1 Maggie Constantine, MD, FRCPC Resident, Transfusion Medicine UBC TMR Journal Club – November 7,...

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Maggie Constantine, MD, FRCPCResident, Transfusion Medicine

UBCTMR Journal Club – November 7, 2007

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Prevention of joint disease in hemophiliaBackground Joint disease

Hemarthrosis Acute inflammation

Pain, swelling, loss of function Predisposition to future bleeding Chronic synovial hypertrophy

Destruction of cartilage Loss of joint space Hemophiliac arthropathy

Carcao M, Aledort L. Blood Rev. 2004;18:101-113.

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Prevention of joint disease in hemophiliaBackground - Staging/Grading joint disease

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Prevention of joint disease in hemophiliaBackground - Staging/Grading joint disease

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Prevention of joint disease in hemophiliaBackground - Prophylaxis or no prophylaxis

Prophylaxis (primary) Treatment by IV injection of factor concentrate in

anticipation of and in order to prevent bleeding (Consensus statement. Haemophilia 2003)

FVIII at least twice a week FVIII 25-40 U/kg given on alternate days (min 3

days/week) Commence prior to age 2 or 3 - prior to joint

damage

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Prevention of joint disease in hemophiliaBackground - Prophylaxis, the benefits

Malmo (Sweden) experience 25 year experience 60 patients - both severe hemophilia A and B Virtually no bleeds and maintenance of perfect joints if:

Started prophylaxis at a very young age (1-2 years old) FVIII given in large doses (2000-9000 U/kg/year)

Joints already damaged prior to prophylaxis underwent progressive deterioration despite prophylaxis

Irrespective of future bleeding in joints

Nilsson IM et al. J Intern Med 1992;232:25-32.

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Prevention of joint disease in hemophiliaBackground - Prophylaxis, the benefits

Aledort L et al. J Intern Med 1994;236:391-9. On-demand vs prophylaxis Prophylaxis

Fewer joint bleeds Fewer total bleeding episodes Better initial and final orthopedic and radiological scores Annual use of factor concentrates was 3 times higher

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Prevention of joint disease in hemophiliaBackground - Prophylaxis, the recommendations

1994, National Hemophilia Foundation with World Federation of Hemophilia and WHO Prophylaxis considered optimal therapy for children with

severe hemophilia Prophylaxis be instituted early with trough levels >/= 1% Need to evaluate joints, document complications and

costs Prophylaxis to be considered for other age groups

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Prevention of joint disease in hemophiliaBackground - AHCDC

Provide prophylaxis (primary and secondary) to patients in accordance with AHCDC recommendations and best practice.

http://www.ahcdc.ca/documents/CanadianHemophiliaStandardsFirstEdition070612_1.pdf

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Prevention of joint disease in hemophiliaBackground - AHCDC Recent studies suggest that prophylactic infusion to

maintain clotting-factor levels above 0.01 U/mL (more than 1% activity) at all times prevents most episodes of spontaneous bleeding into joints and preserves joint function.<19-23> Clinical studies are now underway in Canada to find the proper dose, and to confirm the efficacy and cost-benefit ratio of this mode of management. Studies are also needed to assess the safety, efficacy and cost-benefit ratio of continuous versus pulse coagulation-product infusion in prophylactic therapy.

http://www.ahcdc.ca/vWDManagement.html

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Prevention of joint disease in hemophiliaBackground - Prophylaxis, the gap analysis

North American hemophilia treatment centers Survey Prophylaxis: only 51% of boys with severe

hemophilia A under 18 yo 30% of severe hemophilia A </= 5 yo were

receiving full dose prophlaxis

Blanchette VS et al. Haemophilia 2003;19(Suppl 9):19-26.

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Prevention of joint disease in hemophiliaBackground - Prophylaxis, why the gap

Burdens Cost Frequent veni-puncture

Need for CVC CVC complications - thrombosis (20-60%, not all with

inhibitors), infection, malfunction

Thrombotic complications Inhibitor development

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Manco-Johnson et al. NEJM 2007;357(6)Study summary Whether prophylaxis prevents joint hemorrhage

and damage Multicenter Randomized, open-label

Prophylaxis vs intensive replacement August 1996 to April 2005 Long list of disclosures: Bayer HealthCare

donated the FVIII (otherwise no other role)

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Manco-Johnson et al. NEJM 2007;357(6)Study summary

Inclusion Age less than 30 mos FVIII activity level of 2 U/dL or less History of two or fewer hemorrhages into each

index joint Normal baseline joint imaging Undetectable levels of FVIII inhibitor Normal platelet count Normal joint motion

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Prophylaxis FVIII 25 IU /kg q2d Hemarthroses

FVIII 40 IU/kg Prophylaxis resumed

the next day

Episodic Treated only at the time of

clinically recognized hemarthroses

FVIII 40 IU/kg at the time of joint hemorrhage

20 IUkg at 24 hours and 72 hours after first dose

Continue infusions of 20 IU/kg q2d until pain and impairment of mobility resolved

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Primary outcome Preservation of index-

joint structure Determined by MRI

and plain-film x-ray at completion of study

Joint failure: subchondral cyst,

surface erosion, joint-space narrowing

Secondary outcomes # of joint and other

bleeding events Number of infusions Total units of FVIII

administered

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Power calculation Pilot data indicating that normal joint structure would be

maintained in 70% of children receiving prophylaxis and 20% of those receiving enhanced episodic therapy

Estimated proportions of loss of participants were 10% for follow-up

64 participants needed to detect a significant difference between the two treatments with a two-sided test (0.05 alpha level and 95% power)

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Radiologists blinded to treatment arm Randomization was performed centrally

and stratified by site in permuted blocks of 2, 4 or 6

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Manco-Johnson et al. NEJM 2007;357(6)Study summary Protocol failure

Allowance for “early termination of participation” if (also defined as serious adverse events)

Development of FVIII inhibitor Life-threatening hemorrhage Bone/cartilage damage on joint imaging (death also a serious adverse event)

Withdrawn from study if FVIII inhibitor titre >25 BU on duplicate testing over 3 mos Recurrent life-threatening hemorrhage Early joint evaluation showed bone or cartilate damage

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Statistical analysis Primary outcome

Proportion of children in whom normal joint structure was maintained, as determined by MRI or x-ray

Intention-to-treat analysis

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Manco-Johnson et al. NEJM 2007;357(6)Study summary - Results

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Prophylaxis MRI P Value

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Prevention of joint disease in hemophiliaManco-Johnson et al. NEJM 2007;357(6)

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Manco-Johnson et al. NEJM 2007;357(6)Study summary - Discussion and Conclusions

> 1/2 of joint abnormalities detected by MRI were not apparent on x-ray “We believe that MRI is the preferable imaging

technique for young boys with hemophilia.”

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# of clinically evident hemarthroses correlated weakly with the primary outcome “…chronic microhemorrhage into the joints….

Causes deterioration of joints without clinical evidence of hemarthroses and that prophylaxis prevents this subclinical process.”

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“This study demonstrates the efficacy of prophylaxis with recombinant factor VIII in reducing the incidence of joint hemorrhages, life-threatening hemorrhages, and other hemorrhages in and in lowering the risk of joint damage…”

“However, the high cost of recombinant factor VIII is a barrier to widespread acceptance of prophylaxis.”

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Manco-Johnson et al. NEJM 2007;357(6)Critical appraisal

Randomized? YES - centrally and stratified by site in permuted blocks of 2,4, or 6

Follow-up complete? NO A priori assumption of 10% loss of participants in follow-up 1 in episodic-therapy arm “lost to follow-up”

Intention-to-treat analysis? YES Blinded? NO

Patients and clinicians were not blinded Radiologists reading MRI and x-rays were blinded

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Groups similar at start of trial? YES Aside from experimental intervention - groups

treated similarly? Unclear Compliance 96% in prophylaxis group 98% in episodic

But did participants receive additional rFVIII?

RR of joint damage in the episodic group by MRI is 6.1 (95% CI, 1.5 to 24.4) by x-ray 5.2 (95% CI, 0.65 to 41.5)

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How would the results of this study change my clinical practice? % of episodic patients with joint disease=51.5% % of prophylaxis patients with joint disease=21.8% AAR = 29.6% NNT=3.36 (95% CI 1.9 to 13.6) If cost is not a concern, then YES I would recommend

prophylaxis to severe hemophilia A boys to start prior to 30 mos of age, to prevent joint disease in index joints.

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Maggie Constantine, MD, FRCPCResident, Transfusion Medicine

UBCTMR Journal Club – November 7, 2007

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1 Maggie Constantine, MD, FRCPC Resident, Transfusion Medicine UBC TMR Journal Club – November 7,...

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