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Prophylaxis in countries with limited resources – can it be done? .. Should it be done?

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  1. Prophylaxis in countries with limited resources – can it be done? .. Should it be done? Dr Manuel Carcao Paediatric Hematologist, Hospital for Sick Children; Associate Professor, University of Toronto

  2. Thanks to (Organizers; the WFH & Bayer) for inviting me to Lebanon Honor to be here in your country

  3. Hemophilia A severe bleeding disorder

  4. Patients not on Prophylaxis = On demand Wed Tues Mon Tues Thurs Fri Sat Sun Mon

  5. Patients not on Prophylaxis = On demand Patient is always at high risk of bleeding Wed Tues Mon Tues Thurs Fri Sat Sun Mon <1% = highest risk of bleeding

  6. Prophylaxis Time at risk of bleeding greatly reduced Protected Protected Protected Tues Wed Mon Thurs Fri Sat Sun Mon <1% 2 days / wk = highest risk of bleeding

  7. Prophylaxis Protected Protected Protected Wed Mon Tues Thurs Fri Sat <1% Sleeping Sleeping Every 3 days = highest risk of bleeding

  8. Prophylaxis Always Protected Wed Mon Tues Thurs Fri Sat <1% Every 2 days = highest risk of bleeding

  9. Hemophilia Without Prophylaxis < 1% 1-5% >5%

  10. Hemophilia Without Prophylaxis Develop joint disease in early childhood < 1% 1-5% >5%

  11. Prophylaxis: Definitions • “Administration of factor on a regular basis to prevent bleeding and to preserve (short & long-term) health” Consensus Conference on Prophylaxis ( London, UK 2002 )

  12. Prophylaxis: Definitions • Primary Prophylaxis started at a very young age( ≤ 2 yr ) prior to development of joint disease • Secondary Prophylaxis commenced at a older age after some joint disease

  13. Prophylaxis: Definitions

  14. Goals of Prophylaxis 1) Prevent acute bleeds

  15. 2) Prevent Limb/Life threatening bleeds Ileopsoas muscle Hip bleed  AVN Intracranial

  16. 3) Prevent development of hemophilic arthropathy

  17. 4) Keep patients with hemophilia healthy and active

  18. Goals of prophylaxis • Developed countries: “Perfect joints” • Developing countries: more modest • Decrease bleeding • Improve quality of life (QoL) • Delay progression of joint disease

  19. Lessons in Prophylaxis • Prophylaxis results in better clinical outcomes • Prophylaxis should ideally start early • Patients have different prophylaxis needs • There are many burdens associated with Prophylaxis • Low and Intermediate dose Prophylaxis is an option

  20. Lessons in Prophylaxis • Prophylaxis results in better clinical outcomes • Prophylaxis should ideally start early • Patients have different prophylaxis needs • There are many burdens associated with Prophylaxis • Low and Intermediate dose Prophylaxis is an option

  21. Benefits of Prophylaxis:↓ bleeding 27 boys with severe hemophilia Median Age (yr) at start of prophylaxis = 6.2 yr HA 15 – 25 U/kg 3/wk HB 15 – 25 U/kg 2/wk 15 (90% less) 1.5 On demand On Prophylaxis Liesner et al. BJH 1996; 92:973 -8

  22. Benefits of Prophylaxis:↓ bleeding Pts with severe hemophilia 90% less 3X more Smith et al: J Pediatr 1996; 129: 424-31.

  23. OR 90% less 90% less 25-40 U/kg every other day = Full dose “Malmo” prophylaxis Manco-Johnson M.J. et al, NEJM, 2007; 357: 535-44

  24. Prophylaxis leads to better joints Prophylaxis On demand (Full dose = Malmö) Patients enrolled by age 2.5 yrs Mean Joint Physical exam score Age Manco-Johnson M.J. et al, NEJM, 2007; 357: 535-44

  25. Prophylaxis leads to better joints Prophylaxis On demand (Full dose = Malmö) Large difference in joint scores after only a few years Patients enrolled by age 2.5 yrs Mean Joint Physical exam score Age Manco-Johnson M.J. et al, NEJM, 2007; 357: 535-44

  26. Prophylaxis leads to other clinical benefits

  27. Lessons in Prophylaxis • Prophylaxis results in better clinical outcomes • Prophylaxis should ideally start early • Patients have different prophylaxis needs • There are many burdens associated with Prophylaxis • Low and Intermediate dose Prophylaxis is an option

  28. Netherlands: 76 men with severe haemophilia A were evaluated at 19 yrs of age Mean Pettersson (Xray) scores at age 19 yrs (n=16) 2 (n=34) 8 (n=26) 11.5 Worse joint disease Fisher et al (Blood, 2002)

  29. Netherlands: 76 men with severe haemophilia A were evaluated at 19 yrs of age Mean Pettersson (Xray) scores Age at starting prophylaxis at age 19 yrs < 4 yrs (n=16) 2 4-7 yrs (n=34) 8 ≥ 8 yrs (n=26) 11.5 Worse joint disease Fisher et al (Blood, 2002)

  30. Sweden: 55 boys with SHA followed for median (11 yrs) from starting prophylaxis All pts received full dose prophylaxis (Ljung, Haemophilia 2002)

  31. Sweden: 55 boys with SHA followed for median (11 yrs) from starting prophylaxis Start Prophylaxis early All pts received full dose prophylaxis (Ljung, Haemophilia 2002)

  32. Lessons in Prophylaxis • Prophylaxis results in better clinical outcomes • Prophylaxis should ideally start early • Patients have different prophylaxis needs • There are many burdens associated with Prophylaxis • Low and Intermediate dose Prophylaxis is an option

  33. Patients are different & have different bleeding predispositions Age at 1st joint bleed Frequency of bleeding Biological differences 2-3 fold Differences in PK Differences in physical activities

  34. Patients are different & have different bleeding predispositions Age at 1st joint bleed Frequency of bleeding Prophylaxis needs may be very different Biological differences 2-3 fold Differences in PK Differences in physical activities

  35. Lessons in Prophylaxis • Prophylaxis results in better clinical outcomes • Prophylaxis should ideally start early • Patients have different prophylaxis needs • There are many burdens associated with Prophylaxis • Low and Intermediate dose Prophylaxis is an option

  36. Benefits vs. “Burdens” of prophylaxis Benefits of Prophylaxis  Burdens of Prophylaxis • Venous access • Cost Many

  37. Cost Prophylaxis is expensive

  38. Costs of prophylaxis vs. on demand change over time Prophylaxis: Cost  Same costs 3 X higher Consumption of factor U / kg On demand: Cost  Age of patient in Years From A. Shapiro

  39. Cost may not rise very much low/intermediate dose prophylaxis On demand switching

  40. 84 boys/adults switched from on demand to prophylaxis (25 U/kg given 2 or 3 X / wk) 90% less 39% more Tagliaferri A et al. Haemophilia 2008; 14:945-51

  41. 84 boys/adults switched from on demand to prophylaxis (25 U/kg given 2 or 3 X / wk) Prophylaxis: Only a bit more expensive than on demand (but much more effective) 90% less 39% more Tagliaferri A et al. Haemophilia 2008; 14:945-51

  42. Lessons in Prophylaxis • Prophylaxis results in better clinical outcomes • Prophylaxis should ideally start early • Patients have different prophylaxis needs • There are many burdens associated with Prophylaxis • Low and Intermediate dose Prophylaxis is an option

  43. Experiences of low / intermediate dose prophylaxis in developing countries C. China B. Iran A. Thailand

  44. A) Thailand • 1 year Pilot study on LOW DOSE prophylaxis in 6 hemophilic boys (ages 11-16; median 12 yr) with severe/moderate hemophilia A • Prophylaxis regimen • 8-10 U/kg 2 X/wk • Plasma derived FVIII concentrate (not specified) Chuansumrit A et al., 1995. 26(2):243-6.

  45. A) Thailand: Results • Bleeds per pt per year • Hospitalization days per pt per year • Cost of prophylaxis was $7,200 US/pt/yr On demand: 11.5 On prophylaxis: 2.3 On demand: 15.8 On prophylaxis: 0 Chuansumrit A et al., 1995. 26(2):243-6.

  46. B) Iran • 6 month Retrospective review of 25 boys (0-9 yrs of age) with severe hemophilia A On INTERMEDIATE DOSE prophylaxis: (15 U/kg 3 X/wk) 11 boys (1 institution) On demand: 14 boys (2 institutions) Daliri et al. Intern J Tech Assess Health Care 2009; 25:584-7.

  47. B) Iran (90% less) 2.5 X more Daliri et al. Intern J Tech Assess Health Care 2009; 25:584-7.

  48. C) China • 34 Children (ages: 3-18) with Severe (n=13 pts) OR Moderate (n=21 pts) Hemophilia A OR B AND established joint disease • Placed on 12 wk LOW DOSE prophylaxis • Doses: • 10 U/kg 2X / wk for hemophilia A • 20 U/kg 1X / wk for hemophilia B ≈1,100 U/kg/yr R. WU et al. Hemophilia 2011.

  49. Results Severe hemophilia (n=13) Moderate hemophilia (n=21) 12 8.6 2.6 0.9 On demand Prophylaxis On demand Prophylaxis 12 wk period 12 wk period 12 wk period 12 wk period

  50. Results • Improvement in joint function Most patients • Reduced school absences On demand: 21 days lost / child On prophylaxis: 1.4 days lost / child R. WU et al. Hemophilia 2011.