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High-Dose or Low-Dose Aspirin Application in the Initial Phase of Kawasaki Disease: A Meta-Analysis and Systematic Review
The initial dose of aspirin for Kawasaki disease (KD) is controversial to a great extent. In order to compare the efficacy of high-dose and low-dose aspirin in the treatment of KD, this study included articles containing information on the treatment of KD with aspirin before August 2021, which were collected from public databases. The results of different studies were summarized and weighted by an inverse variance model, and heterogeneity was assessed using the Q-test and I2. A meta-analysis of 12258 patients from nine retrospective studies was conducted. In general, no significant differences between high-dose and low-dose groups were found in the incidence of coronary artery abnormality (CAA) (RR = 1.154; 95% CI = 1.027–1.316) and the incidence of intravenous immunoglobulin (RR = 0.926; 95% CI = 0.594–1.441). But high-dose aspirin might be linked to the shortened duration of fever (RR = −0.134; 95% CI = −0.203–0.064) as well as hospitalized stay (RR = −1.263; 95% CI = −1.392–1.122). Conclusion. For the treatment of the acute phase of KD, low-dose aspirin plus intravenous immunoglobulin could be as effective as high-dose aspirin in preventing CAA. Nonetheless, high-dose aspirin might be related to reducing fever time and hospitalization time.
Kawasaki disease (KD), also known as mucosal cutaneous lymph node syndrome, is an acute, self-limited vasculitis that predominantly affects children under five years of age [1,2]. Initial symptoms include high fever, inflammation of the skin mucosa, and neck lymphadenopathy. Coronary artery abnormalities (CAA), usually developing in 15% to 25% of all patients during the first two weeks of the disease, are regarded as the most severe complication of KD . At present, KD is considered to be one of the most main causes for acquired heart disease among children in developed countries [4,5].
Although the cause of KD is still unclear, recent studies have observed the dysfunction of innate immune responses in the process of CAA . At the initial stage of the disease, neutrophils infiltrated into the adventitia of the coronary artery wall from the intima. Inflammation leads to the destruction of the structural integrity of the coronary arteries and laminar flow. Therefore, treatment against inflammation and platelet thrombosis is widely accepted as primary care.
In order to prevent coronary artery complications, the American Heart Association recommended giving 2 g/kg intravenous immunoglobulin (IVIG) plus 80–100 mg/kg/day high-dose aspirin (acetylsalicylic acid, ASA) in the acute stage of KD . Similarly, IVIG (2 g/kg) plus 30–50 mg/kg/day of moderate-dose aspirin was recommended by the Japanese Society of Pediatric Cardiology and Cardiosurgery until the patient had no fever . After that, patients need to receive low-dose aspirin (3–5 mg/kg/day) for 6–8 weeks. The combined application of aspirin and IVIG at a high dose (>30 mg/kg/day) might exert strong anti-inflammatory, anti-platelet, and immunomodulatory functions. It is worth noting that although the therapeutic effect of IVIG is recognized as the key measure to prevent the formation of CAA in KD, the appropriate dose of aspirin is still widely controversial.
Many studies, including clinical trials and meta-analyses, show that the efficacy of low-dose aspirin (3–5 mg/kg/day) in treating KD is not inferior to that of high-dose aspirin (>30 mg/kg/day) [9,10]. In addition, the adverse effects of high-dose aspirin, including anemia, gastrointestinal bleeding, Reye syndrome, and sensorineural hearing loss, have attracted people's attention for a long time .
Hence, the initial dose of aspirin used in the initial stage of KD is a highly controversial subject. It is necessary to conduct a comprehensive meta-analysis by using the latest clinical evidence to comprehensively evaluate and compare the effects of high-dose aspirin and low-dose aspirin in the initial treatment of KD.
2.1. Research Type
Controlled studies or cohort studies published in China and abroad are the research type; languages are limited to Chinese and English.
2.2. Study Population
The study population was based on the subjects who meet KD-related diagnostic criteria and at the stage of initial use of aspirin, regardless of gender.
2.3. Intervention Measure
Children in the experimental group were treated with high-dose or low-dose aspirin, while children in the control group were treated with different drugs or different doses of aspirin than those in the experimental group.
2.4. Inclusion and Exclusion Criteria
The Population-Intervention-Comparison-Outcome (PICO) strategy was applied for data inclusion. Generally, the stratified patients were children with a clear diagnosis of KD. All qualified studies include IVIG plus aspirin intervention in the treatment of acute KD. The comparison was made between the administration of high-dose (>30 mg/kg/day) aspirin and low-dose (<10 mg/kg/day) aspirin in KD treatment. The observed results included the incidence of CAA, the incidence of IVIG resistance, the duration of fever, and hospitalized stay.
2.5. Literature Search Strategy
An extensive literature search was conducted using keywords [‘Kawasaki syndrome’ OR ‘Lymph node syndrome, mucocutaneous’ OR ‘Kawasaki disease’] AND [‘Aspirin’ OR ‘Acetylsalicylic Acid’ OR ‘Acid, Acetylsalicylic’ OR ‘2-(Acetyloxy)benzoic Acid’ OR ‘Acylpyrin’ OR ‘Aloxiprimum’ OR ‘Colfarit’ OR ‘Dispril’ OR ‘Easprin’ OR ‘Ecotrin’ OR ‘Endosprin’ OR ‘Magnecyl’ OR ‘Micristin’ OR ‘Polopirin’ OR ‘Polopiryna’ OR ‘Solprin’ OR ‘Solupsan’ OR ‘Zorprin’ OR ‘Acetysal’] in [Title/Abstract] to acquire potential qualified studies from public databases of PubMed, Web of Science, Ovid, EMBASE, and Cochrane Library before August 2021. Written language was restricted to English. The selected paper was composed of two authors (L.K. and W.L.) independently to determine whether a study was suitable for inclusion. A third author (G.L.) joined and reassessed the paper when disagreement occurred. After the differences were resolved, all the papers unanimously supported by the authors were selected for meta-analysis.
2.6. Data Extraction
Data from selected papers were collected by two authors (L.K. and G.L.) independently. Information was collected, including publication year, first author’s name, the total number of enrolled patients, clinical characteristics, aspirin dose, IVIG dose, quality evaluation of the study (NOS score), and major and minor outcomes of the patients.
2.7. Quality Evaluation
All enrolled studies received a methodological evaluation by two authors (L.K. and G.L.), respectively, using Newcastle–Ottawa scale (NOS) scoring system. The assessment was based on criteria of participant enrollment, comparability of different treatments, and outcome measurements. Briefly, studies with more than six stars were regarded as high quality and suitable for further analysis.
2.8. Statistical Analysis
After data extraction and evaluation as mentioned above, the relative risk (RR) for dichotomous outcomes and the mean difference (MD) for continuous outcomes were calculated. Statistical analysis was performed using Stata 16.0 statistical software. Results from different studies were pooled and weighted via the inverse variance model. A two-tailed P value of less than 0.05 was considered statistically significant. Once the studies were synthesized, the heterogeneity was assessed with the Q test and I2. Values of I2 less than 25%, from 25 to 50%, and over 50% represented a low, moderate, and high level of heterogeneity, respectively. In addition, subgroup analysis regarding the different aspirin dosages and sample sizes as well as meta-regression test was subsequently performed to exclude inner bias among studies.
3.1. Target Study Enrollment
The model included in the literature is shown in Figure 1. After eliminating duplicates, a total of 614 studies were selected from databases. After reviewing titles and abstracts, 116 articles of interest were identified. All the 116 papers were read in full to evaluate the suitable meta-analysis paper. Finally, nine retrospective cohort studies (RCS) were selected for further analysis.
3.2. Demographic and Clinical Characteristics of Enrolled Studies
The clinical features of all selected studies are summarized in Table 1 [11–19]. According to the recommendations of the American Heart Association and the Japanese Circulation Society, all studies used the same dose of IVIG and different doses of aspirin for treatment. For counting, 12258 involved patients were divided into 2495 patients in the high-dose aspirin group and 9763 patients in the low-dose aspirin group.
Of the nine registered studies, six applied 80 mg/kg as high-dose aspirin treatment, while the other three applied 30 mg/kg. Unanimously, the low-dose aspirin group used a dose of 3–5 mg/kg. Moreover, all studies have reported that the incidence of CAA formation is the main result (Table 2). For secondary outcomes, five studies reported the incidence of IVIG resistance, three studies reported the duration of fever, and three studies reported the length of hospitalized days. Notably, eight out of nine studies received more than six stars in the NOS scoring system, which reflected that they were suitable for further meta-analysis.
3.3. Incidence of Coronary Artery Abnormality
All the CAA occurrence data in the studies were imported into the software Stata SE, and the fixed Mantel–Haenszel model was used to compare between the high-dose and low-dose aspirin groups (Figure 2). The level of heterogeneity was considered at a low level with I2 = 17.6, and P = 0.286 (RR = 1.154 and 95%CI = 1.027–1.316). The result indicated no significant difference between the two groups in CAA incidence. The publication bias was checked with Egger’s test. A P value of 0.579 showed that no obvious publication bias was observed.
According to different aspirin doses recommended by American and Japanese societies for the initial treatment of KD, North America usually uses a high-dose choice of over 80 mg/kg, while Asia often uses a dose of over 30 mg/kg. Therefore, subgroup analysis was further applied to check if different high-dose strategies affect CAA formation (Figure 3). In line with general results previously, subgroups using ≥80 mg/kg or ≥30 mg/kg aspirin exposed only little difference in CAA incidence.
Subsequently, a meta-regression analysis was conducted to determine whether some factors had a significant influence on heterogeneity. Potential factors including the choice for high-dose aspirin treatment and sample size underwent meta-regression analysis. The results showed that the dose of aspirin has little impact on heterogeneity with P value = 0.655 and 95% CI = −1.052–0.750. Similarly, the size of the study might also not have a significant correlation with heterogeneity with P value = 0.775 and 95% CI between −0.759–0.978.
3.4. Incidence of IVIG Resistance
To date, cases with IVIG resistance reported in five out of nine studies were also input into Stata software for analysis (Figure 4). Surprisingly, the result revealed no significant difference between the two groups in the incidence of IVIG resistance (RR = 0.926; 95% CI = 0.594–1.441). However, high heterogeneity (I2 = 90.2%; P = 0.001) implied that inner differences might exist among studies and further investigation is required.
3.5. Duration of Fever and Length of Hospitalization
In addition, other secondary outcomes were evaluated, including the duration of fever and the length of hospitalization. In specific, three studies provided information about the duration of moderate heterogeneous fever (Figure 5). Unsurprisingly, compared with the low-dose group, high dose of aspirin is associated with a shorter duration of fever, reflecting the potential beneficial effects of increasing aspirin dose.
In addition, the length of hospital stay was also checked using data from three papers (Figure 6). Inconsistent with the previous report, the application of high-dose aspirin might be a factor cutting the length of stay in the hospital . Nevertheless, the high heterogeneity was not to be neglected.
In the years after KD was first reported, pediatricians soon realized that a small number of patients died suddenly within two to three weeks after the fever began. It was not long until doctors found that CAA was the main cause of the accidental death [21,22]. Nowadays, in developed countries, KD is recognized as the leading cause of acquired heart disease in children . In the 1980s, a series of clinical trials laid the foundation of the standard treatment of KD. The efficiency single shot of high-dose IVIG plus aspirin has been learned and soon established as the standard therapy for preventing the development of CAA in KD [24,25]. Nevertheless, the dose of aspirin has been controversial for a long time, and its specific mechanism is still unclear.
Because of its anti-inflammatory and antithrombotic properties, aspirin has been used for KD treatment long before it was applied as IVIG, but there is little information about its role in preventing CCA. When evidence accumulated and the predominant role of IVIG in managing CCA formation was eventually established, high-dose aspirin was applied concomitantly and hence added to the standard protocol of KD treatment. Nonetheless, unlike the appropriate dose of IVIG, which has been clarified and accepted unanimously, the optimal dose of aspirin in KD treatment has been debated for a long time. Recent studies proposed that the usage of low-dose aspirin (3–5 mg/kg per day) was not inferior to the higher-dose mentioned above. One study has proposed that the incidence of growing CAA changes little when aspirin was applied in high dose, low dose, and no aspirin at all.
According to these previous reports, the meta-analysis of our study demonstrated that there is no obvious correlation between aspirin dose and the incidence of CAA with minimal heterogeneity. Additionally, the quality and results of the selected cohort were evaluated by NOS score, meta-regression test, and sensitivity analysis. Factors including publication bias, sample size, dosage selection of the high-dose group, or discordant results from individual studies might have no significant impact on the overall conclusion. Although the etiology of KD and KD-related arteritis is still not clear, several factors have been noticed as candidate genes in KD. For example, the activation of immune cells (neutrophil and T cell) and multiple cytokines (TNF-α, IL-6, and IL-10) have been reported to be involved in the pathogenesis of KD and artery injury [26,27]. Unfortunately, the pharmaceutical mechanism of aspirin in CAA formation remains obscure, and well-designed randomized clinical trials would be needed in the future.
Generally, IVIG resistance occurs in 10% of patients, who have a significantly high risk of CAA and other adverse effects . Therefore, the incidence rate of IVIG would be crucial for the outcome of KD patients. Surprisingly, our result showed that there was no preference in the risk of IVIG resistance. However, the high heterogeneity in the analysis was not to be overlooked. In fact, two retrospective studies (Dhanrajani 2018  and Kim 2016 ) with a large sample size concluded that high-dose aspirin was positively linked to reducing the risk of IVIG resistance. Besides, another meta-analysis also carried out a similar conclusion, indicating the complex nature of the subject . Last but not least, a high-dose aspirin was related to a shorter fever time and shorter hospital stay of KD patients, which may be due to the anti-inflammatory property of aspirin.
Based on the meta-analysis, our study has several limitations. Firstly, despite the study aimed to include as many qualified studies as possible, few studies were missing or disputably discarded. Secondly, as all the enrolled papers were retrospective studies, more randomized clinical trials should be added to the analysis to minimize the intrinsic differences between studies. Finally, most studies contained only records of short-term follow-up. The long-term effect of aspirin as the treatment for KD is still unclear.
To conclude, the meta-analysis of our study clearly indicated that the dose of aspirin poses no obvious effects on preventing CAA as well as IVIG resistance in KD patients. However, high-dose aspirin might be linked to a shorter febrile and total hospital stay, compared to patients with low-dose aspirin.
All data applied in this study are included in the published form of the article. Request for more information about datasets would be welcome by contacting the corresponding author.
Conflicts of Interest
The authors declare that they have no conflicts of interest.
K. L. and L. W. collected data and performed analysis and interpretation of the data. L. G. designed the study. K. L. wrote the draft of the manuscript. L. G. helped in revising the manuscript.
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