Presentation title

The need for rapid bleed control

Peter Noun, MD

Chief Department of Paediatrics Haematology-oncology Lebanese 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 underdiagnosed 2 and undertreated 3 • (e.g. Diagnostic rate: South Africa 52%, India 12%..) 2 • 75% receive no treatment 3 • If untreated, hemophilia is associated with a high mortality and morbidity • Premature death- around 13 years of age 4 but now, emerging problem of aging hemophilia population in the developed world 5 • • Arthropathy with crippling pain and motor dysfunction 1 Exposure to blood-born viruses with plasma-derived products 1 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 FIX 1 • • 20%–50% of people with hemophilia develop inhibitors 2 • • usually transient and of little clinical significance 3,4 persist in approximately 20% of people with hemophilia A and 1% of people with hemophilia B 3,4 .

Inhibitor patients do not bleed more frequently 5 are more difficult to treat 6 but bleeding 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 Roberts HR & Escobar MA. Williams Hematology. 2006; Plate XXV-46. • Often requires more intensive or prolonged therapy Gilbert MS. World Federation of Hemophilia, 1997.

Rodriguez-Merchan EC. World Federation of Hemophilia, 2008.

Haemophilic arthropathy: progression from haemarthrosis to arthropathy Haemorrhage Synovial Inflammation Synovial Hypertrophy Synovial Impingement Recurrent Haemarthroses Direct synovial invasion of articular cartilage Cartilage Damage Enzymatic degradation Arthropathy

Adapted from Luck JV et al. J Am Acad Orthop 2004;12(4):234-245.

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 matrix 1,2 •

Direct mechanism

• • Short-term exposure of cartilage to whole blood results in inhibition of cartilage-matrix synthesis 3,4 Adverse effects on the joint depend on the blood load (exposure time and blood concentration) and individual parameters 3 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

Bleeding Into Joint Synovium-mediated inflammatory changes 1 Synovial hypertrophy and neovascularisation 1 Cartilage-mediated degenerative changes 1,2 Cartilage/bone destruction 1 Haemophilic Arthropathy

1.

2.

Lafeber FP et al. Haemophilia 2008;14(suppl 4):3-9.

Roosendaal G et al. Haemophilia 2008;6:4-10.

Haemophilic arthropathy: progressive effect

Normal Joint Acute Bleeding Chronic Synovitis Early Arthritis End-Stage Arthritis

Luck JV al. J Am Acad Orthop Surg 2004;12:234-245.

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 haemophilia 1 • Patients with inhibitors have haemostasis that is more difficult to control 2 • • • Longer bleeding episodes Increased risk for synovitis and target joint development

Increased prevalence of joint disease and arthropathy

• Development of arthropathy: progressive joint damage 3 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

Prevention of Bleeding

Optimal Outcome

Orthopedic Intervention Rapid Hemostatic Control

•Effective coverage:very costly!

•Early initiation •Dose optmization

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 treatment 3-5 • Long-term prophylaxis 6-8 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

• Overall comparison of results of treatment with rFVIIa for peripheral muscular haemorrhages

Study



Dosage g/kg/dose Compassionate care 60-120 Dose-finding 70 35 US home treatment 90 * Tense muscle/compartment syndrome Mean time interval from bleed onset to 1 st rFVIIa treatment 5 days 9 hours 9 hours 1.2 hours Percentage achieving excellent or effective response 63% 73% * 72% 53% 92% Mean number of rFVIIa doses given 13.6

64.8

* 3.6

3.5

2.3

Lusher JM. Eu J Haemotol 1998; 61(suppl 63):7-10.

Correlation between early treatment & efficacy

Improved Success with Early Treatment 100 90 80 70 60 50 40 30 20 10 0

US Home treatment study Dose-finding study (70 µg/kg) Compassionate-use database

0 5 10 20 30 40 50 60 70 80 r 2 = 0.6042

90 100 110 120 Time to initial treatment (hours)

Lusher JM. Eur J Haematol Suppl. 1998;63:7-10.

Correlation between early treatment & doses required for haemostasis

Fewer Doses Required with Early Treatment 14 12 10 8 6 4 2 0 0 5 10 20 r 2 = 0.9978

US Home treatment study Dose-finding study (70 µg/kg) Compassionate-use database

30 40 50 60 70 80 90 Time to initial treatment (hours) 100 110 120

Lusher JM. Eur J Haematol Suppl. 1998;63:7-10.

Early treatment associated with improved success

Treatment outcome

Effective Partially effective or failure P Value

Episodes N (%)

42 (79%)

Median interval to initial treatment (h)

0.6 (0.3-11.8)

Median doses given (N)

1.5 (1-4) 11 (21%) 2.7 (0.3-11.9) P=0.02

3 (1-4) 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)

n=123 bleeds in 16 inhibitor patients Time Hours

70 60 50 40 30 20 10 0 7.4 h 38 h

Time to Treatment

14.5 h 65.7 h

Time to Resolution

10,517 31,947

Total Costs Cost YTL 35,000 30,000 25,000 20,000 15,000 10,000 5,000 0 Kavakli K et al. Haemophilia 2010 May;16(3):487-94.

Registry data analysis: Czech Republic

128 bleeding episodes treated with rFVIIa with 60.2 % of bleeds treated within the first 2h

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 Salaj P et al. Haemophilia 2009;15:752-9.

Key results (1)

• rFVIIa provided effective haemostasis for all 128 bleeding episodes • rFVIIa treatment effective within 2 hours of bleeding onset appears to be even more 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 the total amount of rFVIIa required per bleed versus multiple doses significantly decreased • No thromboembolic events dose Salaj P et al. Haemophilia 2009;15:752-9.

were reported for any rFVIIa

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 with 1 • Longer time to bleed resolution • • Increased number of doses utilised Increased treatment costs • Time required to control bleed clinically relevant 2 • • • • 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.