometrial biopsies, without any evidence ofhyperplasia or malignancy. They found a significantly higher rateof cystic glandular dilatation in women in the mifepristone group(5/8 women biopsied) compared with the placebo group (1/11women biopsied) (OR 16.67; 95% CI 1.36 to 204.03). Fiscella2006 also reported a higher rate of cystic glandular dilatation inthe mifepristone group.No study showed liver function test alterations.

1.11 Cost-effectiveness

No study reported this outcome.



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D I S C U S S I O N

Summary of main results

This systematic review included three RCTs, with small samples,which resulted in limited overall quality. Therefore, the analysisgenerated an overall low quality of evidence. These results limitrecommendations for the use of mifepristone in current clinicalpractice for the treatment of fibroids.Three comparisons were meta-analysed: relief of bleeding (twoRCTs); reduction of average fibroid volume (three RCTs) and re-duction of uterine volume (two RCTs). However, none of the threestudies has enough subjects to rule out type II errors. There issignificant reduction of bleeding but no significant reductions inuterine and fibroid volume. The reduction of bleeding is probablydue to the progesterone receptor modulator effect of mifepristoneand not by a direct effect of reducing fibroid size.Fiscella 2006 reported significant improvements (P < 0.001) forspecific measured aspects of QoL. Treatment with mifepristonewas also associated with gains in energy and health status andconcomitant reductions in fatigue and pain.Available data suggest that, compared with placebo, mifepristonewas better in relieving heavy menstrual bleeding. The availabledata suggest that mifepristone had no effect on the average sizeof fibroids and showed a non-significant effect (P = 0.35) on re-duction of uterine volume. Some improvements in QoL in symp-tomatic women were noted. Mifepristone increased the occurrenceof endometrial changes found on biopsy. The significance of thesechanges has yet to be elucidated (Mutter 2008) as these appearto be different from the possibly pre-malignant endometrial hy-perplasia associated with unopposed oestrogen treatment. In ad-dition, Narvekar et al showed that low-dose mifepristone inhibitsendometrial proliferation and upregulates androgen receptor ex-pression (Narvekar 2004). The included trials had small numbersof participants and the possibility of type I and II errors cannot beexcluded. This reduces the ability to influence clinical decision-making. While there was no statistically significant heterogeneity,there remains the potential for clinical heterogeneity owing to thedifferences in doses used in the trials.

Overall completeness and applicability ofevidence

There were only three small studies from three different countrieswith three different dose regimens identified and only one studyconsidered QoL using the UFS-QoL scale. The patients in thestudies can be considered to be representative of the populationof pre-menopausal women with uterine fibroids.

Quality of the evidence

See: Summary of findings for the main comparison, Summary offindings 3 and Summary of findings 4. Tables were developed inGRADE PRO 2011).According to the GRADE system used by the review authors, thequality of the evidence was rated as low.Every trial included stated that efforts were made to blind theparticipants and the staff to the administration of the medica-tion. However, the effect of mifepristone in diminishing or stop-ping heavy menstrual bleeding was likely to have been discernible,which may have had an effect on the blinding. Although it is un-likely that this fact affected objective measurements like fibroidor uterus size, incidence of endometrial hyperplasia and bleedingpatterns, it may have had some influence in a differential way onsubjective self-reported outcomes related to QoL (e.g. UFS-QoLscale, 5-point Likert scale).One of the studies (Fiscella 2006) showed differences in baselinecharacteristics (body mass index, uterine volume) that may haveaffected the measured outcomes.Overall, few participants were lost to follow-up and this was un-likely to influence the measure of effect.

Potential biases in the review process

The literature search was very exhaustive; therefore, the risk ofpublication bias is low. All important decisions regarding the in-clusion and exclusion of the articles, as well as those related to theanalysis, were made by discussion and consensus.

Agreements and disagreements with otherstudies or reviews

A Cochrane review (Liu 2009) compared the Huoxue Sanjie herbaldecoction with mifepristone. Both interventions showed no sig-nificant difference in the disappearance of uterine fibroids, thenumber of patients with shrinking of uterine fibroids or the av-erage uterine volume. The authors found that the decoction wasless effective than mifepristone on reducing the average uterus size(MD 23.23 cm3; 95% CI 17.85 to 28.61).

A U T H O R S ’ C O N C L U S I O N S

Implications for practice

Mifepristone was shown to reduce heavy menstrual bleeding andimprove fibroid-specific quality of life in pre-menopausal womenwith fibroids. The lack of reduction in fibroid volume suggeststhat at present this medication is not recommended as a therapyfor uterine fibroids.



Implications for research

Further well-designed large RCTs are needed, including compar-isons of mifepristone at different doses with placebo. In addition,studies comparing the efficacy of a number of progesterone re-ceptor modulators including mifepristone, ulipristil and asoprisnil(among others) would provide important clinical evidence.

A C K N O W L E D G E M E N T S

Thanks to Marian Showell TSC MDSG for her help with the ex-haustive search, and James Spies and Jane Clarke for their contri-bution to the development of the protocol for this review. Thanksto Dr Juan Carlos Vazquez from National Endocrinology Institutein Havana, Cuba for his comments and suggestions.

R E F E R E N C E S

References to studies included in this review

Bagaria 2009 {published data only}

Bagaria M, Suneja A, Vaid NB, Guleria K, Mishra K. Low-dose mifepristone in treatment of uterine leiomyoma: a

randomised double-blind placebo-controlled clinical trial.The Australian & New Zealand Journal of Obstetrics &Gynaecology 2009;49(1):77–83. [PUBMED: 19281585]

Engman 2009 {published data only}Engman M, Granberg S, Williams A, Meng C, Lalitkumar

P, Gemzell-Danielsson K. Mifepristone for treatment ofuterine leiomyoma. A prospective randomized placebo

controlled trial. Human Reproduction 2009;24(8):1870–9.

Fiscella 2006 {published data only}

Fiscella K, Eisinger SH, Meldrum S, Feng C, FisherSG, Guzick DS. Effect of mifepristone for symptomatic

leiomyomata on quality of life and uterine size: arandomised controlled trial. Obstetrics & Gynecology 2006;

108:1381–7. [PUBMED: 17138770]

References to studies excluded from this review

Carbonell 2008 {published data only}

Carbonell Esteve JL, Acosta R, Heredia B, Pérez Y,Castañeda MC, Hernández AV. Mifepristone for the

treatment of uterine leiomyomas. Obstetrics & Gynecology2008;112:1029–36. [PUBMED: 18978102]

Eisinger 2003 {published data only}

Eisinger SH, Meldrum S, Fiscella K, le Roux HD, GuzickDS. Low-dose mifepristone for uterine leiomyomata.

Obstetrics & Gynecology 2003;101(2):243–50. [PUBMED:12576246]

Eisinger 2005 {published data only}Eisinger SH, Bonfiglio T, Fiscella K, Meldrum S, Guzick

DS. Twelve-month safety and efficacy of low-dosemifepristone for uterine myomas. Journal MinimallyInvasive Gynecology 2005;12(3):227–33. [PUBMED:15922980]

Reinsch 1994 {published data only}

Reinsch RC, Murphy AA, Morales AJ, Yen SS. The effectsof RU 486 and leuprolide acetate on uterine artery blood

flow in the fibroid uterus: a prospective, randomised study.American Journal Obstetrics and Gynecology 1994;170(6):

1623–7. [PUBMED: 8203418]

Yang 1996 {published data only}

Yang Y, Zheng S, Li K. Treatment of uterine leiomyomaby two different doses of mifepristone. Chinese JournalObstetrics and Gynecology 1996;31(10):624–6. [PUBMED:9275461]

Zeng 1998 {published data only}

Zeng C, Gu M, Huang H. A clinical control study onthe treatment of uterine leiomyoma with gonadotrophin

releasing hormone agonist or mifepristone. Zhonghua fuchan ke za zhi 1998;33(8):490–2.

Additional references

Begg 1994

Begg C, Mazumdar M. Operating characteristics of a rankcorrelation test for publication bias. Biometrics 1994;50:

1088–101.

Drinville 2007

Drinville SJ, Memarzadeh S. Bengn disorders of the uterinecorpus. In: DeCherney AH editor(s). Current Diagnosis& Treatment Obstetrics & Gynecology. 10. New York:McGraw-Hill, 2007:639–53.

Duval 2000

Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias

in meta-analysis. Biometrics 2000;56:455–63.

Egger 1997Egger MDG, Schneider M, Minder C. Bias in meta-analysis

detected by a simple, graphical test. British Medical Journal1997;315:629–34.

Farquhar 2002

Farquhar CM, Steiner CA. Hysterectomy rates in theUnited States 1990-1997. Obstetrics & Gynecology 2002;99

(2):229–34.

Garzo 1988

Garzo VG, Liu J, Ulmann A, Baulieu, Yen SSC. Effectsof an antiprogesterone (RU-486) on the hypothalamic-

hypophysealovarian-endometrial axis during the luteal phaseof the menstrual cycle. The Journal of Clinical Endocrinologyand Metabolism 1988;66:508–16.

GRADE PRO 2011GRADE Working Group. GRADE Profile Software.

GRADE Working Group, 2011.



Guarnaccia 2001

Guarnaccia MM, Rein MS. Traditional surgical approachesto uterine fibroids: abdominal myomectomy and

hysterectomy. Clinical Obstetrics & Gynecology 2001;44:385–400.

Hart 2001Hart R, Khalaf Y, Yeong CT, Seed P, Taylor A, Braude P.

A prospective controlled study of the effect of intramuraluterine fibroids on the outcome of assisted conception.

Human Reproduction 2001;16:2411–7.

Higgins 2011

Higgins JPT, Green S (editors). Cochrane Handbookfor Systematic Reviews of Interventions Version 5.1.0

[updated March 2011], The Cochrane Collaboration, 2011.Available from www.cochrane-handbook.org.

Hopewell 2007a

Hopewell S, Clarke MJ, Lefebvre C, Scherer RW.Handsearching versus electronic searching to identify

reports of randomised trials. Cochrane Database of SystematicReviews 2007, Issue 2.

Hopewell 2007b

Hopewell S, McDonald S, Clarke MJ, Egger M. Greyliterature in meta-analyses of randomized trials of health

care interventions. Cochrane Database of Systematic Reviews2007, Issue 2.

Istre 2007

Istre O. Conservative treatment of fibroids. GynecologicalSurgery 2007;4(2):73–8.

Kawaguchi 1989

Kawaguchi K, Fujii S, Konishi I, Nanbu Y, Nonogaki H,Mori T. Mitotic activity in uterine leiomyomas during

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# Indicates the major publication for the study



C H A R A C T E R I S T I C S O F S T U D I E S

Characteristics of included studies [ordered by study ID]

Bagaria 2009

Methods Study design: double-blind RCTTotal study duration: 3 months

Participants Total number: 40 participants20 randomised to IG and 20 randomised to CGLosses to follow-up: IG: 1, CG: 435 participants (IG: 19; CG: 16) completed all 3 moths of follow-upSetting: the gynaecological outpatient department of University College of Medical Sci-ences and Guru Teg Bahadur Hospital, DelhiCountry: IndiaInclusion criteria:

• pre-menopausal women with uterine fibroids. Specific inclusion criteria were notstated by the study authorsExclusion criteria:

• pregnancy or breast feeding• major medical morbidity such as ovarian, cervical or uterine malignancy; presence

of liver, respiratory (asthma), renal, heart disease, pelvic inflammatory disease or anyother adnexal pathology

• patient necessitating early surgical intervention for uterine leiomyoma• hormonal contraception or any hormonal therapy in the previous 3 months

Age (mean ± SD): IG: 40.3 ± 6.8 years, CG: 41.1 ± 9.3 yearsBaseline imbalances: both groups were comparable for baseline parameters

Interventions IG: mifepristone 10 mg/day, prepared from 200 mg tablet at the start of the study usinglactose as filler, oral dosesCG: placebo capsules containing lactose filler, oral doses

Outcomes Leiomyoma volume (mL):• assessments were performed by abdominal and vaginal uterine ultrasonography.

Volumes were calculated using the Viscomi formula (4/3 ! W/2 x L/2 x T/2) where Wis uterine width, L is uterine length and T is uterine thicknessUterine volume (mL):

• assessments were performed by abdominal and vaginal uterine ultrasonography.Volumes were calculated using the formula: 4/3 ! abc where a, b and c represent radiiof the sphere in 3 dimensionsOther symptoms: monthly assessmentSeverity of the symptoms was graded according to the visual analogue scale while quan-tification of blood loss was done using pictorial blood loss assessment chart:

• pelvic pain• pelvic pressure• bladder pressure• low back pain• rectal pain• intercourse pain



Bagaria 2009 (Continued)

• urinary frequency• menstrual blood loss

Pregnancy rates: the study did not address this outcomeHaemoglobin levels (mg/dL): at the end of treatmentLiver function test: at the end of treatmentAdverse events:

• endometrial pathology: endometrial biopsy at baseline and 3-months aftertreatment termination. Diagnostic criteria not stated

• amenorrhoea: number of participants who were amenorrhoeic at 3 months• hot flushes: changes in prevalence at 3 months. How measures were taken was not

stated by the study authors• recurrence rate of symptoms: the study did not address this outcome• others: prevalence of: nausea, vomiting, diarrhoea, headache, decreased libido,

fatigue, weakness

Notes 1. The study was approved by the ethical committee of the department of UniversityCollege of Medical Sciences and Guru Teg Bahadur Hospital

2. Financial support was not stated

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selectionbias)

Low risk Computer-generated random tables, ran-domising packets to contain either activedrug or placebo

Allocation concealment (selection bias) Low risk Sequentially numbered drug packets ofidentical appearance

Blinding (performance bias and detectionbias)Participants

Unclear risk “The patients and the investigator werenot aware of the drug being dispensed.”Probably participants and study personnelcould have guessed the group allocation,but the review authors judge that the mainoutcomes and the outcome measurements(leiomyoma volume and related symptoms:bleeding patterns) are not likely to be in-fluenced by lack of blindingAlthough there is no risk of bias in the out-come measurements (leiomyoma volumeand related symptoms: bleeding patterns), this statement is unclear for performancebias

Blinding (performance bias and detectionbias)study personnel

Unclear risk Although there is no risk of bias in the out-come measurements (leiomyoma volumeand related symptoms: bleeding patterns), this statement is unclear for performance



Bagaria 2009 (Continued)

bias

Blinding (performance bias and detectionbias)outcome assessors

Unclear risk Not stated

Incomplete outcome data (attrition bias)All outcomes

High risk No reasons for missing data provided - “lostto follow-up”

Selective reporting (reporting bias) Low risk The published report includes all expectedoutcomes

Other bias High risk Imprecision, only 35 participants with fewoutcomes

Engman 2009

Methods Study design: randomised, double-blind, placebo-controlled studyTotal study duration: 3 months

Participants Total number: 3014 randomised to IG and 16 randomised to CG2 women dropped out during the course of the study (IG: 0, CG: 2)28 participants completed all 3 months of follow-up (IG: 14, CG: 14)Setting: the Karolinska University Hospital, StockholmCountry: SwedenInclusion criteria:

• “Healthy, non-pregnant women, referred for evaluation to the outpatient clinicowing to leiomyoma-related problems indicating surgical intervention” (diagnosticcriteria not stated)Exclusion criteria:

• pregnancy• “any history of breast cancer or other malignancy, bleeding not possible to control

with tranexamic acid and iron medication - abnormal mammogram and breast biopsy -adnexal abnormality, suspicion of leiomyosarcoma... abnormal FSH or LH levels orany other hormonal dysfunction of significance; laboratory findings that would givesuspicion of blood, liver or renal dysfunction, abnormal pap smear at screening or anycontraindications to the use of mifepristone”

• any steroid therapy in the previous 3 monthsAge (mean ± SD): IG: 40.8 ± 4.7 years, CG: 40.9 ± 7.6 yearsBaseline imbalances: groups were comparable for age, parity, BMI, endometrial doublelayer thickness at baseline

Interventions IG: mifepristone 50 mg (one quarter of 200 mg Mifegyne), every other day with therapystarting on the first day of cycle, oral dosesCG: vitamin B tablets (one quarter of TrioBe Recip), visually identical to mifepristoneas placebo



Engman 2009 (Continued)

Outcomes Primary outcome:• uterine leiomyoma size: measuring (by vaginal uterine ultrasonography) the 3

largest diameters (A, B and C) in 2 planes in approximately perpendicular x, y and zaxis directions. Volume was calculated using the formula for an ellipsoid, 0.523 x A x Bx C. Measurements were made or supervised every 4 weeks until the surgery by thesame operator

• measurements for both dominant myoma volume and total myoma volumeSecondary outcomes:

• uterine blood flow: using a flow velocity waveform according to the formula: PI:(S-D)/TAMAX. PI and peak flow were measured in the uterine arteries, the peripheraland central leiomyoma vessels

• bleeding: assessed by using daily menstrual logs and pictorial bleeding charts. Amonthly blood loss index was calculated from menstrual history by assigning values 1to 4 to each day of spotting, indicating light, moderate and heavy flow, respectively,and then summing the results

• leiomyoma and general symptoms: assessed using a 5-point Likert scale items (0 =no symptoms; 4 = very severe). The scores were registered weekly and summarised forevery 4-week period (range 0 to 16) and compared within and between the treatmentgroups at 4, 8 and 12 weeks of treatment

• local symptoms:$ pelvic pain$ pelvic pressure$ bladder pressure$ low back pain$ rectal pain$ urinary frequency$ intercourse pain

• and general hormone-related symptoms including hot flushes, headache, nausea,vomiting, diarrhoea, mood fluctuation, libido, weakness and fatigueAdverse events:

• endometrial pathology: endometrial biopsy at baseline and 3 months wereevaluated by an expert investigator blinded to treatment

• amenorrhoea: number of participants who were amenorrhoeic at 3 months• liver function testing, other hormones and routine blood parameters: baseline and

at the end of the studyRecurrence rate of symptoms: not reported

Notes 1. The study was approved by the Ethics committee at Karolinska Institutet2. The study was supported by grants from the Swedish Research Council.

Karolinska Institutet and Stockholm city county/Karolinska Institutet

Risk of bias



Low risk Random computer-generated list



Engman 2009 (Continued)

Allocation concealment (selection bias) Low risk Medication was packed and coded by thepharmacy


Unclear risk “Patients and study staff were blinded totreatment group”. Owing to the marked ef-fect in bleeding patterns and hot flushes,participants/study personnel could havebeen aware of treatment assignments. Thereview authors judge that the objective out-comes of leiomyoma size and bleeding pat-terns are not likely to be influenced by lackof blinding. But subjective outcomes as hotflushes (which had a significant differencebetween groups) could have been affectedby this awareness in this studyAlthough there is no risk of bias in the out-come measurements (leiomyoma volumeand related symptoms: bleeding patterns), this statement is unclear for performancebias


Unclear risk Although there is no risk of bias in the out-come measurements (leiomyoma volumeand related symptoms: bleeding patterns), this statement is unclear for performancebias




Low risk Reasons for missing outcome data unlikelyto be related to true outcome. Reasons forexclusion are uncontrollable bleeding inone case, elevated serum FSH in another

Selective reporting (reporting bias) Low risk The published reports include all expectedoutcomes. Protocol available on clinicaltri-als.gov NCT00579475

Other bias High risk The questionnaire used for leiomyoma-re-lated symptoms is described by study au-thors as not validated and had low sensitiv-ity



Fiscella 2006

Methods Study design: randomised, double-blind, placebo-controlled studyTotal study duration: 6 months

Participants Total number: 4222 randomised to IG and 20 randomised to CG5 women dropped out during the course of the study (IG: 2, CG: 3)39 participants began the trial and participated for at least 1 month. 37 participantscompleted all 6 months of follow-up3 dropped out before 1 month of prescription (IG: 2, CG: 1). 1 dropped out after 1month of prescription and 1 after 3 months of prescription (IG: 0, CG: 3)Setting: Departments of Family Medicine, Obstetrics and Gynecology, Biostatistics, andCommunity & Preventive Medicine, School of Medicine and Dentistry, University ofRochester, Rochester, New YorkCountry: USInclusion criteria:

• 18 years or older, pre-menopausal women, with moderately severe leiomyoma-related symptoms (> 39 on the Uterine Fibroid Symptom Quality of Life SymptomSeverity Subscale)

• total uterine volume % 160 mL, and at least• 1 leiomyoma that was % 2.5 cm measured by vaginal and abdominal ultrasound

Exclusion criteria:• pregnancy or intended to become pregnant in the next 6 months• major medical morbidity or severe anaemia, active mental illness, elevated liver

enzymes or substance abuse• use of short-acting hormones in the past 3 months, use of GnRH analogues or

other long-acting hormonal medications in the past 6 monthsAge (mean ± SD): IG: 48.8 ± 6.2 years, CG: 43.2 ± 4.7 yearsBaseline imbalances: “the two groups were well-matched for baseline characteristics withthe exception of body mass index and baseline uterine volume”

Interventions IG: mifepristone 5 mg/day, oral dosesCG: placebo capsules daily, identical in weight and appearance to mifepristone

Outcomes Primary outcome:• mean change in leiomyoma specific overall QoL (using Uterine Fibroid Symptom

- Quality of Life) scale 1 to 100, with higher scores indicating better QoL. The studysuggests significant improvements (P < 0.001) for specific QoL. Treatment withmifepristone also was associated with significant gains in energy and health status andconcomitant reductions in fatigue and pain. The author provided raw data forindividual indicators of the QoL and reduction of the values of the Uterine FibroidSymptoms - Quality of Life measuresSecondary outcomes:

• global health status: measured by the Medical Outcomes 36-item Short Form[SF-36] survey

• global pain: measured by McGill Pain Questionnaire$ each of these questionnaires was administered at baseline, 1 month, 3 months

and 6 months, except the McGill Pain Questionnaire, which was assessed monthly$ upper and lower limits, and whether high or low score is good, was not

stated by study authors



Fiscella 2006 (Continued)

• bleeding: assessed by using daily menstrual logs and pictorial bleeding charts. Amonthly blood loss index was calculated from menstrual history by assigning values 1to 4 to each day of spotting, indicating light, moderate, and heavy flow, respectively,and then summing the results

• uterine size (mL): uterine volume and leiomyoma size were assessed by vaginal orabdominal ultrasonogram, or both, at baseline, 1 month, 3 months and 6 months.Volume changes were analysed. The uterus was measured in 3 planes and a totalvolume calculated

• pregnancy rates• presence and intensity of likely leiomyoma symptoms: assessed monthly using a

5-point Likert scale items:$ pelvic pain$ pelvic pressure$ bladder pressure$ low back pain$ rectal pain$ urinary frequency$ intercourse pain

• drug adverse effects, including hot flushes, headache, nausea, vomiting, moodswings, diarrhoea, decreased libido, weakness, fatigue and nervousnessAdverse events:

• endometrial pathology: endometrial biopsy at baseline and 6 months• amenorrhoea: number of participants who are amenorrhoeic at 6 months• alterations in liver function testing: mean changes at 1, 3 and 6 months• recurrence rate of symptoms: not reported

Notes 1. The study was approved by the University of Rochester Institutional ReviewBoard. Women were paid for each study visit to defray their expenses

2. The study was supported by funding from the National Institute for Child Healthand Human Development. Athenium Laboratories (New York, NY) supplied the drugat cost

Risk of bias



Low risk Blocked randomisation, using a computerrandom number generator

Allocation concealment (selection bias) Low risk Sequentially numbered, opaque, sealed en-velopes


Unclear risk “Capsules were indistinguishable in all as-pects of their outward appearance. For eachdrug an identically matched placebo wasavailable”. However, study authors statedthat 19 of 20 (95%) women in the treat-ment group correctly guessed that theyhad been receiving mifepristone because of




the dramatic improvements in symptoms,including cessation of bleeding amongwomen in the intervention group. The re-view authors judge that objective outcomessuch as leiomyoma size and bleeding pat-terns are not likely to be influenced by lackof blinding. However, leiomyoma-specificQoL (primary aim of this study) as wellas global QoL could have been affected byawareness of treatment allocationAlthough there is no risk of bias in the out-come measurements (leiomyoma volumeand related symptoms: bleeding patterns), this statement is unclear for performancebias


Unclear risk Although there is no risk of bias in the out-come measurements (leiomyoma volumeand related symptoms: bleeding patterns), this statement is unclear for performancebias




Unclear risk “All 42 women who were randomised wereincluded in the analysis, including the threewho provided only baseline measures andtwo more who withdrew later” No reasonsgiven for loss of outcome dataMethod of imputation not described

Selective reporting (reporting bias) Unclear risk Insufficient information to judge ’yes’or ’no’. Non-significant symptom datahas not been reported. Protocol avail-able on clinical trials.gov and gives sim-ilar information to methods section(NCT00133705)

Other bias High risk The study had baseline imbalance:• body mass index (IG: mean: 31.7 kg/

m2, SD: 8.7 kg/m2, and CG: mean: 27.2kg/m2, SD: 5.6 kg/m2)

• uterine volume (IG: mean: 719 mL,SD: 663 mL, CG and mean: 449 mL,SD: 236 mL

• risk of selection bias because the useof blocked randomisation in a blinded




trial (small size) where the blinding isbroken. Such as imbalance could suggestfailure of randomisation to balance knownand unknown confounders factors

• participants were permitted to useanalgesics. Although analgesic use did notdiffer between groups, inappropriateadministration of a co-intervention couldhave biased the global pain outcome

BMI: body mass index; CG: control group; FSH: follicle-stimulating hormone; GnRH: gonadotrophin-releasing hormone; IG: inter-vention group; LH: luteinising hormone; QoL: quality of life; RCT: randomised controlled trial; SD: standard deviation.

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Carbonell 2008 The study compared different dosages of mifepristone

Eisinger 2003 The study compared different dosages of mifepristone

Eisinger 2005 The study compared different dosages of mifepristone (companion to Eisinger 2003)

Reinsch 1994 Data were provided as percentages, in a useless fashion for analysis

Yang 1996 Non-randomised design

Zeng 1998 Non-randomised design



D A T A A N D A N A L Y S E S

Comparison 1. Mifepristone compared with placebo

Outcome or subgroup titleNo. ofstudies

No. ofparticipants Statistical method Effect size

1 Relief of bleeding 2 77 Peto Odds Ratio (Peto, Fixed, 95% CI) 17.84 [6.72, 47.38]2 Relief of pain 1 Peto Odds Ratio (Peto, Fixed, 95% CI) Totals not selected

2.1 Relief of dysmenorrhoea 1 Peto Odds Ratio (Peto, Fixed, 95% CI) 0.0 [0.0, 0.0]2.2 Relief of pelvic pain 1 Peto Odds Ratio (Peto, Fixed, 95% CI) 0.0 [0.0, 0.0]

4 Uterine Fibroid SymptomQuality of Life

1 Mean Difference (IV, Fixed, 95% CI) Subtotals only

5 Reduction in average fibroidvolume

3 99 Std. Mean Difference (IV, Fixed, 95% CI) 0.02 [-0.38, 0.41]

6 Reduction in uterine volume 2 72 Mean Difference (IV, Fixed, 95% CI) -77.24 [-240.62, 86.14]

7 Adverse events 2 54 Odds Ratio (M-H, Random, 95% CI) 27.45 [4.06, 185.56]

Analysis 1.1. Comparison 1 Mifepristone compared with placebo, Outcome 1 Relief of bleeding.

Review: Mifepristone for uterine fibroids

Comparison: 1 Mifepristone compared with placebo

Outcome: 1 Relief of bleeding

Study or subgroup Mifepristone PlaceboPeto

Odds Ratio WeightPeto

Odds Ratio

n/N n/N Peto,Fixed,95% CI Peto,Fixed,95% CI

Bagaria 2009 (1) 16/19 0/16 55.1 % 27.02 [ 7.25, 100.70 ]

Fiscella 2006 (2) 9/22 0/20 44.9 % 10.72 [ 2.49, 46.06 ]

Total (95% CI) 41 36 100.0 % 17.84 [ 6.72, 47.38 ]Total events: 25 (Mifepristone), 0 (Placebo)

Heterogeneity: Chi?? = 0.85, df = 1 (P = 0.36); I?? =0.0%

Test for overall effect: Z = 5.78 (P < 0.00001)

Test for subgroup differences: Not applicable

0.001 0.01 0.1 1 10 100 1000

Favours placebo Favours mifepristone

(1) 10/mg/day for 3 months

(2) 5mg/day for 3 months



Analysis 1.2. Comparison 1 Mifepristone compared with placebo, Outcome 2 Relief of pain.



Outcome: 2 Relief of pain

Study or subgroup Mifepristone PlaceboPeto

Odds RatioPeto

Odds Ratio

n/N n/N Peto,Fixed,95% CI Peto,Fixed,95% CI

1 Relief of dysmenorrhoea

Bagaria 2009 12/15 2/11 10.93 [ 2.37, 50.51 ]

2 Relief of pelvic pain

Bagaria 2009 5/15 2/11 2.10 [ 0.38, 11.71 ]

0.1 0.2 0.5 1 2 5 10


Analysis 1.4. Comparison 1 Mifepristone compared with placebo, Outcome 4 Uterine Fibroid Symptom

Quality of Life.



Outcome: 4 Uterine Fibroid Symptom Quality of Life

Study or subgroup Experimental ControlMean

DifferenceMean

Difference

N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Fiscella 2006 20 50.05 (24.07) 17 17 (21.79) 33.05 [ 18.27, 47.83 ]

Subtotal (95% CI) 0 0 0.0 [ 0.0, 0.0 ]Heterogeneity: not applicable

Test for overall effect: Z = 0.0 (P < 0.00001)


-100 -50 0 50 100




Analysis 1.5. Comparison 1 Mifepristone compared with placebo, Outcome 5 Reduction in average fibroid

volume.



Outcome: 5 Reduction in average fibroid volume

Study or subgroup Experimental Control

Std.Mean

Difference Weight

Std.Mean

Difference


Bagaria 2009 19 95.8 (181) 16 118.3 (243.4) 35.5 % -0.10 [ -0.77, 0.56 ]

Engman 2009 12 106 (113.3) 15 118 (59.26) 27.2 % -0.13 [ -0.89, 0.63 ]

Fiscella 2006 20 114.1 (29.7) 17 94.1 (113.9) 37.3 % 0.24 [ -0.40, 0.89 ]

Total (95% CI) 51 48 100.0 % 0.02 [ -0.38, 0.41 ]Heterogeneity: Chi?? = 0.75, df = 2 (P = 0.69); I?? =0.0%

Test for overall effect: Z = 0.09 (P = 0.93)


-1 -0.5 0 0.5 1

Favours experimental Favours control

Analysis 1.6. Comparison 1 Mifepristone compared with placebo, Outcome 6 Reduction in uterine volume.



Outcome: 6 Reduction in uterine volume

Study or subgroup Experimental ControlMean

Difference WeightMean

Difference


Bagaria 2009 19 188 (203.5) 16 281.1 (417.2) 53.2 % -93.10 [ -317.07, 130.87 ]

Fiscella 2006 20 478.3 (444.3) 17 537.5 (291) 46.8 % -59.20 [ -298.05, 179.65 ]

Total (95% CI) 39 33 100.0 % -77.24 [ -240.62, 86.14 ]Heterogeneity: Chi?? = 0.04, df = 1 (P = 0.84); I?? =0.0%



-500 -250 0 250 500




Analysis 1.7. Comparison 1 Mifepristone compared with placebo, Outcome 7 Adverse events.



Outcome: 7 Adverse events

Study or subgroup Experimental Control Odds Ratio Weight Odds Ratio

n/N n/N

M-H,Random,95%

CI

M-H,Random,95%

CI

Engman 2009 5/8 1/11 58.2 % 16.67 [ 1.36, 204.03 ]

Bagaria 2009 12/19 0/16 41.8 % 55.00 [ 2.86, 1056.67 ]

Total (95% CI) 27 27 100.0 % 27.45 [ 4.06, 185.56 ]Total events: 17 (Experimental), 1 (Control)

Heterogeneity: Tau?? = 0.0; Chi?? = 0.39, df = 1 (P = 0.53); I?? =0.0%



0.001 0.01 0.1 1 10 100 1000


A P P E N D I C E S

Appendix 1. MEDLINE search strategy

<1950 to August Week 4 2009>

1 exp Leiomyoma/ (14375)2 exp Fibroma/ (10225)3 fibroid$.ti,ab,sh. (2647)4 fibroma$.ti,ab,sh. (13514)5 fibromyoma$.ti,ab,sh. (526)6 (uter$ adj3 myoma$).ti,ab,sh. (2296)7 Leiomyoma$.ti,ab,sh. (15778)8 or/1-7 (30634)9 Mifepristone/ (4453)10 Mifepristone.ti,ab,sh. (4822)11 mifegyne.ti,ab,sh. (11)12 mifeprex.ti,ab,sh. (9)13 r38486.ti,ab,sh. (1)14 ru-38486.ti,ab,sh. (416)15 ru-486.ti,ab,sh. (1495)16 or/9-15 (5268)17 8 and 16 (86)18 randomized controlled trial.pt. (280165)19 controlled clinical trial.pt. (80498)



20 randomized.ab. (189021)21 placebo.ab. (115356)22 cross-over studies/ (24836)23 (crossover or cross-over or cross over).tw. (43875)24 clinical trials as topic.sh. (146150)25 randomly.ab. (136940)26 trial.ti. (82239)27 or/18-26 (663847)28 humans.sh. (10982011)29 27 and 28 (598163)30 29 and 17 (21)31 from 30 keep 1-21 (21)

Appendix 2. EMBASE search strategy

1980 to 2009 Week 35>

1 Leiomyoma/ (4671)2 Fibroma/ (3071)3 Uterus Myoma/ (5748)4 fibroid$.tw. (2548)5 fibroma$.tw. (4514)6 fibromyoma$.tw. (159)7 (uter$ adj3 myoma$).tw. (1248)8 Leiomyoma.tw. (3873)9 or/1-8 (17497)10 Mifepristone/ (6862)11 Mifepristone$.tw. (1847)12 Lunarette.tw. (1)13 Mifegyne.tw. (160)14 Mifeprex.tw. (81)15 Ru 38486.tw. (808)16 Ru 486.tw. (3259)17 Ru38486.tw. (297)18 Ru486.tw. (1540)19 Ru 486 6.tw. (2)20 or/10-19 (7213)21 Clinical Trial/ (553624)22 Randomized Controlled Trial/ (172938)23 exp randomization/ (27016)24 Single Blind Procedure/ (8471)25 Double Blind Procedure/ (73817)26 Crossover Procedure/ (21683)27 Placebo/ (130648)28 Randomi?ed controlled trial$.tw. (34707)29 Rct.tw. (2891)30 random allocation.tw. (645)31 randomly allocated.tw. (10460)32 allocated randomly.tw. (1362)33 (allocated adj2 random).tw. (565)34 Single blind$.tw. (7642)35 Double blind$.tw. (86500)



36 ((treble or triple) adj blind$).tw. (141)37 placebo$.tw. (112693)38 prospective study/ (85065)39 or/21-38 (726966)40 case study/ (6306)41 case report.tw. (122424)42 abstract report/ or letter/ (508941)43 or/40-42 (635252)44 39 not 43 (701604)45 9 and 44 and 20 (90)46 from 45 keep 1-90 (90)

Appendix 3. CENTRAL search strategy

<3rd Quarter 2009>

1 exp Leiomyoma/ (283)2 exp Fibroma/ (1)3 fibroid$.ti,ab,sh. (178)4 fibroma$.ti,ab,sh. (17)5 fibromyoma$.ti,ab,sh. (11)6 (uter$ adj3 myoma$).ti,ab,sh. (113)7 Leiomyoma$.ti,ab,sh. (332)8 or/1-7 (473)9 Mifepristone/ (278)10 Mifepristone.ti,ab,sh. (376)11 mifegyne.ti,ab,sh. (0)12 mifeprex.ti,ab,sh. (0)13 r38486.ti,ab,sh. (0)14 ru-38486.ti,ab,sh. (1)15 ru-486.ti,ab,sh. (102)16 or/9-15 (391)17 8 and 16 (11)18 from 17 keep 1-11 (11)

Appendix 4. CINAHL search strategy

1 exp Leiomyoma/2 exp Fibroma/3 fibroid$.ti,ab,sh.4 fibroma$.ti,ab,sh.5 fibromyoma$.ti,ab,sh.6 (uter$ adj3 myoma$).ti,ab,sh.7 Leiomyoma$.ti,ab,sh.8 or/1-79 Mifepristone/10 Mifepristone.ti,ab,sh.11 mifegyne.ti,ab,sh.12 mifeprex.ti,ab,sh.13 r38486.ti,ab,sh.14 ru-38486.ti,ab,sh.15 ru-486.ti,ab,sh.



16 or/9-1517 8 and 1618 exp clinical trials/19 Clinical trial.pt.20 (clinic$ adj trial$1).tw.21 ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$3 or mask$3)).tw.22 Randomi?ed control$ trial$.tw.23 Random assignment/24 Random$ allocat$.tw.25 Placebo$.tw.26 Placebos/27 Quantitative studies/28 Allocat$ random$.tw.29 or/18-2830 29 and 1731 from 30 keep 1-2

Appendix 5. Study eligibility

Date

Extractor

Trial authors

Publication year

Journal

1) Design

Described as randomised?If no then exclude . If yes go to questions 2

YesNoUnclear

2) Participants

(a) YesNoUnclear

(b) YesNoUnclear

If ’no’, exclude. Otherwise go to question (3).

3) Interventions



(Continued)

YesNoUnclear

YesNoUnclear

If ’no’ to (a) or (b), exclude.

Final decision

Include (if all ’yes’)Exclude (if any ’no’)Unclear

Excluded or unclear because:

If ’unclear’, action taken:

Appendix 6. Data extraction form

Date:

Extractor (initials):

Trial authors:

Year of publication:

Journal:

Study setting

(1) Participants

Inclusion criteria: Exclusion criteria:

Median or mean age: Ethnicity

Age range: Gravidity

Were all treatment groups comparable atbaseline:

YesNoUnclear



(Continued)

If no or unclear, describe any differences:

Notes:

2) Interventions Tx 1 Tx2

Tx used

Formulation used

Route

Dose

Duration

Timing and frequency

Notes

(3) Outcomes

Further information:

Trialists contacted for more information: yes no

Address

Ph

Email

Data

Comments



W H A T ’ S N E W

Last assessed as up-to-date: 18 November 2011.

Date Event Description

23 March 2012 New search has been performed New secondary outcomes added: reduction in uterine volume and fibroid-spe-cific quality of life

H I S T O R Y

Protocol first published: Issue 2, 2009

Review first published: Issue 8, 2012

Date Event Description

13 April 2008 Amended converted to new review format

13 December 2006 New citation required and major changes Substantive amendment

C O N T R I B U T I O N S O F A U T H O R S

For the full review:

MT: lead author, conceived, designed, coordinated and wrote up the review

LO: co-author, conceived and designed the review, participated in data extraction, management and interpretation, and in writing upthe review

AS: co-author, participated in data extraction, management and interpretation, and in writing up the review

AR: co-author, participated in data extraction, management and interpretation, and in writing up the review

PS: co-author, participated in data interpretation and in writing up the review

D E C L A R A T I O N S O F I N T E R E S T

Peter Stone is a member of a group of clinicians previously responsible for the registration of mifepristone in New Zealand.



S O U R C E S O F S U P P O R T

Internal sources

• IHCAI Foundation, Costa Rica.

External sources

• No sources of support supplied

D I F F E R E N C E S B E T W E E N P R O T O C O L A N D R E V I E W

Addition of two secondary outcomes, reduction in uterine volume measured by ultrasonography or Magnetic Resonance Imaging(MRI) and Uterine Fibroid Symptom Quality of Life.

The protocol states that a random-effects model would be used but this was changed to a fixed effects model after discussion with thestatistician.



Mifepristone for uterine fibroids

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