Acute myocardial infarction caused by Kawasaki disease requires more intensive therapy: Insights from the Japanese registry of All Cardiac and Vascular Diseases—Diagnosis Procedure combination

Kawasaki disease (KD) induces coronary arteritis, which causes subsequent coronary aneurysms, and contributes to acute myocardial infarction (AMI). However, the differences regarding real‐world treatment selection and mortality between AMI‐complicated KD and AMI due to typical atherosclerosis (AMI‐non KD) are unknown.


| Data source
This survey used data from the JROAD-DPC, a nationwide claim database, which was launched in 2004 by the JCS that provides primary data from an annual survey. All teaching hospitals with cardiovascular beds are registered with the JROAD because its participation is mandatory for physicians to become boardcertified cardiologists in Japan. However, the JROAD database does not include individual patient data. The DPC system is a case-mix patient classification system launched by the Ministry of Health, Labor, and Welfare of Japan in 2002 and contains patient demographics and disease-specific data for each patient. The JROAD-DPC database was created by combining the JROAD data derived from a JCS national survey in 2012 and the DPC database. The validity of the DPC database is generally high, especially that of primary diagnoses and procedure records. (2) admission-precipitating diagnosis, (3) most resourceconsuming diagnosis, (4) second most resource-consuming diagnosis, or (5) comorbidities present on admission. Figure 1 shows the flow diagram of the present study. A total of 305,244 patients were diagnosed with AMI as (1) main diagnosis, (2) admission-precipitating diagnosis or (3) most resource-consuming diagnosis. Because KD was first reported in Japan in 1967 and patients were diagnosed when they were infants or young children, patients over 60 years old were excluded from the present study. Finally, a total of 70,300 AMI patients between 0 and 60 years old were analyzed. Among these AMI patients, 70,227 (99.9%) did not have KD (AMI-non KD), and only 73 (0.1%) patients had KD as present or past illness (AMI-KD). In the present study, we compared the differences in treatment and prognosis between AMI-non KD and AMI-KD patients.

| Data collection
Patient characteristics at the time of admission, including age, sex, height, weight, body mass index (BMI), Brinkman index, and comorbidities, were extracted from the claim database. Comorbidities were determined using ICD-10 codes. Invasive treatments during hospitalization, such as PCI, coronary artery bypass grafting (CABG), and intracoronary thrombolysis (ICT), were also extracted from the claim database. Thrombolytic therapy agents were also extracted. In addition, PCI procedures such as percutaneous old balloon angioplasty (POBA), stent and rotablator, and the usage of mechanical support, such as intra-aortic balloon pump (IABP), percutaneous cardiopulmonary support (PCPS), Impella (intravascular microaxial left ventricular assist device), respirator and dialysis, were also extracted from the claim database. Medications that were still being taken at discharge including anticoagulants, antiplatelets, angiotensin converting enzyme inhibitor (ACE-I), angiotensin II receptor blocker (ARB), β-blocker, αβ-blocker and statin were extracted from the claim database. The JROAD-DPC database includes mortality data during hospitalization and after discharge; therefore, short-time mortality data were extracted in the present study.

| Statistical analysis
Categorical variables are expressed as numbers and percentages, and continuous variables are presented as the median (interquartile range). Changes of categorical variables and continuous variables were evaluated using the Chi-square test and Mann-Whitney U test, respectively. Bivariate study analysis was performed by simple logistic regression with calculation of the odds ratio and 95% confidence interval. Multivariate analysis was performed using multiple logistic regression analysis. The threshold for significance was p < 0.05. All statistical analyses were conducted using SPSS version 25.0 (SPSS). Table 1 shows the characteristics of the AMI-non KD (n = 70,227) and AMI-KD patients (n = 73). Compared with the AMI-non KD patients, the AMI-KD patients were younger, included fewer males, and had a lower body weight, BMI and Brickman index. In addition, the AMI-KD patients had a lower incidence of coronary risk factors, such as hypertension, diabetes mellitus and dyslipidemia, than the AMI-non KD patients. Of note, more AMI-KD patients were in Killip class 3 or 4 than the AMI-non KD patients, even though the AMI-KD patients were younger. Table 2 shows treatments during hospitalization and patient prognosis. The percentage of patients who received each revascularization therapy was different between the AMI-non KD and the AMI-KD patients. PCI was selected more often in the AMInon KD patients, whereas CABG was selected more often in the AMI-KD patients. In addition, stentless PCIs using POBA or rotablator were performed more often in the AMI-KD patients.

| RESULTS
Moreover, thrombolytic therapy such as ICT and intravenous coronary thrombolysis with urokinase or monteplase was more often performed in the AMI-KD patients. Compared with the AMI-non KD patients, more the AMI-KD patients needed mechanical support, such as IABP, PCPS and respirator. Medications at discharge were also different. More patients with AMI-KD were treated with anticoagulant therapy using warfarin. Although aspirin was similarly administered in both the AMI-non KD and AMI-KD patients, clopidogrel was less frequently administered in the AMI-KD patients.
In addition, the use of ACE-I/ARB and statin was lower in the AMI-KD patients. Of note, in-hospital cardiopulmonary resuscitation (CPR) incidence was higher in the AMI-KD patients. On the other hand, regarding short and middle-term prognosis, death in 24 h, 7 days, and 30 days after admission were similar between the AMI-non KD and AMI-KD patients. In addition, the length of hospital stay was longer in the AMI-KD patients, despite almost the same the medical costs. Table 3 presents the impact of KD on therapies and prognosis assessed by simple and multivariate regression analysis (n = 70,300). In the multivariate regression analysis adjusted for age, sex, and institution code, KD was significantly associated with lower frequency of PCI and higher frequency of CABG, ICT, intravenous coronary thrombolysis with urokinase or monteplase, mechanical supports by IABP, PCPS or respirator, and in-hospital CPR.
In contrast, presence of KD was not associated with death in 24 h, 7 days, 30 days after admission, and in-hospital death. Even after being adjusted for CABG, these results did not substantially change. Table 4 shows the impact of KD among the AMI patients who underwent PCI (n = 59,298). Focusing on PCI procedure, KD was associated with POBA without stent, rotablator and rotablator without stent, as well as with in-hospital CPR, death in 24 h and 7 days after admission, whereas it was not associated with death in 30 days after admission and in-hospital death.

| DISCUSSION
The major findings of this study using the JROAD database were as follows: (1) revascularization therapy through CABG, rather than PCI, was performed more often in AMI-KD patients than AMI-non KD  Therefore, the 2020 JCS guidelines recommended the usage of warfarin, but not P2Y12 inhibitor, in combination with low-dose aspirin for patients with past history of AMI (Class IIa, level C). 6 Consistent with the recommendation, our data showed that warfarin was more frequently administered at discharge in the AMI-KD patients.
With regard to revascularization therapy, primary PCI is recommended in the early phase of ST-segment elevation myocardial infarction (STEMI) in the 2018 JCS guidelines (class I, evidence level A). 12 As primary PCI has improved the prognosis of STEMI, performance rate of primary PCI in these patients has progressively increased, even in geriatric patients. 13 The safety of early discharge after primary PCI in low risk patients has also been reported. 14 Although primary PCI is also recommended for STEMI complicated with KD (class I, evidence level C) in the 2020 JCS guidelines, 6 there is not enough evidence regarding whether primary PCI should be performed in children with coronary aneurysms complicating KD.
Several studies have shown that PCI for KD resulted in lower efficacy compared with CABG, because PCI needed repeat-revascularization therapy more often and improved ischemia proportion less often. 15,16 In addition, KD patients tended to have coronary chronic total occlusion lesions 17 and multi-vessel lesions. 18

| CONCLUSIONS
The present study using the JROAD-DPC database revealed that, compared with patients with AMI-non KD, more AMI-KD patients underwent non-PCI strategies such as CABG, ICT, and intravenous coronary thrombolysis, and required intensive therapy using IABP, PCPS, or a respirator, but presented similar in-hospital mortality.
When KD patients underwent PCI, stentless PCI using balloon angioplasty or rotablator was performed more often in those with AMI-complicated KD than in those with AMI-non KD. These findings provide new insights into the treatment strategy for AMIcomplicated KD.

ACKNOWLEDGMENTS
We appreciate the contributions of all the investigators, clinical research coordinators, and data managers involved in the JROAD-DPC study.

CONFLICTS OF INTEREST
The authors declare no conflicts of interest.

DATA AVAILABILITY STATEMENT
The data underlying this article were provided by Japanese Circulation Society under licence/by permission. Data will be shared on request to the corresponding author with permission of Japanese Circulation Society.