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GN: FINAL WORD

Madelon van Wely1, Irene Kwan2, Anna L Burt3, Jane Thomas4, Andy Vail5, Fulco Van der Veen6, Hesham G Al-Inany

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WHY DO WE NEED THIS TALK

To update our knowledge and understanding

To provide evidence for decision-makers To provide our patients with best care

based on Evidence

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BUT

EVIDENCE

IS NOT ALL THE SAME

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EVIDENCE

THE EVIDENCE PYRAMID

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WHY SR ARE ON THE TOP

Rigorous methodology Peer reviewed Relatively large sample size Ensures the highest quality evidence (based

on RCT)

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RCT ANATOMYParticipants

R a

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Intervention Group

Control Group

Follow-up

Follow-up

Intervention Group

Control Group

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IVF/ICSI CYCLES

Multifollicular development is still an integral component for ovarian stimulation in IVF / ICSI cycles (Keck et al, 2005)

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In The Market

VS

rec FSHHuman derived Gn

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HOW TO KNOW

large randomised trial is needed to estimate the difference between human derived Gn and rFSH (van Wely et al., 2003).

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SAMPLE SIZE CALCULATION FOR SUCH RCT For a study to have 80% power to detect a difference

of 5% in ongoing pregnancies (or live births), it will need to randomise over 2400 women (Andersen et al, 2006)

Which is unlikely to happen (huge fund and long duration)

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SO THE SOLUTION

systematic review and meta-analysis of randomised trials comparing the effectiveness of hMG versus rFSH following a long down-regulation protocol in IVF-ICSI cycles

HOWEVER,

 Several systematic reviews and one international Health Technology Assessment report compared rFSH with urinary gonadotrophins (hMG, FSH-P, FSH-HP) Daya 1998; Larizgoitia 2000; Agrawal 2000; Daya 2002;Van Wely 2003;NCC-WCH 2004;Al-Inany 2003; Al-Inany 2008;Coomarisamy 2008).

EXOGENOUS GONADOTROPIN THERAPY

The goal:

EFFECTIVENESS

Meta-analysis :Al-Inany et al, 2005

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hMG (363/ 1453) vs. rFSH (324/ 1484)

(P < 0.04; O.R = 1.20, 95% CI = 1.01 - 1.42)

Al-Inany et al., RBM Online, (2008)

Live birth rate

RECENTLY RELEASED

ONGOING PREGNANCY/ LIVE-BIRTH RATE

Study or Subgroup2.6.1 Fostimon vs. RecFSH

Abate 2009Aboulghar 2009Baker 2008Mohamed 2006Selman 2002Selman 2009Subtotal (95% CI)

Total eventsHeterogeneity: Tau² = 0.00; Chi² = 1.46, df = 5 (P = 0.92); I² = 0%Test for overall effect: Z = 1.22 (P = 0.22)

2.6.2 Metrodin-HP vs. RecFSH

Bergh 1997Franco 2000Frydman 2000Hoomans 1999Hugues 2001Lenton 2000Nardo 2000Righini 1998Schats 2000Subtotal (95% CI)

Total eventsHeterogeneity: Tau² = 0.00; Chi² = 3.35, df = 8 (P = 0.91); I² = 0%Test for overall effect: Z = 1.70 (P = 0.09)

Events

901929195220

229

361625236

204

2043

193

Total

2154276

12813360

654

11660

13985328535

139249940

Events

732029184118

199

402125257

27122056

233

Total

1864276

12913465

632

11960

13984568375

139247

1002

Weight

35.5%7.7%

13.2%11.7%22.1%9.7%

100.0%

16.1%7.9%

12.9%10.8%3.4%

10.4%3.3%

10.7%24.5%

100.0%

M-H, Random, 95% CI

1.11 [0.75, 1.66]0.91 [0.39, 2.14]1.00 [0.52, 1.92]1.07 [0.54, 2.16]1.46 [0.88, 2.42]1.31 [0.61, 2.80]1.16 [0.91, 1.47]

0.89 [0.51, 1.54]0.68 [0.31, 1.47]1.00 [0.54, 1.84]0.88 [0.45, 1.71]1.62 [0.49, 5.31]0.64 [0.32, 1.26]0.68 [0.20, 2.27]1.00 [0.51, 1.95]0.71 [0.46, 1.11]0.83 [0.66, 1.03]

Intervention Control Odds Ratio Odds RatioM-H, Random, 95% CI

0.2 0.5 1 2 5Favours Control Favours Intervention

CONFLICTING RESULTS

Two reviews compared rFSH to urinary FSH and found higher pregnancy rates per cycle started for rFSH (Daya 2002, updated from Daya 1998).

Three reviews compared rFSH versus urinary gonadotrophins (hMG, FSH-P, FSH-HP together) and found no evidence of a difference between these two groups (Larizgoitia 2000;Al-Inany 2003;NCC-WCH 2004).

MOREOVER

Three  reviews compared rFSH with hMG and and reported evidence of a difference in live birth and clinical pregnancy rate per cycle between rFSH and hMG (Van Wely 2002;Al-Inany 2008;Coomarisamy 2008).

CONFOUNDING FACTORS

Firstly, gonadotrophin-releasing hormone (GnRH) agonists and GnRH antagonist are often used in conjunction with gonadotrophins to facilitate cycle control and achieve pituitary down-regulation in ovarian stimulation during assisted reproductive treatment cycles.

INFLUENCE OF PHARMACEUTICAL COMPANIES

Secondly many trials have been performed by pharmaceutical companies and the conflict of interest may have introduced bias.

CRYO EMBRYOS

Thirdly, it is now customary to freeze supernumerary embryos and to transfer frozen/thawed embryos if transfer of fresh embryos has failed.

OBJECTIVES

 To compare the effectiveness of recombinant gonadotrophin (rFSH) with the three main types of urinary-derived gonadotrophins (i.e. hMG, FSH-P and FSH-HP) for ovarian stimulation in women undergoing IVF or ICSI treatment cycles.

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HP-FSH

HP-hMG

hMG

recFSH

Study

It fills in a gap in evidence as recombinant FSH was compared to hMG and to HP-hMG but no one compared hMG to HP-hMG

TYPES OF STUDIES  

Randomised controlled trials only. Quasi-randomised controlled trials, in which

allocation was, for example, by alternation or reference to case record number or to dates of birth, were excluded.

Crossover trials were excluded since the design is not appropriate in this context (Vail 2003)

TYPES OF PARTICIPANTS

 Normogonadotrophic (defined as having normal serum concentration of FSH and LH) women undergoing fresh and/or frozen-thawed IVF or ICSI treatment cycles

PRIMARY OUTCOMES

 Effectiveness:live birth per woman or, if not reported, pregnancy ongoing beyond 20 weeks per woman

Adverse:Rate of severe OHSS per woman

SECONDARY OUTCOMES  

Effectiveness: frozen-thawed embryo transfers

Clinical pregnancy rate

Adverse:Multiple pregnancy rate Miscarriage rate per woman

42 RCTS including 8 abstracts form congress

proceedings) met all selection criteria and were included in the review.

The total number of participants was 9606

RESULTS

There was no evidence of a difference in live birth or pregnancy ongoing beyond 20 weeks (28 trials, N=7339; OR 0.97, 95% CI 0.87 - 1.08) for rFSH versus urinary gonadotrophins.

Meaning 25% live birth rate (22-26% in different centers)

SUBGROUP ANALYSIS: HMG VS RFSH

There were significantly less live births after rFSH as compared to hMG (11 trials, N=3197; OR 0.84, 95% CI 0.72 - 0.99).

This means that for a live birth rate of 25%, use of rFSH instead would be expected to result in a live birth rate between 19% and 25%.

ACCORDING TO DOWNREGULATION

There was no evidence of a difference in live birth between rFSH and urinary gonadotrophins for any of the downregulation protocols

(antagonist protocol, N=280; OR 0.88, 95% CI 0.53 - 1.45),

(long GnRHa protocol, N=6437; OR 0.98, 95% CI 0.87 - 1.10),

(short GnRHa protocol, N=402; OR 0.84, 95% CI 0.54 - 1.31),

(no downregulation, N=220; OR 1.17, 95% CI 0.62 - 2.20)

SEVERE OHSS

There was no evidence of a difference in the primary safety outcome OHSS

(32 trials, N=7740; OR 1.18, 95% CI 0.86 - 1.61).

Typical rate of 2% OHSS

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HOW TO INTERPRET THE FIGURES!

A benefit from recombinant FSH would be displayed graphically to the left of the centre-line.

A benefit from hMG would be displayed graphically to the right of the centre-line

LIVE BIRTH RATE

OHSS

DOWN REGULATION PROTOCOL

FRESH/FROZEN CYCLES

INFLUENCE OF PHARMACEUTICAL COMPANIES

MULTIPLE PREGNANCY

MISCARRIAGE

CONCLUSION

Gonadotrophins are

Gonadotrophins are

Gonadotrophins

ECONOMIC ANALYSIS

IVF/ICSI cycle, there are probabilities- Pregnancy- No pregnancy- Abortion- Repeat trial (usually up to 3 cycles)- Stop trial

EXAMPLE : HMG, 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

3392

Continue

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

MARKOV EV ANALYSIS: RFSH

rFSH: By the end of the 3rd cycle, the individual’s probability of ending at re-starting the cycle is 6.6%, in ongoing pregnancy is 35.9%, and in discontinuing IVF is 57.5 %

% Start Cycle

% Pregnancy

% Stop IVF

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0.2

0.4

0.6

0.8

1

1.2

1 2 3 stop

Cycle

Pro

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MARKOV EV ANALYSIS: HMG

% Start Cycle

% Pregnancy

% Stop IVF

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0.2

0.4

0.6

0.8

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1.2

1 2 3 stop

Cycle

Pro

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hMG: By the end of the 3rd cycle, the individual’s probability of ending at re-starting the cycle is 6%, in ongoing pregnancy is 40.8%, and in discontinuing IVF is 53.2 %

HOW TO MAKE DECISION ABOUT DRUG

THANK YOU

Dr. Hesham Al-Inany MD, PhDe-mail : kaainih@yahoo.com