Aspirin-free strategy for percutaneous coronary intervention in acute coronary syndrome based on the subtypes of acute coronary syndrome and high bleeding risk: the STOPDAPT-3 trial

Abstract

Background and aims

High bleeding risk (HBR) and acute coronary syndrome (ACS) subtypes are critical in determining bleeding and cardiovascular event risk after percutaneous coronary intervention (PCI).

Methods and results

In 4476 ACS patients enrolled in the STOPDAPT-3, where the no-aspirin and dual antiplatelet therapy (DAPT) strategies after PCI were randomly compared, the pre-specified subgroup analyses were conducted based on HBR/non-HBR and ST-segment elevation myocardial infarction (STEMI)/non-ST-segment elevation ACS (NSTE-ACS). The co-primary bleeding endpoint was Bleeding Academic Research Consortium (BARC) type 3 or 5, and the co-primary cardiovascular endpoint was a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or ischaemic stroke at 1 month. Irrespective of the subgroups, the effect of no-aspirin compared with DAPT was not significant for the bleeding endpoint (HBR [N = 1803]: 7.27 and 7.91%, hazard ratio (HR) 0.91, 95% confidence interval (CI) 0.65–1.28; non-HBR [N = 2673]: 3.40 and 3.65%, HR 0.93, 95% CI 0.62–1.39; Pinteraction = 0.94; STEMI [N = 2553]: 6.58 and 6.56%, HR 1.00, 95% CI 0.74–1.35; NSTE-ACS [N = 1923]: 2.94 and 3.64%, HR 0.80, 95% CI 0.49–1.32; Pinteraction = 0.45), and for the cardiovascular endpoint (HBR: 7.87 and 5.75%, HR 1.39, 95% CI 0.97–1.99; non-HBR: 2.56 and 2.67%, HR 0.96, 95% CI 0.60–1.53; Pinteraction = 0.22; STEMI: 6.07 and 5.46%, HR 1.11, 95% CI 0.81–1.54; NSTE-ACS: 3.03 and 1.71%, HR 1.78, 95% CI 0.97–3.27; Pinteraction = 0.18).

Conclusion

In patients with ACS undergoing PCI, the no-aspirin strategy compared with the DAPT strategy failed to reduce major bleeding events irrespective of HBR and ACS subtypes. The numerical excess risk of the no-aspirin strategy relative to the DAPT strategy for cardiovascular events was observed in patients with HBR and in patients with NSTE-ACS.

Graphical Abstract

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Introduction

The STOPDAPT-3 (ShorT and OPtimal Duration of Dual AntiPlatelet Therapy-3) trial aimed to compare the aspirin free strategy with dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) in terms of the major bleeding and cardiovascular events. The no-aspirin strategy compared with the DAPT strategy failed to reduce major bleeding within 1 month after PCI. Moreover, there was a signal suggesting an excess of coronary events in the no-aspirin group relative to the DAPT group. The excess risk of the no-aspirin group relative to the DAPT group for coronary events was more prominent in patients with acute coronary syndrome (ACS) than in those with non-ACS.¹

There are two important subgroup factors among ACS patients that could affect the effect of the no-aspirin strategy relative to the DAPT strategy on major bleeding and cardiovascular events: high bleeding risk (HBR) and types of ACS (ST-segment elevation myocardial infarction [STEMI] and non-ST-segment elevation ACS [NSTE-ACS]). In real-world clinical practice, ACS patients with HBR exhibited unacceptably high bleeding event rates especially during the acute phase.² STEMI and NSTE-ACS have their own distinct characteristics in terms of the pathophysiology and patients’ backgrounds, which might lead to different cardiovascular and bleeding risk profiles. To further investigate the effect of the no-aspirin strategy relative to the DAPT strategy, we conducted the pre-specified subgroup analyses based on HBR and subtypes of ACS among the ACS population in the STOPDAPT-3 trial.

Methods

Study population

STOPDAPT-3 was a physician initiated, prospective, multicentre, open-label, adjudicator blinded randomized clinical trial, where we compared the bleeding and cardiovascular endpoints between the experimental group of 1-month prasugrel monotherapy without aspirin and the control group of 1-month DAPT with aspirin and prasugrel in patients planned for PCI using cobalt–chromium everolimus-eluting stent (CoCr-EES: Xience^TM series, ABBOTT Vascular) implantation. This study was registered at ClinicalTrials.gov with identifier of NCT04609111. Informed consents were obtained before coronary angiography in eligible patients including those ACS patients with planned emergency coronary angiography. If the written informed consents were unable to be obtained due to serious clinical conditions, the verbal informed consents were to be obtained from patients or legal representatives and the written informed consents shall be obtained after the stabilization of clinical condition. Kyoto University Certified Review Board approved the study protocol. The detailed study protocol and results were published elsewhere.¹ In brief, a total of 6002 patients with ACS regardless of HBR or non-ACS with HBR were enrolled between January 2021 to April 2023 from 72 centres in Japan, and were randomly allocated immediately before PCI in a one-to-one ratio to either prasugrel monotherapy without aspirin (no-aspirin group) or to 1-month DAPT with aspirin and prasugrel (DAPT group).

Just after randomization, a loading dose of prasugrel 20 mg was administered in both groups. A loading dose of aspirin 162–200 mg were also administered in aspirin-naïve patients in the DAPT group. Prasugrel 3.75 mg/day in the no-aspirin group, and aspirin 81–100 mg/day and prasugrel 3.75 mg/day in the DAPT group were continued up to 1 month after PCI.^3,4 At the 1-month (30–59 days) visit, prasugrel was switched to clopidogrel and was to be continued up to 1 year in the no-aspirin group, while prasugrel was discontinued and aspirin monotherapy was to be continued up to 1 year in the DAPT group.

After exclusion of 5 patients who did not receive PCI for the absence of suitable coronary lesions, 1 patient who had been enrolled in another clinical trial, and 30 patients who withdrew consent, the original full analysis set consisted of 5966 patients including 2984 patients in the no-aspirin group and 2982 patients in the DAPT group. In the present analysis, after excluding 1490 patients with non-ACS, 4476 patients with ACS (2242 in the no-aspirin group and 2234 in the DAPT group) were divided into the two subgroups based on the Academic Research Consortium (ARC)-HBR definitions.⁵ Additionally, ACS patients were also divided into the STEMI and NSTE-ACS subgroups, according to the current guideline classification (Figure 1).⁶

As a part of exploratory analyses, the HBR/non-HBR subgroups were further subdivided into STEMI/NSTE-ACS subgroups. In addition, the HBR subgroup was also subdivided based on the number of the ARC-HBR major criteria met: 2 or more, and 1 or less. We conducted an additional analysis excluding the co-primary bleeding events within the first 48 h in each HBR/non-HBR and STEMI/NSTE-ACS subgroup.

Outcome measures and definitions

The outcomes of the STOPDAPT-3 trial were assessed at 1 month after randomization as the primary analysis and at 2 months as the secondary analysis to assess the influence of switching antiplatelet therapy at the 1-month (30–59 days) visit. The co-primary bleeding endpoint was major bleeding defined as the Bleeding Academic Research Consortium (BARC) type 3 or 5, and the co-primary cardiovascular endpoint was a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or ischaemic stroke.⁷ The major secondary endpoint was a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, ischaemic stroke, or major bleeding (BARC 3 or 5), which represented net adverse clinical outcomes for cardiovascular and bleeding events. Myocardial infarction and stent thrombosis were defined by the ARC criteria.⁷ The definitions of other secondary endpoints were described in the supplemental materials. The independent clinical event committee adjudicated all the clinical events in a blinded fashion to the assigned group.

Statistical analysis

Categorical variables were presented as number and percentage and were compared using the χ² test. Continuous variables were expressed as mean ± standard deviation or median with interquartile range and were compared using the Student t test or Wilcoxon Rank-Sum test depending on their distributions. The cumulative incidences of the endpoints were estimated by the Kaplan–Meier method. The risks of HBR relative to non-HBR, STEMI relative to NSTE-ACS as well as the no-aspirin group relative to the DAPT group for the endpoints were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs) by the Cox proportional hazard model. We also analysed the treatment-by-subgroup interaction in the effects of the no-aspirin group compared with the DAPT group in the HBR and non-HBR subgroups as well as in the STEMI and NSTE-ACS subgroups for the co-primary bleeding and cardiovascular endpoints. All P values were two-sided and P values <0.05 were considered statistically significant. All analyses were performed with JMP version 16.1 software (SAS Institute Inc., Cary, NC) and R version 4.2.3 (R Foundation for Statistical Computing, Vienna, Austria).

Results

Study population in the HBR/non-HBR subgroups among ACS patients

Among the present study population of 4476 patients with ACS in the STOPDAPT-3 trial, there were 1803 patients with HBR (40.3%) (no-aspirin group: N = 915, DAPT group: N = 888) and 2673 patients without HBR (59.7%) (no-aspirin group: N = 1327, DAPT group: N = 1346) (Figure 1). Patients with the ARC-defined HBR major criteria were not common in the present study population including the small proportion of patients with severe chronic kidney disease (7.0%) and severe anaemia (6.7%), whereas patients with the ARC-defined HBR minor criteria were much more common including age ≥75 years (37.9%), moderate chronic kidney disease (37.8%), and moderate anaemia (16.4%) (Supplementary material online, Table S1).

Baseline characteristics and medications in the HBR/non-HBR subgroups

Baseline characteristics of patients with HBR were obviously different from those without HBR. Patients with HBR were older, and more often women, more often had low body-mass index, and more often presented with NSTE-ACS. Compared to patients without HBR, patients with HBR more often had comorbidities such as prior myocardial infarction, prior stroke, prior heart failure, atrial fibrillation and diabetes as well as those comorbidities specified in the ARC-HBR criteria. Regarding the procedural characteristics, patients with HBR more often underwent PCI with femoral approach and had higher prevalence of intra-aortic balloon pumping use despite less emergent procedure than those without HBR. As for medications, patients with HBR more often received antiplatelet therapy before the index PCI. Beta-blockers and statins were less often prescribed at discharge in patients with HBR than those without HBR (Table 1). Baseline characteristics and medications were well balanced between the no aspirin and DAPT groups except for the lower prescription rate of proton pump inhibitors in the no-aspirin group than in the DAPT group in both the HBR and non-HBR subgroups (Supplementary material online, Table S2).

The vast majority of study patients received the protocol-specified antiplatelet therapy in both the no-aspirin and DAPT groups regardless of HBR and non-HBR (Supplementary material online, Figure S1).

Clinical outcomes in the HBR/non-HBR subgroups

The incidence of the co-primary bleeding endpoint at 1 month was much higher in patients with HBR than in those without HBR (7.58 and 3.52%, HR 2.21, 95% CI 1.70–2.87, P < 0.001) (Supplementary material online, Table S3). In patients with HBR, the incidences of the co-primary bleeding endpoint were 7.27% in the no-aspirin group and 7.91% in the DAPT group (HR 0.91, 95% CI 0.65–1.28, P = 0.59), while in patients without HBR, those were 3.40 and 3.65%, respectively (HR 0.93, 95% CI 0.62–1.39, P = 0.73). There was no significant treatment-by-subgroup interaction for HBR in terms of the co-primary bleeding endpoint (P interaction = 0.94) (Figure 2A and Table 2).

The incidence of the co-primary cardiovascular endpoint was also much higher in patients with HBR than those without (6.83 and 2.62%, HR 2.66, 95% CI 1.99–3.57, P < 0.001). The incidences of coronary events in patients with and without HBR were 0.74 and 0.71% (HR 1.03, 95% CI 0.51–2.08, P = 0.94) for definite or probable stent thrombosis, and 1.08 and 0.90% (HR 1.19, 95% CI 0.65–2.17, P = 0.57) for any unplanned coronary revascularization (Supplementary material online, Table S3). In patients with HBR, the event rates for the co-primary cardiovascular endpoint were 7.87% in the no-aspirin group and 5.75% in the DAPT group (HR 1.39, 95% CI 0.97–1.99, P = 0.07), while in patients without HBR, those were 2.56 and 2.67%, respectively (HR 0.96, 95% CI 0.60–1.53, P = 0.85). There was no significant treatment-by-subgroup interaction for HBR in terms of the co-primary cardiovascular endpoint (P interaction = 0.22), although there was a numerical excess of the risk of the no-aspirin group relative to the DAPT group for the co-primary cardiovascular endpoint in patients with HBR (Figure 2B and Table 2). The excess risk of the no-aspirin group relative to the DAPT group was significant for the cardiovascular endpoint in 2 months in patients with HBR (Supplementary material online, Figure S3). There also was a numerical excess risk of the no-aspirin group relative to the DAPT group for definite or probable stent thrombosis and any unplanned coronary revascularization in patients with HBR (Table 2).

Study population in the STEMI/NSTE-ACS subgroups

Among 4476 ACS patients, there were 2553 patients with STEMI (57.0%) (no-aspirin group: N = 1253, DAPT group: N = 1300) and 1923 patients with NSTE-ACS (43.0%) (no-aspirin group: N = 989, DAPT group: N = 934) (Figure 1).

Baseline characteristics and medications in the STEMI/NSTE-ACS subgroups

Compared to patients with NSTE-ACS, patients with STEMI were younger and more often had severe clinical presentation such as cardiac arrest or ventricular fibrillation, cardiogenic shock, and concurrent heart failure on admission. Patients with STEMI less often had comorbidities including prior myocardial infarction, prior heart failure, atrial fibrillation, and haemodialysis as well as had lower prevalence of the ARC-HBR, whereas they had more left ventricular dysfunction than those with NSTE-ACS. As for the procedural characteristics, patients with STEMI had higher prevalence of emergent procedure, femoral approach, and haemodynamic support device use than those with NSTE-ACS. Regarding medications before PCI, antiplatelet agents and anticoagulants were less often prescribed in patients with STEMI than in those with NSTE-ACS. In contrast, regarding medications at discharge, patients with STEMI more often received anticoagulants, beta-blockers, and proton pump inhibitors (Table 3). Baseline characteristics and medications were well balanced between the no-aspirin group and the DAPT group except for the lower prescription rate of proton pump inhibitors in the no-aspirin group than in the DAPT group in both the STEMI and NSTE-ACS subgroups (Supplementary material online, Table S4).

The vast majority of the study patients received the protocol-specified antiplatelet therapy in both groups of patients with STEMI and NSTE-ACS (Supplementary material online, Figure S2).

Clinical outcomes in the STEMI/NSTE-ACS subgroups

The incidence of the co-primary bleeding endpoint at 1 month was much higher in patients with STEMI than those with NSTE-ACS (6.57 and 3.28%, HR 2.03, 95% CI 1.52–2.72, P < 0.001) (Supplementary material online, Table S5). In patients with STEMI, the incidences of the co-primary bleeding endpoint were 6.58% in the no-aspirin group and 6.56% in the DAPT group (HR 1.00, 95% CI 0.74–1.35, P = 1.00), while in patients with NSTE-ACS, those were 2.94 and 3.64%, respectively (HR 0.80, 95% CI 0.49–1.32, P = 0.38). There was no significant treatment-by-subgroup interaction for the STEMI/NSTE-ACS subgroups in terms of the co-primary bleeding endpoint (P interaction = 0.45) (Figure 3A, and Table 4).

The incidence of the co-primary cardiovascular endpoint at 1 month was also much higher in patients with STEMI than those with NSTE-ACS (5.76 and 2.39%, HR 2.44, 95% CI 1.75–3.40, P < 0.001). Moreover, there was a higher incidence of definite or probable stent thrombosis (1.03 and 0.31%, HR 3.30, 95% CI 1.36–8.02, P = 0.008), and a numerically higher incidence of any unplanned coronary revascularization (1.19 and 0.68%, HR 1.76, 95% CI 0.92–3.37, P = 0.09) in patients with STEMI than in those with NSTE-ACS (Supplementary material online, Table S5). In patients with STEMI, the incidences of the co-primary cardiovascular endpoint were 6.07% in the no-aspirin group and 5.46% in the DAPT group (HR 1.11, 95% CI 0.81–1.54, P = 0.51), whereas in patients with NSTE-ACS, those were 3.03% in the no-aspirin group and 1.71% in the DAPT group (HR 1.78, 95%CI 0.97–3.27, P = 0.18). There was no significant treatment-by-subgroup interaction for the STEMI/NSTE-ACS subgroups in terms of the co-primary cardiovascular endpoint (P interaction = 0.18), although the magnitude of excess risk of the no-aspirin group relative to the DAPT group was numerically greater in patients with NSTE-ACS than in those with STEMI (Figure 3B and Table 4).

Definite or probable stent thrombosis at 1-month occurred in 15 patients (1.22%) in the no-aspirin group and in 11 patients (0.85%) in the DAPT group in patients with STEMI, and in 4 patients (0.41%) in the no-aspirin group and in 2 patients (0.21%) in the DAPT group in patients with NSTE-ACS (Table 4).

The co-primary bleeding and cardiovascular endpoints during 2 months were presented in Supplementary material online, Figure S4.

Clinical outcomes in the exploratory subgroups

The effect of no aspirin compared with DAPT for the co-primary bleeding endpoint was not significant in all the subgroups stratified by HBR/non-HBR and STEMI/NSTE-ACS subgroups, while the incidence of the co-primary cardiovascular endpoint was significantly higher in the no-aspirin group than in the DAPT group among the HBR/NSTE-ACS subgroup (6.28 and 2.76%, HR 2.32, 95% CI 1.15–4.67) (Supplementary material online, Table S6).

In patients with HBR, who met 2 or more ARC-HBR major criteria, the incidence of the co-primary bleeding endpoint was numerically lower in the no-aspirin group than in the DAPT group (12.9 and 19.4%, HR 0.62, 95% CI 0.32–1.24). Regardless of the number of the ARC-HBR major criteria met, the incidence of the co-primary cardiovascular endpoint was numerically higher in the no-aspirin group than in the DAPT group (Supplementary material online, Table S7).

Even after excluding the co-primary bleeding events within the first 48 h, the effect of no-aspirin strategy compared with DAPT for reducing bleeding events remained uncertain (Supplementary material online, Table S8).

Discussion

The main findings of the present analyses in the ACS patients enrolled in the STOPDAPT-3 were the followings: (1) The no-aspirin strategy compared with the DAPT strategy failed to reduce major bleeding within 1 month after PCI regardless of HBR and regardless of STEMI or NSTE-ACS; (2) Despite no significant treatment-by-subgroup interactions, the magnitude of excess risk of the no-aspirin strategy compared with the DAPT strategy for cardiovascular events was numerically greater in patients with HBR than in those with non-HBR, and in patients with NSTE-ACS than in those with STEMI.

The trade-off between bleeding and cardiovascular events by DAPT is a critical concern in patients undergoing PCI, and there is an increasing interest in HBR in this population. Several randomized control trials have reported that shorter duration of DAPT reduced major bleeding events without increasing ischaemic events particularly in patients with HBR.^8–14 ACS patients not only have high cardiovascular event risks but also have increased bleeding risks early after PCI, and the bleeding risks are even more exaggerated in the presence of HBR.² Indeed, the incidence of major bleeding was much higher in patients with HBR than in those with non-HBR in the present study. However, the benefit of the no-aspirin strategy for reducing bleeding events was not observed even in patients with ACS and HBR. ACS patients with HBR compared with those without HBR were much older and presented with more serious conditions such as cardiogenic shock necessitating the use of haemodynamic support devices. Removing aspirin may not be so much effective to prevent bleeding related to the serious conditions of patients with ACS.

HBR is also known to be associated with an increased risk of cardiovascular events.^2,15,16 In this study, which included exclusively patients with ACS, the numerical excess risk of the no-aspirin group relative to the DAPT group for cardiovascular events was observed in patients with HBR but not in those without HBR. An in vitro study involving healthy volunteers suggested that the potent inhibition of platelet aggregation induced by prasugrel alone were comparable to that with aspirin and prasugrel, indicating minimal additional effect of aspirin on the inhibition of platelet aggregation.¹⁷ However, an observational study reported that the prescription of less intensive antiplatelet regimens and DAPT disruption due to bleeding events might be associated with higher risk of cardiovascular events.¹⁸ In particular, the rate of DAPT disruption is higher in patients with HBR.¹⁶ Therefore, the need for aspirin to reduce cardiovascular events might be greater in ACS patients with HBR than in those without HBR, despite their higher bleeding risk.

It is well-known that STEMI is associated with higher risks of death and recurrent cardiovascular events than NSTE-ACS and non-ACS.^2,19 Due to its high ischaemic risks, severe presentation, and need for emergency PCI procedure, the prevalence of patients with STEMI in the recent randomized trials of shorter DAPT was relatively low or even excluded.^20,21 In our previous STOPDAPT-2 ACS trial, although the prevalence of STEMI was fairly high (56.2%), those patients with severe in-hospital complications or in serious clinical conditions were largely excluded from the study.²² Furthermore, the pilot studies investigating the no-aspirin strategy after PCI also excluded patients with STEMI.^23,24 In the present study including large number of patients with STEMI, removal of aspirin did not reduce major bleeding particularly in patients with STEMI. This might be because patients with STEMI more often presented with severe conditions predisposing to those types of bleeding events such as cardiac tamponade or non-PCI access site bleeding due to haemodynamic support device use, which might not be preventable by the no-aspirin strategy. In the meantime, the magnitude of the excess cardiovascular event risk of the no-aspirin group relative to the DAPT group seemed to be

somewhat more pronounced in patients with NSTE-ACS than in patients with STEMI. One of the possible reasons for this discrepancy might be the higher prevalence of prior cardiovascular diseases and the greater lesion complexity in patients with NSTE-ACS than in those with STEMI. In fact, some studies reported a higher cardiovascular event risk in patients with NSTE-ACS compared to those with STEMI during mid- to long-term follow-up.^25,26 However, this study is the first large-scale randomized trial to evaluate the effect of no-aspirin strategy including patients with STEMI and comparing them to those with NSTE-ACS. It remains unknown what was the detailed mechanism behind the greater excess cardiovascular event risk with aspirin removal in patients with NSTE-ACS than in those with STEMI. The need for aspirin to reduce cardiovascular events might be greater in patients with NSTE-ACS than in those with STEMI, despite their higher bleeding risk, and further research is warranted to validate this hypothesis and to elucidate its underlying mechanism.

Study limitations

There are several limitations in the present study. First, the study hypothesis was not proven in the main analysis, and given the inclusion of only ACS patients in this study, the present subgroup analyses would not have adequate power for a meaningful interpretation. Additionally, there was no treatment-by-subgroup interaction for both the co-primary bleeding and cardiovascular endpoints between ACS and non-ACS subgroups in the main analysis, although the subgroup analyses in this study are focusing on ACS subtypes and HBR/non-HBR in ACS patients. The most influential factors affecting bleeding events might not solely be the presence or absence of HBR and ACS subtypes but rather other characteristics such as the use of haemodynamic support devices. Therefore, these subgroup analyses should be considered exploratory. Second, it is well known that Japanese patients with coronary artery disease have lower ischaemic risk, but had higher bleeding risk compared with US and European patients.²⁷ In addition, we cannot rule out the possibility of a selection bias that lower risk patients were enrolled compared with real-world clinical practice. Despite the inclusion of patients with oral anticoagulants or those with severe condition such as cardiogenic shock requiring haemodynamic support device, this potential bias should be acknowledged. Third, the common clinical practice for ACS patients in Japan may be different from that in other countries. In Japan, the reduced dose of prasugrel was approved, and ticagrelor is not commonly used as the first line drug for ACS patients. Also, we used the reduced doses of prasugrel at loading/maintenance of 20/3.75 mg, which were only approved in Japan.^3,4 Even the reduced dose of prasugrel was associated with an increased risk of bleeding, without significant differences in in-hospital mortality and stent thrombosis, compared with standard-dose clopidogrel.²⁸ Additionally, the prevalence of intracoronary imaging guided PCI is much higher than that in USA and Europe. Therefore, extreme caution should be paid when extrapolating the current study results outside Japan. Fourth, we included only patients who underwent PCI using CoCr-EES, which may affect the external validity of the study results to those with other types of stents.

Conclusions

In patients with ACS undergoing PCI, the no-aspirin strategy compared with the DAPT strategy failed to reduce major bleeding events irrespective of HBR and ACS subtypes. The numerical excess risk of the no-aspirin strategy relative to the DAPT strategy for cardiovascular events was observed in patients with HBR and in patients with NSTE-ACS.

Acknowledgement

We appreciate the study co-investigators for their invaluable contributions in enrolling patients, collecting follow-up data, and adjudicating clinical events. We also appreciate the coordination and support provided by the members of the Research Institute for Production Development.

Funding

This work was supported by Abbott Vascular Japan.

Conflict of interest Y.O. reports lecturer's fee from Abbott Medical Japan.

M.N. reports honoraria from Abbott Medical Japan, Daiichi Sankyo, Medtronic, Terumo, Japan Lifeline, Asahi Intecc, Bristol Myers Squibb, Otsuka, Amgen, Sanofi, Takeda, and Bayer.

H.W. reports personal fees from Abbott Medical Japan during the conduct of the study as well as personal fees from Daiichi Sankyo, Kowa, Abiomed, Bayer, Pfizer, Bristol-Myers Squibb, and Otsuka outside the submitted work.

T.M. reports lecturer's fees from AstraZeneca, Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Kowa, Pfizer and Tsumura; manuscript fees from Bristol-Myers Squibb and Pfizer; advisory board for Novartis and Teijin.

S.S. reports personal fees from Abbott Medical Japan and Daiichi Sankyo outside the submitted work.

T.K. reports grants from Abbott Medical Japan and Boston Scientific and being an advisory board member of Abbott Medical Japan and Terumo Japan. No other disclosures were reported.

Data availability

The data underlying this article will be shared on reasonable request to the corresponding author.

References