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Presentation title
The need for rapid bleed
controlPeter Noun, MD
Chief Department of Paediatrics
Haematology-oncologyLebanese Hospital, Geitawi
Tyr, July 31st 2010
Haemophilia facts
• Worldwide incidence of Haemophilia A is 1 in every 5,000 men (haemophilia B is 5 times less common)1
About half million cases world wide
• Hemophilia is underdiagnosed2 and undertreated3
• (e.g. Diagnostic rate: South Africa 52%, India 12%..) 2
• 75% receive no treatment3
• If untreated, hemophilia is associated with a high mortality and morbidity
• Premature death- around 13 years of age4 but now, emerging problem of aging hemophilia population in the developed world5
• Arthropathy with crippling pain and motor dysfunction1
• Exposure to blood-born viruses with plasma-derived products1
1.World Federation of Hemophilia Guidelines 2005. 2. WFH Global survey, 2002. 3.Isarangkura P. Haemophilia 2002 . 4. Evatt BL et al. Haemophilia 2000.
5. WFH Congress Newsletter, 2010. 6.
Inhibitors-the greatest hemophilia complication in the 21st century
• Inhibitors are neutralising antibodies of factors VIII (FVIII) or IX (FIX) which make clotting factor replacement ineffective
• Typically, inhibitors develop in early childhood within 10–20 exposure days to FVIII or FIX1
• 20%–50% of people with hemophilia develop inhibitors2
• usually transient and of little clinical significance3,4
• persist in approximately 20% of people with hemophilia A and 1% of people with hemophilia B3,4.
• Inhibitor patients do not bleed more frequently5 but bleeding are more difficult to treat6
1. World Federation of Hemophilia Guidelines 2005. 2.Ettingshausen C et al. Blood Coag Fibrinolysis. 2005;16 Suppl 1:S27–S31.
3. Gouw S. et al. J Thromb Haemost. 2007;5:1383–1390. 4. DiMichele D et al..Thromb Haemost.2002;87:52–57.
5.Gringeri et al. The COCIS Study. Blood (2003);102: 2358-63. 6. Morfini et al. Haemophilia (2007)13:606-612.
Haemophilia patients with inhibitors
• ESOS: In contrast to patients without inhibitors haemophilia patients with inhibitors suffer from
• Higher rate of hospitalisation for orthopaedic procedures• More orthopaedic complications• Increased levels of arthropathy
• Reduced mobility• Joint pain• Poorer overall outcome
• Generally, inhibitor patients have a lower quality of life compared to non-inhibitor patients
These outcome gaps between inhibitor and non-inhibitor patients need to be addressed and closed
Morfini M et al. Haemophilia 2007;13:606-12.ESOS: European Study on Orthopaedic Status of Haemophilia Patients with Inhibitors
Joint bleeds are by far the most frequent
• Joints(60%)
• Muscles
• Nose and gums
• Gut
• Kidneys
• Head and neck bleeding
Haemophilic arthropathy: impact of recurrent bleeding/synovitis
• Increased propensity for spontaneous bleeds
• Chronic pain
• Limb deformities
• Limited mobility / range of motion
• Need for assistive devices such as crutches, walking aids or wheelchairs
• Often requires more intensive or prolonged therapy
Gilbert MS. World Federation of Hemophilia, 1997.Rodriguez-Merchan EC. World Federation of Hemophilia, 2008.
Roberts HR & Escobar MA. Williams Hematology. 2006; Plate XXV-46.
Haemophilic arthropathy: progression from haemarthrosis to arthropathy
Adapted from Luck JV et al. J Am Acad Orthop 2004;12(4):234-245.
SynovialImpingement
RecurrentHaemarthroses
SynovialHypertrophy
HaemorrhageSynovial
Inflammation
CartilageDamage
Arthropathy
Direct synovial invasion of articular cartilage
Enzymaticdegradation
Haemophilic arthropathy: pathophysiology of arthropathy after haemarthrosis
• Indirect mechanism• Iron (as haemosiderin) in red blood cells
• accumulates in synovium • stimulates pro-inflammatory cytokines that
inhibit the formation of cartilage matrix1,2
• Direct mechanism• Short-term exposure of cartilage to whole blood results
in inhibition of cartilage-matrix synthesis3,4
• Adverse effects on the joint depend on the blood load (exposure time and blood concentration) and individual parameters3
1. Roosendaal G & Lafeber FP. In: Caviglia HA, Solimeno LP, eds. Orthopedic Surgery in Patients With Hemophilia. New York: Springer; 2008:5-15.
2. Lafeber FP et al. Haemophilia 2008;14(suppl 4):3-9. 3. Jansen NWD et al. Arthritis Rheum 2007;56:199-207.4. Jansen NWD et al. Osteoarthr Cartil 2009;17:433-440.
Haemophilic arthropathy: summary of pathophysiology
Haemophilic Arthropathy
Bleeding Into Joint
Synovium-mediated inflammatory changes1
Cartilage-mediateddegenerative changes1,2
Synovial hypertrophy and neovascularisation1
Cartilage/bone destruction1
1. Lafeber FP et al. Haemophilia 2008;14(suppl 4):3-9.2. Roosendaal G et al. Haemophilia 2008;6:4-10.
Haemophilic arthropathy: progressive effect
Luck JV al. J Am Acad Orthop Surg 2004;12:234-245.
End-Stage ArthritisEarly ArthritisChronic SynovitisAcute BleedingNormal Joint
Consequences of arthropathy
• Irreversible damage to the joint cartilage• Soft-tissue contractures• Muscle atrophy• Angular deformities• Loss of motion• Pain• Decreased quality of life
1. Morfini M et al. Haemophilia 2007;13:606-612. 2. World Federation of Hemophilia. Guidelines for the Management of Hemophilia. World
Federation of Hemophilia, 2005.
Joint disease: inhibitor versus non-inhibitor patients
• Inhibitors: most serious complication of haemophilia1
• Patients with inhibitors have haemostasis that is more difficult to control2
• Longer bleeding episodes• Increased risk for synovitis and target joint development• Increased prevalence of joint disease and
arthropathy
• Development of arthropathy: progressive joint damage3
1. Berntorp E et al. Haemophilia 2006; 12 (Suppl 6): 1-7.2. Leissenger CA. Haemophilia 1999; 5 (Suppl 3): 25-32.3. Rodriguez-Merchan EC. Semin Thromb Hemost 2003; 29: 585-94.
Orthopaedic status of patients with haemophilia and inhibitors
• Higher rate of hospitalisation for recurrent musculoskeletal bleeding
• Reduced patient mobility • Significantly increased rate of joint disease • Worse joint scores
• Articulation in knees, ankles and elbows
• Worse mean radiologic scores in the knees• Increased absence from school or work • Reduced quality of life
Morfini M et al. Haemophilia 2007;13:606-612.
Key treatment goals for inhibitor patients
Prophylaxis
•Early initiation
•Dose optmization
•Effective coverage:very costly!
How do we achieve these therapeutic goals?
• Inhibitor eradication: Immune tolerance induction therapy• Factor VIII
• Efficacy rates 70% to 85%• Factor IX
• Less well established• Success rate of approx. 30%
• Treatment and prevention of bleeding: ‘’Bypassing agents’’• pd aPCC: Efficacy rates: 64% 80%2
• rFVIIa: • Efficacy rates 81% to 91%2
• Effective in patients undergoing major orthopaedic surgery• Both products
• Home treatment3-5
• Long-term prophylaxis6-8
1. DiMichele D. World Federation of Hemophilia, Montreal, Quebec, Canada 2008. 2. Knight C et al. Adv Ther 2009;26:68-88.3. Negrier C et al. Haemophilia 2006;12:4-13. 4. Gomperts E. Haemophilia 2006;12:14-9.5. Key NS et al. Thromb Haemost 1998;80:912-8. 6. Hilgartner MW et al. Haemophilia 2003;9:261-8.7. Konkle BA et al. J Thromb Haemost 2007;5:1904-13. 8. Morfini M et al. Haemophilia 2007;13:502-7.
Impact of early treatment
• Clinical guidelines emphasise importance of rapid initiation of treatment, preferably within 2 hours in non-inhibitor patients to decrease
• Quantity of blood within joint• Risk of synovitis, target joint development and arthropathy• Total utilisation of replacement therapy
• Early treatment with rFVIIa in inhibitor patients • Increased efficacy • Decreased utilisation of product
1. World Federation of Hemophilia. Guidelines for the Management of Hemophilia. 2005.
2. Colvin BT et al. Haemophilia 2008;14:361-74.3. Lusher JM. Eu J Haemotol 1998; 61 (suppl 63): 7-10.
NovoSeven® room temperature stable- a new formulation to improve access
• May be stored in/outside the refrigerator-up to 25°C for 2 years: improved portability for home treatment immediate use: no need to bring to room temperature
• New –higher concentration of reconstituted product:• Lower infusion volume(40%): faster administration• Easier dose calculation: 1mg= 1ml
• New rounded strength vials: 1 mg, 2mg, 5 mg
Impact of early treatment
StudyDosage
g/kg/dose
Mean time interval from
bleed onset to 1st rFVIIa treatment
Percentage achieving
excellent or effective response
Mean number of rFVIIa doses
given
Compassionate care
60-120 5 days63%73%*
13.664.8*
Dose-finding7035
9 hours9 hours
72%53%
3.63.5
US home treatment
90 1.2 hours 92% 2.3
*Tense muscle/compartment syndrome
Lusher JM. Eu J Haemotol 1998; 61(suppl 63):7-10.
• Overall comparison of results of treatment with rFVIIa for peripheral muscular haemorrhages
Correlation between early treatment & efficacy
Lusher JM. Eur J Haematol Suppl. 1998;63:7-10.
Improved Success with Early Treatment
Excellen
t/eff
ecti
ve r
esp
on
se (
%)
0
10
20
30
40
50
60
70
80
90
100
10 20 30 40 50 60 70 80 90 100 110 1200 5
r2 = 0.6042
Time to initial treatment (hours)
US Home treatment study
Dose-finding study (70 µg/kg)
Compassionate-use database
Correlation between early treatment & doses required for haemostasis
Lusher JM. Eur J Haematol Suppl. 1998;63:7-10.
Fewer Doses Required with Early Treatment
Time to initial treatment (hours)
r2 = 0.9978
0
2
4
6
8
10
12
14
0 5 10 20 30 40 50 60 70 80 90 100 110 120
Mean
doses g
iven
(N
)
US Home treatment study
Dose-finding study (70 µg/kg)
Compassionate-use database
Early treatment associated with improved success
Treatment outcome
EpisodesN (%)
Median interval to initial
treatment (h)
Median doses given (N)
Effective 42 (79%) 0.6 (0.3-11.8) 1.5 (1-4)
Partially effective or failure
11 (21%) 2.7 (0.3-11.9) 3 (1-4)
P Value P=0.02 P=0.007
Adapted from Santagostino E et al. Br J Haematol 1999;104:22-26.
Early treatment with rFVIIa in haemophilia/ inhibitors(retrospective analysis in 4 Turkish centers)
Time to Treatment Time to Resolution0
10
20
30
40
50
60
0
5,000
10,000
15,000
20,000
25,000
30,000
35,000
Time Hours
Total Costs
Cost YTL
70
10,517
7.4 h
38 h
65.7 h
14.5 h
31,947
Kavakli K et al. Haemophilia 2010 May;16(3):487-94.
Home/Outpatient
Hospital
n=123 bleeds in 16 inhibitor patients
Costs for resolving a bleed by earlier home/outpatient treatment
≥ 2.5 times lower than the costs of hospital treatment (p < 0.001)
Registry data analysis: Czech Republic
Treatment with rFVIIa within 2 h of bleeding onset more than halved the incidence of re-bleeding
Fewer re-bleeding episodes
with a single dose of rFVIIa
128 bleeding episodes treated with rFVIIa with 60.2 % of bleeds treated within the first 2h
Salaj P et al. Haemophilia 2009;15:752-9.
Key results (1)
• rFVIIa provided effective haemostasis for all 128 bleeding episodes
• rFVIIa treatment within 2 hours of bleeding onset appears to be even more effective than treatment after 2 hours of bleeding onset in controlling re-bleeding
• Re-bleeds: 5.2 % and 13.7 % of patients treated ≤ 2 and > 2 hours
• For treatment within 2 hours of bleeding:• Higher and lower doses of rFVIIa provide comparable efficacy• Re-bleeds: 5.7 % and 5.9 % of patients receiving < 120 µg/kg
and > 250 µg/kg
• If unable to treat within 2 hours:• Most effective course of action is to initiate therapy with high-dose rFVIIa• Re-bleeds: 0 % and 15.8 % with > 250 µg/kg and < 120 µg/kg
Salaj P et al. Haemophilia 2009;15:752-9.
Key results (2)
• 80 % of bleeding episodes were treated at home
• 62 % of bleeds were managed with one rFVIIa injection
• Higher initial doses of rFVIIa tended to decrease the total number of injections required per bleeding episode
• Use of a single dose of rFVIIa significantly decreased the total amount of rFVIIa required per bleed versus multiple doses
• No thromboembolic events were reported for any rFVIIa dose
Salaj P et al. Haemophilia 2009;15:752-9.
Salaj P et al. Haemophilia 2009;15:752-9.
Registry data analysis in inhibitor patients
• Treatment within 2h of onset reduced the incidence of
re-bleeding by 50%
• These results from the HemoRec registry highlight the importance of immediate access to treatment &use of an appropriate starting dose
• Reduction of bleeding through rapid bleeding control should improve patient quality of life and reduce long-term treatment costs
Salaj P et al. Haemophilia 2009;15:752-9.
Impact of early treatment
• Delayed treatment associated with1 • Longer time to bleed resolution• Increased number of doses utilised• Increased treatment costs
• Time required to control bleed clinically relevant2
• Duration of pain• Amount of product utilised• Potential long-term joint damage• Resultant long-term costs of orthopaedic interventions
1. Kavakli K et al. Haemophilia 2010 May;16(3):487-94. 2. Knight C et al. Adv Ther 2009;26:68-88.