Upload
kika161
View
220
Download
0
Embed Size (px)
Citation preview
8/7/2019 Clin Endocrinol 2009.70(2).p.311-21
1/12
Clinical Endocrinology (2009) 70, 311321 doi: 10.1111/j.1365-2265.2008.03369.x
2009 The AuthorsJournal compilation 2009 Blackwell Publishing Ltd 311
O R I G I N A L A R T I C L E
BlackwellPublishingLtd
Clomiphene citrate, metformin or both as first-step approach
in treating anovulatory infertility in patients with polycystic
ovary syndrome (PCOS): a systematic review of head-to-head
randomized controlled studies and meta-analysis
Stefano Palomba*, Renato Pasquali, Francesco Orio Jr and John E. Nestler
*Chair of Gynecology & Obstetrics, University Magna Graecia of Catanzaro, Italy,
Chair of Endocrinology, University of
Bologna, Italy,
Endocrinology, Faculty of Exercise Sciences, University Parthenope of Naples, Italy,
Division of Endocrinology
and Metabolism, Virginia Commonwealth University, Richmond, VA, USA
Summary
Background
To date, no systematic review or meta-analysis has been
published of direct head-to-head studies comparing clomiphene
citrate (CC) vs.
metformin, or the combination of both drugs as
first-line therapy in anovulatory polycystic ovary syndrome (PCOS)
patients seeking pregnancy. The aim of the current paper was to
define, if possible, the best evidence-based recommendations regarding
the use of CC and/or metformin as the initial treatment of PCOS
women with anovulatory infertility.
Design
Systematic review and meta-analysis of the head-to-head
randomized controlled trials (RCTs) available in the literature.
Methods
A bibliographic search was performed using the following
bibliographic databases: Medline, EMBASE, Biological Abstracts,
Cochrane Controlled Trials Register and Cochrane Database of
Systematic Reviews. Reference lists of included studies, other
relevant review articles and textbooks were checked for additional
citations of interest.
Results
Four head-to-head RCTs were identified and qualified
for inclusion in the analysis. No difference in fertility improvement
was observed comparing CC with metformin (O
R
= 122, 95% CI
023655, P
= 0815), whereas a significant (
P
8/7/2019 Clin Endocrinol 2009.70(2).p.311-21
2/12
312
S. Palomba et al.
2009 The Authors
Journal compilation 2009 Blackwell Publishing Ltd, Clinical Endocrinology
, 70
, 311321
A previous meta-analysis
11
aimed to evaluate the effect on
live-birth rate of metformin, CC or both drugs in therapy nave
PCOS patients was published. Furthermore, some studies included
in that meta-analysis did not evaluate the live birth rate,
1316
whereas
in others
16,17
metformin pretreatment was scheduled. In addition,
the conclusions on metformin vs.
CC comparison were drawn using
data analysed with a fixed effects models,
17
even if a significant data
heterogeneity was detected in both pregnancy and live-birth rates.
Recently, a RCT
18
comparing CC, metformin or the combinationof both in Asian women with PCOS was published and that data has
not been included in any of the previous meta-analyses.
712
To date, no systematic review or meta-analysis was specifically
aimed to evaluate the reproductive efficacy of CC, metformin, or
the combination of both drugs as first-line therapy in anovulatory
PCOS patients seeking pregnancy using head-to-head comparisons.
Based on these considerations, the aim of the present report was to
search and review systematically all RCTs available in the literature
to define, if possible, the best evidence-based recommendations
regarding the use of these drugs administered alone or in com-
bination as initial treatment of PCOS women with anovulatory
infertility.
Materials and methods
Ethics
No institutional review board approval was required because only
published data were analysed.
Search strategy
A bibliographic search was performed using the following search
terms: anovulation, infertility, polycystic ovary syndrome, PCOS,
sterility; exposure: antiestrogens, clomiphene citrate, insulin-
sensitizing drug, metformin, ovulation induction; and outcome of
interest abortion, adverse events, compliance, live birth, menses,
menstruation, ovulation and pregnancy. To eliminate bias, no
study filter or language limit was applied.
The following bibliographic databases were searched: Medline
(from January 1966 to January 2008), EMBASE (from January
1980 to January 2008), Biological Abstracts, Cochrane Controlled
Trials Register and Cochrane Database of Systematic Reviews.
Reference lists of included studies, other relevant review articles
and textbooks were checked for additional citations of interest.
Titles and abstracts were screened and potential relevant articles
were identified. Bibliographies of review and retrieved studiesalso were searched for candidate articles. Successively, identified
articles were reviewed for inclusion and exclusion criteria.
The search was run every 3 weeks between January 2008 and
March 2008 to identify new articles.
Only RCTs were identified and head-to-head studies were
selected for the analysis. Specifically, retrospective, casecontrol,
nonrandomized and quasi-randomized trials and case reports/series
were excluded. Two independent reviewers, not blinded at any point
to the authors or sources of publication, identified and selected
the RCTs that met the inclusion criteria. Disagreements between the
two reviewers were resolved by discussion and final decision by the
first author (S.P).
Study populations
The population consisted of women with well defined diagnosis
of PCOS based on the presence of chronic oligo-anovulation
and/or clinical/biochemical hyperandrogenism and/or ovarian
morphology on ultrasonography [National Institute of Health(NIH)
19
and the European Society for Human Reproduction and
Embryology/American Society of Reproductive Medicine (ESHRE/
ASRM)
1
] or other not validated criteria and who were treated for
anovulatory infertility.
All selected studies included the following information:
demographic characteristics [specifically, age and body mass index
(BMI)], criteria used to diagnose PCOS (chronic oligo-anovulation,
oligo-amenorrhea, biochemical/clinical hyperandrogenism, polycystic
ovary at ultrasound), dosages and protocols used for administered
drugs, previous treatment(s) for inducing ovulation, presence of
glucose intolerance or diabetes mellitus, exclusion of male or tubal
factors of infertility and/or subfertility.
Interventions
Three different types of interventions were analysed: CC vs.
metformin, CC plus metformin vs.
CC, and CC plus metformin vs.
metformin. All dosages and schedules for CC and metformin admin-
istration are included in the present review.
Endpoints
Our primary end-point was the live birth rate.
20
Secondary end-points
were the rates of ovulation, pregnancy, abortion and discontinuation
for adverse events.
Studies quality
Quality of the included trials was assessed using the Cochrane
guidelines.
21
The following characteristics were assessed for each
study: allocation concealment, blinding, intention-to-treat (ITT)
analysis and follow-up. The allocation concealment was graded
as adequate (A), unclear (B), or inadequate (C) according to criteria
provided by the Cochrane Menstrual Disorders and Subfertility
Group.
22
Blinding was reported as yes/no/not reported for investi-
gators, patients, outcome assessors, or data analysts. The use of ITT
analysis was recorded and coded as yes/no. Finally, the follow-upperiod was also reported.
Statistical analysis
The outcome measures, defined as dichotomous data, were the pro-
portions of patients reporting ovulation, pregnancy, abortion, live
birth and discontinuation for adverse events, respectively. The analysis
of treatment effect was performed on an ITT basis considering
dropouts and missing data as treatment failures and per-protocol
basis considering the results from evaluated patients alone.
8/7/2019 Clin Endocrinol 2009.70(2).p.311-21
3/12
First-step approach for anovulatory PCOS
313
2009 The Authors
Journal compilation 2009 Blackwell Publishing Ltd, Clinical Endocrinology
, 70
, 311321
Results for each study were expressed as OR with 95% CI
and combined for meta-analysis to calculate a pooled estimate of
treatment effect for each outcome across studies.
To measure the heterogeneity (the variation in study outcomes
between studies), we used Cochran Q
-test, which is calculated as the
weighted sum of squared differences among individual study effects
and the pooled effect across studies, with the weights being those
used in the pooling method. A Cochran Q
-test P = 005 represents
statistical homogeneity.
For data with statistical homogeneity, the MantelHaenszel
method was used for calculating the weighted summary OR under
the fixed effects model. On the other hand, the random-effects model
of meta-analysis was used in the presence of unexplained statisticalheterogeneity.
A P
-value < 005 of 95% CI not containing 10 OR was considered
statistically significant.
The statistical analysis was performed by use of StatsDirect
software (release 262, 19 February 2007).
Results
The flow-chart of the study selection according to Quality of Report-
ing of Meta-analyses (QUOROM) guidelines
23
is shown in Fig. 1.
Seven RCTs
1315,18,2426
met the initial eligibility criteria. Given
our primary end-point,
20
three studies
1315
were excluded, as the
treatment effectiveness on live-births was not analysed.
Thus, a total of four RCTs
18,2426
were included and analysed
in the present systematic review. Table 1 summarizes the quality of
the RCTs enclosed.
All four articles
18,2426
were published in the English language
between 2005 and 2008 in international journals of very good
quality, i.e. The Journal of Clinical Endocrinology and Metabolism,
The British Medical Journal, The New England Journal of Medicine
and Fertility and Sterility
, as defined by high impact factors and
their ranking in the Journal Citation Report (JCR). Two studies were
performed in Europe,
24,25
one in the United States (U.S),
26
and onein Asia.
18
The allocation concealment was adequately explained in
all studies. Treatment was blinded to both patients and investigators
in three studies,
2426
whereas in one study
18
neither investigators
nor patients were blinded to the treatments. In only one study,
26
data
analysis followed the ITT principle. Two studies
24,26
had a six-month
follow-up period followed by nine-month extension in pregnant
patients to evaluate live births, whereas only a six-month follow-up
was provided for the other two studies.
18,25
The characteristics of the included populations are summarized
in Table 2. Whereas, the treatments received were shown in Table 3.
Fig. 1 Trial flow chart.
8/7/2019 Clin Endocrinol 2009.70(2).p.311-21
4/12
314
S. Palomba et al.
2009 The Authors
Journal compilation 2009 Blackwell Publishing Ltd, Clinical Endocrinology
, 70
, 311321
Outcomes
The analysis of treatment effect was performed both on an ITT basis
and per-protocol basis, and no difference was detected. Therefore,
only the meta-analyses on a per-protocol are shown.
CCvs.
metformin
Three RCTs evaluated the efficacy of CC vs.
metformin.
18,24,26
Descriptive data
In the study by Palomba et al
.,
24
the cumulative ovulation rate was
similar in women treated with CC or metformin (620%
vs.
840%,
respectively), whereas the pregnancy rate was higher (320% vs.
620%, respectively) and the abortion rate was lower (120% vs.
60%, respectively) in women treated with metformin compared
with those treated with CC. There was no statistical difference in live
births (180% vs.
52%, respectively) in women treated with CC vs.
metformin although a trend (
P = 007) favouring the metformin
group was present.
The subsequent study by Legro et al
.
26
reported markedly different
results. In this study, CC was markedly superior to metformin in
increasing cumulative ovulation rate (751% vs.
553, respectively),
pregnancy (297% vs.
120%, respectively) and live births (225% vs.
72%, respectively). There was no significant difference in abortions
(225% vs.
72%, respectively) between CC and metformin.
Lastly, in the study by Zain et al
.
18
the cumulative ovulation rate
was higher in CC than metformin (590% vs. 237%, respectively),
whereas no differences between groups was reported in pregnancy
(154% vs.
79%, respectively) and live births (154% vs.
79%,
respectively). No abortion was reported in any group.
The rate of discontinuation for adverse events was similar
between treatments in both studies by Palomba et al
.
24
(20% for
each treatment arm) and Legro et al
.
26
(19% vs.
29% for CC
and metformin group, respectively). No drop-out because of
drug-related side-effects was observed in the study by Zain et al
.
18
Meta-analysis
When the data of these studies
18,24,26
were combined, the effect
of metformin did not differ from CC with respect to cumulative
ovulation rate (OR = 155, 95% CI 040599, P
= 0527), pregnancy
rate (OR = 122, 95% CI 023655, P
= 0815), or live birth rate
(OR = 117, 95% CI 016861,P
= 0881) (Fig. 2). However, significant
(
P < 00001) heterogeneity was detected for all three end-points
(Fig. 2).
Similarly, the effect of metformin did not differ from CC with
respect to the rates of abortion (OR = 158, 95% CI 077325,
P
= 0219) or of discontinuation for adverse events (OR = 071,
95% CI 022225, P
= 0765) (Fig. 2). For these two parameters
no significant heterogeneity (
P
= 0219 and 0765, respectively) was
detected (Fig. 2).
Metformin plus CCvs.
CC
Three RCTs evaluated the efficacy of metformin plus CC vs.
CC.
18,25,26
Descriptive data
The combination of metformin plus CC was no more effective
than CC alone in inducing ovulation in the study by Moll et al
.
25
(640% vs. 719%, respectively) and by Zain et al.18
(684% vs. 590%,
respectively), whereas in the study by Legro et al.26
the combination
was significantly (P = 0041) more effective than CC alone (833%
vs. 751%, respectively).
Combination therapy was no better than CC alone with regard
to rates of pregnancy [(396% vs. 456%, respectively) and (383%
vs. 297%, respectively)], abortion [(117% vs. 105%, respectively)
Table 1. Quality assessment of the included RCTs
Study Year of publication Country Allocation concealment Blinding ITT Follow-up
A: Adequate A: Investigators
B: Unclear B: Patients
C: inadequate C: Outcome assessors
Palomba et al.24
2005 Italy A A: Yes No Six cycles plus 9-
B: Yes month extension for
C: Not reported pregnant patients
Moll et al.25
2006 The Netherlands A A: Yes No Six cycles
B: Yes
C: Not reported
Legro et al.26
2007 United States A A: Yes Yes Six cycles plus 9-
B: Yes month extension for
C: Yes pregnant patients
Zain et al.18
2008 Asia A A: No No Six cycles
B: No
C: No
ITT, intention-to-treat; RCTs, randomized controlled trials.
8/7/2019 Clin Endocrinol 2009.70(2).p.311-21
5/12
First-step approach for anovulatory PCOS 315
2009 The Authors
Journal compilation 2009 Blackwell Publishing Ltd, Clinical Endocrinology, 70, 311321
Fig. 2 Comparison CC vs. metformin.
Table2.
Characteristicsoftheincluded
populations
Study
Primaryend-point
Sample(n)
DiagnosisofPCOS
Age(years)
BMI(kg/m2)
Insulinresistance
Previousinfertility
treatments
Exclusionofothercausesforinfertility/sub-fertility
Palombaeta
l.2
4
Pregnancyrate
100
NIHcriteria(1992)
2034