Post on 22-Aug-2014
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PROGESTERONE FOR LPS: META-ANALYSIS AND COST BENEFIT ANALYSIS
Hesham Al-Inany, M.D, PhD
OUTLINE OF THIS TALK What is the problem? How to deliver solid evidence if available Different modalities for LPS Vaginal capsules vs gel Conclusion
LUTEAL PHASE IN ART CYCLES Iatrogenic luteal phase defect
due to supraphysiological steroid levels in stimulated cycles
Fatemi et al. Hum Reprod Update. 2007
QUESTIONS TO BE ANSWERED What is the best strategy for LPS Is combined strategy more effective How to choose between different
modalities :-(Safety, Effectiveness /
convenience/ cost)
OUTLINE OF THIS TALK What is the problem? How to deliver solid answer for these
questions? Different modalities for LPS Vaginal capsules vs gel Comments Conclusion
THE BEST EVIDENCE FOR DIFFERENT TYPES OF QUESTION
Level Treatment Prognosis Diagnosis
I Systematic Review of …
Systematic Review of …
Systematic Review of …
II Randomised trial
Cohort studies
Cross sectional
III
7WHY RCTS?
ParticipantsR
a n
d o
m l
y
A s
s i
g n
e d
Intervention Group
Control Group
Follow-up
Follow-up
Intervention Group
Control Group
ADVANTAGES OF SR Larger numbers & power Critical appraisal of studies
THE USE OF PROGESTERONE IN IVF
Nosarka et al. 2005.
Cochrane Review 2011
Pregnancy rates are significantly reduced in ovarian stimulation without luteal phase support
DOES THE PROTOCOL AFFECT??? Both agonists & Antagonists protocols require
luteal phase support (Kahraman et al, 2010)
OUTLINE OF THIS TALK What is the problem? How to deliver solid evidence if available Different modalities for LPS Vaginal capsules vs gel Conclusion
ELEMENTS OF LUTEAL PHASE SUPPORT HCG: 1500-2000 IU i.m. q3d for 4 doses from
oocyte retrieval P4: from oocyte retrieval to 7-10 weeks
1) Progesterone in oil 25-100 mg i.m. qd
2) Utrogestan® 200 mg p.o. or vag. tid 3) Crinone® gel 90 mg vag. aod or bid
Combined strategyhCG + P4E2 + P4Prednisolone + P4
PRITTS, 2002
– hCG versus no treatment: significantly better
– IM and vaginal progesterone and versus no treatment: significantly better
– hCG = vaginal and IM progesterone
BUT increased risk of OHSS associated with hCG use!
A SYSTEMATIC REVIEW: P+E2 VS. P (GELBAYA ET AL, 2008)
PROGESTERONE PLUS PREDNISOLONE & LOW DOSE ASPIRIN
No benefit on CPR (Mollo et al,2003, Ezzeldin et al, 2003).
ROLE OF PROGESTERONE
2.0
2.5
3.0
3.5
4.0
4.5
Day 15 Day 16 Day 17 Day 18 Day 19 Day 20
UC Frequency/min
0%
5%
10%
15%
20%
25%
<3.0 3.1-4.0 4.1-5.0 >5.0
(Fanchin et al, 1998)(De Ziegler et al, 1996)
Impl
anta
tion
Rat
e
UC/min
UC = uterine contractions.
Progesterone in LPS
IM P Oral P Vaginal P
ROUTE
.
AVAILABLE IN THE MARKET Synthetic Natural Micronised Provera - Cyclogest - Utrogestan
caps Depo-provera - Utrogest caps Norplant - Prontogest -
Progestan caps Megestrol acetate - Ellios
caps Nomegestrol acetate - Endometrin
tab Northinderone - Crinone 8%
gel Duphaston
IM PROGESTERONE Effective Painful (long, thick needles) Occasional sterile abscess Occasional allergic reaction (oil vehicle)* Needs to be administered by nurse, husband Acute eosinophilic pneumonia associated with IM administration
of progesterone as luteal phase support after IVF: 5 case reports
* Bouckaert et al. Human Reproduction 2004; 19(8), 1806-1810
ENDOMETRIAL DIFFUSION: TARGETED DELIVERYMICRONISED VAGINAL PROGESTERONE
Four hours after application
Bulletti et al. Hum Reprod. 1997;12:1073.
Progressive diffusion of progesterone from the cervix to the fundus of the uterus
One hour after application
OUR SR: Vaginal vs. IM progesterone - CPR
Vaginal vs. IM progesterone – Ongoing pregnancy rate
Vaginal vs. IM progesterone – Live birth rate
IN OOCYTE DONATION RECIPIENTS vaginal progesterone showed better results
than intramuscular injection The study was small and retrospective
• Berger BM, Phillips JA., 2012
VAGINAL P4: 65% OF THE USE
http://www.ivf-worldwide.com/survey/survey-progesterone-results.html , August 2009
ORAL PROGESTERONE the convenience of oral administration is
attractive, However, the first-pass hepatic metabolism
after oral administration requires higher doses
The clinical efficacy of oral progesterone has been debated
The vaginal administration of P results in a greater bioavailability with less relative variability than oral P (Levine & Watson, 2000).
Vaginal vs. oral progesterone - Clinical pregnancy rate
Vaginal vs. oral progesterone – Ongoing pregnancy rate
OUR SR
Statistically significant retarded endometrial development (“out phase endometrium”) in artificial
cycles treated with oral dydrogesterone has been reported in several studies
Pellicer et al, 1989; Li et al, 1994, Fatemi et al, 2007
DGSide effects
SedationDrowsiness
DG can not be given vaginal
ORAL DG VS MICRONISED PROGESTERONE
AUTHORISED BODIES APPROVAL neither Duphaston nor Cyclogest are
approved (worldwide) for Luteal Phase Support indication in ART
Only few trials available for Cyclogest:
OUTLINE OF THIS TALK What is the problem? How to deliver solid evidence if available Different modalities for LPS Vaginal : Capsules vs gel Conclusion
UTEROGESTAN VS CRINONE: LARGEST STUDY
Ganesh et al, Fertil Steril 2011
Our SR : Vaginal progesterone vs. Crinone 8% gel - Clinical pregnancy rate
Vaginal progesterone vs. Crinone 8% gel – Live birth rate
DOSE ?? Sensitivity analysis performed by excluding
one trial in which vaginal P gel was administered twice instead of once on a daily basis did not reveal any difference (OR 1.30, 95% CI 0.93–1.81; P¼.118).
Our meta-analysis confirm previous findings from other trials that there is no difference in effectiveness between vaginal P gel and vaginal capsules when used in IVF/ICSI cycles
MINOR SIDE EFFECTS
(perineal irritation, leaking out, interference with coitus) may limit the gel in favor of capsules Pezino et al (2004)
HOW TO MAKE DECISION ABOUT DRUG
Crinone vs
Uterogestan
Utrogestan® (200mg/caps) 400-600 mg/day 0.96 - 1.44€/dayEndometrin® (100 mg tablet) 200-300 mg/day 8.86 – 13.29€/dayCrinone® (8% vaginal gel) 90-180 mg/day 3.83 - 7.66€/day
i.eGel is at least 4 times more expensive than Capsules
4 € x 2weeks of LPS = ~65€ differenceIf repeated 3 cycles: 195 €
COST
ECONOMIC ANALYSIS IVF/ICSI cycle, there are probabilities- Pregnancy- No pregnancy- Abortion- Repeat trial (usually up to 3 cycles)- Stop trial
EXAMPLE : 1ST CYCLE
Start Cycle
10,000
Ovum PickupNo OHSS
Ovum PickupOHSS
9810
190
Fertilization& Transfer
No Oocytes
373+7=380
9437+183=9620
ClinicalPregnancy
-ve βHCG
2982
6638
OngoingPregnancy
Miscarriage
405
2577
3246
3392Continue
Stop
Goal!
Therefore, for a cohort of 10,000 individuals the expected, mathematically exact, outcome at the end of the 1st cycle is 380+405+3392 = 4177 patients who will restart the cycle, and 2577 who achieved ongoing pregnancy, and 3246 who gave up on IVF from the first trial
END RESULTS 10,000 cohort women will cost at least
1,400,000€ difference in case of gel over capsule
What would be the impact of such difference??? With crinone: lower number of women
restarting cycle, and higher number of women stopping cycle
With Uterogestan: higher number of women restarting the cycle and lower number of women stopping cycle
WHEN DO YOU START PROGESTERONE?1. Day of hCG
2. Day of OPU
3. Day of ET (day 3)
4. Day of ET (day 5)
Polling Question
HOW LONG SHOULD PROGESTERONE BE ADMINISTERED?
1. Positive hCG
2. Up to 7 wks pregnancy
3. Up to 12 wks pregnancy
4. Up to 34 ws if multiple pregnancy
Polling Question
IN ALL CONDITIONS cost-effectiveness is optimal with Vaginal
progesterone caps regimen (Polyzos et al, 2009)
PATIENT PREFERENCES A recent era of developing patient
preferences studies to evaluate the patient acceptability and satisfaction for a certain modality of treatment ove r the other
Unfortunately, no studies have been done in the field of luteal phase support.
CONCLUSIONS (BY EVIDENCE)
LPS is important in IVF/ICSI cycles hCG better not used in LPS as it increases
OHSS IM progesterone has many side effects Oral progesterone is debatable Micronised progesterone has solid evidence
of effectiveness and convenience Micronised capsules are more cost effective
than progesterone gel