Transcript Slide 1

Maggie Constantine, MD, FRCPC
Resident, Transfusion Medicine
UBC
TMR Journal Club – November 7, 2007
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Prevention of joint disease in hemophilia
Background
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Joint disease
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Hemarthrosis
Acute inflammation
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Pain, swelling, loss of function
Predisposition to future bleeding
Chronic synovial hypertrophy
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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 hemophilia
Background - Staging/Grading joint disease
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Prevention of joint disease in hemophilia
Background - Staging/Grading joint disease
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Prevention of joint disease in hemophilia
Background - Prophylaxis or no prophylaxis
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Prophylaxis (primary)
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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 hemophilia
Background - Prophylaxis, the benefits
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Malmo (Sweden) experience
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25 year experience
60 patients - both severe hemophilia A and B
Virtually no bleeds and maintenance of perfect joints if:
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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
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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 hemophilia
Background - Prophylaxis, the benefits
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Aledort L et al. J Intern Med 1994;236:391-9.
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On-demand vs prophylaxis
Prophylaxis
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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 hemophilia
Background - Prophylaxis, the recommendations
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1994, National Hemophilia Foundation with World
Federation of Hemophilia and WHO
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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 hemophilia
Background - AHCDC
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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 hemophilia
Background - AHCDC
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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 costbenefit 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 hemophilia
Background - Prophylaxis, the gap analysis
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North American hemophilia treatment
centers
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Survey
Prophylaxis: only 51% of boys with severe
hemophilia A under 18 yo
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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 hemophilia
Background - Prophylaxis, why the gap
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Burdens
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Cost
Frequent veni-puncture
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Need for CVC
 CVC complications - thrombosis (20-60%, not all with
inhibitors), infection, malfunction
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Thrombotic complications
Inhibitor development
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Manco-Johnson et al. NEJM 2007;357(6)
Study summary
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Whether prophylaxis prevents joint hemorrhage
and damage
Multicenter
Randomized, open-label
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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
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Inclusion
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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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Manco-Johnson et al. NEJM 2007;357(6)
Study summary
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Prophylaxis
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FVIII 25 IU /kg q2d
Hemarthroses
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FVIII 40 IU/kg
Prophylaxis resumed
the next day
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Episodic
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Treated only at the time of
clinically recognized
hemarthroses
FVIII 40 IU/kg at the time
of joint hemorrhage
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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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Manco-Johnson et al. NEJM 2007;357(6)
Study summary
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Primary outcome
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Preservation of indexjoint structure
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Determined by MRI
and plain-film x-ray at
completion of study
Joint failure:
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Secondary outcomes
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# of joint and other
bleeding events
Number of infusions
Total units of FVIII
administered
 subchondral cyst,
surface erosion, jointspace narrowing
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Manco-Johnson et al. NEJM 2007;357(6)
Study summary
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Power calculation
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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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Manco-Johnson et al. NEJM 2007;357(6)
Study summary
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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
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Protocol failure
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Allowance for “early termination of participation” if (also
defined as serious adverse events)
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Development of FVIII inhibitor
Life-threatening hemorrhage
Bone/cartilage damage on joint imaging
(death also a serious adverse event)
Withdrawn from study if
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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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Manco-Johnson et al. NEJM 2007;357(6)
Study summary
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Statistical analysis
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Primary outcome
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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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Manco-Johnson et al. NEJM 2007;357(6)
Study summary - Results
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Manco-Johnson et al. NEJM 2007;357(6)
Study summary - Results
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Manco-Johnson et al. NEJM 2007;357(6)
Study summary - Results
Prophylaxis
MRI
P Value
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Manco-Johnson et al. NEJM 2007;357(6)
Study summary - Results
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Prevention of joint disease in hemophilia
Manco-Johnson et al. NEJM 2007;357(6)
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Manco-Johnson et al. NEJM 2007;357(6)
Study summary - Results
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Manco-Johnson et al. NEJM 2007;357(6)
Study summary - Results
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Manco-Johnson et al. NEJM 2007;357(6)
Study summary - Results
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Manco-Johnson et al. NEJM 2007;357(6)
Study summary - Discussion and Conclusions
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> 1/2 of joint abnormalities detected by MRI
were not apparent on x-ray
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“We believe that MRI is the preferable imaging
technique for young boys with hemophilia.”
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Manco-Johnson et al. NEJM 2007;357(6)
Study summary - Discussion and Conclusions
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# of clinically evident hemarthroses
correlated weakly with the primary outcome
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“…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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Manco-Johnson et al. NEJM 2007;357(6)
Study summary - Discussion and Conclusions
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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
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Randomized? YES - centrally and stratified by site
in permuted blocks of 2,4, or 6
Follow-up complete? NO
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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
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Patients and clinicians were not blinded
Radiologists reading MRI and x-rays were blinded
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Manco-Johnson et al. NEJM 2007;357(6)
Critical appraisal
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Groups similar at start of trial? YES
Aside from experimental intervention - groups
treated similarly? Unclear
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Compliance 96% in prophylaxis group
98% in episodic
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But did participants receive additional rFVIII?
RR of joint damage in the episodic group
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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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Manco-Johnson et al. NEJM 2007;357(6)
Critical appraisal
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How would the results of this study change my
clinical practice?
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% 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, FRCPC
Resident, Transfusion Medicine
UBC
TMR Journal Club – November 7, 2007
Comments? Questions?
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