Selective progesterone receptor modulators (SPRMs) for uterine fibroids

Ally Murji; Lucy Whitaker; Tiffany L Chow; Mara L Sobel

doi:10.1002/14651858.CD010770.pub2

Cochrane Database of Systematic Reviews

Moduladores selectivos de los receptores de progesterona (MSRP) para los miomas uterinos

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DOI:

https://doi.org/10.1002/14651858.CD010770.pub2 Copiar DOI

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Cochrane Database of Systematic Reviews

Versión publicada:

26 abril 2017see what's new

Tipo:

Intervention

Etapa:

Review

Grupo Editorial Cochrane:

Grupo Cochrane de Ginecología y fertilidad

Copyright:

Copyright © 2017 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

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Autores

Ally Murji

Correspondencia a: Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Canada

[email protected]

[email protected]
Lucy Whitaker

Simpson Centre for Reproductive Health, Royal Infirmary of Edinburgh, Edinburgh, UK
Tiffany L Chow

University of Toronto, Toronto, Canada
Mara L Sobel

Department of Obstetrics and Gynecology, Mount Sinai Hospital, University of Toronto, Toronto, Canada

Contributions of authors

All review authors contributed equally in drafting and reviewing the protocol and review.

Sources of support

Internal sources

None, Other.

External sources

None, Other.

Declarations of interest

AM participated in a speakers bureau or served on the advisory board for Allergan (manufacturer of ulipristal acetate in Canada), Abbvie (manufacturer of leuprolide), Bayer, Hologic and Medtronic.

MS, TC and LW have no conflicts of interest to declare.

Acknowledgements

We acknowledge the significant contributions of Drs Hilary OD Critchley and Andrew H Horne to the review.

Many thanks to Marian Showell, Information Specialist with the Cochrane Gynaecology and Fertility Group, and Vicky Lynham, at Sidney Liswood Library Mount Sinai Hospital, Toronto, Ontario, for help in devising and executing the literature search strategy.

Many thanks also to Professor Joseph Beyenne, Professor of Biostatistics, Faculty of Health Sciences, McMaster University, Hamilton, who assisted with statistical analysis and imputation of missing data.

Version history

Published

Title

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Authors

Version

2017 Apr 26

Selective progesterone receptor modulators (SPRMs) for uterine fibroids

Review

Ally Murji, Lucy Whitaker, Tiffany L Chow, Mara L Sobel

https://doi.org/10.1002/14651858.CD010770.pub2

2013 Oct 16

Selective progesterone receptor modulators (SPRMs) for uterine fibroids

Protocol

Ally Murji, Andrew W Horne, Lucy Whitaker, Mara L Sobel, Hilary OD Critchley

https://doi.org/10.1002/14651858.CD010770

Differences between protocol and review

Secondary outcomes

We removed the outcome that looked at recurrence rate over time. When conducting the review, we found this outcome to be not workable as it applied only to the post‐randomisation subgroup.

Measures of treatment effect

We added a paragraph to explain how SMDs would be interpreted because we wished to ensure that they would be interpreted in a consistent manner in the review.

Unit of analysis issues

In the protocol, we stated, "Change in fibroid size data will be analysed based on the number of fibroids tracked and not the number of patients". We decided that we would not pool any data not analysed per woman but would include them in an additional table, because we wished to avoid a unit of analysis error.

Dealing with missing data

We added a sentence to make it clear that when data manipulation was undertaken (such as imputing standard deviations or calculating medians from means), we obtained statistical advice and imputed the data using methods included in an appendix. Our rationale was that we wished to be transparent about our methods.

Subgroup analyses

The protocol stated that subgroup analyses would be undertaken "if sufficient data were available". Because "sufficient data" was poorly defined, we specified that this would mean more than five studies.

Sensitivity analyses

The protocol stated that we would conduct the following sensitivity analyses.

Exclusion of studies with high risk of bias.
Application of a fixed‐effect model.
Exclusion of unpublished studies.
Exclusion of trials for which data were imputed for primary outcomes.
Exclusion of studies that used unpublished rating scales or scales that had not been validated to assess for symptom relief.

We decided not to conduct the third and fifth sensitivity analyses in the list above because we considered that these factors would be reflected in an assessment of study risk of bias, and we changed the wording of the fourth subgroup analysis to "if alternative imputation strategies had been implemented" because it allows consideration of a wider range of scenarios for imputation of data.

Overall quality of the body of evidence: 'Summary of findings' tables

We added a paragraph explaining the methods we would use to compile 'Summary of findings' tables, and we added details of a second comparison because this information was not included in the protocol.

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

Female; Humans;

PICO

Population

Intervention

Comparison

Outcome

El uso y la enseñanza del modelo PICO están muy extendidos en el ámbito de la atención sanitaria basada en la evidencia para formular preguntas y estrategias de búsqueda y para caracterizar estudios o metanálisis clínicos. PICO son las siglas en inglés de cuatro posibles componentes de una pregunta de investigación: paciente, población o problema; intervención; comparación; desenlace (outcome).

Para saber más sobre el uso del modelo PICO, puede consultar el Manual Cochrane.

Figure 1

Study flow diagram.

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Figure 2

Risk of bias graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

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Figure 3

Risk of bias summary: review authors' judgements about each risk of bias item for each included study.

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Figure 4

Forest plot of comparison: 1 SPRM versus placebo, outcome: 1.1 Change in symptom severity score (QoL).

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Figure 5

Forest plot of comparison: 1 SPRM versus placebo, outcome: 1.2 Change in health‐related quality of life score.

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Figure 6

Forest plot of comparison: 1 SPRM versus placebo, outcome: 1.3 Change in menstrual blood loss.

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Figure 7

Forest plot of comparison: 2 SPRM versus leuprolide acetate, outcome: 2.1 Change in symptom severity score (QoL).

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Figure 8

Forest plot of comparison: 2 SPRM versus leuprolide acetate, outcome: 2.2 Change in health‐related quality of life score.

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Figure 9

Forest plot of comparison: 2 SPRM versus leuprolide acetate, outcome: 2.3 Change in menstrual blood loss.

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Analysis 1.1

Comparison 1 SPRM versus placebo, Outcome 1 Change in symptom severity score (QoL).

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Analysis 1.2

Comparison 1 SPRM versus placebo, Outcome 2 Change in health‐related quality of life score.

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Analysis 1.3

Comparison 1 SPRM versus placebo, Outcome 3 Change in menstrual blood loss.

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Analysis 1.4

Comparison 1 SPRM versus placebo, Outcome 4 Amenorrhoea.

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Analysis 1.5

Comparison 1 SPRM versus placebo, Outcome 5 Change in uterine volume.

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Analysis 1.6

Comparison 1 SPRM versus placebo, Outcome 6 SPRM‐associated endometrial changes.

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Analysis 2.1

Comparison 2 SPRM versus leuprolide acetate, Outcome 1 Change in symptom severity score (QoL).

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Analysis 2.2

Comparison 2 SPRM versus leuprolide acetate, Outcome 2 Change in health‐related quality of life score.

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Analysis 2.3

Comparison 2 SPRM versus leuprolide acetate, Outcome 3 Change in menstrual blood loss.

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Analysis 2.4

Comparison 2 SPRM versus leuprolide acetate, Outcome 4 Amenorrhoea.

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Analysis 2.5

Comparison 2 SPRM versus leuprolide acetate, Outcome 5 Change in pelvic pain.

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Analysis 2.6

Comparison 2 SPRM versus leuprolide acetate, Outcome 6 Percent change in uterine volume.

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Analysis 2.7

Comparison 2 SPRM versus leuprolide acetate, Outcome 7 SPRM‐associated endometrial changes.

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Summary of findings for the main comparison. SPRM versus placebo

SPRM vs placebo
Patient or population: women with uterine fibroids Setting: outpatient clinic Intervention: SPRM Comparison: placebo
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Risk with placebo	Risk with SPRM	Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
Quality of life: change in symptom severity score measured with Uterine Fibroid Symptom Quality of Life Scale (UFS‐QoL): scale 0 to 100		Mean change in symptom severity score (QoL) in the intervention group was 20.04 points lower (26.63 lower to 13.46 lower), indicating improvement in symptom severity with SPRM treatment for 3 months	‐	171 (4 RCTs)	⊕⊕⊕⊝ MODERATE^a
Quality of life: change in health‐related quality of life score measured with UFS‐QoL: scale 0 to 100		Mean change in health‐related quality of life score in the intervention group was 22.52 points higher (12.87 higher to 32.17 higher), indicating improvement in quality of life with SPRM treatment for 3 to 6 months	‐	200 (4 RCTs)	⊕⊕⊕⊝ MODERATE^a	1 RCT (Fiscella 2006) reported outcomes at 6 months. Remaining studies had a 3‐month follow‐up period
Abnormal uterine bleeding: change in menstrual blood loss		Mean change in menstrual blood loss in the intervention group was 1.11 points lower (1.38 lower to 0.83 lower), indicating a decrease in menstrual blood loss with SPRM treatment for 3 months	‐	310 (3 RCTs)	⊕⊕⊕⊝ MODERATE^a	Measured by PBAC score or similar menstrual pictorial score. PBAC score ≥ 100 correlates with menorrhagia, which is defined as > 80 mL menstrual blood loss
Abnormal uterine bleeding: amenorrhoea	29 per 1000	477 per 1000 (237 to 961) with 3 to 6 months of SPRM treatment	OR 82.50 (37.10 to 183.90)	590 (7 RCTs)	⊕⊕⊕⊝ MODERATE^a	1 RCT (Fiscella 2006) reported outcomes at 6 months. Remaining studies had a 3‐month follow‐up period
Pelvic pain (measured subjectively)		No conclusions could be drawn owing to variability in estimates		629 (7 RCTs)
Adverse effects: SPRM‐associated endometrial changes	77 per 1000	351 per 1000 (176 to 697) with 3 months of SPRM treatment	OR 15.12 (6.45 to 35.47)	405 (5 RCTs)	⊕⊕⊝⊝ LOW^a,b
*Risk in the intervention group (and its 95% confidence interval) is based on mean risk in the comparison group and relative effect of the intervention (and its 95% CI) CI: confidence interval; OR: odds ratio
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to the estimate of effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of effect but may be substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
^aDowngraded one level as publication bias suspected because no small negative studies included. Also, many studies were conducted and not published ^bDowngraded one level because of serious issues with indirectness of evidence when criteria for evaluating endometrial specimens differed between studies

Summary of findings for the main comparison. SPRM versus placebo

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Summary of findings 2. SPRM versus leuprolide acetate for uterine fibroids

SPRM versus leuprolide acetate for uterine fibroids
Patient or population: uterine fibroids Setting: outpatient clinic Intervention: SPRM Comparison: leuprolide acetate
Outcomes	*Anticipated absolute effects (95% CI)**		Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
Outcomes	Risk with leuprolide acetate	Risk with SPRM	Relative effect (95% CI)	Number of participants (studies)	Quality of the evidence (GRADE)	Comments
Quality of life: change in symptom severity score measured with Uterine Fibroid Symptom Quality of Life Scale (UFS‐QoL): scale 0 to 100		Mean change in symptom severity score (QoL) in the SPRM group was 3.7 points lower (9.85 lower to 2.45 higher) compared with the leuprolide group at 3 months	‐	281 (1 RCT)	⊕⊕⊕⊝ MODERATE^a
Quality of life: change in health‐related quality of life score measured with UFS‐QoL: scale 0 to 100		Mean change in health‐related quality of life score in the SPRM group was 1.06 points higher (5.73 lower to 7.85 higher) compared with the leuprolide group at 3 months	‐	281 (1 RCT)	⊕⊕⊕⊝ MODERATE^a
Abnormal uterine bleeding: change in menstrual blood loss (measured using PBAC score)		Mean change in menstrual blood loss in the SPRM group was 6 points higher (40.95 lower to 52.95 higher) compared with the leuprolide group at 3 months	‐	281 (1 RCT)	⊕⊕⊝⊝ LOW^a,b	PBAC score ≥ 100 correlates with menorrhagia, which is defined as > 80 mL menstrual blood loss
Abnormal uterine bleeding: amenorrhoea	804 per 1000	828 per 1000 (732 to 933) at 3 months	OR 1.14 (0.60 to 2.16)	280 (1 RCT)	⊕⊕⊕⊝ MODERATE^a
Pelvic pain (measured using McGill Pain Questionnaire: range 0 to 45)		Mean change in pelvic pain in the SPRM group was 0.01 points lower (2.14 lower to 2.12 higher) than in the leuprolide group at 3 months	‐	281 (1 RCT)	⊕⊕⊕⊝ MODERATE^a
Adverse effects: SPRM‐associated endometrial changes	119 per 1000	585 per 1000 (340 to 1000) after 3 months of treatment	OR 10.45 (5.38 to 20.33)	301 (1 RCT)	⊕⊕⊕⊝ MODERATE^a
*Risk in the intervention group (and its 95% confidence interval) is based on mean risk in the comparison group and relative effect of the intervention (and its 95% CI) CI: confidence interval; OR: odds ratio
GRADE Working Group grades of evidence High quality: We are very confident that the true effect lies close to the estimate of effect Moderate quality: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of effect but may be substantially different Low quality: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of effect Very low quality: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect
^aDowngraded one level as publication bias strongly suspected ^bDowngraded one level owing to serious issue with imprecision as point estimate has very wide confidence interval

Summary of findings 2. SPRM versus leuprolide acetate for uterine fibroids

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Table 1. Mifepristone studies

Study	Participants	Daily dose	Control	Follow‐up (months)
Esteve 2013	124	5 mg	Placebo	3
Fiscella 2006	42	5 mg	Placebo	6
Bagaria 2009	40	10 mg	Placebo	3
Liu 2015	62	10 mg	Placebo	3
Prasad 2013	132	10 mg	Placebo	3
Reinsch 1994	14	25 mg	Leuprolide acetate	3
Engman 2009	30	50 mg	Vitamin B	3

Table 1. Mifepristone studies

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Table 2. Ulipristal acetate studies

Study	Participants	Daily dose	Control	Follow‐up (months)
Bigatti 2014	Unknown	5 mg	No treatment	Not stated
Donnez 2012	242	5 or 10 mg	Placebo	3
Donnez 2012a	303	5 or 10 mg	Leuprolide acetate	3
Levens 2008	22	10 or 20 mg	Placebo	3
Nieman 2011	42	10 or 20 mg	Placebo	3

Table 2. Ulipristal acetate studies

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Table 3. Asoprisnil studies

Study	Participants	Daily dose	Control	Follow‐up (months)
Chwalisz 2007	129	5 or 10 or 25 mg	Placebo	3
Wilkens 2008	33	10 or 25 mg	Placebo	3

Table 3. Asoprisnil studies

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Table 4. Change in fibroid volume: SPRM versus placebo

Study	SPRM type	SPRM			Placebo
		MD	SD	n	MD	SD	n	Finding
Bagaria 2009	Mifepristone	‐41.5 cc	220.59	19	0.6 cc	266.63 cc	16	No significant difference
Engman 2009	Mifepristone	‐10.0 cc	107.39	12	‐16.0 cc	98.54 cc	15	No significant difference
Esteve 2013	Mifepristone	‐37.0 cc	96.24	58	4.0 cc	99.1 cc	47	Favours SPRM
Donnez 2012	Ulipristal acetate	‐16.88%	31.34	165	3.0%	31.63	45	Favours SPRM
Nieman 2011	Ulipristal acetate	‐20.5%	20.6	26	7.0%	25.0	12	Favours SPRM
cc: cubic centimetres MD: mean difference n: fibroids tracked SD: standard deviation

Table 4. Change in fibroid volume: SPRM versus placebo

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Table 5. Change in fibroid volume (%): SPRM versus leuprolide

Study	SPRM			Leuprolide
	MD	SD	n	MD	SD	n	Finding
Donnez 2012a	‐39.03%	37.92	188	‐53.0%	24.44	93	Favours leuprolide
MD: mean difference n: fibroids tracked SD: standard deviation

Table 5. Change in fibroid volume (%): SPRM versus leuprolide

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Comparison 1. SPRM versus placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change in symptom severity score (QoL) Show forest plot	4	171	Mean Difference (IV, Random, 95% CI)	‐20.04 [‐26.63, ‐13.46]

2 Change in health‐related quality of life score Show forest plot	4	200	Mean Difference (IV, Random, 95% CI)	22.52 [12.87, 32.17]

3 Change in menstrual blood loss Show forest plot	3	310	Std. Mean Difference (IV, Random, 95% CI)	‐1.11 [‐1.38, ‐0.83]

4 Amenorrhoea Show forest plot	7	590	Odds Ratio (IV, Random, 95% CI)	82.50 [37.01, 183.90]

5 Change in uterine volume Show forest plot	4	419	Std. Mean Difference (IV, Random, 95% CI)	‐0.63 [‐0.91, ‐0.36]

6 SPRM‐associated endometrial changes Show forest plot	5	405	Odds Ratio (IV, Random, 95% CI)	15.12 [6.45, 35.47]

Comparison 1. SPRM versus placebo

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Comparison 2. SPRM versus leuprolide acetate

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Change in symptom severity score (QoL) Show forest plot	1	281	Mean Difference (IV, Random, 95% CI)	‐3.70 [‐9.85, 2.45]

2 Change in health‐related quality of life score Show forest plot	1	281	Mean Difference (IV, Random, 95% CI)	1.06 [‐5.73, 7.85]

3 Change in menstrual blood loss Show forest plot	1	281	Mean Difference (IV, Random, 95% CI)	6.00 [‐40.95, 52.95]

4 Amenorrhoea Show forest plot	1	280	Odds Ratio (M‐H, Random, 95% CI)	1.14 [0.60, 2.16]

5 Change in pelvic pain Show forest plot	1	281	Mean Difference (IV, Random, 95% CI)	‐0.01 [‐2.14, 2.12]

6 Percent change in uterine volume Show forest plot	2	295	Mean Difference (IV, Random, 95% CI)	25.94 [20.49, 31.39]

7 SPRM‐associated endometrial changes Show forest plot	1	301	Odds Ratio (M‐H, Random, 95% CI)	10.45 [5.38, 20.33]

Comparison 2. SPRM versus leuprolide acetate

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Citado por:

Autores

Contributions of authors

Sources of support

Internal sources

External sources

Declarations of interest

Acknowledgements

Version history

Differences between protocol and review

Secondary outcomes

Measures of treatment effect

Unit of analysis issues

Dealing with missing data

Subgroup analyses

Sensitivity analyses

Overall quality of the body of evidence: 'Summary of findings' tables

Keywords

MeSH

Medical Subject Headings (MeSH) Keywords

Medical Subject Headings Check Words

PICO

PICO

Population

Intervention

Comparison

Outcome

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