Cost-Effectiveness of Dapagliflozin for Chronic Kidney Disease in Japan

Abstract

Background: The cost-effectiveness of sodium-glucose cotransporter 2 (SGLT2) inhibitors for chronic kidney disease (CKD) has not been evaluated in Japan, so we analyzed the cost-effectiveness of dapagliflozin, an SGLT2 inhibitor, for CKD stages 3a and 3b.

Methods and Results: We used the Markov model for CKD to assess the costs and benefits associated with and without dapagliflozin from a health system perspective. We estimated the incremental cost-effectiveness ratio (ICER), expressed as per quality-adjusted life-years (QALYs). An ICER <5 million Japanese yen (JPY)/QALY was judged to be cost-effective. The effect of dapagliflozin on renal and cardiovascular events was based on published clinical trials. In patients with CKD stage 3a, the ICER of dapagliflozin over standard treatment was 4.03 million JPY/QALY gained. With a cost-effectiveness threshold of 5 million JPY/QALY gained, the cost-effectiveness probability of dapagliflozin over standard treatment was 52.6%. In patients with CKD stage 3b, the ICER of dapagliflozin over standard treatment was 0.12 million JPY/QALY gained. The cost-effectiveness probability of dapagliflozin over standard treatment was 75.2%.

Conclusions: The results seemed to show acceptable cost-effectiveness when dapagliflozin was used for CKD stage 3b. On the other hand, cost-effectiveness of dapagliflozin for CKD stage 3a was ambiguous, and further validation is needed.

In recent years, the number of patients with heart failure (HF) has rapidly increased in Japan as the number of older people has increased, and is termed a “heart failure pandemic”.¹ Chronic kidney disease (CKD) is an important risk factor for HF,² so its treatment should curb the increase in patients with HF.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been reported to be useful for treating CKD,³ although they were originally developed as drugs that lower blood glucose concentrations by inhibiting glucose reabsorption in the renal proximal tubule.⁴ Many studies have shown that SGLT2 inhibitors not only improve glycemic control in patients with diabetes, but also suppress cardiovascular events in those patients.^5–9 Many renal protective effects of SGLT2 inhibitors in diabetic patients have been reported,^6,7,10 as well as efficacy for CKD.³ The Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) trial³ was a randomized, controlled trial that examined the effectiveness of dapagliflozin, an SGLT2 inhibitor, for CKD, in the presence or absence of diabetes. It showed that dapagliflozin prevented HF and hemodialysis (HD), and improved the prognosis in patients with CKD. The efficacy of SGLT2 inhibitors for CKD was also confirmed in a meta-analysis that included subanalyses of randomized, controlled trials of SGLT2 inhibitors in patients with diabetes.¹¹ Prescribing SGLT2 inhibitors to patients with CKD may be useful in preventing HF, but the number of patients with CKD is extremely large. In Japan approximately 8 million patients have CKD stage 3a and 1 million have CKD stage 3b, and prescribing SGLT2 inhibitors to all CKD patients may increase medical costs.¹²

The rapid increase in medical expenses has become a social problem in Japan. Since 2019, cost-effective analyses, which provide a guide to the effective use of limited medical resources, have been incorporated into the Japanese medical administration system. Studies have been performed on the cost-effectiveness of SGLT2 inhibitors for diabetes,^13–17 and some have also investigated the cost-effectiveness of SGLT2 inhibitors for HF.^18–20 Although there have been cost-effectiveness studies on SGLT2 inhibitors for CKD with and without diabetes mellitus in various countries, none has examined the cost-effectiveness of SGLT2 inhibitors for CKD in Japan.^21–23 The frequency of cardiovascular and renal events differs between the USA, Asian countries and Japan, and the medical systems also differ, so cost-effectiveness perspectives will not be the same. There are differences in the gross national product between Thailand and Japan, and therefore cost-effectiveness assessment results may differ between these countries. Herein, an analysis of the cost-effectiveness of SGLT2 inhibitors for CKD in Japan was the aim of this study, focusing on dapagliflozin.

Methods

An economic model was developed to evaluate the cost-effectiveness of dapagliflozin for CKD. We used the data from a large-scale clinical trial involving patients with CKD that was not limited to diabetic nephropathy. The model compared patients with and without dapagliflozin under standard treatment over a 20-year observation period from the perspective of the Japanese healthcare system. The Markov model was used to predict death, introduction of HD, and HF in Japanese patients with CKD stage 3a (estimated glomerular filtration rate: 45–59 mL/min/1.73 m²) and those with CKD stage 3b (estimated glomerular filtration rate: 30–44 mL/min/1.73 m²). The frequency of introducing HD and the incidence of HF differ greatly between CKD stages 3a and 3b. Therefore, the cost-effectiveness of dapagliflozin was evaluated separately for CKD stages 3a and 3b. The effect of dapagliflozin was estimated on basis of the DAPA-CKD trial,³ which was a randomized, controlled trial that investigated the efficacy of dapagliflozin in 4,304 patients with CKD. It reported that dapagliflozin was effective for preventing HF and HD, and improving the prognosis in patients with CKD, regardless of the presence or absence of diabetes. To determine the event incidence in our study, we used data from the Chronic Kidney Disease Japan Cohort (CKD-JAC), which is an important CKD registry study in Japan.^24–26 The CKD-JAC was a multicenter, prospective cohort study of patients aged between 20 and 75 years, in which 2,966 patients with stage 3, 4 or 5 CKD in Japan were observed for 4 years. Patients visited a clinic every 6 months for a direct follow-up visit. The main analysis of the present study was the incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY). On the basis of previous studies in Japan, the ICER defined <5 million Japanese yen (JPY)/QALY as cost-effective.^27,28 This analysis was conducted in accordance with the Integrated Health and Economic Assessment and Reporting Standards statement and Japanese guidelines.^28,29

This study was granted an exemption from a request for ethical approval by the Institutional Review Board of The University of Tokyo (reference no. 2021375NIe).

Model

The Markov model in combination with Monte Carlo simulations was used to estimate the efficacy and cost of dapagliflozin in patients with CKD stage 3a or stage 3b. The Markov model is a system that has multiple internal states and stochastic transitions between these states; the future state is determined only by the present state. The Markov model started from the CKD state and moved to hospitalization for HF, HD, and death based on the event (Figure 1). If there was no event, the model remained in the CKD state. The Markov models were evaluated with an annual cycle.

Figure 1.

Markov model of the effects of dapagliflozin on chronic kidney disease (CKD). Patients were classified into 1 of 4 health conditions: CKD, hemodialysis (HD), hospitalization for heart failure (HF), and death. The model applies to each annual cycle. Each year, patients can move in the direction of any arrow. In this model, all patients started with the condition of CKD.

Population and Intervention

The target patients were from the CKD-JAC study.^24–26 The average age was 60.3 years, 62% of patients were male, 38% had diabetes, 94% had hypertension, and 24% had vascular disease. Standard treatment was based on guidelines, such as energy restriction, salt restriction, protein restriction, smoking cessation, and blood pressure control, with a stable optimized dose of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker.^30,31 In the dapagliflozin group, 10 mg of dapagliflozin was used once daily in addition to standard treatment.

Time Horizon

The observation period of the model was set to 20 years, which was considered to be sufficient to estimate cost-effectiveness of dapagliflozin, because the target patients in the model were in their 60 s. Taking into consideration the effect of the observation period on the results, a scenario analysis evaluated observation periods of 10 or 30 years.

Mortality and Morbidity

Table 1 shows the morbidity and mortality of the standard treatment and dapagliflozin groups of patients with CKD stage 3a or stage 3b.^{3,11,24–26,32,33} In the models for CKD stage 3a and CKD stage 3b under standard treatment, annual mortality, introduction of HD, and hospitalization for HF rates were 0.4%, 0.45%, and 0.1%, and 0.7%, 1.31%, and 0.6%, respectively.^24–26 The event-lowering effect of dapagliflozin was not significantly different between CKD stages 3a and 3b; therefore, the same values were used.¹¹ The effect on mortality, need for HD, and hospitalization for HF was 0.69, 0.66, and 0.71, respectively.³

Table 1. Main Parameters Used in the Model

Parameter	Value (range for probabilistic sensitivity analyses)	Reference
Death (%)	CKD stage 3a, 0.4	24, 25
	CKD stage 3b, 0.7
Hemodialysis (%)	CKD stage 3a, 0.45	25, 26
	CKD stage 3b, 1.31
Hospitalization for HF (%)	CKD stage 3a, 0.1	24, 25
	CKD stage 3b, 0.6
Intervention effect
Death	0.69 (0.53–0.88)	3
Hemodialysis	0.66 (0.48–0.90)	3
Hospitalization for HF	0.71 (0.55–0.92)	3
Cost (/year) (JPY)
CKD follow-up cost	337,000 (160,000–570,000)	37, Expert opinion
Dapagliflozin treatment	100,000	Estimate
Hospitalization for HF cost	1,055,000 (36,000–4,100,000)	14
Hemodialysis cost	5,094,000 (4,200,000–6,090,000)	38
Death cost	1,900,000 (1,100,000–2,800,000)	39
Utility
CKD	0.88 (0.86–0.91)	34
Hospitalization for HF	0.68 (0.64–0.72)	35
Hemodialysis	0.77 (0.24–1.0)	36

CKD, chronic kidney disease; HF, heart failure; JPY, Japanese yen.

Utility

In this analysis, QALYs were measured using the EuroQol 5 dimension (EQ-5D) questionnaire, and used as a measure of results. On the basis of previous studies, quality of life (QOL) for CKD, HD, and hospitalization for HF were set to 0.88, 0.77, and 0.68, respectively.^34–36 In accordance with Japanese guidelines, all utilities were discounted at 2%/year.^28,29

Costs

Economic estimates were carried out from the perspective of the Japanese healthcare system. Costs included medicine, outpatient visits, and hospitalization costs, but did not include transportation or family care costs. Dapagliflozin (10 mg) costs 274 JPY, and the annual cost is estimated to be 100,000 JPY. Table 1 shows the cost data and their sources. The cost of follow-up and complications was estimated from previous studies.^14,37–39 In accordance with Japanese guidelines, all costs were discounted at 2%/year.^28,29 In this study, 1 US dollar was considered to be 115 JPY.

Scenario Analyses

Several scenario analyses were performed to investigate the validity of the main analysis. We performed a scenario analysis that estimated the therapeutic effect from the data of a meta-analysis of SGLT2 inhibitors for CKD.¹¹ Hazard ratios for death, dialysis, and HF were 0.82, 0.68, and 0.61, respectively. We performed a scenario analysis when the frequency of events was similar to that in the DAPA-CKD trial. In that scenario, the annual mortality rate, HD introduction rate, and HF incidence rate were set higher than in the main analysis (CKD-JAC). We performed a scenario analysis when the mortality-lowering effect of dapagliflozin was 0% or 15%. We also performed a scenario analysis when the reduction in HD effect of dapagliflozin was 0%. Additionally, we performed a scenario analysis for diabetic nephropathy. On the basis of previous reports, we hypothesized that diabetic nephropathy increases annual mortality, the introduction of HD, and the HF incidence.⁴⁰ We performed a scenario analysis when the observation period was 10 or 30 years. We conducted a scenario analysis considering the deterioration of renal function over time in CKD. The Markov model was changed in the renal function deterioration model (Supplemental Figure). Items such as renal function deterioration over time and mortality rate for each renal function were described in existing studies (Supplementary Table).^24,26,41,42

Sensitivity Analyses

Several sensitivity analyses were performed to ensure the robustness of this study. A one-way deterministic sensitivity analysis was performed to evaluate the effects of QOL and cost parameters, and the results were summarized in a tornado diagram. In a probabilistic sensitivity analysis, we statistically examined the effects of uncertainty on all input parameters. The parameter distribution (β or γ distribution) was selected according to the type of parameter. We estimated the range of parameters, and ran 100,000 simulations and created cost-effectiveness plots. On the basis of a previous report, the cost-effectiveness cutoff point was set at 5 million JPY.^27,28 We created a cost-effectiveness tolerance curve and defined a maximum willingness-to-pay as a threshold of 5 million JPY/QALY to assess the probability that one treatment would be more cost-effective than another. The analyses were performed using TreeAge Pro 2020 software (TreeAge Software, LLC, Williamstown, MA, USA).

Results

Main Results

The main results of the analysis are shown in Table 2. In patients with CKD stage 3a, over the 20-year observation period, the costs of dapagliflozin and standard treatment were 10.1 million JPY and 8.9 million JPY, respectively. The effects were 16.9 QALYs and 16.6 QALYs, respectively. The ICER of dapagliflozin over standard treatment was 4.03 million JPY/QALY gained. In patients with CKD stage 3b, over the 20-year observation period, the costs of dapagliflozin and standard treatment were 12.8 million JPY and 12.7 million JPY, respectively. The effects were 16.2 QALYs and 15.6 QALYs, respectively. The ICER of dapagliflozin over standard treatment was 0.12 million JPY/QALY gained.

Table 2. Cost-Effectiveness of Dapagliflozin

Arm	Cost (JPY)	QALY	ICER/QALY (JPY)
CKD stage 3a
Dapagliflozin	10.1 million (6.5–14.7 million)	16.9 (12.1–19.3)	4.03 million
Standard treatment	8.9 million (5.1–13.6 million)	16.6 (11.9–19.0)
CKD stage 3b
Dapagliflozin	12.8 million (8.7–17.8 million)	16.2 (11.7–18.5)	0.12 million
Standard treatment	12.7 million (8.4–17.9 million)	15.6 (11.3–17.9)

CKD, chronic kidney disease; ICER, incremental cost-effectiveness ratio; JPY, Japanese yen; QALY, quality-adjusted life-year.

Scenario Analyses

The results of the scenario analyses are shown in Table 3. In the scenario analysis based on the meta-analysis results, the ICER of dapagliflozin over standard treatment of CKD stage 3a was 4.92 million JPY/QALY gained, and the ICER of CKD stage 3b was 0.91 million JPY/QALY gained. In patients with CKD stage 3a, the ICER of dapagliflozin over standard treatment was 0.38 million JPY/QALY gained, assuming that the frequency of events was similar to that in the DAPA-CKD trial. In the scenario that considered renal function deterioration, the ICER of dapagliflozin was dominant (less cost and more effect) in CKD stage 3a. Additionally, the ICER of dapagliflozin over standard treatment was 9.91 million JPY/QALY gained, assuming that the reduction in HD effect of dapagliflozin was 0%.

Table 3. Scenario Analyses

Dapagliflozin vs. standard treatment	ICER/QALYs (JPY)
CKD stage 3a
Meta-analysis	4.92 million
DAPA-CKD population	0.38 million
CKD with DM	2.36 million
Mortality reduction: 0%	10.32 million
Mortality reduction: 15%	5.68 million
HD reduction: 0%	9.91 million
Time horizon: 10 years	11.40 million
Time horizon: 30 years	2.27 million
Renal function deterioration model	Dominant
CKD stage 3b
Meta-analysis	0.91 million
DAPA-CKD population	Dominant
CKD with DM	Dominant
Mortality reduction: 0%	Dominant
Mortality reduction: 15%	Dominant
HD reduction: 0%	5.53 million
Time horizon: 10 years	2.56 million
Time horizon: 30 years	Dominant
Renal function deterioration model	Dominant

DAPA-CKD, Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease; DM, diabetes mellitus; HD, hemodialysis. Other abbreviations as in Table 2.

In patients with CKD stage 3b, the ICER of dapagliflozin over standard treatment was dominant (less cost and more effect) in various scenarios. However, the ICER of dapagliflozin was 5.53 million JPY/QALY gained, assuming that the reduction in HD effect of dapagliflozin was 0%.

Deterministic Sensitivity Analysis

Differences in the cost-effectiveness ratio results based on the various one-way sensitivity analyses are shown in Figure 2. In CKD stage 3a, the tornado diagram showed that the QOL value of CKD had the greatest effect on the ICER among the parameters of cost and QOL (Figure 2A). The cost and QOL of hospitalization for HF had little effect on the ICER. In CKD stage 3b, the cost of HD had the greatest effect on the ICER, followed by the cost of CKD (Figure 2B). The QOL value of hospitalization for HF and the QOL value of HD had little effect on the ICER.

Figure 2.

Tornado plots showing results from deterministic one-way analysis. The vertical axis shows the change in parameter, and the horizontal axis shows the change in the incremental cost-effectiveness ratio (ICER) value. Each parameter is changed in consideration of the probability distribution, and shows how much the ICER changes with a change in the parameter. In chronic kidney disease (CKD) stage 3a, the effect of the quality of life (QOL) value for CKD was large, and the effect of the QOL value and cost value for hospitalization for heart failure (HF) was small (A). In CKD stage 3b, the effect of the parameters was small as a whole compared with that in CKD stage 3a (B). The effect of the cost value of hemodialysis (HD) and the cost value of CKD was large, and the effect of QOL values of HF and HD was small. EV, estimated value; WTP, willing to pay.

Probabilistic Sensitivity Analysis

The simulated cost-effectiveness of dapagliflozin is shown in Figure 3. In CKD stage 3a, many points were distributed almost evenly above and below the line for an ICER of 5 million JPY/QALY gained (Figure 3A). In CKD stage 3b, the improvement of QALYs with dapagliflozin was larger than with standard treatment, and many points were distributed below the line of 5 million JPY/QALY gained (Figure 3B). The dapagliflozin cost-effectiveness acceptability curves over standard treatment are shown in Figure 4. With a cost-effectiveness threshold of 5 million JPY/QALY gained, the dapagliflozin cost-effectiveness probability over standard treatment was 52.6% in patients with CKD stage 3a (Figure 4A). The dapagliflozin cost-effectiveness probability over standard treatment was 75.2% in patients with CKD stage 3b (Figure 4B).

Figure 3.

Cost-effectiveness plots for dapagliflozin over standard treatment in (A) chronic kidney disease (CKD) stage 3a and (B) CKD stage 3b based on 100,000 simulations with a decision-analytic model. Ellipses show 95% confidence intervals. Solid lines show the willingness-to-pay with a slope of 5 million Japanese yen/quality-adjusted life-year (QALY) gained. The red dots distributed above the solid line indicate poor cost-effectiveness, and the green dots distributed below the solid line indicate good cost-effectiveness. In patients with CKD stage 3a (A), costs of dapagliflozin were higher than those for standard treatment, achieving more QALYs than standard treatment. In patients with CKD stage 3b (B), costs of dapagliflozin were slightly higher than those for standard treatment, achieving better QALYs than standard treatment.

Figure 4.

Dapagliflozin cost-effectiveness acceptability curve compared with standard treatment. The vertical dotted line shows willingness-to-pay at 5 million Japanese yen. (A) Dapagliflozin was incrementally cost-effective compared with that of standard treatment in 52.6% of simulations in CKD stage 3a. (B) Dapagliflozin was incrementally cost-effective compared with that of standard treatment in 75.2% of simulations in patients with CKD stage 3b.

Discussion

The addition of dapagliflozin was cost-effective in patients with CKD stage 3b, with an ICER <5 million JPY/QALY gained, compared with standard treatment. In most of the scenario analyses, the addition of dapagliflozin for patients with CKD stage 3b gained more QALYs at less cost and was more cost-effective compared with standard treatment. In patients with CKD stage 3a, the ICER was <5 million JPY/QALY in the main analysis, but exceeded 5 million JPY/QALY in many scenario analyses. In the sensitivity analysis, the probability that an ICER would be just less than 5 million JPY was 52%. Our findings suggest that the cost-effectiveness of dapagliflozin for CKD stage 3a should be carefully evaluated.

This study showed that dapagliflozin was cost-effective for CKD stage 3b. The acquisition of QALYs in the dapagliflozin group was much higher than in the standard treatment group because dapagliflozin has a strong effect on renal and cardiac events. Not only the main analysis based on DAPA-CKD, but also the scenario analysis based on the meta-analysis was cost-effective for dapagliflozin. Therefore, dapagliflozin is likely to be cost-effective for CKD stage 3b. The tornado diagram showed that the cost of HD had a large effect on the ICER. The reduction in the need for HD by SGLT2 inhibitors was shown in the meta-analysis.¹¹ Taken together, the findings indicated that dapagliflozin showed acceptable cost-effectiveness because the rate of introduction of maintenance HD and the HD cost (5 million JPY/patient/year) were lower in the dapagliflozin group compared with the standard treatment group. Previous studies have also shown good cost-effectiveness of SGLT2 inhibitors for CKD.^21–23 Consequently, SGLT2 inhibitors may be cost-effective for CKD stage 3b.

In the main analysis of CKD stage 3a, the ICER was 4 million JPY/QALY, which was judged to be just cost-effective, but many of the scenario analyses showed that the addition of dapagliflozin was not cost-effective. The probability sensitivity analysis also showed a 52% chance of dapagliflozin being cost-effective for CKD stage 3a. The difference in cost-effectiveness between CKD stage 3a and stage 3b might be due to the difference in prevalence of events, especially the introduction of HD. In patients with CKD stage 3a, the rate of introduction of HD was 0.45%/year, and few patients needed to initiate HD. Therefore, improvement in the cost-effectiveness of dapagliflozin resulting from its effect on reducing HD was limited. Furthermore, in patients with CKD stage 3a, a scenario analysis of high-risk patients, such as those with diabetic nephropathy, suggested that dapagliflozin was cost-effective especially for high-risk patients. Additionally, dapagliflozin showed dominant cost-effectiveness for CKD stage 3a in the scenario analysis considering the inhibitory effect on renal function deterioration. A study in the USA that examined CKD stage 3a showed that dapagliflozin was cost-effective.²² We believe that the low event incidence in the CKD-JAC, which is a Japanese cohort study, led to a different tendency from the finding in the USA. Cost-effectiveness of dapagliflozin for CKD stage 3a in a Japanese population with a low event incidence needs to be carefully evaluated.

The results of this study were compared with those of other studies of the cost-effectiveness of SGLT2 inhibitors. A cost-effectiveness study of empagliflozin in patients with diabetes in the USA showed good cost-effectiveness.¹³ The cost-effectiveness of SGLT2 inhibitors in patients with diabetes is also being investigated in Japan. The ICER of empagliflozin in patients with diabetes was 415,849 JPY/QALY, which was good.¹⁴ A cost-effectiveness study of dapagliflozin in patients with HF using DAPA-HF data in the USA showed good cost-effectiveness.¹⁹ The cost-effectiveness of empagliflozin in Japanese patients with HF was examined using EMPEROR-Reduced data, and the cost-effectiveness was $24,046/QALY, which was good.²⁰ SGLT2 inhibitors are considered to be cost-effective because they have a good event-lowering effect for patients with diabetes and HF. SGLT2 inhibitors have also shown good event-lowering effects in patients with CKD in randomized, controlled trials.¹¹ In previous studies in other countries, SGLT2 inhibitors were cost-effective for CKD.^21–23 Consistent with those previous studies, the cost-effectiveness of SGLT2 inhibitors for CKD stage3b is considered to be acceptable in Japan. However, there are some differences between CKD stage 3a and stage 3b.

Study Limitations

First, this was a model-based study in which the results of various previous studies were combined and analyzed. Therefore, various biases might not have been excluded. Adequately reflecting information on renal function, age, sex, and baseline medication in the model was difficult. There may be different definitions for hospitalization for HF in the collected studies. We attempted to collect data as objectively as possible, conducted various scenario analyses and sensitivity analyses, and made efforts to lower the bias. We attempted to perform analysis as conservatively as possible, and were careful not to overestimate the therapeutic effect. Second, this model did not consider cardiovascular events, such as myocardial infarction and cerebral infarction. Dapagliflozin lowers the rate of myocardial infarction.^5–8 Cost-effectiveness of dapagliflozin may change when cardiovascular events are taken into consideration. Third, the side effects of dapagliflozin (especially urinary tract infection) were not included in the model. However, a Japanese cohort study did not show an increase in urinary tract infection caused by SGLT2 inhibitors,⁴³ which suggests that this side effect of dapagliflozin has limited influence on cost-effectiveness. Fourth, the main analysis did not take into account renal function deterioration. Dapagliflozin showed improved cost-effectiveness in the scenario analysis considering the decrease in renal function, and dapagliflozin’s cost-effectiveness may be even better when considering its inhibitory effect on deterioration in renal function. Fifth, because the CKD-JAC is a registry study, it may not accurately reflect the actual clinical practice of CKD.

Conclusions

Dapagliflozin seemed to show acceptable cost-effectiveness when used for CKD stage 3b. However, its cost-effectiveness for CKD stage 3a was ambiguous, and further validation is needed.

Acknowledgment

We thank Ellen Knapp, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript. This work was supported by JSPS KAKENHI (grant no. JP 19K10479).

Disclosures

The authors have no financial relationships relevant to this article to disclose. H.M. and I.K. are members of Circulation Journal’s Editorial Team.

Conflicts of Interest

The authors declare no conflicts of interest associated with this manuscript.

IRB Information

This study was granted an exemption from requesting ethical approval by the Institutional Review Board of The University of Tokyo (reference no. 2021375NIe).

Data Availability

This study used data that have already been published.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circj.CJ-22-0086

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