1-Year Safety of 3-Month Dual Antiplatelet Therapy Followed by Aspirin or P2Y₁₂ Receptor Inhibitor Monotherapy Using a Bioabsorbable Polymer Sirolimus-Eluting Stent

Abstract

Background: This study evaluated the safety of 3-month dual antiplatelet therapy (DAPT) after implantation of a bioresorbable polymer sirolimus-eluting stent (BP-SES) and compared P2Y₁₂ inhibitor with aspirin monotherapy 3 months after DAPT.

Methods and Results: Patients who underwent percutaneous coronary intervention using BP-SES were enrolled and followed for 1 year. Patients with a history of stent thrombosis were excluded. The primary endpoint was a composite of all-cause death, myocardial infarction, stroke (ischemic and hemorrhagic), definite or probable stent thrombosis, and severe bleeding at 12 months. The BP-SES arm of the CENTURY II trial was used as a conventional DAPT group for comparison. After DAPT, patients were maintained on either aspirin (n=846) or a P2Y₁₂ inhibitor (n=674 patients). In all, 1,695 patients were enrolled in the study across 65 centers. The primary endpoint occurred in 4.3% of patients at 1 year. After propensity score adjustment, the incidence of the primary endpoint was not inferior in those receiving DAPT for 3 months compared with conventional DAPT (5.5%; P_{non-inferiority} <0.0001). The incidence of the primary endpoint and severe bleeding did not differ between the aspirin and P2Y₁₂ inhibitor monotherapy groups.

Conclusions: After adjustment, 3-month DAPT was not inferior to longer DAPT after BP-SES implantation in terms of net adverse clinical events. There was no difference in bleeding and thrombotic events between P2Y₁₂ inhibitor and aspirin monotherapy after 3 months DAPT.

The Ultimaster bioresorbable polymer sirolimus-eluting stent (BP-SES, Terumo Corporation, Tokyo, Japan) is a new-generation drug-eluting stent (DES) that has a lower risk of thrombosis than the first-generation DES and is associated with less neoatherosclerosis than the durable polymer DES.^1,2 Because bleeding events after percutaneous coronary intervention (PCI) are associated with worse outcome than stent thrombosis, many dual antiplatelet therapy (DAPT) studies have demonstrated the safety and efficacy of a shorter duration of DAPT.^3–5 These studies indicate that a short duration of DAPT has comparable clinical outcomes to 12-month DAPT in patients with a high bleeding risk (HBR) undergoing PCI, although the definition of HBR varies among studies.^6–10 Recently, the Academic Research Consortium for HBR (ARC-HBR) has published a standardized definition of HBR.¹¹

Aspirin is usually prescribed as subsequent monotherapy after discontinuation of DAPT; however, aspirin causes more gastrointestinal bleeding^12,13 and has less potent antiplatelet effects than P2Y₁₂ receptor inhibitors.¹⁴ Therefore, P2Y₁₂ inhibitor monotherapy after discontinuation of DAPT could be a viable treatment option, and 4 large-scale randomized clinical studies demonstrated that P2Y₁₂ inhibitor monotherapy after discontinuation of DAPT had comparable results to conventional 12-month DAPT.^15–17 However, no study thus far has evaluated the safety and efficacy of P2Y₁₂ inhibitor monotherapy after DAPT compared with aspirin monotherapy after BP-SES implantation.

Therefore, in the present study we sought to evaluate: (1) the safety of 3-month DAPT followed by monotherapy after BP-SES implantation; and (2) the effectiveness of P2Y₁₂ inhibitor monotherapy versus aspirin monotherapy after 3-month DAPT.

Methods

Study Population

The present study was a multicenter, open-label, prospective observational study designed to consecutively enroll patients undergoing PCI using BP-SES and who were suitable for 3-month DAPT. Patients aged ≥20 years who had coronary artery lesions treated with BP-SES and provided written informed consent were included in the study. Patients with previous stent thrombosis, those unable to comply with follow-up, and those participating in other clinical trials were excluded. Enrollment had to be completed before hospital discharge after informed consent had been obtained. Clinical details of medical care were obtained for all patients at each participating study site at the time of enrollment, at hospital discharge, and 3 and 12 months after stent implantation. For study subjects who could not visit study sites because of hospital transfer or other reasons, prespecified investigations were performed through written, telephone, or other contact. The incidence of cardiovascular events and hemorrhagic events during the 12-month period after stent implantation was evaluated. The control group (receiving conventional DAPT) consisted of the BP-SES arm of the Clinical Evaluation of New Terumo Drug-Eluting Coronary Stent System in the Treatment of Patients with Coronary Artery Disease (CENTURY II) trial. The results of the CENTURY II trial have been published in detail elsewhere.¹⁸

Antiplatelet Regimen

The DAPT regimen consisted of aspirin 81–100 mg and P2Y₁₂ inhibitors for 3 months. Periprocedural DAPT was left to the investigators’ discretion. The P2Y₁₂ inhibitor used was either prasugrel 3.75 mg or clopidogrel 75 mg, with the decision as to which drug was used let to the discretion of the attending physician. Patients were instructed to change from DAPT to single antiplatelet therapy (SAPT) at 3 months. Prior to enrollment of the first patient, each of the study sites nominated which antiplatelet drug was to be discontinued after 3 months. Forty-three institutes decided to continue SAPT with aspirin, whereas 22 decided to continue SAPT with a P2Y₁₂ inhibitor.

Data Monitoring and Quality Assurance

The study was managed by independent clinical research organizations and a core laboratory responsible for data monitoring, management, and analysis. All data were collected by clinical research coordinators and stored on an electronic data collection platform. All clinical events were adjudicated by an independent clinical event committee. The organization of the study is summarized in Supplementary Table 1.

The present study was conducted in accordance with the ethical principles that have their origins in the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects (www.mhlw.go.jp), and in compliance with the study protocol. The study protocol was approved by the certified review board of Hattori Clinic, approved by Japanese Ministry of Health, Labor and Welfare according to the Law of Clinical Trials Act (jRCTs031180420). This study was also registered at Clinicaltrials.gov (NCT02837003) and the UMIN Clinical Trials Registry (UMIN000022695) before the trial started.

Endpoints

The primary endpoint was a composite of all-cause death, myocardial infarction (MI), stroke (ischemic and hemorrhagic), ARC definite or probable stent thrombosis,¹⁹ and serious bleeding (Bleeding Academic Research Consortium Type 3 or 5)²⁰ in the 12 months after stent implantation. The major secondary endpoint was the incidence of each event, compared between the aspirin and P2Y₁₂ inhibitor SAPT instigated after 3-month DAPT. Other secondary endpoints were major adverse cardiovascular event (MACE), comprising cardiovascular death, MI, and clinically driven target lesion revascularization (TLR), and the incidence of safety and efficacy events, such as all-cause death, cardiac death, MI, stroke (ischemic and hemorrhagic), revascularization (target vessel revascularization [TVR] and TLR), rehospitalization due to angina pectoris, transient ischemic attack (TIA), and stent thrombosis, during the 3- and 12-month periods after stent implantation. Clinical events were defined as in the CENTURY II trial (Supplementary Table 2).¹⁸

Statistical Analysis

Sample size was calculated based on the non-inferiority design. Data from the CENTURY II trial¹⁸ were used as a conventional DAPT group. In the CENTURY II trial, the incidence of the primary endpoint in the BP-SES arm was 6.5% in the total cohort. To prove the non-inferiority of shorter DAPT with a margin of 3.5% and power of 0.80, it was calculated that 1,350 evaluable subjects would be needed. To accommodate for loss to follow-up, the sample size in the present study was set at 1,500 subjects (Supplementary Table 3).

Propensity score subclassification adjustment analysis was used for comparisons with the historical control. Because a prior survey revealed that the participating study sites would continue aspirin or thienopyridine in an almost equivalent number of patients, the incidence of events was also compared between patients receiving aspirin and those receiving thienopyridine.

Propensity scores were obtained using a logistic regression model, and background factors to be used in this model were determined by an analysis performed before all other analyses. For the determination of propensity scores, bias reduction, the overlap of propensity scores between the 2 study populations, and the need for trimming were considered to determine the number of categories. If there was missing data for any item to be used as a propensity score, the data were imputed stochastically by focusing on the distribution of the item. In the estimation of propensity scores, the following baseline characteristics were used: age, male sex, body mass index, diabetes, hypertension, current smoker, end-stage renal failure, hemodialysis, prior stroke, heart failure, peripheral vascular disease, acute MI, unstable angina, stable coronary artery disease, prior PCI, prior coronary artery bypass grafting, number of lesions treated, multivessel disease, left main coronary artery, left anterior descending artery, left circumflex artery, right coronary artery, number of stents implanted, reference vessel diameter, minimum lumen diameter, diameter stenosis, thrombus, chronic total occlusion, bifurcation, moderate or heavy calcification, and SYNTAX score. The Kaplan-Meier method was used to graphically compare the incidence of events in the present study with the incidence of events in the CENTURY II trial. Furthermore, Kaplan-Meier curves adjusted for propensity scores were used to compare the incidence of events between the present study and the CENTURY II trial. The percentage of subjects continuing DAPT in the CENTURY II trial was 90% at 9 months and 66% at 12 months. Therefore, when the incidence of events in the present study was compared with the incidence of events in the CENTURY II trial, the same analysis as above was performed on subgroups of subjects according to the duration of continuation of DAPT in the CENTURY II trial.

All statistical analyses were performed by independent statisticians at the Biostatistical Research Corporation (Tokyo, Japan).

Results

Baseline Characteristics

From October 2016 to March 2018, 1,695 patients of the 1,711 patients treated with BP-SES were enrolled in the study across 65 centers in Japan. Patient flow is shown in Figure 1. Patient and lesion demographics are summarized in Table 1 and Table 2. More than half the patients had small vessel disease and the mean length of the implanted stent was relatively long in this population. Proton pump inhibitors (PPI) and statins were prescribed in 84.6% and 82.1% of the patients, respectively. When applying modified ARC-HBR criteria (Supplementary Table 4) to the present study population, 840 of the 1,695 patients (49.6%) were classified as HBR.¹² The DAPT regimen at the time of discharge was aspirin plus clopidogrel in 42.6% of patients and aspirin plus prasugrel in 57.4%. Compared with the CENTURY II trial, patients in the present study were older, with more diabetes, hypertension, severe chronic kidney disease and prior stroke, but less peripheral vascular disease (Supplementary Table 5). Three-month follow-up was completed in 1,686 patients (99.5%) and clinical outcomes are summarized in Supplementary Table 6.

Figure 1.

Patient flow. BP-SES, bioresorbable polymer sirolimus-eluting stent; DAPT, dual antiplatelet therapy; DES, drug-eluting stent.

Table 1. Baseline Patient and Procedural Characteristics for the 1,695 Patients Included in the Present Study

Age, (years)	69.7±10.6
Age ≥75 years	613/1,694 (36.2)
Male sex	1,301 (76.8)
BMI (kg/m2)	24.3±3.5
Diabetes	666 (39.3)
Hypertension	1,354 (79.9)
Dyslipidemia	1,370 (80.8)
Current smoker	342/1,576 (21.7)
Severe CKD	221 (13.0)
Hemodialysis	89 (5.3)
Prior stroke	176/1,693 (10.4)
Heart failure	213 (12.6)
Atrial fibrillation	139 (8.2)
Peripheral vascular disease	111/1,650 (6.7)
Clinical diagnosis
AMI	260 (15.3)
STEMI	198 (11.7)
NSTEMI	62 (3.7)
Unstable angina	222 (13.1)
Stable coronary artery disease	790 (46.6)
Silent ischemia	377 (22.2)
Old myocardial infarction	97 (5.7)
Previous GI bleeding	39 (2.3)
Previous peptic ulceration	37 (2.2)
Previous carotid artery disease	65 (3.8)
Malignancy	149 (8.8)
Anemia (Hb <11.0 g/dL)	162/1,661 (9.8)
Prior PCI	659 (38.9)
Prior CABG	48 (2.8)
Family history of coronary artery disease	263 (15.5)
Access site
Femoral	215 (12.7)
Radial	1,389 (81.9)
Brachial	77 (4.5)

Data are presented as the mean±SD or n (%), with the total number of patients (denominator) indicated where it differs from that of the total cohort. AMI, acute myocardial infarction; BMI, body mass index; CABG, coronary artery bypass grafting; CKD, Chronic kidney disease; GI, gastrointestinal; Hb, hemoglobin; NSTEMI, non-ST elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction.

Table 2. Baseline Angiographic Lesion Characteristics for 1,665 Patients Included in the Present Study

No. lesions treated	1.2±0.4
Target vessel location
LMCA	25 (1.5)
LAD	916 (55.0)
LCx	371 (22.3)
RCA	460 (27.6)
Thrombus	153 (9.2)
Chronic total occlusion	22 (1.3)
In-stent restenosis	29 (1.7)
Bifurcation	700 (42.0)
Moderate or heavy calcification	276 (16.6)
Small vessel (≤2.75 mm)	1,013 (60.8)
Long lesion (>18 mm)	621/1,495 (41.5)
SYNTAX score	9.2±6.2
No. stents	1.3±0.6
Total stent length (mm)	31.8±18.3
Lesion length (mm)	19.0±11.3
Preprocedural QCA
Reference vessel diameter (mm)	2.6±0.6
Minimum luminal diameter (mm)	0.8±0.4
Diameter stenosis (%)	69.7±15.1
Post-procedural QCA
Minimum luminal diameter (mm)	2.6±0.5
Diameter stenosis (%)	12.4±5.9
Acute gain (mm)	1.8±0.6

Data are presented as the mean±SD or n (%), with the total number of patients (denominator) indicated where it differs from that of the total cohort . LAD, left anterior descending; LCx, left circumflex; LMCA, left main coronary artery; RCA, right coronary artery; QCA, quantitative coronary angiography.

DAPT Discontinuation and 1-Year Clinical Outcomes

DAPT was discontinued in 81.3% of patients at 2–4 months, which was the longest allowance range, and in 96.4% at 12 months. The antiplatelet agents continued based on initial declarations by the participating institutes were aspirin in 945 patients (55.8%) and a P2Y₁₂ inhibitor in 750 patients (44.2%). However, 63 patients (3.7%) did not discontinue the assigned medications. The reasons for prolonged DAPT were ischemic events (n=10 patients), attending physicians’ judgment (n=17), patients’ request (n=5), protocol non-compliance (n=26), or unknown (n=5).

Complete 1-year follow-up was obtained in 1,616 patients (95.3%). During the 1-year follow-up, 25 patients died and 19 were lost to follow-up. The primary endpoint occurred in 4.3% of patients at 1 year. After propensity score adjustment, the incidence of the primary endpoint in the present cohort and the CENTURY II (control) group was comparable (4.3% vs. 5.5%, respectively) and 3-month DAPT was demonstrated to be non-inferior to conventional DAPT (P<0.0001; Figure 2).

Figure 2.

Incidence of the primary endpoint of all-cause death, myocardial infarction (MI), stroke and stent thrombosis (ST), and bleeding events (Bleeding Academic Research Consortium [BARC] Type 3 or 5). Compared with conventional dual antiplatelet therapy (DAPT) in the CENTURY II trial, 3-month DAPT was found to have a comparable incidence of the primary endpoint (P_{non-inferiority} <0.001). UCB, upper confidence bound.

Because DAPT was switched to SAPT 3 months after PCI, we performed Landmark analysis at 3 months. Landmark analysis demonstrated that the incidence of thrombotic events, comprising cardiovascular death, MI, stroke and stent thrombosis, was relatively low in patients with 3-month DAPT compared with conventional DAPT (0.9% vs. 2.0%, respectively; adjusted hazard ratio [aHR] 0.46; 95% confidence interval [CI] 0.14–1.44; P=0.18; Figure 3A). Similarly, the incidence of bleeding events was numerically lower in the 3-month DAPT than conventional DAPT group (0.5% vs. 1.6%, respectively; aHR 0.33; 95% CI 0.10–1.08; P=0.07), although the difference did not reach statistical significance (Figure 3B). The cumulative incidence of MACE was 2.7% at 1 year; and the incidence of other clinical events is shown in Figure 4.

Figure 3.

Landmark analysis of thrombotic events, comprising cardiovascular death, myocardial infarction (MI), stroke and stent thrombosis (ST), and bleeding events (Bleeding Academic Research Consortium [BARC] Type 3 or 5) in the present study (3-month dual antiplatelet therapy [DAPT]) and the CENTURY II trial (12-month DAPT). (A) From 3 to 12 months after percutaneous coronary intervention (PCI), patients with 3-month DAPT had a numerically lower incidence of thrombotic events than those with 12-month DAPT (0.9% vs. 2.0%, respectively). (B) Beyond 3 months after PCI, the incidence of bleeding was numerically lower in the 3-month DAPT group, although the difference did not reach statistical significance (0.5% vs. 1.6%, respectively). CI, confidence interval; HR, hazard ratio.

Figure 4.

Rates of all clinical event rates at 3 and 12 months after percutaneous coronary intervention for patients in the present study. The primary endpoint consisted of all-cause death, myocardial infarction (MI), stroke and stent thrombosis (ST), and bleeding events (Bleeding Academic Research Consortium [BARC] Grade 3 or 5). TLR, target lesion revascularization.

Comparison of Continued Medications

After DAPT, 846 patients continued with aspirin and 674 continued with P2Y₁₂ inhibitors as SAPT. The baseline characteristics did not differ between the 2 groups except for ACS indications, current smoking, and prior stroke (Supplementary Table 7). The incidence of the composite endpoint and severe bleeding did not differ between the groups continuing with aspirin or a P2Y₁₂ inhibitor (Figure 5). In addition, there were no significant differences in other clinical events between the aspirin and P2Y₁₂ inhibitor groups (Supplementary Figure).

Figure 5.

Landmark analysis of clinical events between aspirin and P2Y₁₂ inhibitor monotherapy from 3 months after percutaneous coronary intervention. There were no significant differences for each endpoint between the aspirin and P2Y₁₂ inhibitor monotherapy groups. CI, confidence interval; HR, hazard ratio.

Discussion

The main findings of this prospective study, which included a high proportion of HBR patients and a large number of patients with small vessel disease, were that: (1) the incidence of clinical adverse events was comparable between 3-month DAPT and 12-month DAPT after PCI with BP-SES; (2) 3 months after PCI, the incidence of thrombotic events (comprising cardiovascular death, MI, stroke, and stent thrombosis) and bleeding events appeared to be lower in the 3-month DAPT than 12-month DAPT group, as revealed by Landmark analysis; and (3) after PCI using BP-SES, clinical adverse events were comparable between P2Y₁₂ inhibitor and aspirin SAPT after the initial 3-month DAPT.

BP-SES is a new-generation DES comprised of a cobalt chromium bare metal stent platform with thin struts and a bioabsorbable polymer with sirolimus. Large randomized trial and registries have compared the clinical efficacy and safety of BP-SES with those of second-generation DES.^18,21,22 However, no data has been reported regarding the safety and efficacy of short DAPT after PCI using BP-SES, although previous randomized clinical trials did demonstrate the safety and utility of short DAPT after implantation of other DES.^3–5 Therefore, this study sought to assess the safety of short DAPT in patients undergoing PCI with BP-SES with few exclusion criteria. Notably, the proportion of patients with high thrombotic and bleeding risks seemed to be higher in the present cohort, even though such patients are usually excluded from randomized clinical trials. Thus, the findings of the present study could be applicable to the general PCI population.

Although several studies of short DAPT after DES implantation in HBR populations have been reported,^6,8,9 the present study is the first study of short DAPT after BP-SES implantation that has included both HBR and non-HBR patients. In addition, all other short DAPT studies for HBR patients have used only an aspirin monotherapy regimen after the DAPT period. In contrast, P2Y₁₂ inhibitor monotherapy was also included in the present study based on decisions made by participating centers prior to enrollment of subjects. Aspirin has been the gold standard antiplatelet therapy for coronary artery disease for more than 40 years.¹³ However, aspirin has an indirect action to inhibit platelet aggregation²³ and is less effective than P2Y₁₂ inhibitors in reducing ischemic events.²⁴ Aspirin is a non-steroidal anti-inflammatory drug that can induce considerable gastric mucosal injury.¹² In this regard, P2Y₁₂ inhibitor monotherapy may be more suitable for SAPT than aspirin monotherapy.²⁵ To the best of our knowledge, the present study is the first comparison of aspirin and P2Y₁₂ inhibitor monotherapy after DAPT; we found no differences in clinical adverse events between these 2 monotherapies. However, because this study was originally designed to evaluate the non-inferiority of 3-month DAPT after BP-SES implantation, the number of subjects may not be sufficient to assess the effects of P2Y₁₂ inhibitor monotherapy on clinical outcomes. Direct randomized comparison with proper statistical power would be necessary to confirm the efficacy and safety of P2Y₁₂ inhibitor monotherapy compared with standard SAPT using aspirin.

Recently, the ARC-HBR has proposed a standard definition of bleeding risk in the PCI population.¹¹ Approximately 20% of the patients in western countries meet the ARC-HBR definition of HBR,¹¹ compared with half the patients in the present study. Nevertheless, in the present study the actual incidence of severe bleeding was very low, even in the HBR population. This may be explained by the majority of patients being prescribed a PPI concomitant with antiplatelet therapy in this study. In general, gastrointestinal (GI) bleeding is a major cause of bleeding complications during antiplatelet therapy; indeed, nearly half the bleeding events in this study were GI bleeding. A recent study demonstrated that antiplatelet therapy with the routine use of PPIs was significantly associated with a lower incidence of GI bleeding than antiplatelet therapy without PPI.²⁶ Thus, the high rate of administration of PPIs in the present study may have reduced the incidence of bleeding events. In addition, patients with HBR, which accounted for half the study population, have higher thrombotic events, including MI or stroke, than non-HBR patients.²⁷ Given the results of the Clopidogrel Versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) study, P2Y₁₂ inhibitors prevent thromboembolic events in atherosclerotic disease.²⁴ Therefore, P2Y₁₂ inhibitor monotherapy after short DAPT may be a good therapeutic option to reduce adverse events in HBR patients to prevent GI bleeding caused by aspirin.

Study Limitations

This study was not a randomized controlled trial but used a patient-level propensity score-adjusted historical control group. Because reimbursement for P2Y₁₂ inhibitor monotherapy was restricted in some districts of Japan, randomization of SAPT agents was not possible in this study. Instead, each site could choose the antiplatelet agent used in subsequent SAPT after the initial 3-month DAPT. To minimize bias, propensity score adjustment was performed, although propensity score-adjusted analysis may not have totally compensated for the selection bias in this study, because considerable baseline differences were observed. In the comparison of aspirin and P2Y₁₂ inhibitor monotherapy after DAPT, the sample size for each monotherapy group was not calculated and patients were not randomized to monotherapy. Therefore, the safety and efficacy of each antiplatelet monotherapy cannot be conclusively stated. Further investigations may be warranted to compare the clinical efficacy of P2Y₁₂ inhibitor vs. aspirin monotherapy. Because the CENTURY II trial strictly collected post-procedural serum troponin-T concentrations, the incidence of MI may be high due to high periprocedural MI compared with the rate in the present study. However, the incidence of periprocedural MI was less than 2% in this study, and that was lower than the difference in the primary endpoint between this study and the CENTURY II trial. Moreover, we used the Landmark analysis beyond 3 months to assess the non-inferiority of short DAPT, therefore the difference in periprocedural MI, which occurred within 3 months after PCI, may not have affected the results of Landmark analysis beyond 3 months.

Conclusions

This study demonstrated that 3-month DAPT was non-inferior compared with an adjusted cohort of longer DAPT after BP-SES implantation in terms of net adverse clinical events. P2Y₁₂ inhibitor monotherapy was almost equivalent to aspirin monotherapy after 3 months in terms of both bleeding and thrombotic events.

Acknowledgement

The authors thank Toshihito Furukawa, PhD (Biostatistical Research Corporation, Tokyo, Japan), for developing the statistical design and performing statistical analyses.

Sources of Funding

This study was funded by Terumo Corporation. The sponsor was not involved in the study conduct, data collection, statistical analysis, or writing of the manuscript.

Disclosure

K.K. has received lecture fees from Terumo Corporation. J.A. and K.T. have received speaking honoraria from Terumo Corporation. J.Y. has received grants from Terumo Corporation. The remaining authors have no conflicts of interest to declare.

IRB Information

This study was approved by the Certified Review Board of Hattori Clinic (jRCTs031180420, March 12, 2019). The study was originally approved by Teikyo University Review Board (No. 15-216).

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-20-0644

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