Maggie Constantine, MD, FRCPC Resident, Transfusion Medicine UBC

Maggie Constantine, MD, FRCPC Resident, Transfusion Medicine UBC TMR Journal Club – November 7, 2007

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.

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

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

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.

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

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

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

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

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.

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

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)

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

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

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

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

Manco-Johnson et al. NEJM 2007;357(6)Study summary • Radiologists blinded to treatment arm • Randomization was performed centrally and stratified by site in permuted blocks of 2, 4 or 6

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

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

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

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

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

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.”

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

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

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

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

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

Maggie Constantine, MD, FRCPC Resident, Transfusion Medicine UBC TMR Journal Club – November 7, 2007 Comments? Questions?

Maggie Constantine, MD, FRCPC Resident, Transfusion Medicine UBC