Transcript GnRH antagonists in Assisted Coception

What is a systematic review
 a review strives to comprehensively
identify and track down all the
literature on a given topic
 incorporates a specific statistical
strategy
“Meta-analysis”
for
assembling the results of several
studies into a single estimate”.
Introduction
 Current practice:
 “GnRH agonist long protocol”
 Effective
 Midluteal
GnRH antagonists
 Immediate suppression
 Dramatic reduction in duration
 Lower number of hMG ampoules
If comparable clinical outcome
 These benefits would justify a change
from the standard long protocol of GnRH
agonists to the new GnRH antagonist
regimens.
Objective : Antagonist Vs GnRH-a
Cycle
Day 2-3
Day 6
of FSH
Day of
hCG
FSH
GnRH antagonist
Cycle
Day 21-24
down
regulation
2-4 weeks
Day of
hCG
GnRH agonist
FSH
Search Strategy
 On-line searching of the MEDLINE and
EMBASE databases and the Cochrane
Menstrual
Disorders and Subfertility
Group's Specialized Register from 1982 to
2001, and hand searching of bibliographies of
relevant publications and reviews, and
abstracts of scientific meetings.
Selection criteria
 Only randomized controlled studies
comparing different protocols of GnRH
antagonists with GnRH agonists in
assisted conception cycles were
included in this review
Primary outcomes
 prevention of premature LH surge
 pregnancy rate per woman
Secondary outcomes
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number of oocyte retrieved per cycle
pregnancy rate per oocyte retrieval
pregnancy rate per embryo transfer
spontaneous miscarriage rate
E2 level on day of hCG
Duration of GnRH analogue treatment
Secondary outcomes (cont.)
 Amount of gonadotrophins used
 Incidence of ovarian hyperstimulation
syndrome
 Cost effectiveness as determined by
cost per pregnancy
Description of studies
 Albano 2000
 Olivennes 2000
 The European Orgalutran Study Group
2000
 The North American trial 2001
 The European-middle East Orgalutran
Study Group2001
Regimens used
 A fixed protocol of GnRH antagonist
(GnRH antagonist was given in a fixed day
of the cycle ) was compared to the long
protocol GnRH agonist
 Single high-dose regimen (Olivennes
2000)
 Multiple low-dose regimen (other trials)
Methodological quality
 In general, the quality of the five trials was
high.
 All were multicenter RCTs.
 All trials had parallel design with true
randomisation.
 None of the trials were double blinded
 None of these trials used power
calculation to detect differences in
pregnancy rates
 In all trials, collected data included only
one treatment cycle
 The authors of the trials were contacted
for extra information.
Results
 GnRH antagonist : 1211 subjects
 GnRH agonist: 585 subjects
 Total 1796 subjects
Premature LH surge
 No significant difference between the
GnRH agonist and antagonist in the
prevention of premature LH surge
 OR 1.76 (95%C.I. 0.75-4.16)
 R.R 1.54 (95%C.I. 0.65,3.64)
Clinical Pregnancy per woman
 Pregnancy rate was significantly lower in
the antagonist group
 OR 0.79 (95% C.I.,0.63-0.99)
ATE : 5%
The number needed to treat
NNT : 20
 For
every
20
subfertile
couples
undergoing
IVF/
ICSI
program,ONE
additional successful pregnancy can be
expected in the GnRH agonist treated
group
Subgroup Analysis
 In Ganerilix sponsored trials
OR was 0.78 (0.61, 1.01)
 Excluding Olivennes trial
OR was 0.80 (0.63, 1.01)
ATE and NNT were not different.
Clinical Pregnancy / Oocyte Retrieval
 OR was 0.77 (95% C.I., 0.61-0.96)
in favor of the GnRH agonist long protocol
over the antagonist fixed protocol
Clinical Pregnancy / ET
 OR was 0.76 (95% C.I., 0.60-0.97)
in favor of the long GnRH agonist protocol
over the antagonist fixed protocol.
Spontaneous miscarriage Rate
 OR 1.03 (95% C.I., 0.52,2.04)
Risk difference was 0.00
This result was consistent in the different
subgroup analysis
Multiple pregnancy rate
 OR 0.74 (95% C.I 0.48, 1.16)
 Risk difference (-0.05 C.I –0.14-0.03)
Number of oocytes retrieved
 There was a statistically significant
lower number of oocytes retrieved in the
antagonist protocol.
 OR -1.86 (95% C.I. -2.47 , -1.25)
Incidence of severe OHSS
 RR 0.51 (95% C.I. 0.22, 1.18)
 Risk difference -0.01 (-0.02, 0.00)
OHSS (cont.)
 Exclusion of Olivennes trial
RR 0.56 (95% C.I. 0.22-1.42)
 Ganerilix trials
RR 1.46 (95% C.I. 0.33, 6.41)
Duration of ovarian stimulation
 OR was -1.12 (95% C.I., -1.45, -0.80)
in favor of the fixed antagonist regimen over
the GnRH agonist long protocol
Duration of cycle treatment
Dramatic reduction in the duration of the
cycle in favor of the the antagonist
regimen.
 OR was -20.69
(95% C.I., -21.33, -20.06)
Amount of Gonadotropin Used
 The weighted mean difference in
amount of gonadotrophin used was
-3.34 (95% C.I. -5.2, -1.47 ) ampoules
more for the long protocol compared
to the antagonist protocols
Cost effectiveness
 This outcome could not be estimated as
no available data in the text and no
extra information on this issue could be
obtained. Ideally, cost effectiveness
should be expressed in term of cost /
pregnancy. Then cost of complications
should be added (OHSS , multiple
pregnancy).
Comments
 This is the first prospective metaanalysis on GnRH antagonist and the
first prospective systematic review
in the field of gynecology.
Outcome Summary
 No significant difference in prevention of
LH surge
 Lower number of oocytes retrieved
 Lower pregnancy rate inspite of transfer of
an equal number of embryos
 No significant difference in prevention of
severe OHSS
 The use of a fixed protocol that starts
GnRH administration on a fixed day of the
cycle with a fixed dose should be reevaluated.
 Impact of GnRH antagonist on the
endometrium and subsequent
implantation potential should be
examined.
 Data on women with polycystic ovary
syndrome need to be obtained.
 There was no evaluation of menopausal
symptoms that develop with agonist
administration.
Cycle programming
 Although the antagonists allow short
treatment regimens it causes planning
problems within the centres. To
overcome this practical problem some
advocate the programming of the cycle
with oral contraceptives but this has
an immediate negative effect on the
duration
of
the
treatment!
Implications for Practice
 GnRH
antagonists'
fixed
protocol
facilitates short and simple protocol for
ovarian
stimulation
in
assisted
conception. However, in view of the
available data, there is a small but
statistically significant lower pregnancy
rate
that
necessitates
counseling
subfertile couples before recommending
change from GnRH agonist to antagonist.
Implications for research
 The GnRH antagonist flexible protocol
should be the area of research in the
future
 Cost effectiveness analysis should be
carried out to evaluate the difference
between the two protocols regarding cost
per pregnancy.