KiDrug Alert Journal Club - Critical Review of "Efficacy of immunoglobin plus prednisone for prevention of coronary artery abnormalities in severe Kawasaki disease (RAISE study): A randomized, open-label, blinded-endpoints trial"

Abstract

The standard treatment of Kawasaki disease (KD) in the acute phase is intravenous immunoglobulin (IVIG) plus aspirin. Few researchers have investigated alternative and adjunct treatments as ‘rescue’ strategies for patients with KD who do not respond to the standard regimens. Corticosteroids have been investigated for several decades as a possible therapy for KD, with mixed results.
The RAISE study group conducted a randomized controlled trial to assess the efficacy of adjunct therapy with corticosteroids for KD. Specifically, they investigated whether addition of prednisolone to IVIG with aspirin reduces the incidence of coronary artery abnormalities. RAISE study was a multicenter, prospective, open-label, blinded end points trial conducted at 74 hospitals in Japan between September 2008 and December 2010. 248 patients were enrolled. All had severe disease with a Kobayashi1 risk score ?5, indicating a high risk of nonresponse to immunoglobulin therapy and subsequent coronary artery involvement. Participants were randomly assigned into two groups; the control group received standard therapy consisting of IVIG 2 g/kg over 24 h with aspirin 30 mg/kg per day until defervescence, followed by aspirin 3–5 mg/kg/ day for at least 28 days after fever onset (n = 123, IVIG group); the second group (corticosteroid group) received a similar regimen with the addition of intravenous prednisolone 2 mg/kg/day in three divided doses for 5 days, then orally, if fever resolved within 5 days, and followed by a 15-day dose taper period after C-reactive protein (CRP) levels normalized (n= 125). In addition, the corticosteroid group received 0.5 mg/kg per day of the histamine (H2) receptor antagonist famotidine, for gastric protection. The primary outcome of the study was determined as the incidence of coronary artery abnormalities during the study period. A two- dimensional echocardiography exam was performed during drug treatment and four weeks after. In addition, clinical characteristics were recorded including fever duration, need for adjuvant therapy, and measurement of serum inflammatory markers.
There were no differences in the baseline characteristics between the two treatment groups. The mean age of cohort patients at enrollment was 31.5 months and 13% were younger than six months. The incidence of coronary artery anomalies was significantly lower in the prednisolone adjuvant group compared with the IVIG group. Four patients (3%) in the former developed coronary anomalies compared with 28 patients (23%) in the latter; risk difference 0.20, 95% CI 0.12–0.28, P <0.001) at 1-2 weeks after disease onset. At week 4 Only 4 of 120 patients (3%) receiving corticosteroids as adjuvant therapy compared with 15 of 120 patients (13%) in the IVIG group had coronary artery abnormalities (P = 0.014). Secondary outcomes included faster resolution of fever (mean of 1 day vs of 2 days, in the corticosteroid vs. control group, respectively; P <0.0001), less use of rescue therapies (13% vs. 40%, respectively; P <0.0001), and greater reductions in inflammatory markers in the corticosteroid group.
There were no mortalities and no significant differences in adverse event risk between the groups. Transient adverse effects were noted in three patients in the corticosteroid group and two patients in the IVIG group, all resolved spontaneously. The authors concluded that the addition of prednisolone to the standard regimen of IVIG improves coronary artery outcomes in Japanese patients with resistant KD. They suggested that studies of intensified treatment for KD in a mixed ethnic population are warranted.