Date Published: May 22, 2019
Publisher: Public Library of Science
Author(s): Xiaolan Zheng, Peng Yue, Lei Liu, Changqing Tang, Fan Ma, Yi Zhang, Chuan Wang, Hongyu Duan, Kaiyu Zhou, Yimin Hua, Gang Wu, Yifei Li, Wisit Cheungpasitporn.
Kawasaki disease (KD) is now the leading cause of acquired heart disease in children in developed countries. Intravenous immunoglobulin (IVIG) and aspirin were considered as the standard initial treatment of KD for decades. However, the optimal dose of aspirin has remained controversial. In recent years, many studies compared the efficacy of low-dose with high-dose aspirin in the acute phase of KD, but the results have not always been consistent. Therefore, we performed this meta-analysis to evaluate the efficacy of low-dose aspirin compared with high-dose for the initial treatment of KD.
Studies related to aspirin therapy for KD were selected from PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, and Google scholar through Mar 25th, 2019. Data were analyzed using STATA Version 15.1. Additionally, publication bias and sensitivity analysis were also performed by STATA version 15.1.
Six studies were included in our analysis of the rate of coronary artery lesion (CAL), five reports for IVIG-resistant KD (rKD), and four for the duration of fever and hospitalization. However, no significant differences were found between low-dose and high-dose aspirin groups in the incidence of CAL (risk ratio (RR), 0.85; 95%CI (0.63, 1.14); P = 0.28), the risk of rKD (RR, 1.39; 95%CI (1.00, 1.93); P = 0.05), and duration of fever and hospitalization (the mean standard deviation (SMD), 0.03; 95%CI (-0.16, 0.22); P = 0.78).
Low-dose aspirin (3–5 mg·kg-1·d-1) may be as effective as the use of high-dose aspirin (≥30 mg·kg-1·d-1) for the initial treatment of KD. Further well-designed randomized clinical trials are needed to evaluate the efficacy of low-dose aspirin for the initial treatment of KD.
Kawasaki disease (KD) is an acute, self-limited febrile vasculitis of unknown cause that predominantly affects children under five years of age . KD is now the most common cause of acquired heart disease in children in developed countries . In general, KD is regarded as an innate immune disorder resulting from the exposure of a genetically predisposed individual to microbe-derived innate immune stimulants . However, the etiology and pathogenesis of KD are still unclear. In addition, coronary artery aneurysm (CAA) is a severe cardiovascular complication of KD, and timely initiation of treatment with intravenous immunoglobulin (IVIG) has reduced the incidence of CAA from 25% to ≈4% . Moreover, previous studies found that thrombocytosis is universal in the subacute stage of KD [5–7]. Furthermore, the degree of platelet activation was closely associated with the presence of coronary artery complications in the acute stage of KD . Therefore, anti-inflammatory and anti-platelet therapies are the primary treatments for KD.
As the most common cause of acquired heart disease in children in many countries [2,32,33], the timeline of using aspirin in the acute phase of KD originated earlier than that of using single high-dose IVIG . However, recent studies [35,21] indicated that the risk of CAL was not related to the aspirin dose, which depended only on the timing and dosage of IVIG. Furthermore, patients who received high-dose aspirin faced a higher risk of medication side effects, including dose-dependent minor bleeding events and gastric injuries . Therefore, we conducted this meta-analysis and found no increased risk of CAL in the low-dose group compared with the high-dose group. This result suggested that high-dose aspirin administration aimed at reducing the risk of CAL may not be required in the acute phase of KD.
Our study has several limitations. First, the number of included studies was small. Thus, the result of Egger’s publication bias test and the meta-regression analysis should be treated with caution. Second, most studies lacked information about adverse effects, which might interfere with the comparison of efficacy between the two groups. Third, due to high-dose aspirin being widely recommended by guidelines, the low-dose aspirin group was relatively small in most studies, leading to inevitable bias. Additionally, although the current study is not registered and there may be slight deviations, we strictly followed the system evaluation steps. Besides, all of the included studies were nonrandom and retrospective trials, which could lead to biased results. Finally, as none of the studies involved in our meta-analysis used a standard non-inferiority study design, we could not evaluate the non-inferiority of low-dose aspirin in the present study, which should be a more appropriate study design to address this issue.
In conclusion, treatment with low-dose aspirin compared with high-dose aspirin showed no significant difference in the incidence of CAL, the risk of rKD, or the length of fever or hospital stay in the acute phase of KD. Therefore, low-dose aspirin (3–5 mg·kg-1·d-1) may be as effective as the high-dose aspirin (≥30 mg·kg-1·d-1) for the initial treatment of KD. More prospective studies (ideally randomized clinical trials with uniform criteria and a larger number of patients) are needed to evaluate the efficacy of low-dose aspirin for the initial treatment of KD.