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

2 Prevention of joint disease in hemophilia Background 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:

3 Prevention of joint disease in hemophilia Background - Staging/Grading joint disease

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5 Prevention of joint disease in hemophilia Background - 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 U/kg given on alternate days (min 3 days/week) Commence prior to age 2 or 3 - prior to joint damage

6 Prevention of joint disease in hemophilia Background - 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 ( 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.

7 Prevention of joint disease in hemophilia Background - Prophylaxis, the benefits Aledort L et al. J Intern Med 1994;236: 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

8 Prevention of joint disease in hemophilia Background - 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

9 Prevention of joint disease in hemophilia Background - AHCDC Provide prophylaxis (primary and secondary) to patients in accordance with AHCDC recommendations and best practice.

10 Prevention of joint disease in hemophilia Background - 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. 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.

11 Prevention of joint disease in hemophilia Background - 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.

12 Prevention of joint disease in hemophilia Background - 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

13 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)

14 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

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

16 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

17 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)

18 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

19 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

20 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

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

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

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

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

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

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

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

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

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

30 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.”

31 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.”

32 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.”

33 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

34 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)

35 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.

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