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!

(Cochrane Rev., 2011)

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.

WHICH TYPE OF PROGESTERONE???

Progesterone in LPS

IM P Oral P Vaginal P

ROUTE

.

COMPOSITION

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

THANK YOU!