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.