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"

Main Article Content

Yousef Etoom
Rudaina Banihani
Yaron Finkelstein

Keywords

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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.

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References

1. Kobayashi T, Inoue Y, Takeuchi K, Okada Y, Tamura K, Tomomasa T, et al. Prediction of intravenous immunoglobulin unresponsiveness in patients with Kawasaki disease. Circulation 2006 Jun 6;113(22):2606-12. PubMed PMID: 16735679. Epub 2006/06/01. eng.
2. Kawasaki T, Kosaki F, Okawa S, Shigematsu I, Yanagawa H. A new infantile acute febrile mucocutaneous lymph node syndrome (MLNS) prevailing in Japan. Pediatrics 1974 Sep;54(3):271-6. PubMed PMID: 4153258. Epub 1974/09/01. eng.
3. Morens DM, Anderson LJ, Hurwitz ES. National surveillance of Kawasaki disease. Pediatrics 1980 Jan;65(1):21-5. PubMed PMID: 7355030. Epub 1980/01/01. eng.
4. Newburger JW, Fulton DR. Kawasaki disease. Current Opinion in Pediatrics 2004 Oct;16(5):508-14. PubMed PMID: 15367843. Epub 2004/09/16. eng.
5. Newburger JW, Takahashi M, Gerber MA, Gewitz MH, Tani LY, Burns JC, et al. Diagnosis, treatment, and long-term management of Kawasaki disease: a statement for health professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease in the Young, American Heart Association. Pediatrics. 2004 Dec;114(6):1708-33. PubMed PMID: 15574639. Epub 2004/12/03. eng.
6. Kato H, Sugimura T, Akagi T, Sato N, Hashino K, Maeno Y, et al. Long-term consequences of Kawasaki disease. A 10- to 21-year follow-up study of 594 patients. Circulation 1996 Sep 15; 94(6): 1379-85. PubMed PMID: 8822996. Epub 1996/09/15. eng.
7. Dajani AS, Taubert KA, Gerber MA, Shulman ST, Ferrieri P, Freed M, et al. Diagnosis and therapy of Kawasaki disease in children. Circulation 1993 May;87(5):1776-80. PubMed PMID: 8491037. Epub 1993/05/01. eng.
8. Durongpisitkul K, Gururaj VJ, Park JM, Martin CF. The prevention of coronary artery aneurysm in Kawasaki disease: a meta-analysis on the efficacy of aspirin and immunoglobulin treatment. Pediatrics 1995 Dec;96(6):1057-61. PubMed PMID: 7491221. Epub 1995/12/01. eng.
9. Sano T, Kurotobi S, Matsuzaki K, Yamamoto T, Maki I, Miki K, et al. Prediction of non-responsiveness to standard high-dose gamma-globulin therapy in patients with acute Kawasaki disease before starting initial treatment. European Journal of Pediatrics 2007 Feb;166(2):131-7. PubMed PMID: 16896641. Epub 2006/08/10. eng.
10. Egami K, Muta H, Ishii M, Suda K, Sugahara Y, Iemura M, et al. Prediction of resistance to intravenous immunoglobulin treatment in patients with Kawasaki disease. The Journal of Pediatrics 2006 Aug;149(2):237-40. PubMed PMID: 16887442. Epub 2006/08/05. eng.
11. Son MB, Gauvreau K, Ma L, Baker AL, Sundel RP, Fulton DR, et al. Treatment of Kawasaki disease: analysis of 27 US pediatric hospitals from 2001 to 2006. Pediatrics 2009 Jul;124(1):1-8. PubMed PMID: 19564276. Epub 2009/07/01. eng.
12. Durongpisitkul K, Soongswang J, Laohaprasitiporn D, Nana A, Prachuabmoh C, Kangkagate C. Immunoglobulin failure and retreatment in Kawasaki disease. Pediatric Cardiology 2003 Mar-Apr;24(2):145-8. PubMed PMID: 12457253. Epub 2002/11/29. eng.
13. Sleeper LA, Minich LL, McCrindle BM, Li JS, Mason W, Colan SD, et al. Evaluation of Kawasaki disease risk-scoring systems for intravenous immunoglobulin resistance. The Journal of Pediatrics 2011 May;158(5):831-5. PubMed PMID: 21168857. Pubmed Central PMCID: PMC3075321. Epub 2010/12/21. eng.
14. Newburger JW, Sleeper LA, McCrindle BW, Minich LL, Gersony W, Vetter VL, et al. Randomized trial of pulsed corticosteroid therapy for primary treatment of Kawasaki disease. The New England Journal of Medicine 2007 Feb 15;356(7):663-75. PubMed PMID: 17301297. Epub 2007/02/16. eng.