Transcript Efficacy of immunoglobulin plus prednisolone for prevention of

SCH Journal Club
Immunoglobulin plus prednisolone in
severe Kawaski disease (RAISE study)
Steph Borg
22 November 2012
Aim
• To assess the efficacy of primary prednisolone treatment
as an addition to conventional treatment with intravenous
immunoglobulin
The Clinical Question
Population
Patients with Kawasaki’s disease
Intervention
IV immunoglobulin plus prednisolone
Comparison
IV immunoglobulin
Outcome
Reduce incidence of coronary artery abnormalities
Design
Randomised, controlled, non blinded trial
Efficacy of immunoglobulin plus prednisolone
for prevention of coronary artery
abnormalities in severe Kawaski disease
(RAISE study): a randomised, open label
blinded-endpoints trial
Kobayahi T, Saji T, Takeuchi et al
The Lancet 2012 Vol 379: 1613-20
SCH current practice/guidelines
• Immunoglobulin IV 2g/kg within 10days of fever
developing
– 2nd dose can be given
• Aspirin – high dose 80-100mg/kg/day in 4 divided doses
until fever settled
• Steroids, infliximab and cyclophosphamide can be used
in refractory patients in conjunction with
rheumatology/immunology
Methods
• Sep 2008 – Dec 2010
• 74 Japanese hospitals
• Diagnostic criteria
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Fever persisting 5 days or more
Bilateral conjunctival congestion
Changes of lips and oral cavity
Polymorphous exanthema
Changes of peripheral extremities
Acute non purulent cervical lymphadenopathy
• 5 items required for diagnosis
Methods
• Exclusion criteria
– Low risk score, history Kawasaki disease, diagnosed after day 9
of illness, coronary artery abnormalities at diagnosis, other
significant medical disorders
• Randomly assigned to either IVIG or IVIG + prednisolone
• Median duration of prednisolone treatment 21 days
Outomes
• Primary endpoint
– Incidence of coronary artery abnormalities during the study period
(Week 1 ,2 ,4)
• Secondary endpoints
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Coronary abnormalities after 4 weeks
Z scores of coronary arteries
Incidence of need for additional rescue treatment
Duration of fever after enrolment
CRP at week 1 and week 2
Serious adverse events
Are the results valid?
• Did the trial address a clearly focussed issue?
– Yes
• Was the assignment of patients to treatment randomized
– Yes
• Where all of the patients entered accounted for at its
conclusion
– Yes
Are the results valid?
• Where patients, health workers and study personnel
blind to treatment
– No one blinded except those assessing echos
• Where the groups similar at the start of the trial?
– Closely matched
• Aside from the experimental intervention where the
groups treated equally?
– Nearly - except no placebo for prednisolone
What are the results?
• June 2010
– Interim analysis after enrolment of 200th patient
• Significant difference in incidence of coronary artery
abnormalities between the 2 groups (p<0.0001)
• Dec 2010
– Study terminated early
Incidence of coronary artery abnormality
• During study period
– IVIG + Pred 4/121 (3%)
– IVIG 28/121 (23%)
• risk difference 0.20; CI 0.12-0.28; NNT = 5
• At week 4
– IVIG + Pred 4/120 (3%)
– IVIG
15/20 (13%)
• Risk difference 0.09; CI 0.02-0.16; NNT = 10
Coronary artery abnormalities
• Z-score for proximal right coronary arteries, left main
coronary artery, proximal left anterior descending
arteries lower in IVIG + prednisolone group at all time
points
• Fever resolution faster in IVIG + pred vs IVIG group
Secondary endpoints
• Fever resolution faster in IVIG + pred group
• Non response to primary therapy was significantly less in
IVIG +pred group
• No difference in the rate of relapse between groups
Adverse events
• In the IVIG + pred group
– WCC and HCT higher at week 1,2 and 4
– Neutrophils higher at week 1 and 2
– Cholesterol higher at weeks 1,2 and 4
Serious adverse events
• 3/121 IVIG + pred
– 2 patients – high total cholesterol
– 1 patient - neutropenia
• 2/121 IVIG
– High total cholesterol
– Non-occlusive thrombus left coronary artery
Can the results be applied to the local
population?
• Japanese population
• 2 US studies showed no difference between groups
– But … used pulsed corticosteroids, single dose
Were all clinical important outcomes
considered?
• Insufficient follow up to assess
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Severe bacterial infection
Thrombosis
Bone mineral loss
Osteonecrosis
Ophthalmic power
• Insufficient statistical power to exclude adverse events