JJCC-02436; No of Pages 7
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Contents lists available at ScienceDirect

Journal of Cardiology
journal homepage: www.elsevier.com/locate/jjcc

Original Article

Cost-effectiveness analysis of inﬂiximab for the treatment of Kawasaki
disease refractory to the initial treatment: A retrospective cohort study
Tomoyuki Takura (PhD), Sayaka Horiuchi (MD) ⁎Department of Healthcare Economics and Health Policy, Graduate School of Medicine, The University of Tokyo, Tokyo, Japana r t i c l e

i n f oArticle history:
Received 28 December 2021
Received in revised form 4 February 2022
Accepted 7 March 2022
Available online xxxx
Keywords:
Mucocutaneous lymph node syndrome
Inﬂiximab
Intravenous immunoglobulin
Cost-effectiveness analysis

a b s t r a c t
Background: Inﬂiximab (IFX) treatment is approved in Japan for health insurance coverage in patients with Kawasaki disease (KD). This study aimed to compare the cost-effectiveness of IFX and other therapeutic strategies
for KD refractory to initial treatment, including intravenous immunoglobulin (IVIG), steroids, immunosuppressants, and plasma exchange therapy.
Methods: This multicenter, retrospective cohort study utilized data from the public medical insurance system ofJapan. The target population included those who received treatment for KD between April 2012 and March 2019.
Eligibility criteria were as follows: 1) initial onset of KD, 2) age < 15 years at onset, and 3) administration of 3rdline treatment if the 1st line treatment was IVIG alone or 2nd line treatment if the 1st line treatment was a combination of IVIG and steroids, in accordance with Japanese guidelines (2012). Those with KD-related cardiovascular complications before admission and those with congenital cardiac disease were excluded. The primary
outcome was cost-effectiveness, which was calculated based on the number of admission events per annum divided by medical expenses per annum (times/10,000 US dollars). The Wilcoxon test was applied to analyze thedifference in cost-effectiveness between patients who had received IFX and those who had not.
Results: Among 1267 patients with KD, 25 received IFX treatment, while 206 received another treatment after the
disease was designated refractory to initial treatment. The frequency of steroid use during initial IVIG treatment(a predictor of severity) was higher in the non-IFX group than in the IFX group (70.4% vs. 32.0%, p < 0.001) but
became comparable after propensity-score matching. Our analysis indicated that IFX was more cost-effective
than other treatments [1.04 (0.86, 1.34) vs. 1.38 (1.03, 1.79) (times/10,000 US dollars), p = 0.006].
Conclusions: IFX treatment may be more cost-effective than non-IFX treatment for patients with KD that is refractory to initial treatment.
© 2021 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved. This is an open access article
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction
Kawasaki disease (KD) is a vasculitis syndrome speciﬁc to childrenthat mainly affects small- and medium-sized arteries. Cardiac sequelae
such as coronary artery aneurysm (CAA), which occurs in 2–3% of
patients treated for KD [1], can lead to signiﬁcant morbidity or evenmortality [2,3]. However, CAA can be prevented by suppressing inﬂammation early in acute phase treatment.
Initiation of intravenous immunoglobulin (IVIG) (2 g/kg) within 10
days of fever onset has been conﬁrmed to reduce the risk of CAA by approximately 20% (from 25% to <5%) [4–8]. High-dose IVIG (2 g/kg) or
combination with steroid therapy as 1st line treatment has reduced
rates of cardiac sequelae in Japan [9]. However, approximately 20% of⁎ Corresponding author at: Department of Healthcare Economics and Health Policy,
Graduate School of Medicine, The University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo,
Japan.
E-mail address: sayakahoriuchi@gmail.com (S. Horiuchi).

cases remain refractory to 1st line treatment [1]. Refractory cases havebeen associated with a higher risk of cardiac sequelae than that observed in responders, with studies reporting that 48.6–54.0% of patientswith refractory KD may develop CAA [10,11]. Therefore, selection of additional treatments that can suppress inﬂammation is important in refractory cases.
In 2015, the Japanese health insurance system began covering IFX
for the treatment of KD, leading to increases in its use for refractory
cases [12,13]. Several studies have reported that additional IVIG [14],steroid [14], immunosuppressant [15], and plasma exchange [16,17]
treatments are effective in preventing cardiovascular complications inpatients with KD refractory to initial treatment, respectively. However,few studies have compared the effectiveness of these strategies in refractory cases with that of monoclonal antibodies or anti-cytokine biologics, including IFX. A 2019 systematic review that investigated 2ndline therapy in patients with IVIG-refractory KD reported no differencesin coronary outcomes, although they noted that IFX signiﬁcantly reduced the duration of fever when compared with IVIG or steroids [18].

https://doi.org/10.1016/j.jjcc.2022.03.005
0914-5087/© 2021 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved. This is an open access article under the CC BY-NC-ND license (http://creativecommons.
org/licenses/by-nc-nd/4.0/).

Please cite this article as: T. Takura and S. Horiuchi, Cost-effectiveness analysis of inﬂiximab for the treatment of Kawasaki disease refractory to
the in..., Journal of Cardiology, https://doi.org/10.1016/j.jjcc.2022.03.005

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condition of KD; 2) age under 15 years at the time of onset; and 3) administration of 3rd line treatment if the 1st line treatment was IVIG
alone or 2nd line treatment if the 1st line treatment was a combinationof IVIG and steroids.
Exclusion criteria were as follows: 1) recurrent KD, 2) existence ofcoronary/cardiovascular complications prior to admission, and 3) congenital cardiac disease.
The study participants were extracted from TheBD by using age at thetime of medical consultation, main disease name (ICD-10 code), and medical treatment for KD. The dataset contains detailed information on testing, diagnosis, medication, surgery, and any other clinical interventions
with date of initiation. It also contains both suspected and conﬁrmed disease names. Based on the information, we restricted study participants toonly conﬁrmed KD cases. We also conﬁrmed the certainty of diagnosis bychecking testing linked to disease name. Then we searched for all treatments for KD that were prescribed during the target period to identify
the order and number of treatments. As treatment interventions were
not labeled according to the order of initiation in the dataset, we identiﬁed 1st and 2nd line treatment according to the guidelines (2012) byidentifying treatments related to conﬁrmed KD during the initial admission. The identiﬁcation was based on available data such as prescribed
medicines with date of initiation and linked disease name. Then we organized the identiﬁed treatment lines in chronological order. The day on
which additional treatment for refractory KD was initiated was regarded
as the index date, based on the guidelines (2012) (i.e. the date on which
3rd line treatment for refractory KD was initiated when 1st line treatment
included IVIG only or the date on which 2nd line treatment was initiatedwhen 1st line treatment included combination therapy with IVIG and steroids) [22]. Although new guidelines for the medical treatment of acutestage KD in Japan were published in October 2020 [23], the guidelines(2012) were used given that the study participants received treatment
prior to publication of the new guidelines. The study participants were
followed up from the index date until death, loss to follow-up in TheBD,
or the end of the observation period (Fig. 1).

Another study reported that IFX may shorten the duration of hospitalization and consequently reduce medical costs when compared with asecond IVIG treatment for refractory KD [19].
Previous studies have suggested the potential superiority of IFX overother treatments in terms of cost-effectiveness. However, it remains inconclusive whether IFX is more effective in reducing CAA than other therapeutic options. Given the reduced incidence of CAA [9], conducting aclinical trial to evaluate the effectiveness of each treatment in preventing
CAA would not be feasible. Moreover, in real-world settings, additional
treatment for refractory cases may be more complex. Therefore, it is necessary to evaluate the effectiveness of overall treatment for refractory KD
during the acute phase in a real-world setting rather than in an “ideal”
clinical trial setting. The actual beneﬁt of treatment options should be
discussed in terms of both clinical gain and medical expenses [20].
Therefore, in the present study, we aimed to compare the costeffectiveness of IFX and its effectiveness in reducing cardiovascularcomplications with that of non-IFX options for the treatment of KD refractory to initial treatment using real-world data.
Methods
Study design and settingThis multicenter retrospective longitudinal cohort study involved
the use of a large database that includes medical service data examinedby a specialized public organization (Social Insurance Medical Fee Payment Fund), in accordance with the format stipulated by the Ministryof Health, Labour, and Welfare (MHLW Notiﬁcation: Vol. 0831 No. 1).
We selected medical economic big data (TheBD: The Tokyo University
Health Economy Big Data, Supplementary material and the databaseoverview (Online Table 1)) [20,21], which included medical service
bills gathered from public insurers (including health insurance societiesof companies) throughout Japan between April 2012 and March 2019,representing coverage for 7 million insured patients.
As for the sample composition by year, 2016 accounted for the largest proportion (22.1% of the total). Medical information accounted for6.18 million results, while dispensing information accounted for 6.20
million results (including duplications). The patient-based hospitalization rate was 13.5% (including duplications), and the average percentage of male patients for all years was 46.8%. This database is updated
every 6 months. All data on disease name, testing, medication, surgery,any other medical interventions with dates of initiation and related
costs are linked in chronological order using unique IDs for each patient.
During each biannual update, transfer of data for insured persons ismanaged, and adjustments are made according to relocation of medical
facilities. TheBD has been used in several studies that have evaluated theeconomic aspects of medical interventions (Supplementary material
and the database overview (Online Table 1)).

Exposure of interest
The main exposure of interest was receipt of IFX as additional treatment for KD that had been considered refractory to initial treatment.
There is no biosimilar of IFX available in Japan.
Participants who received IFX at any time after the index date wereallocated to the IFX group irrespective of other additional therapies. Participants who did not receive IFX as an additional treatment were allocated to the non-IFX group. Additional treatments other than IFX
included IVIG, steroids, ulinastatin, immunosuppressants, and plasma
exchange [22].
Measurement of effectiveness

Study participants

The primary endpoint was cost-effectiveness, deﬁned as the ratio of
the number of admissions due to KD-related events to the total medical
expenses during the same period (times/10,000 USD). Both the numberof admissions and total medical expenses were converted to annual
amounts after counting the totals for the full observation period, as
this period varied across study participants. The time horizon was set
as 1 year because this is the recommended minimum duration offollow-up for KD irrespective of cardiovascular complications [24], andmost participants had records available 1 year from the index date.
Admission due to KD-related events was deﬁned as initial admission
for treatment in the acute phase or readmission due to recurrent KD or
cardiovascular complications during the observation period. Medical
expenses were deﬁned as all inpatient, outpatient, and laboratory expenses during the same observation period. All services related to the
management of KD or KD-related cardiovascular complications werecovered, including testing/diagnosis, pharmacotherapy, treatment/
surgery, hospitalized recuperation, rehabilitation, outpatient treatment.

The study included patients with KD who had received additional
treatment for KD that was considered refractory to initial treatment. Refractory cases are typically deﬁned based on the presence of persistentor recurrent fever following completion of the initial treatment. However, TheBD does not include data related to fever. Therefore, refractory
cases of KD were identiﬁed based on the receipt of additional treatment
for KD in accordance with the “Clinical Guideline for Medical Treatmentof Acute Stage Kawasaki Disease (2012)” during the same episode of admission, under the assumption that patients with fever would receivenecessary additional treatment in Japan [22]. According to the guidelines (2012), IFX is recommended as 3rd line treatment if the 1st line
treatment was IVIG alone or as 2nd line treatment if the 1st line treatment was combination therapy with IVIG and steroids.
The eligibility criteria were as follows: 1) initial onset of KD with an
ICD-10 code of M30.3, a code that corresponds to the pathological2

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Fig. 1. Study timeline.
IFX, inﬂiximab; IVIG, intravenous immunoglobulin; TheBD, The Tokyo University Health Economy Big Data.

The medical cost was converted from Japanese yen to US dollars using amean rate of 112.23 yen per one US dollar, which was the exchange rate
in 2017. We did not apply the discount rate but instead used the medical
cost in 2017, when most study participants received treatment.
The secondary endpoint was the incidence of cardiovascular complications during the total observation period. Cardiovascular complications were deﬁned as coronary artery complications or any othercardiovascular complications (e.g. ischemic heart disease, valvular abnormalities, arrhythmias, and cardiac or respiratory dysfunction) diagnosed after the onset of KD.

Sub-group analysis
We also performed a sub-group analysis to compare the characteristics and incidence of cardiovascular complications between those who
received IFX as 2nd or 3rd line treatment [22] and those who received
IFX later. This analysis did not involve statistical tests due to the limited
sample size.
Ethical approval and informed consent
This medical economics study, which involved the use of big data,
was given comprehensive approval in March 2019 by the Institutional
Review Board of the University of Tokyo Hospital (screening no:2018167NI). As we used database records for analysis, the need for informed consent was waived (opt-out format).

Analytical methods
Patient background characteristics were compared between thetreatment groups. Student's t-tests or Wilcoxon rank-sum tests andchi-square tests were used for continuous and categorical variables, as
appropriate. Primary and secondary outcomes were summarized andcompared between the two treatment groups using a Wilcoxon ranksum test with a signiﬁcance level of 5%. All analyses were performed
using Stata/MP 16.0 (StataCorp, College Station, TX, USA).

Statement of patient and public involvement
Neither the patients nor the public were involved in the design, conduct, reporting, or dissemination of our research.

Propensity-score matching

Results

For sensitivity analysis, propensity-score (PS) matching was performed by adjusting for differences in background characteristics between the two groups because there was a signiﬁcant difference in theuse of steroids during initial treatment. The signiﬁcance level was set
to 5%, and all tests were two-tailed. PS matching was performed using
sex, age, incomplete KD, liver dysfunction at initial admission, dehydration at initial admission, use of steroids during initial IVIG treatment,
number of IVIG treatments at the initial admission, and the year of theinitial admission. These variables were selected to control for the severity of KD and risk factors for coronary artery complications. Previous
studies have reported that male sex [25], age ≤ 12 months [25,26], resistance to initial IVIG [27,28], and delay in diagnosis [29] are risk factors
for severe KD. However, we could not consider delays in diagnosis or
biomarkers [30] in the propensity score because information regarding
symptom onset and the results of laboratory tests are not recorded in
TheBD. Instead, we considered liver dysfunction and dehydration at initial admission as proxies for disease severity. Incomplete KD was determined according to the registered disease name in TheBD. We could notverify the diagnosis of incomplete KD, as the database does not contain
information regarding symptoms.

Among 7 million patients registered in TheBD, 1267 KD patients met
eligibility criteria for the current study. This was close to the number of
expected cases of KD based on the incidence rate reported in the nationwide survey of KD in Japan (313.4 per 100,000 per year among children
from 0 to 4 years of age on average in 2012–2018) [1]. IFX was used in
26 patients with refractory KD (Fig. 2). One patient was excluded fromthe IFX group and allocated to the non-IFX group since he had received
IFX at the time of recurrence long after the initial treatment. The nonIFX group included 206 patients.
Table 1 shows the background characteristics of the study participants according to treatment group. The proportion of men, mean age,and proportion of incomplete KD were comparable between the IFX
and non-IFX groups. The frequency of steroid use during initial IVIG
treatment was higher in the non-IFX group than in the IFX group(70.4% vs. 32.0%, p < 0.001). However, this frequency became comparable between the two groups after PS matching (32.0% vs. 32.0%) (Online
Table 2, Online Fig. 1).
The median follow-up periods were 366 days [302, 602] in the IFX
group and 467 days [347, 844] in the non-IFX group (Table 2), respectively. The numbers of admissions per annum were 1.21 [0.97, 2.09]
3

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Fig. 2. Study participants. *One patient was excluded from the IFX group and allocated to the non-IFX group since he had received IFX at the time of recurrence long after the initial treatment.
IFX, inﬂiximab; IVIG, intravenous immunoglobulin; KD, Kawasaki disease; TheBD, The Tokyo University Health Economy Big Data.

Discussion

and 1.65 [0.82, 2.31] for the IFX and non-IFX groups (p = 0.645), respectively. The total medical cost per annum was 10,939 USD [8321, 22,950]
in the IFX group and 10,656 USD [6445, 21,549] in the non-IFX group (p= 0.468). The numbers of admissions per medical cost (time/104 USD)
were 1.04 [0.86, 1.34] and 1.42 [0.99, 1.83] in the IFX and non-IFX
groups (p = 0.008), respectively. In the PS-matched analysis, the respective numbers of admissions per medical cost (time/104 USD) for
the IFX and non-IFX groups were 1.04 [0.86, 1.34] and 1.38 [1.03, 1.79](p = 0.006).
During the full observation period, the frequency of cardiovascularand coronary artery complications was lower in the IFX group than in
the non-IFX group (Table 3). However, this difference was not statistically signiﬁcant.
Table 4 compares the background characteristics and outcome measures between patients who received IFX as 2nd or 3rd line treatment[or earlier (i.e. early treatment group)] and patients who received IFX
later (later treatment group). Seven patients received IFX after 3 andmore treatments with alternative medications. The number of days tothe initiation of IFX in the early and late treatment groups was 4.6 ±2.3 and 8.6 ± 5.3, respectively. Medical costs and the incidence of cardiovascular complications tended to be lower in the early treatmentgroup than in the later treatment group; however, statistical analysisof this difference was not possible given the limited number of patients.

The present ﬁndings indicated that use of IFX for KD refractory to initial treatment may be more cost-effective than other treatment options.
After PS matching, improvements in outcomes (numbers of admissions)were observed, and medical costs were slightly lower in the IFX groupthan in the non-IFX group. Consequently, the position was close to“dominant” in the cost-effectiveness plane, and the performance wasconsidered excellent [31,32]. This means that expanded use of IFX for
KD refractory to intimal treatment may reduce both disease and economic burden.
A cost-effectiveness analysis generally compares the costs associatedwith drug therapy (or full practice) with the clinical outcome (or safety)of the intervention [33]. Therefore, our analysis was slightly unusual inthat we compared the cumulative number of admissions (events during
the observation period) per cumulative cost of public health insurance
between patients who received IFX and those who did not. This was because it was difﬁcult to perform statistical analyses due to the limited
number of patients with cardiovascular complications. However, as
most readmissions occur due to the existence of cardiovascular complications, we considered the number of admissions a good surrogate forhealth outcomes. Although the difference was not signiﬁcant, the incidence of cardiovascular complications tended to be lower in the IFX
group than in the non-IFX group. This tendency may be reﬂected in
the number of admissions, which was signiﬁcantly lower in the IFX
group than in the non-IFX group.
We aimed to capture the cost-effectiveness of treatment during theoverall period from the standpoint of a public insurer with the wide perspective including patients with various backgrounds and severity ofcomplications in different health facilities. We consider that choice ofinitial treatment can inﬂuence long-term health outcomes through severity of complications. Therefore, we have adjusted for surrogates ofrisk factors for coronary artery complications such as use of steroid as
the combination therapy for the 1st line treatment. However, thedataset did not contain data on size of the coronary artery complicationor other relevant data on severity. The lack of information on the severity of complications was a limitation of this study. Nonetheless, even if
available, ability of the clinical information of severity such as z-score
to adjust the variation in the cost-effectiveness may be limited becauseof measurement errors due to variations among examiners. It was

Table 1
Participant characteristics according to treatment group (N = 231).
Variables
Baseline
Sex
Male
FemaleAge at onset (year)
Incomplete KD
Use of steroids during initial IVIG treatment
Number of IVIG treatments at the ﬁrst admission

IFX(n = 25)

Non-IFX(n = 206)

16 (64.0)
9 (36.0)
3.0 [1.6]
1 (4.0)8 (32.0)
2.2 [0.7]

134 (65.1)
72 (35.0)
2.5 [1.9]
11 (5.3)
145 (70.4)
2.5 [0.8]

p-Valuea

0.917

0.213
0.776
<0.001
0.186

Numbers are presented as n (%), mean [standard deviation].
IFX, inﬂiximab; IVIG, intravenous immunoglobulin; KD, Kawasaki disease.
a
The Wilcoxon rank-sum test was applied.
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Table 2Comparison of the number of admissions, medical costs, and cost-effectiveness.
Unmatched

Before annual conversion

PS matched

IFX(N = 25)

Non-IFX(N = 206)Median[Q2, Q3]

Median[Q2, Q3]

IFX(N = 25)

Non-IFX(N = 100)

p-Valuea

Follow-up duration (days)

366 [302, 602]

467 [347, 844]

0.166

–

–

–

Number of admissions

1.56 [1.0, 2.0]

2.19 [1.0, 2.0]

0.007

–

–

–

Total medical cost (USD)

15,574.2[10,904.0, 18,988.9]

19,420.1[9699.8, 20,880.2]

0.842

–

–

–

UnmatchedPS matched

IFX(N = 25)

Non-IFX(N = 206)Median[Q2, Q3]

Median[Q2, Q3]

Number of admissions (per annum)

1.21[0.97, 2.09]

1.65[0.82, 2.31]

Total medical cost (USD per annum)

10,939[8321, 22,950]
1.04[0.86, 1.34]

10,656[6445, 21,549]
1.42[0.99, 1.83]

After annual conversion

Number of admissions per medical cost (time/104 USD per annum)

IFX(N = 25)

Non-IFX(N = 100)

Median[Q2, Q3]

Median[Q2, Q3]

0.645

1.21
[0.97, 2.09]

1.79[0.86, 3.25]

0.319

0.468

10,939[8321, 22,950]
1.04[0.86, 1.34]

11,791[7433, 26,209]
1.38[1.03, 1.79]

0.941

p-Valuea

0.008

p-Valuea

0.006

IFX, inﬂiximab; PS, propensity score; SD, standard deviation; USD, United States dollars.
a
The Wilcoxon rank-sum test was applied.

of databases containing detailed clinical information and those withlarger sample sizes are required to verify the effects of early initiationof IFX treatment on health outcomes in patients with KD refractory toinitial treatment.
The strength of this study is that TheBD contains representative data
for a large number of patients and hospitals across Japan, meaning thatthe results can be generalized to the Japanese population. Secondly,
TheBD data reﬂect the real-world situation of KD treatment in Japan.
Analyses of real-world data are most suitable for cost-effectivenessanalysis. However, this study was not without limitations. First, thesample size, especially in the IFX group, was not large enough to perform statistical comparisons of the occurrence of cardiovascular complications. As IFX is a relatively new medicine that has only been coveredby public health insurance since 2015, its use in patients with KD remains limited to some hospitals despite a recent increase [12,13]. Second, several clinical variables are not included in the database, such as
fever, symptoms, biomarker levels, and size of coronary artery aneurysm. The presence of fever is clinically important when attempting to
conﬁrm refractory cases [22,23]; however, in this study, cases inwhich additional treatments were performed were regarded as refractory instead. This assumption is reasonable, as patients can usually receive necessary treatment in the Japanese medical system. Symptoms

reported that there is heterogeneity in z-score calculation especiallywhen coronary artery dimensions vary [34]. Further study will beneeded to consider the severity of complications in calculation of costeffectiveness using the standardized measurement methods.
Cumulative medical costs, the element of cost-effectiveness, are reported to be skewed to the severe cardiovascular lesions [35,36]. Although the medical fee system does not change the unit price basedon category of complications of KD, we also see the skewness in medical
costs among patients with coronary artery complications in this study,
reﬂecting a displacement in consumption of medical resources. Thus,
we consider that severity of complications is reﬂected in the cumulative
medical cost of the medical service bills produced based on the content(pharmacotherapy, inpatient treatment) and density (number of times,
number of days) of medical treatments. Overall, we consider that the severity of complications is an important factor for both health outcomes
and cumulative medical cost, but its inﬂuence on cost-effectiveness islimited.
Additionally, the present preliminary study indicates that earlier initiation of IFX (as 2nd or 3rd line treatment) may reduce the risk of cardiovascular complications as well as medical costs in patients withinitially refractory KD. Notably, patients who receive IFX after several
other treatments may exhibit severe disease and have a high risk of developing cardiovascular complications [12]. However, it was difﬁcult toevaluate the potential reverse causation, as the chronological order of
IFX initiation and the onset of cardiovascular complications was notclear based on the medical big data used in this study. Further studies

Table 4Comparison of characteristics and outcome measures with respect to timing of IFX initiation (N = 25).
Variable

Table 3Comparison of outcome measures according to treatment group (N = 231).
IFX(n = 25)

Non-IFX(n = 206)

p-Valuea

Additional treatment during the ﬁrst admission
Plasma exchange
2 (8.0)Immunosuppressant
1 (4.0)20 (9.7)
22 (10.7)

0.783
0.292

At the end of observation period
Cardiovascular complications
Coronary artery complications

70 (34.0)
48 (23.3)

0.316
0.198

Variables

6 (24.0)
3 (12.0)

Numbers are presented as n (%).
IFX, inﬂiximab.
a
The Wilcoxon rank-sum test was applied.

Early(N = 18)

Late(N = 7)

Baseline
Sex
Male
FemaleAge (years)

13 (72.2)
5 (27.8)
3.1 [1.7]

3 (42.9)
4 (57.1)
2.9 [1.2]

At the end of the observation period
Days to IFX initiation
Total medical cost (USD)
Cardiovascular complications
Coronary artery complications

4.6 [2.3]
1490 [754]
3 (16.7)
1 (5.6)8.6 [5.3]
1730 [658]
2 (28.6)
2 (28.6)

Numbers are presented as n (%) or mean [standard deviation] values.
IFX, inﬂiximab; USD, United States dollars.
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TT and SH had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

are also important for conﬁrming cases of incomplete KD. We considered patients to have incomplete KD if the disease name “incompleteKD” was registered in the database, although the frequency of incomplete KD may have been underestimated if not all cases of incomplete
KD were registered. Furthermore, measurements of biomarker levels
are necessary to control for disease severity [37], and the lack of thesedata may have affected the comparability of the two groups. Nonetheless, we attempted to make the two groups homogeneous by applying
PS matching using available data such as sex, age, type of KD, existenceof liver dysfunction and dehydration at admission, and the use of steroids during initial IVIG treatment. Notably, the use of steroids duringinitial IVIG treatment has been associated with disease severity, andsuch treatment is recommended for patients with high risk scores [9].
Third, only the months of diagnosis and treatment were available forsome participants. Without the exact date of diagnosis and treatment
initiation, it was difﬁcult to determine whether cardiovascular complications preceded the initiation of treatment. We excluded patients diagnosed with cardiovascular/coronary artery complications before thedate of admission only when data were available. Patients who received
IFX at a later time may have developed complications before treatment,
which may have resulted in underestimation of the effectiveness of IFX.
Also, we had to assume the timing of additional treatment based on
available data such as name and dose of medicines, timing of testing,and diagnosis for some patients who did not have date of treatment initiation. This uncertainty may have led to bias to some extent. Fourth, ourcost-effectiveness analysis considered only limited events such as thenumber of admissions. Coronary artery and cardiovascular complications, which are clinically important outcomes, were not consideredowing to the limited number of events. Finally, the present study did
not consider quality of life (QoL), which is an important health outcome
in cost-effectiveness analysis [38]. QoL information was not available inthe dataset, and QoL has not been measured in Japanese patients with
KD. Further research is required to evaluate the incremental costeffectiveness ratio (ICER) using QoL data. Despite these limitations,
our study offers important implications for clinical practice and future
research.

Data sharing
Owing to the sensitive nature of the data collected for this study,
data supporting the ﬁndings of the study are available from the corresponding author upon reasonable request.
Declaration of competing interest
The authors have nothing to declare.
Acknowledgments
This work was reported at the 13th International Kawasaki Disease
Symposium held on October 29–31, 2021.
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Conclusion
The results of the current study indicate that IFX may be more costeffective than other treatment options in patients with KD refractory toinitial treatment with IVIG. Our ﬁndings may aid clinicians in selecting
additional treatment strategies in this population. Although the frequency of cardiovascular/coronary artery complications was lower in
the IFX group and those in whom IFX treatment was initiated early, statistical analysis of these differences was not possible due to the small
number of patients. Further studies with the larger number of participants are required to conﬁrm the differences in health outcomes between patients treated with and without IFX and between early andlater initiation of IFX. Analyses of the ICER that consider patient QoL
also remain necessary.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.jjcc.2022.03.005.
Funding
This work was supported by Ministry of Health, Labour, and Welfareof Japan (19FC2001). The funding agency was not involved in the study
design, data analysis, or interpretation of the present ﬁndings.
CRediT authorship contribution statement
SH conceptualized the study. TT and SH designed the study and analysis strategy. SH performed data analysis, and TT and SH interpreted thedata. TT and SH drafted the manuscript and approved the ﬁnal version.
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