GnRH antagonists

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safer drug with similar live birth rates

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  • 06/28/11
  • 06/28/11
  • 06/28/11
  • * *
  • * *
  • 06/28/11
  • IBSA Institut Biochimique SA 28/06/11
  • GnRH antagonists

    1. 1. kasr al ainy school of Medicine Cairo University CHANGING ATTITUDES IN OVARIAN STIMULATION
    2. 2. CHANGING ATTITUDE IS A FACT OF LIFE <ul><li>To improve efficacy : better results: pregnancy </li></ul><ul><li>To improve safety : less complications: OHSS </li></ul>
    3. 3. THE BEST MODEL <ul><li>Breech Trial </li></ul>
    4. 4. WHAT ABOUT GYNECOLOGY <ul><li>HRT: WHI study </li></ul>
    5. 5. IVF <ul><li>Safety comes first </li></ul>
    6. 6. 16 follicles 12 mature oocytes 14 oocytes Extras frozen if good 2 to 3 transferred 9 fertilize normally 5 divide normally 30-40% of couples 4 stop dividing & sperm Typical progression
    7. 7. OHSS is the most serious complication of ovulation induction.
    8. 8. PROTOCOLS FOR IVF GnRH Antagonist Protocols GnRH Agonist Protocols 225 IU per day (150 IU Europe ) Individualized Dosing of FSH/HMG 250 mg per day antagonist Individualized Dosing of FSH/HMG GnRHa 1.0 mg per day up to 21 days 0.5 mg per day of GnRHa 225 IU per day (150 IU Europe ) Day 6 of FSH/HMG Day of hCG Day 1 of FSH/HMG Day 6 of FSH/HMG Day of hCG 7 – 8 days after estimated ovulation Down regulation Day 2 or 3 of menses Day 1 FSH/HMG
    9. 9. SHOULD BE EVIDENCE BASED <ul><li>RCT </li></ul><ul><li>Systematic Reviews </li></ul>
    10. 10. AL-INANY & ABOULGHAR, 2001
    11. 11. AL-INANY ET AL., 2006 <ul><li>O.R = 0.82, 95% CI = 0.68 to 0.97 </li></ul>
    12. 12. AL-INANY ET AL., 2010 <ul><li>45 RCTs </li></ul><ul><li>7532 participants </li></ul><ul><li>Many subgroup analyses: </li></ul><ul><li>- Poor responders </li></ul><ul><li>- PCOS </li></ul><ul><li>- OCP pretreatment </li></ul><ul><li>- LH stability examined </li></ul><ul><li>- Cetrotide vs. ganerilix </li></ul><ul><li>- Fixed vs. flexible protocol </li></ul><ul><li>Conclusion differed </li></ul>
    13. 13. IT IS JUSTIFIED TO <ul><li>Shift from GnRH agonist to GnRH antagonist for IVF/ ICSI cycles </li></ul>
    14. 14. WHY: (AL-INANY ET AL, 2010)
    15. 15. HOW TO EXPLAIN <ul><li>OHSS is an uncommon complication </li></ul><ul><li>Uncommon complications need large number of participants to show if there is a real difference between two drugs </li></ul><ul><li>In our current situation: agonist vs. antagonist </li></ul><ul><li>OHSS in agonist group: 3.74% (84/3165) </li></ul><ul><li>OHSS in antagonist group: 1.91% (149/ 2252) </li></ul>
    16. 16. NUMBER NEEDED TO HARM <ul><li>NNH= 25 (95%CI = 19 to 36) </li></ul><ul><li>This clinically means : for every 25 women underoing downregulation by Agonist , you may expect one more case of severe OHSS </li></ul>
    17. 17. CANCELLATION FOR RISK OF OHSS
    18. 18. CONSIDERING CYCLES CANCELLED FOR RISK OF OHSS <ul><li>Then the difference will more statistically significant if cancellation was not done </li></ul><ul><li>This difference is highly significant both from statistical significance and clinical significance </li></ul>
    19. 19. <ul><li>So we may say confidently that GnRH antagonist is safer than GnRH agonist in IVF/ ICSI cycles </li></ul>
    20. 20. LIVE BIRTH RATE
    21. 21. CPR
    22. 22. MISCARRIAGE RATE
    23. 23. IN FAVOR OF ANTAGONIST <ul><li>much shorter duration of GnRH analogue treatment (OR -20.90, 95% CI -22.20 to -19.60) </li></ul><ul><li>less days of stimulation (OR -1.54, 95% CI -2.42 to -0.66). </li></ul><ul><li>reduction in the amount of gonadotrophins (OR -4.27, 95% CI -10.19 to 1.65) </li></ul>
    24. 24. 3. 0 ampoules less with GnRH antagonists p<0.0 7 FSH requirement
    25. 25. 1. 1 less days with antagonists p<0.001 Duration of FSH treatment
    26. 26. HOW TO EXPLAIN IMPROVED EFFICACY <ul><li>LH-instability incidence per woman randomised: defined as any fluctuation in LH-level, either a LH-surge or rise in LH-concentration as defined by the study protocol </li></ul>
    27. 27. LH STABILITY: AGONIST VS. ANATGONIST
    28. 28. FIXED DOSE PROTOCOL
    29. 29. Flexible antagonist stimulation
    30. 30. Meta-analysis of clinical pregnancy rate in fixed and flexible protocols for GnRH antagonist protocols Al-Inany et al. 2005
    31. 31. FURTHER ANALYSIS <ul><li>LH instability is more reported in studies using flexible antagonist protocol </li></ul><ul><li>Al-Inany et al, 2005 showed fixed protocol achieve better results than flexible </li></ul><ul><li>Clinicians tend to use fixed protocol more now </li></ul><ul><li>Thus better LH stability </li></ul>
    32. 32. SO OUR CONCLUSION: <ul><li>There are no significant differences in the efficacy of GnRH antagonist and long agonist protocols with a significant reduction in the incidence of severe OHSS with the antagonist. </li></ul>
    33. 33. BUT NOT ALL DOCTORS WOULD GO FOR ANTAGONIST
    34. 34. (GNRH) ANTAGONISTS: OFF LABEL INDICATION <ul><li>unique Idea </li></ul><ul><li>Administration during GnRH agonist cycle </li></ul><ul><li>when follicle reach ~16mm and E2 level > 4000pmol </li></ul><ul><li>Decrease but Continue hMG (step down protocol) </li></ul><ul><li>Monitor by E2 </li></ul><ul><li>Not more than 3 days </li></ul>
    35. 35. VALUE <ul><li>allow continued stimulation while rapidly decreasing the E2 level to a range that is clinically acceptable. </li></ul>
    36. 37. OUR RESULTS Parameter Coasting (n = 96) Antagonist (n = 94) P-value Age (years) 30.0 ± 4.9 29.6 ± 4.6 NS Duration of infertility (years) 6.64 ± 4.45 7.07 ± 4.3 NS No. of HMG injections 30.52 ± 8.9 29.94 ± 8.8 NS Days of stimulation 1 9.1 ± 1.5 9.4 ± 1.5 NS Peak oestradiol (pg/ml) 5087 ± 1589 5305 ± 1680 NS Oestradiol on day of HCG (pg/ml) 2605 ± 790 2721 ± 699 NS Range of oestradiol on day of HCG (pg/ml) 1110–4136 1223–4093 NS Day of intervention 2.82 ± 0.97 1.74 ± 0.91 <0.0001 No. of oocytes 14.06 ± 5.20 16.5 ± 7.60 0.02 No. of MII oocytes 11.13 ± 4.60 13.14 ± 6.60 NS No. of fertilized oocytes   7.97 ± 3.80   9.14 ± 4.70 NS No. of high quality embryos   2.21 ± 1.10   2.87 ± 1.20 0.0001 No. of embryos transferred   2.83 ± 0.50   2.79 ± 0.40 NS No. of cryopreserved embryos   4.50 ± 3.93   5.77 ± 4.87 NS Clinical pregnancy (%) 46/96 (47.9) 52/94 (55.3) NS Multiple pregnancy (%) 15/46 (32.6) 17/52 (32.7) NS
    37. 38. THE FUTURE <ul><li>Simplifying IVF procedure </li></ul><ul><li>ELONVA </li></ul>
    38. 39. JUST A QUESTION <ul><li>Would u change ur protocol from agonist to antagonist?? </li></ul>
    39. 40. SIMPLE, SHORTER SAFER
    40. 41. WHY CHANGING ATTITUDE <ul><li>For Tomorrow Better </li></ul><ul><li>Health </li></ul>
    41. 42. THANK YOU Dr. Hesham Al-Inany MD, PhD e-mail : hesham@khosoba.com

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