Current Thinking in Haemophilia - Prophylaxis Dr Julia Phillips - PowerPoint PPT Presentation

Current Thinking in Haemophilia - Prophylaxis Dr Julia Phillips Wellington, NZ

Acute bleeds in severe haemophilia  Predominantly into joints and muscle  Painful

Chronic musculoskeletal damage  Quality of life is associated with orthopaedic status in people with haemophilia Scalone L. et al Haemophilia 2006;12:154-162

Prophylaxis  “ Regular infusions of factor concentrate given for more than 2 months with the intention of preventing bleeding and the musculoskeletal complications of bleeding ”

Rationale for prophylaxis  People with moderate haemophilia (1-5%) have fewer musculoskeletal complications than people with severe haemophilia (<1%) 1  Converting severe haemophilia to moderate haemophilia with factor replacement would reduce the incidence of musculoskeletal complications 2 1. Ahlberg A. Acta Orthop Scand 1965;77(S):3-132. 2. Nilsson IM et al. J Int Med 1992;232:25-32

Prophylaxis Primary started before the second large joint bleed and before age 3 yrs Secondary started after 2 or more large joint bleeds or after age 3 yrs Tertiary started after the onset of joint disease Intermittent given to prevent bleeding for short periods of time WFH guidelines for the management of hemophilia 2012

Prophylaxis  Severe haemophilia A (and B) - primary - secondary - tertiary  Haemophilia with inhibitors

Primary prophylaxis

Swedish experience  Primary prophylaxis in severe haemophilia since 1958  Start before 1 st joint bleed  Usually age 1-3 yrs Nilsson IM et al. J Intern Med 1992;232:25-32.

Swedish prophylaxis Factor dose Frequency Haemophilia A 25-40 iu/kg iv 3-4 x per week Haemophilia B 25-40 iu/kg iv 2 x a week Nilsson IM et al. J Intern Med 1992;232:25-32.

Swedish experience Age at evaluation 3-6 yr 7-12 yr 13-17 yr 18-23 yr 24-32 yr Number of pts 6 9 20 10 15 Mean age at start of 1.1 1.2 2.6 4.9 7.0 treatment Annual joint bleeds 0.1 0.1 3 5.6 5.0 Orthopaedic joint score 0 0 1.2 2.9 6.6 Radiologic joint score 0 0 4.8 14.2 20.6 Nilsson IM et al. J Intern Med 1992;232:25-32.

Swedish experience After 25 years:-  Full dose prophylaxis (FVIII/IX >1%) was 100% effective in preventing arthropathy  Less than full dose prophylaxis or late prophylaxis did not completely prevent significant arthropathy Nilsson IM et al. J Intern Med 1992;232:25-32.

Joint outcome study  65 boys with severe haemophilia A  Age <30 months  Randomised to primary prophylaxis or ‘ enhanced ’ on demand therapy  Evaluated for bleeding and joint damage at age 6 yrs Manco-Johnson M et al. New England Journal of Medicine 2007;357:535-544

Joint outcome study Prophylaxis  25-40 iu/kg iv alternate days Enhanced on demand  40 iu/kg iv initially, 20 iu/kg iv @ 24 and 72 hrs. Manco-Johnson M et al. New England Journal of Medicine 2007;357:535-544

Joint outcome study  Significantly fewer joint and overall bleeding episodes were seen in prophylaxis group (p<0.001 for both) Manco-Johnson M et al. New England Journal of Medicine 2007;357:535-544

Joint outcome study Proportion of subjects with no MRI evidence of joint damage at age 6yrs:-  prophylaxis arm – 93%  episodic arm – 55% P = 0.002 Manco-Johnson M et al. New England Journal of Medicine 2007;357:535-544

JOS - Conclusions  Prophylaxis is superior to enhanced episodic therapy in preventing bleeding and joint disease in young boys with haemophilia A Manco-Johnson M et al. New England Journal of Medicine 2007;357:535-544

Intracranial haemorrhage  Nested case control study  Prrescribed prophylaxis was associated with a 50% reduction in ICH Witmer C et al. Br J Haem 2011;152(2):211-216

Educational achievement  131 children with haemophilia treated at various US centres on demand or on prophylaxis  Those with less than 12 bleeds in the year before enrolment had significantly greater scores on mathematics, reading and overall achievement Shapiro AD et al. Pediatrics 2001;108:e105

Benefits of prophylaxis  Decreases bleeding episodes, haemophilic arthropathy, longterm morbidity 1-3  Reduces emergency room visits and hospitalisations 3  Improves capacity for physical activity, school attendance and academic performance 1,4  Improves quality of life 3  Enables people to live more normal lives 1 1. Thornburg CD. Pipe SW. Hemophilia 2006:12:198-94. 2. Manco-Johnson MJ et al. NEJM 2007;357:535-544 3. Panicker J et al. Hemophilia 2003;9:272-278 Shapiro AD et al. Pediatrics 2001;108:e105. 4.

Does early prophylaxis increase inhibitor formation? Gouw SC Blood 2007;109:4648-4654

Challenges

Central access?

Factor usage Manco-Johnson M et al. New England Journal of Medicine 2007;357:535-544

Prophylactic approaches in severe haemophilia A FVIII Dose Start Sweden 25-40 iu/kg iv 3-4 x Before first per week joint bleed Dutch 15-30 iu/kg iv 3 x After first joint per week bleed Canada 50 iu/kg iv weekly After first joint escalating to 30 bleed iu/kg iv 2 x per week and 25 iu/kg iv alt days

Canadian vs Swedish 25 boys after 5 yrs on Canadian prophylaxis cf JOS ‘ Swedish ’ prophylaxis  2 x haemarthroses at 1.2 pa  More target joints  All clinically normal joints  Little radiological arthropathy  Osteochondral changes in 50% on MRI Feldman et al. J Thromb Haemost 2006;4(6):1228-1236..

What is the optimal prophylactic regimen?

Breakthrough bleeds correlate with time at low FVIII levels Age 1-6 yrs, n = 44 Age 1-6 yrs, n = 44 10-65 yrs n = 99 Collins PW et al. J Thromb Haemost 2009;7:413-20

Pharmacokinetics 1000 iu MW, 1500 iu Friday 1000 iu alternate days 1000 iu MWF + 500 iu Sunday 500 iu daily P Collins

PK – Individual variation Half life = approx 15 hrs Half-life = approx 6.5 hrs 2.5 2.5 2 2 Log FVIII level log FVIII level (%) 1.5 1.5 1 1 0.5 0.5 0 0 0 5 10 15 20 25 30 0 10 20 30 40 50 60 Hours after infusion Hours after infusion Recovery = 122% Recovery = 140%

Population PK Bjorkman S et al. Blood 2012;119(2):612-618.

Does prophylaxis need to be personalised?

Bleeding in relation to baseline FVIII levels Den Uijl I et al Haemophilia 2011;17:41-4

Subclinical bleeding

Is a 1% trough level the right target?

Duration of primary prophylaxis  European survey  92/218 (42%) discontinued prophylaxis in adolescence  26/92 (28%) restarted Richards M et al. Haemophilia 2007;13:473-479.

“ Prophylaxis in haemophilia should be lifelong ” M Makris. Blood Transfusion 2012;10(2):165- 8.

Secondary prophylaxis WFH “ Regular continuous treatment started after 2 or more large joint bleeds but before the onset of joint disease. ”

ESPRIT  40 boys median age 48-50 months,  no clinical or radiographic evidence of arthropathy  25 iu/kg FVIII iv x 3 per week adjusted up for bleeding or to achieve trough level of 1%, up to 40 iu/kg vs on demand Gringeri A et al. J Thromb Haemost 2011;9(4):700-710

ESPRIT Prophylaxis group had:-  Fewer bleeds  Fewer joint bleeds  Less radiographc evidence of arthropathy  Significantly better QOL Gringeri A et al. J Thromb Haemost 2011;9(4):700-710

Prophylaxis in resource poor environment  66 patients with severe haemophilia A  Secondary prophylaxis  FVIII 10 iu/kg x 2 per week Tang L et al. Haemophilia 2013;19:27-34.

Prophylaxis in resource poor environment  Bleeding significantly reduced - 79% less joint bleeding (p<0.01) - 69% less severe bleeding (p<0.01)  No increase in factor consumption compared to on-demand management. Tang L et al. Haemophilia 2013;19:27-34.

Tertiary prophylaxis WFH “ Regular continuous treatment started after the onset of joint disease to prevent further damage. ”

Orthopedic outcome study  673 people  Severe haemophilia A with established joint disease  +/- Prophylaxis  Observed for 6 yrs Prophylaxis group suffered less progression of arthopathy clinically and radiologically Aledort LM et al. J Int Med 1994;236:391-399.

SPINART  84 subjects, aged 12-50 yrs.  Severe haemophilia A  Randomized study  Prophylaxis 25-35 iu/kg iv x 3/week  Compared to on-demand  Interim analysis shows 93% reduction in bleeding  Final report will also address joint damage and QOL Manco-Johnson M et al. J Thromb Haemost 2013;11(6):1119-1127

UK tertiary prophylaxis study  20 men with severe haemophilia A, aged 30-45 yrs  6 months on demand compared with 6 months prophylaxis (crossover)  Median number haemarthroses reduced from 15 (range 11-26) to 0 (range 0-3). Collins P. J Thromb Haemost 2010;8:83-89.

UK tertiary prophylaxis study  On standard prophylaxis median trough FVIII levels were 6.0 % at 48 hrs and 4% at 72 hrs  Adults may not need as high doses as children for prophylaxis Collins P. J Thromb Haemost 2010;8:83-89.

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