| | |

Received: 7 October 2018    Revised: 5 February 2019    Accepted: 23 May 2019    First published online: 19 June 2019

DOI: 10.1002/ijgo.12868

REVIEW ARTICLE
Gynecology

A systematic review and meta-­analysis of ulipristal acetate for

symptomatic uterine fibroids

Mohamed Ghonim1,2 | Rana Magdy1,2 | Mohamed Sabbour1,2 | 

Mohanad Ghonim1,2 | Ashraf Nabhan2,3,*

1
Extended Modular Program, Faculty
of Medicine, Ain Shams University,
Cairo, Egypt
2
Egyptian Center for Evidence Based
Medicine, Cairo, Egypt
3 Objectives: To assess the effectiveness of UPA in women with symptomatic
Department of Obstetrics and
Gynecology, Faculty of Medicine, Ain Shams
University, Cairo, Egypt
*Correspondence
Ashraf Nabhan, El-Khalifa El Maamoun
Street, Cairo 11351, Egypt.
Email: anabhan@med.asu.edu.eg
Abstract
Background: Uterine fibroids cause menorrhagia and adversely affect quality of ­
life. Ulipristal acetate (UPA) can improve fibroid symptoms.
uterine fibroids.
Search strategy: We searched CENTRAL, MEDLINE, Embase, and CINHAL on December
31, 2018, using relevant search terms. Clinical trials registries were searched for ongo-
ing trials and there were no language restrictions.
Selection criteria: We included randomized controlled trials (RCTs) comparing UPA
with placebo/no treatment/any pharmacological intervention for symptomatic
­uterine fibroids.
Data collection and analysis: Two authors independently screened trials, extracted
data, and assessed the risk of bias in included studies. We used risk ratio (RR) for dichot-
omous outcomes and mean difference (MD) for continuous outcomes, plus their 95%
confidence intervals (CIs).
Main results: We identified six RCTs (1121 participants). Five studies (882 participants)
compared UPA with placebo. UPA significantly achieved amenorrhea (RR 24.54; 95%
CI, 10.82–55.64), reduced blood loss, and improved quality of life with insufficient evi-
dence from RCTs for adverse events. There was insufficient evidence for improved out-
comes when UPA was compared with leuprolide acetate.
Conclusion: Compared with placebo, oral UPA significantly induces amenorrhea,
reduces heavy menses, and improves quality-­of-­life in women with uterine fibroids.

KEYWORDS
Amenorrhea; Health-related quality of life; Leiomyoma; Menorrhagia; Systematic review; Ulipristal
acetate; Uterine fibroids

Symptoms usually take the form of excessive menstrual

1 |  INTRODUCTION
Uterine fibroids, also known as leiomyomas or myomas, are the most
common benign tumors in adult women, with a global prevalence
ranging between 20% and 77%.1,2 The global burden of disease indi-
cates that nearly 159.5 million women currently have uterine fibroids.3
bleeding. This may cause iron deficiency anemia and adversely
affect quality of life. Other symptoms include pelvic pressure
and subfertility.1,2
The management of uterine fibroids includes watchful waiting,
pharmacological drugs, interventional radiology (uterine artery embo-
lization), and surgical options (myomectomy or hysterectomy). The

Int J Gynecol Obstet 2019; 146: 141–148 © 2019 International Federation of |  141
wileyonlinelibrary.com/journal/ijgo  
Gynecology and Obstetrics
 |
142       Ghonim ET AL.

F I G U R E   1   Analytic framework for ulipristal acetate to improve quality of life in women with uterine fibroids.

choice of surgical procedure is guided by patient age and desire to Figure 1 presents an analytic framework of the effects of UPA on
preserve fertility or avoid hysterectomy. relevant health outcomes of women with uterine fibroids.
Pharmacological drugs include nonhormonal therapies (i.e. nonste-
roidal anti-­inflammatory drugs, antifibrinolytics such as tranexamic acid)
or hormonal therapies (i.e. gonadotropin-­releasing hormone agonists,
aromatase inhibitors, selective progesterone receptor modulators).2
Ulipristal acetate (UPA), a selective progesterone receptor modu-
lator, is a relatively pure progesterone antagonist. UPA (also known as
CDB 2914, HRP 2000, RTI 3021-­012, VA2914, and PGL4001) exerts
antiproliferative and apoptotic effects, downregulates growth factors,
reduces collagen synthesis, and produces unique, benign, and revers-
ible changes to the endometrium.4–8
An ideal pharmacological intervention for symptomatic fibroids
would reduce fibroid size and improve menorrhagia, anemia,
and quality of life without adversely affecting fertility or causing
adverse events. New evidence has emerged from recent large
randomized controlled trials (RCTs)9,10 and new pharmacovigi-
lance review of safety.11 This highlights the need for an updated
systematic review assessing the benefits and harms of UPA to
treat women with uterine fibroids, adhering to the PRISMA state-
ment, comprehensively searching all relevant databases, properly
assessing risk of bias in individual trials, and properly developing a
GRADE evidence profile.
The aim of the present review was to assess the benefits and
harms of UPA compared with no intervention, placebo, or any active
pharmacological intervention to treat women with uterine fibroids to
improve patient-­related outcomes.

2 |  MATERIALS AND METHODS

We conducted this systematic review based on a prospectively

prepared protocol. We reported the full review using the Preferred
Reporting Items for Systematic reviews and Meta-­Analyses (PRISMA)
standards.12 The protocol was registered on PROSPERO (interna-
tional prospective register of systematic reviews) with the registration
number CRD42018104885. F I G U R E   2   Study flow diagram.
T A B L E   1   Characteristics of included studies.

Study Sample Duration of

(ACRONYM) Country Study design Trial registration size Age, y Ethnicity Uterine fibroids Trial arms treatment Outcomes reported
Ghonim ET AL.

Donnez 201216 Czech Randomized, NCT00755755 242 18–50 White, Asian At least one Once-­daily oral UPA 13 wk Uterine bleeding at week 13,
(PEARL I) Republic, placebo-­ myoma of ≥3 cm 10 mg vs UPA 5 mg defined as a PBAC score
Hungary, controlled, superi- diameter vs placebo. The (summed over the preceding
India, ority clinical trial 3 arms received 28-­d period) of less than 75,
Romania, concomitant oral total fibroid volume by MRI,
Russian 80 mg iron amenorrhea, hemoglobin,
Federation, hematocrit, and ferritin levels;
Ukraine pain, QOL, AE
Donnez Austria, Randomized, NCT00740831 307 18–50 Black, White, At least one UPA 5 mg (oral tab- 13 wk Uterine bleeding at week 13,
2012b17 Belgium, active-­controlled, Other myoma of ≥3 cm lets) and leuprorelin defined as a PBAC score
(PEARL II) France, noninferiority diameter matching placebo (summed over the preceding
Germany, clinical trial (IMI) vs UPA 10 mg 28-­d period) of less than 75,
Israel, Italy, (oral tablets) and fibroid and uterine volume by
Netherlands, leuprorelin matching ultrasonography, pain, USF
Poland, placebo (IMI) vs symptom-­severity score and
Spain UPA matching pla- a health-­related quality-­of-­
cebo (oral tablets) life score, Hemoglobin levels,
and leuprorelin hematocrit, and ferritin levels,
3.75 mg (IMI) AE
Levens 200819 USA Randomized, NCT00290251 22 25–50 Black, White More than 2 cm in Once-­daily oral UPA Three Leiomyoma volume by MRI,
placebo-­ diameter by MRI 20 mg vs UPA menstrual leiomyoma-­related symptoms,
controlled, superi- 10 mg vs placebo cycles or hemoglobin and hematocrit,
ority clinical trial 90–102 d if UFS-­QOL, AE
amenorrheic
Liu 20179 USA, Canada Crossover rand- NCT02147158 432 18–50 Black, ≥1 discrete uterine Once-­daily oral UPA 12 wk Amenorrhea, time to amenor-
(VENUS II) omized, placebo-­ Non-­black fibroid of any 10 mg vs UPA 5 mg rhea, control of heavy menses,
controlled, size and location vs placebo UFS-­QOL, AE
superiority clinical by transvaginal
trial ultrasound
Nieman 201118 USA Randomized, NCT00290251 42 25–50 Black, More than 2 cm in Once-­daily oral UPA Three Fibroid MRI volume,
placebo-­ Hispanic, diameter by MRI 20 mg vs UPA menstrual Amenorrhea, UFS-­QOL, CBC,
controlled, superi- White 10 mg vs placebo cycles or liver functions and acute care
ority clinical trial 90–102 d if panel, AE
amenorrheic.
Simon 201810 USA Randomized, NCT02147197 157 18–50 Black, A minimum of one Once-­daily oral UPA 12 wk Amenorrhea, time to amenor-
(VENUS I) placebo-­ Hispanic, discrete leiomy- 10 mg vs UPA 5 mg rhea during treatment, control
controlled, superi- White, oma observable vs placebo of heavy menses, total volume
ority clinical trial Asian, Native by transvaginal of the three largest leiomyo-
American or ultrasound mas, UFS-­QOL, health-­related
Alaska native quality of life total score,
endometrial thickness, AE
|

Abbreviations: AE, adverse events; CBC, complete blood count; MRI, magnetic resonance imaging; PBAC, pictorial blood assessment chart; UFS-­QOL, Uterine Fibroid Symptom and Quality of Life assessment;
      143

UPA, ulipristal acetate.

 |
144       Ghonim ET AL.
F I G U R E   3   Risk of bias graph: review authors’ judgements about each risk of bias item presented as percentages across all included studies.
Eligibility criteria for the study were women of reproductive
age with symptomatic uterine fibroids, and the intervention of oral
UPA of all dose regimens and duration of use compared with inter-
vention, placebo, or any active pharmacological intervention. Only
RCTs were included.
Amenorrhea was classed as the primary outcome. Secondary out-
comes included Uterine Fibroid Symptom and Quality of Life (UFS-­
QOL) assessment: symptom severity, control of heavy menstrual
blood loss, and adverse events including endometrial changes. The
length of follow-­up was up to 13 weeks.
We searched the following databases for RCTs on December 31,
2018: Cochrane Central Register of Controlled Trials (CENTRAL),
MEDLINE, Embase, and CINHAL. We also searched ClinicalTrials.gov
and the WHO International Clinical Trials Registry Platform (ICTRP).
We hand-­searched the reference lists of identified studies and previ-
ously published reviews and no language restrictions were employed.
The full search strategy is given in supplementary information Data S1.
We included RCTs in which women with uterine fibroids were
randomly allocated to receive oral UPA or placebo/no treatment/any
active pharmacological intervention. We did not include studies that
limited the comparison to different doses or regimens of UPA.
Two authors independently screened all titles and abstracts for
eligibility. Studies marked for possible inclusion by either reviewer
underwent full-­text review. For studies without adequate information
to determine inclusion or exclusion, the full text was retrieved for fur-
ther assessment. We retrieved and assessed the full text of all studies
that potentially met our eligibility criteria during the screening phase.
Two authors independently assessed each full-­text article based on
the eligibility criteria described above. Disagreements regarding trial
eligibility were resolved by discussion and consensus.
For eligible studies, MG, RM, MS, and MG extracted the duplicate
data using an offline electronic form. Discrepancies were resolved
through discussion or consulting another author (AN). Data were
entered in Review Manager (RevMan) version 5.313 and checked for
accuracy. When information was unclear, the authors of the original
reports were contacted to provide further details.
Details of the study design, participants, intervention and compar-
ators, outcomes, trial registration, and funding sources were extracted.
The risk of bias was assessed using the criteria outlined in the
Cochrane tool.14 Seven domains related to risk of bias were assessed
in each included trial: (1) random sequence generation; (2) allocation
concealment; (3) blinding of participants and personnel; (4) blinding
of outcome assessment; (5) incomplete outcome data; (6) selective
reporting; and (7) other bias. The judgements of the review authors
were categorized as “low,” “high,” or “unclear” risk of bias (detailed
in supplementary information Data S2). Two authors independently
assessed the risk of bias in each trial. Any differences of opinion
regarding assessment of risk of bias were resolved by discussion.
Statistical analysis was performed using RevMan version 5.3.13 The
analysis was based on an intention-­to-­treat principle and included all
randomized women. When trials included multi-­arm interventions, we
combined arms utilizing the same intervention. For crossover trials we
used the data from the first course. For dichotomous data, we presented
results as summary risk ratio (RR) with 95% confidence intervals (CI). For
continuous data, we used the mean difference (MD) with 95% CI.
We used fixed-­effects meta-­analysis for combining data where it is
reasonable to assume that studies are estimating the same underlying
treatment effect, i.e. where trials are examining the same intervention,
and the trials’ populations and methods are judged sufficiently similar.
If we detected substantial statistical heterogeneity (I² statistic ≥50% or
P<0.1), we used random-­effects meta-­analysis to produce an overall
summary if an average treatment effect across trials was considered
clinically meaningful. We presented the random-­effects summary as
the average range of possible treatment effects and presented the
random-­effects estimate with its 95% CI, and the estimates of T² and I².
We investigated reporting biases using funnel plots with visual
assessments for asymmetry, with formal evaluation using Egger's test
as appropriate.
Ghonim ET AL.
F I G U R E   4   Risk of bias summary: review authors’ judgements
about each risk of bias item for each included study. Color Key: Low
risk of bias, + ; Unclear risk of bias, – ; High risk of Bias, ? .
We investigated substantial heterogeneity (I² statistic ≥50% or
P<0.1) by checking the data for accuracy using subgroup analyses or
sensitivity analyses. We planned to carry out subgroup analysis by eth-
nic group: black versus nonblack women.
Sensitivity analyses were performed to explore the effects of
trial quality by omitting studies rated as high or unclear risk of
bias when considering allocation concealment (selection bias) and
incomplete outcome data (attrition bias). We restricted this to the
primary outcome.
We used GRADE Pro GDT software15 to create the summary of
findings table. We used the GRADE approach to create a summary
of the intervention effect and a measure of quality for outcomes. The
GRADE approach uses five considerations (study limitations, consis-
tency of effect, imprecision, indirectness, and publication bias) to assess
the quality of the body of evidence for each outcome. The evidence
was downgraded from “high quality” by one level for serious (or by two
levels for very serious) limitations in the five mentioned ­considerations.
|
      145
AN made GRADE assessments and the decisions on downgrading. All
other authors checked and approved GRADE assessments.
3 | RESULTS
We identified 374 records through database searches, along with
eight additional reports identified through other resources. After
deduplication, 209 records remained. On the initial screening of the
titles and abstracts, 16 records were identified for retrieval to assess
the full text for eligibility. We excluded two full-­text studies: one study
compared the long-­term use of 5 mg versus 10 mg of UPA, while the
second compared repeated courses of 10 mg UPA followed by either
norethisterone or placebo. We finally included six RCTs (published in
13 reports). Eight ongoing trials were also identified (Fig. 2).
The characteristics of the six included studies are summarized in
Table  1. All studies were RCTs. Four studies were multicenter trials:
two from European centers16,17 and two from North American cen-
ters.9,10 Two single-­site studies were conducted in the USA.18,19
Studies included a total of 1121 participants who were random-
ized to UPA (801 women) versus a comparator (320 women). All stud-
ies included women of reproductive age (ranging from 18 to 50 years),
who had symptomatic fibroids (menorrhagia, pelvic pressure). Three
studies diagnosed uterine fibroids by ultrasonography,9,10,16 and three
by MRI.17–19 The ethnic groups of the participants included white,
black, Asian, and Hispanic.
One study17 compared oral UPA 5 and 10  mg daily versus leupro-
lide acetate 3.75  mg monthly. Five studies compared UPA versus pla-
cebo.9,10,16,18,19 Three studies9,10,16 compared UPA 5 and 10 mg versus
placebo and two studies18,19 compared UPA 10 and 20 mg versus placebo.
All included trials reported our review's primary outcome:
women who achieved amenorrhea. Four trials reported symptom
severity based on the Uterine Fibroid Symptom and Quality of Life
(UFS-­QOL) questionnaire. Two studies were at low risk of bias in
all domains. We graded four studies as having unclear risk in the
allocation concealment domain owing to insufficient detail in their
description of study methods. Risk of bias within studies is depicted
in Figures 3 and 4.
3.1 | Effects of interventions
3.1.1 | UPA versus placebo
Five studies compared UPA with placebo.9,10,16,18,19 Amenorrhea was
reported in five trials (882 participants): RR 24.54 (95% CI, 10.82–
55.64) (Fig.  5). Sensitivity analysis included three trials (824 partici-
pants): RR 26.21 (95% CI, 10.64–64.58). UFS-­QOL symptom severity
was reported in three trials (207 participants): mean difference −23.18
(95% CI, −29.79 to −16.56) (Fig. 6). Control of heavy menstrual blood
loss was reported in three trials (825 participants): RR 12.42 (95% CI,
3.38–45.61). Three trials (830 participants) reported adverse events:
RR 1.18 (95% CI, 0.92–1.51). Hot flushes, headache, nausea, and
 |
146       Ghonim ET AL.
F I G U R E   5   Forest plot of comparison: 1 ulipristal acetate vs placebo, outcome: Amenorrhea.
breast discomfort were the most common adverse events in the UPA
groups. Three trials (614 participants) reported progesterone receptor
modulators associated endometrial changes (PAEC): RR 3.14 (95% CI,
1.10–8.95). None of the studies reported any case of adenocarcinoma
or premalignant lesions of the endometrium. Only five cases of endo-
metrial hyperplasia without atypia occurred, one with UPA 5 mg, three
with UPA 10 mg, and one with UPA 20 mg.
3.1.2 | UPA versus leuprolide acetate
One study (295 women) compared UPA with leuprolide acetate.17
For amenorrhea the relative risk was 1.03 (95% CI, 0.92–1.16). For
UFS-­QOL symptom severity the mean difference was −4.15 (95%
CI, −9.99–1.69). For control of heavy menstrual blood loss, the
relative risk was 1.05 (95% CI, 0.97–1.14). For adverse events the
risk ratio was 0.91 (95% CI, 0.82–1.02). The most common adverse
events were hot flushes and headache. The trial reported one case
of simple hyperplasia without atypia in the group receiving UPA
5  mg. There were no cases of endometrial malignancy. PAEC was
observed in 58% of participants receiving UPA 5 mg, 59% of those
receiving UPA 10 mg, and 12% of those receiving leuprolide acetate.
3.2 | Subgroup analysis
There were not enough trials providing relevant data to conduct the
prespecified subgroup analysis by ethnic group.
3.3 | Sensitivity analysis
We carried out the prespecified analysis to explore the effect of trial
quality assessed by concealment of allocation, high attrition rates, or
F I G U R E   6   Forest plot of comparison: 1 ulipristal acetate vs placebo, outcome: UFS-­QOL symptom severity.
both, with poor‐quality studies excluded from the analyses to assess
whether this made any difference to the overall result. When we
removed two trials at high risk of bias for attrition in the comparison of
UPA versus placebo, the results did not change for the primary outcome.
Publication bias was not assessed as there were inadequate
numbers of included trials to properly assess a funnel plot or more
advanced regression-­based assessments.
3.4 | Summary of findings: UPA versus placebo
A summary of findings table was created for the main comparison of
UPA versus placebo for symptomatic uterine fibroids (Table  2). We
found high certainty evidence for amenorrhea and control of heavy
menstrual blood loss, and moderate certainty evidence for improve-
ment in symptom severity and adverse events.
4 | DISCUSSION
Our review synthesized the evidence from six RCTs (1211 participants)
to assess the effectiveness and safety of UPA in women with sympto-
matic fibroids. Results of published trials have shown improvements in
patient-­related outcomes when UPA is compared with placebo. High-­
quality evidence shows that UPA is more effective, compared with
placebo, at inducing amenorrhea in women with symptomatic fibroids.
Moderate-­quality evidence shows that UPA, compared with placebo,
improves symptom severity and decreases menstrual blood loss. At
present, only one RCT with only one active comparator, namely leu-
prolide, has been compared with UPA.
Our literature search was comprehensive; in addition to con-
ducting database searches, we hand-­searched the reference lists of
Ghonim ET AL.       147 |
relevant publications and searched clinical trial databases for ongo-

GRADE Working Group grades of evidence. High certainty: we are very confident that the true effect lies close to that of the estimate of the effect; Moderate certainty: we are moderately confident in the
effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different; Low certainty: our confidence in the effect estimate is limited. The true
effect may be substantially different from the estimate of the effect; Very low certainty: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate
Risk difference with ulipristal

77 more per 1000 (34 fewer

ing trials. We cannot rule out the probability of publication bias since

684 more per 1000 (143

401 more per 1000 (167
the investigators of completed trials have not published the results.

MD 23.18 lower (29.79

lower to 16.56 lower)

more to 2672 more)

more to 930 more)
Subgroup analysis by ethnic group is a caveat owing to a lack of usable
data. The duration of follow-­up needs to be extended in future RCTs

to 218 more)
to assess the long-­term safety of UPA, recurrence of symptoms, and
the need for surgery.

acetate
Two studies were at low risk of bias in all domains. We graded four

The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
studies as having unclear risk in the allocation concealment domain owing
to insufficient detail in their description of study methods. Comparison
of UPA versus placebo yielded high-­quality evidence for our primary out-

The mean UFS-­QOL symptom

Anticipated absolute effects
come. Most of these studies included a relatively small number of par-
ticipants and had statistically significant results. We did not include any
large negative study in this review. The presence of unpublished industry-­

severity was −5.70

Risk with placebo

The total number of participants included in the meta-­analysis is small (less than the number of participants required for a single adequately powered trial).
sponsored studies increases our concern regarding publication bias.

427 per 1000

60 per 1000
17 per 1000
One of the challenges was variable reporting of outcomes in these
studies, particularly the methods of assessing menstrual blood loss
and quality of life parameters. The use of core outcome sets will facili-
tate future reviews and will facilitate future synthesis of evidence.

RR 1.18 (0.92–1.51)
Our findings are consistent with and extend those presented in
a previous review.20 Their meta-­analysis was based on four studies

(10.82–55.64)
Relative effect

(3.38–45.61)
and showed that UPA was associated with improved quality of life

RR 12.42
RR 24.54
(95% CI)
and reduced fibroid size compared with placebo. Our review included
two additional recently published trials. Furthermore, our results
T A B L E   2   Summary of findings: ulipristal acetate compared with placebo for symptomatic uterine fibroids.a

—
are based on a rigorous explicit risk of bias assessment and GRADE
­evidence profile.
The present review focused on UPA, which contrasts with a
evidence (GRADE)b

Cochrane review2 that assessed the effects of all selective progester-

Certainty of the

MODERATEd
MODERATEc
one receptor modulators for uterine fibroids. We focused on analysis
⨁⨁⨁◯

⨁⨁⨁◯
⨁⨁⨁⨁
⨁⨁⨁⨁

of patient-­related outcomes, namely amenorrhea, symptom severity HIGHd

HIGH

quality of life, reduction in heavy menses, and adverse events.

We have moderate-­certainty evidence regarding the undesirable
effects. The reported adverse events included hot flushes, headache,
participants (studies)

breast discomfort, and nausea. None of the included studies reported

Abbreviations: CI, confidence interval; MD, mean difference; RR, risk ratio.

any case of adenocarcinoma or premalignant lesions.

825 (3 RCTs)
882 (5 RCTs)

207 (3 RCTs)

830 (3 RCTs)
Number of

Healthcare providers and women should be aware that on May 31,

2018, the European Medicines Agency (EMA) issued a recommenda-
tion statement regarding the risk of rare but serious liver injury asso-
ciated with the use of UPA.11 This appears to be a rare idiosyncratic
Controlled menstrual blood loss assessed with patient-­

drug-­induced liver injury, with five cases among 765  000 patients
Amenorrhea assessed with patient-­reported follow-

UFS-­QOL symptom severity assessed with patient-­

who have been treated with UPA to date.21 Therefore, EMA has rec-
Adverse events assessed with patient-­reported

ommended certain measures for women with known liver problems:

liver tests before, during, and after stopping treatment, and a card for
reported outcome follow-­up: 12 wk

patients to inform them about the need for liver monitoring and to
There is substantial heterogeneity.

contact their doctor should they develop symptoms of liver injury.11

The present review did not assess repeated courses of UPA.
reported follow-­up: 12 wk

A published RCT demonstrated the efficacy and safety profile

Outcomes follow-­up

of repeated intermittent treatment of symptomatic fibroids with

follow-­up: 12 wk

UPA.22 However, EMA has advised that use of UPA for more than
one treatment course should be restricted to women who are not
­up: 12 wk

eligible for surgery.11

of effect.

Several ongoing clinical trials are examining different regimens of

UPA. Results from these trials may change the estimated size of the
b

d
a

c
 |
148       Ghonim ET AL.
effects, confidence in the effects, and the balance between desirable
and undesirable effects of UPA in our planned updates of this review.
Many of these ongoing trials are comparing UPA with other drugs
rather than with placebo. These results will be of interest, as they will
add to the literature and will inform clinical decision making. We plan
to update this review when new evidence is reported.
In conclusion, evidence suggests that a 3-­month treatment with
oral UPA, compared with placebo, induces amenorrhea, improves
fibroid-­related symptom severity, and controls heavy menstrual
bleeding. There is low-­certainty evidence about undesirable
effects and there is still insufficient evidence regarding UPA versus
­leuprolide acetate.
AUTHOR CONTRI B UTI O N S
All authors contributed jointly to the conception and design of
the review. MG, RM, MS, and MG screened articles for eligibility;
extracted and entered data; assessed risk of bias; and revised the
final draft. AN designed and conducted database searches, revised
the assessment of risk of bias and resolved disagreements; con-
ducted meta-­analyses; created the GRADE summary of findings
table; and wrote the final draft.
ACKNOWLE DG ME NTS
We acknowledge the Egyptian Center for Evidence-­Based Medicine
for providing the electronic data collection form and bibliographic
database access.
CO NFLI CTS OF I NTE RE ST
All authors declare no conflicts of interest.
REFERENCES
1. Fortin C, Flyckt R, Falcone T. Alternatives to hysterectomy: The
burden of fibroids and the quality of life. Best Pract Res Clin Obstet
Gynecol. 2018;46:31–42.
2. Murji A, Whitaker L, Chow TL, Sobel ML. Selective progesterone
receptor modulators (SPRMs) for uterine fibroids. Cochrane Database
Syst Rev. 2017;4:CD010770.
3. GBD 2017 Disease and Injury Incidence and Prevalence Collaborators.
Global, regional, and national incidence, prevalence, and years lived
with disability for 354 diseases and injuries for 195 countries and ter-
ritories, 1990–2017: A systematic analysis for the Global Burden of
Disease Study 2017. Lancet. 2018;392:1789–1858.
4. Croxtall JD. Ulipristal acetate: In uterine fibroids. Drugs.
2012;72:1075–1085.
5. Donnez J, Vázquez F, Tomaszewski J, et  al. Long-­term treatment of
uterine fibroids with ulipristal acetate. Fertil Steril. 2014;101:1565–
73.e1-18.
6. Courtoy GE, Donnez J, Marbaix E, Dolmans M-M. In vivo mechanisms
of uterine myoma volume reduction with ulipristal acetate treatment.
Fertil Steril. 2015;104:426–34.e1.
7. Ferrero S, Vellone VG, Barra F. Pharmacokinetic drug evaluation of uli-
pristal acetate for the treatment of uterine fibroids. Expert Opin Drug
Metab Toxicol. 2018;14:107–116.
8. Xu Q, Ohara N, Liu J, et al. Progesterone receptor modulator CDB-­
2914 induces extracellular matrix metalloproteinase inducer
in cultured human uterine leiomyoma cells. Mol Hum Reprod.
2008;14:181–191.
9. Liu JH, Soper D, Lukes A, et  al. Ulipristal acetate for treatment of
uterine leiomyomas: A randomized controlled trial. Obstet Gynecol.
2018;132:1241–1251.
10. Simon JA, Catherino W, Segars JH, et al. Ulipristal acetate for treat-
ment of symptomatic uterine leiomyomas: A randomized controlled
trial. Obstet Gynecol. 2018;131:431–439.
11. European Medicines Agency. EMA/482522/2018 - Esmya: new mea-
sures to minimise risk of rare but serious liver injury. http://www.
ema.europa.eu/docs/en_GB/docum​ent_libra​ry/Refer​rals_docum​ent/
Esmya_20/Europ​ean_Commi​ssion_final_decis​ion/WC500​253487.
pdf. Accessed August 31, 2018.
12. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items
for systematic reviews and meta-­analyses: The PRISMA statement.
BMJ. 2009;339:b2535.
13. Review Manager (RevMan) [Computer program]. Version 5.3.
Copenhagen: The Nordic Cochrane Centre, The Cochrane
Collaboration; 2014.
14. Higgins JPT, Altman DG, Gøtzsche PC, et  al. The Cochrane
Collaboration's tool for assessing risk of bias in randomised trials.
BMJ. 2011;343.
15. GRADEpro GDT: GRADEpro Guideline Development Tool [Software].
McMaster University, 2015 (developed by Evidence Prime, Inc.).
Available at: gradepro.org; 2015.
16. Donnez J, Tatarchuk TF, Bouchard P, et  al. Ulipristal acetate ver-
sus placebo for fibroid treatment before surgery. N Engl J Med.
2012;366:409–420.
17. Donnez J, Tomaszewski J, Vázquez F, et  al. Ulipristal acetate
versus leuprolide acetate for uterine fibroids. N Engl J Med.
2012;366:421–432.
18. Nieman LK, Blocker W, Nansel T, et  al. Efficacy and tolerability of
CDB-­2914 treatment for symptomatic uterine fibroids: A random-
ized, double-­blind, placebo-­controlled, phase IIb study. Fertil Steril.
2011;95:767–72.e1-2.
19. Levens ED, Potlog-Nahari C, Armstrong AY, et al. CDB-­2914 for uter-
ine leiomyomata treatment: A randomized controlled trial. Obstet
Gynecol. 2008;111:1129–1136.
20. Kalampokas T, Kamath M, Boutas I, Kalampokas E. Ulipristal acetate
for uterine fibroids: A systematic review and meta-­analysis. Gynecol
Endocrinol. 2016;32:91–96.
21. Donnez J. Liver injury and ulipristal acetate: An overstated tragedy?
Fertil Steril. 2018;110:593–595.
22. Donnez J, Donnez O, Matule D, et al. Long-­term medical management
of uterine fibroids with ulipristal acetate. Fertil Steril. 2016;105:165–
173.e4.
S U P P O RT I NG I NFO R M AT I O N
Additional supporting information may be found online in the
Supporting Information section at the end of the article.
Data S1. Full search strategy.
Data S2. Assessment of risk of bias in included studies.