Background Though Aspirin and intravenous immunoglobulin (IVIG) remain the standard treatments for Kawasaki Disease (KD) to minimize coronary artery damage, the duration and dosage of aspirin are inconsistent across hospitals. However, the lack of multi-center randomized trials prevents definitive answers to the impact of high-dose aspirin.

Methods This clinical trial was structured as a prospective, evaluator-blinded, multi-center randomized controlled trial with two parallel arms, aiming to assess the effectiveness of IVIG as a standalone primary therapy of KD in comparison to the combination of IVIG with high-dose aspirin therapy. KD patients were enrolled between September, 2016 and August, 2019. A final cohort of 134 patients were randomly assigned to the standard and test groups with 69 and 65 patients, respectively. The Standard group received IVIG (2 g/kg) along with aspirin (80-100 mg/kg/day) until fever subsided for 48 hours. The test group received IVIG (2 g/kg) alone. Following the initial treatment, both groups received a daily aspirin dose (3-5 mg/kg) for six weeks. The primary outcome measure was the occurrence of coronary artery lesions (CAL) at the 6-8 weeks mark. The secondary outcome is IVIG resistance.

Results The overall rate of CAL in test group decreased from 10.8% at diagnosis to 1.5% and 3.1% at 6 weeks and 6 months, respectively. The CAL rate of standard group declined from 13.0% to 2.9% and 1.4%, with no statistically significant difference (P>0.1) in the frequency of CAL between the two groups. Furthermore, no statistically significant differences were found for treatment (P>0.1) and prevention (P>0.1) effect between the two groups.

Conclusions This marks the first prospective multi-center randomized controlled trial comparing the standard treatment of KD using IVIG plus high-dose aspirin against IVIG alone. Our analysis indicates that addition of high-dose aspirin during initial IVIG treatment is neither statistically significant nor clinically meaningful for CAL reduction.

What is New?

This study represents the first multi-center randomized controlled trial investigating the efficacy of high-dose aspirin or intravenous immunoglobulin (IVIG) during the acute stage of KD. This study assessed the impact of discontinuing high-dose aspirin (80–100 mg/kg/day) on the occurrence of CAL during the acute phase treatment of Kawasaki Disease.

No significant differences were observed between high-dose aspirin plus IVIG treatment and IVIG alone treatment in terms of the frequency of abnormal coronary artery abnormalities. Additionally, our analysis revealed no statistically significant differences in either the treatment effect (the number of cases successfully treated) or prevention effect (the prevention of new cases) between these two treatments.

What Are the Clinical Implications?

Comparison analysis indicated the non-inferiority between two groups with or without high-dose aspirin.

Administering the standard 2 g/kg/day IVIG without high-dose aspirin (80–100 mg/kg/day) during the acute phase therapy for KD does not increase the risk of coronary artery lesions, which are a primary cause of morbidity and mortality in KD patients.

Addition of high-dose aspirin during initial IVIG treatment is not statistically significant or clinically meaningful.

The authors have declared no competing interest.

NCT02951234

This study received funding from the following grants: CMRPG8J1151 CPRPG8F0791 CPRPG8H0051-2 CMRPG8M1431 CMRPG8M1421 and CMRPG8L1241-2 from Chang Gung Memorial Hospital and the NSTC 112-2314-B-182-032-MY3 from National Science and Technology Council of Taiwan to Dr. Ho; and 1R41TR004351-01 from US National Institute of Health to Dr. Ling.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

This study was approved by the Institutional Review Board (IRB) at each site of the participating institutions, including Linkou Chang Gung Memorial Hospital, Kaohsiung Chang Gung Memorial Hospital, Taichung Veterans General Hospital, Kaohsiung Veterans General Hospital, and Tungs' Taichung Metro Harbor Hospital. Informed consent form (ICF) were signed by the patient or a legal guardian.

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(email address: Ming-Chih Lin mingclingmail.com; Chung-Chih Kao cckao2cvyahoo.com; Ken-Pen Weng kenpenwengyahoo.com.tw; Yun Ding dingy1979gmail.com; Chih-Jung Chen james.pedgmail.com; Sheng-Ling Jan sljanvghtc.gov.tw; Kuang-Jen Chien kjchienvghks.gov.tw; Chun-Hsiang Ko adamker01gmail.com; Chien-Yu Lin mmhped.lingmail.com; Wei-Te Lei weite.leigmail.com ; Ling-Sai Chang joycejohnsyokogmail.com; Mindy Ming-Huey Guo mindymhguocgmh.org.tw; Kuender D. Yang yangkd.yehgmail.com; Ho-Chang Kuo erickuo48yahoo.com.tw; Karl G. Sylvester karlsstanford.edu; Zhi Han zhihan01stanford.edu; Lu Tian lutianstanford.edu; Henry Chubb mhchubbstanford.edu; Scott R. Ceresnak ceresnakstanford.edu; Doff McElhinney doffstanford.edu; John C. Whtin cukestanford.edu; Harvey J. Cohen punkostanford.edu; Xuefeng B. Ling bxlingstanford.edu)

The data that support the findings of this study are available from the corresponding author on reasonable request. Participant data without names and identifiers will be made available after approval from the corresponding author and Chang Gung Memorial Hospital. After publication of study findings, the data will be available for others to request.