ArticlesEfficacy of immunoglobulin plus prednisolone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): a randomised, open-label, blinded-endpoints trial
Introduction
Kawasaki disease is an acute systemic vasculitis of unknown cause that affects mainly infants and children and is a major cause of acquired heart disease in developed countries.1 Treatment with high-dose intravenous immunoglobulin plus aspirin resolves inflammation and reduces the occurrence of coronary artery abnormalities.2, 3, 4 However, about 20% of patients have persistent or recurrent fever after completion of intravenous immunoglobulin5 and these patients have a particularly high risk of developing coronary artery abnormalities.6, 7, 8
Although corticosteroids are a useful treatment option for various forms of vasculitis, many physicians have hesitated to use them because a report9 showed a high incidence of coronary artery abnormalities in patients who received a prolonged course of oral prednisolone alone. However, findings from a subsequent retrospective study10 of the effects of corticosteroids in Kawasaki disease showed possible benefits. In a meta-analysis,11 inclusion of corticosteroids in regimens containing aspirin for primary treatment of Kawasaki disease reduced the incidence of coronary artery abnormalities. In 2007, findings from a randomised, placebo-controlled trial12 of the efficacy of a single dose of pulsed intravenous methylprednisolone added to conventional therapy showed that pulsed corticosteroid treatment did not improve coronary artery outcomes. In a randomised, open-label, non-blinded trial,13 intravenous immunoglobulin plus prednisolone decreased the incidence of coronary artery abnormalities and treatment failure; however, the trial had potential methodological flaws.14 We subsequently noted in a retrospective analysis15 that primary treatment with intravenous immunoglobulin plus prednisolone improved coronary and clinical outcomes in patients at high risk for no response to primary intravenous immunoglobulin. Thus, the addition of corticosteroids to intravenous immunoglobulin as primary treatment might offer important therapeutic benefits to such patients with Kawasaki disease at high risk for non-response to primary treatment with intravenous immunoglobulin.
We aimed to assess the efficacy of primary prednisolone treatment as an addition to conventional treatment with intravenous immunoglobulin.
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Study design and patients
We did the Randomized controlled trial to Assess Immunoglobulin plus Steroid Efficacy for Kawasaki disease (RAISE study)—a multicentre, prospective, randomised, open-label, blinded-endpoints, parallel-group study—at 74 hospitals in Japan between Sept 29, 2008, and Dec 2, 2010. We diagnosed Kawasaki disease with the Japanese diagnostic guidelines for Kawasaki disease.16 Eligible participants had a risk score17 of five points or higher, which emphasises the positive predictive value of no
Results
The study started on Sept 29, 2008. We did the pre-planned interim analysis after enrolment of the 200th patient in June, 2010. The analysis showed a significant difference in the incidence of coronary artery abnormalities between the two treatment groups (p<0·0001); therefore, the independent data and safety monitoring committee recommended termination of the study. The study was terminated on Dec 2, 2010. Figure 1 shows the trial profile. Of 2014 patients assessed for trial eligibility, 1436
Discussion
Our findings show that combination treatment with intravenous immunoglobulin plus prednisolone had a significant advantage compared with intravenous immunoglobulin alone for prevention of coronary artery abnormalities, reduced need for additional rescue treatment, and more rapidly resolved fever and inflammatory markers in patients with severe Kawasaki disease (panel). The high incidence of additional rescue treatment in the intravenous immunoglobulin group was because we used the risk score
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