Abstract
Background: No previous studies have evaluated the effect of an aspirin-free strategy for patients undergoing staged percutaneous coronary intervention (PCI).
Methods and Results: We conducted a post hoc subgroup analysis in patients undergoing staged PCI within 1 month in STOPDAPT-3 (n=6,002), which randomly compared prasugrel monotherapy with dual antiplatelet therapy (DAPT) in patients with acute coronary syndrome or high bleeding risk. The co-primary endpoints were major bleeding (Bleeding Academic Research Consortium 3 or 5) and cardiovascular events (a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or stroke) at 1 month. There were 814 patients undergoing staged PCI within 1 month (no-aspirin group, n=401; DAPT group, n=413). The median interval from randomization to the first staged PCI was 8 (interquartile range 5–13) days. More than 90% of the patients received assigned antiplatelet agents at all staged PCI procedures. The effect of no-aspirin relative to DAPT was not different for the co-primary bleeding (3.74% vs. 1.94%; HR 1.94; 95% CI 0.82–4.57) and cardiovascular (3.49% vs. 2.42%; HR 1.44; 95% CI 0.64–3.25) endpoints. The no-aspirin group compared with the DAPT group had a numerically higher incidence of the co-primary cardiovascular endpoint, which occurred after the first staged PCI procedure (2.49% vs. 1.21%; HR 2.07; 95% CI 0.71–6.05).
Conclusions: An aspirin-free prasugrel monotherapy relative to DAPT had numerically higher risks of cardiovascular and major bleeding events in patients undergoing staged PCI at 1 month.
Patients undergoing percutaneous coronary intervention (PCI) for multiple lesions sometimes require multiple procedures to complete revascularization, which is known as a ‘staged PCI procedure’.1–4 Completing PCI for all target lesions in a single session would be ideal to avoid multiple procedures, reduce cost, and treat vulnerable lesions immediately. However, there are some clinical and non-clinical reasons to perform staged PCI procedures in real-world practice.1 Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12
inhibitor is the standard antiplatelet regimen during the periprocedural period in patients undergoing PCI.5–7 In contrast, several single-arm studies suggest the safety and feasibility of an aspirin-free P2Y12
inhibitor monotherapy immediately after PCI.8–10 However, patients requiring staged PCI were not enrolled in these studies. Recently, the STOPDAPT-3 (ShorT and OPtimal Duration of Dual AntiPlatelet Therapy-3) trial demonstrated that an aspirin-free strategy compared with the DAPT strategy failed to reduce major bleeding at 1 month after PCI, with a signal suggesting increased coronary events such as definite or probable subacute stent thrombosis and any unplanned coronary revascularization in patients with acute coronary syndrome or high bleeding risk.11 Because patients undergoing staged PCI were exposed to the risk of periprocedural thrombotic complications by multiple procedures, there is concern regarding the adoption of an aspirin-free strategy for patients undergoing staged PCI.4 In contrast, an aspirin-free strategy might be an attractive regimen in patients undergoing staged PCI because of multiple periprocedural bleeding risk.4 In the present study, we aimed to evaluate the safety and efficacy of an aspirin-free strategy for patients undergoing staged PCI using the data from STOPDAPT-3.
Methods
Study Design and Population
STOPDAPT-3 (NCT04609111) was a physician-initiated, prospective, multicenter, open-label, adjudicator blinded randomized clinical trial where we compared the bleeding and cardiovascular outcomes between an experimental group of 1-month prasugrel monotherapy without aspirin and a control group of 1-month DAPT with aspirin and prasugrel in patients planned for PCI using cobalt-chromium everolimus-eluting stent (CoCr-EES: XienceTM
series, ABBOTT Vascular) implantation. The detailed study protocol and main results are reported elsewhere.11 The study was conducted in accordance with the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan. In brief, a total of 6,002 patients with acute coronary syndrome regardless of Academic Research Consortium high bleeding risk (ARC-HBR) or non-acute coronary syndrome with high bleeding risk were enrolled between January 2021 to April 2023 from 72 centers in Japan, and were randomly allocated immediately before PCI in a 1-to-1 ratio to either prasugrel monotherapy without aspirin (no-aspirin group) or to 1-month DAPT with aspirin and prasugrel (DAPT group).
After randomization, a loading dose of prasugrel 20 mg was administered in both groups. A loading dose of aspirin 162–200 mg was 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. At the 1-month (30–59 days) visit, prasugrel was switched to clopidogrel and was continued up to 1 year in the no-aspirin group, while prasugrel was discontinued and aspirin monotherapy was continued up to 1 year in the DAPT group. The ethical committees in all the participating centers approved the study protocol, and informed consent was obtained from all patients.
The present study was a post hoc subgroup analysis in patients who underwent staged PCI within 1 month in STOPDAPT-3. Among 6,002 patients who underwent randomization, we excluded 5 patients who did not undergo the index PCI due to the absence of suitable coronary lesions, 1 patient who had been enrolled in another clinical trial, 30 patients who withdrew consent, and 5,152 patients who did not undergo the staged PCI within 1 month. Therefore, the population in the present study consisted of 814 patients who underwent the first index PCI and staged PCI within 1 month (Figure 1). Staged PCI was defined as PCI procedures planned at the time of the first index PCI.1 Staged PCI was recommended to be performed within 3 months after the randomization, although the actual execution, timing, and number of staged PCI were left to the discretion of each attending physician. Recommended antiplatelet therapy at the staged PCI before the primary analysis of 1 month was continuing each assigned regimen; only prasugrel 3.75 mg/day should be continued without loading in the no-aspirin group, while aspirin 81–100 mg/day and prasugrel 3.75 mg/day should be continued without loading in the DAPT group. In the no-aspirin group, aspirin should not be administrated even at the time of staged PCI. Planned staged PCI procedures were not regarded as follow-up events, but included in the index PCI procedure. In contrast, any unplanned PCI, even if it was performed before planned staged PCI, was regarded as a follow-up event.
Endpoints
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 ischemic stroke.12 The major secondary endpoint was a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, ischemic 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 Academic Research Consortium criteria.13 The definitions of other secondary endpoints are described in the Supplementary File. The independent clinical event committee adjudicated all the clinical events in a blinded fashion to the assigned group.
Statistical Analysis
Categorical variables are presented as number and percentage and were compared using the chi-square 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 using the Kaplan-Meier method. The effect of the no-aspirin group relative to the DAPT group for the endpoints were expressed as hazard ratios (HRs) with 95% confidence intervals (CIs) using the Cox proportional hazard model. We also evaluated the co-primary bleeding and cardiovascular endpoints that occurred after the first staged PCI procedure. In addition, the sensitivity analyses were performed after excluding patients who did not receive assigned antiplatelet agents at any staged PCI. Furthermore, we conducted the subgroup analysis stratified by acute or non-acute coronary syndrome. All reported P values were 2-sided. P values <0.05 were considered statistically significant. All analysis was performed with R version 4.2.3 (R Foundation for Statistical Computing, Vienna, Austria).
Results
Baseline Characteristics
There were 401 patients in the no-aspirin group and 413 patients in the DAPT group (Figure 1). In the total study population, the mean age was 71.0 years, 78.6% of the patients were men, and 83.7% of the patients presented as acute coronary syndrome (Table 1). The mean estimated glomerular filtration rate (eGFR) was 58.3 mL/min/1.73 m2, and the prevalence of moderate (eGFR 30–59 mL/min/1.73 m2) and severe (eGFR <30 mL/min/1.73 m2
or hemodialysis) chronic kidney disease was 40.5% and 10.0%, respectively. Multivessel PCI targets were presented in 92.6% of patients with a mean number of target lesions of 2.4, and 10.0% of patients had a chronic total occlusion target. Intravascular imaging was used in 93.1% of patients. Baseline characteristics were well balanced between the no-aspirin and DAPT groups, except for the higher prescription rate of proton-pump inhibitors in the DAPT group compared with the no-aspirin group.
Table 1.
Baseline Characteristics
| |
Study population
(n=814) |
No-aspirin group
(n=401) |
DAPT group
(n=413) |
| Patient demographics |
| Age (years) |
71.0±11.3 |
71.0±10.9 |
70.9±11.8 |
| ≥75 |
332 (40.8) |
170 (42.4) |
162 (39.2) |
| Sex, male |
640 (78.6) |
324 (80.8) |
316 (76.5) |
| Body mass index (kg/m2) |
24.2±3.9 |
24.0±3.7 |
24.3±4.1 |
| Clinical presentation |
| Acute coronary syndrome |
681 (83.7) |
333 (83.0) |
348 (84.3) |
| STEMI |
399 (49.0) |
184 (45.9) |
215 (52.1) |
| Door to wire crossing time within 24 h of onset (min) |
45 [34–55] |
46 [32–55] |
45 [36–54] |
| NSTEMI |
187 (23.0) |
102 (25.4) |
85 (20.6) |
| Unstable angina |
95 (11.7) |
47 (11.7) |
48 (11.6) |
| Cardiac arrest or ventricular fibrillation |
7 (0.9) |
3 (0.7) |
4 (1.0) |
| Cardiogenic shock |
35 (4.3) |
15 (3.7) |
20 (4.8) |
| Current heart failure |
168 (20.6) |
81 (20.2) |
87 (21.1) |
| Past history and comorbidities |
| Prior PCI |
91 (11.2) |
47 (11.7) |
44 (10.7) |
| Prior coronary artery bypass grafting |
5 (0.6) |
3 (0.7) |
2 (0.5) |
| Prior myocardial infarction |
42 (5.2) |
24 (6.0) |
18 (4.4) |
| Prior stroke |
67 (8.2) |
27 (6.7) |
40 (9.7) |
| Prior heart failure |
43 (5.3) |
20 (5.0) |
23 (5.6) |
| Atrial fibrillation |
51 (6.3) |
27 (6.7) |
24 (5.8) |
| Diabetes |
346 (42.5) |
171 (42.6) |
175 (42.4) |
| Current smoker |
226 (27.8) |
108 (26.9) |
118 (28.6) |
| Left ventricular ejection fraction (%) |
53.3±10.8 |
53.1±10.4 |
53.5±11.3 |
| Estimated glomerular filtration rate (mL/min/1.73 m2) |
58.3±22.0 |
57.6±21.8 |
59.1±22.1 |
| Moderate chronic kidney disease |
330 (40.5) |
174 (43.4) |
156 (37.8) |
| Severe chronic kidney disease |
81 (10.0) |
38 (9.5) |
43 (10.4) |
| Hemodialysis |
36 (4.4) |
18 (4.5) |
18 (4.4) |
| Cancer history |
72 (8.8) |
28 (7.0) |
44 (10.7) |
| ARC-HBR |
389 (47.8) |
195 (48.6) |
194 (47.0) |
| Procedural characteristics |
| Radial approach |
697 (85.6) |
346 (86.3) |
351 (85.0) |
| Radial approach only |
641 (78.7) |
320 (79.8) |
321 (77.7) |
| Femoral approach |
153 (18.8) |
71 (17.7) |
82 (19.9) |
| Brachial approach |
19 (2.3) |
10 (2.5) |
9 (2.2) |
| No. target lesions |
2.4±0.7 |
2.4±0.7 |
2.4±0.7 |
| Target of ≥2 vessels |
754 (92.6) |
374 (93.3) |
380 (92.0) |
| Target of chronic total occlusion |
81 (10.0) |
36 (9.0) |
45 (10.9) |
| Target of bifurcation lesion |
338 (41.5) |
174 (43.4) |
164 (39.7) |
| Bifurcation 2 stents |
18 (2.2) |
9 (2.2) |
9 (2.2) |
| Target of left main coronary artery |
86 (10.6) |
49 (12.2) |
37 (9.0) |
| No. implanted stents |
2.6±1.1 |
2.7±1.1 |
2.6±1.0 |
| Total stent length (mm) |
71.0±34.9 |
71.1±35.6 |
70.8±34.4 |
| Use of intravascular imaging |
758 (93.1) |
376 (93.8) |
382 (92.5) |
| Intubation |
19 (2.3) |
10 (2.5) |
9 (2.2) |
| Hemodynamic support device use |
80 (9.8) |
35 (8.7) |
45 (10.9) |
| IABP use |
76 (9.3) |
33 (8.2) |
43 (10.4) |
| ECMO use |
2 (0.2) |
2 (0.5) |
0 (0) |
| Impella use |
4 (0.5) |
2 (0.5) |
2 (0.5) |
| Continuous hemofiltration use |
15 (1.8) |
9 (2.2) |
6 (1.5) |
| Medication within 7 days before assignment |
| Antiplatelet agents |
216 (26.5) |
115 (28.7) |
101 (24.5) |
| Aspirin only |
150 (18.4) |
77 (19.2) |
73 (17.7) |
| P2Y12 inhibitors only |
39 (4.8) |
21 (5.2) |
18 (4.4) |
| DAPT |
27 (3.3) |
17 (4.2) |
10 (2.4) |
| Aspirin/prasugrel |
11 (1.4) |
6 (1.5) |
5 (1.2) |
| Aspirin/clopidogrel |
14 (1.7) |
9 (2.2) |
5 (1.2) |
| Anticoagulants |
44 (5.4) |
22 (5.5) |
22 (5.3) |
| Warfarin |
6 (13.6) |
3 (13.6) |
3 (13.6) |
| Direct oral anticoagulants |
38 (86.4) |
19 (86.4) |
19 (86.4) |
| Medication at index PCI |
| Loading of prasugrel |
812 (99.8) |
400 (99.8) |
412 (99.8) |
| Loading of aspirin in the DAPT group |
356 (86.4) |
– |
356 (86.4) |
| Medication after the index PCI or at discharge |
| β-blockers |
546 (70.1) |
269 (70.6) |
277 (69.6) |
| Statins |
736 (94.5) |
357 (93.7) |
379 (95.2) |
| High-intensity statin therapy |
446 (57.3) |
218 (57.2) |
228 (57.3) |
| Proton-pump inhibitors |
707 (90.8) |
334 (87.7) |
373 (93.7) |
Categorical variables are presented as n (%). Continuous variables are presented as mean±SD, or median [interquartile range]. Moderate and severe chronic kidney disease are defined using the criteria in the ARC-HBR (moderate: estimated glomerular filtration rate 30–59 mL/min/1.73 m2; severe: estimated glomerular filtration rate <30 mL/min/1.73 m2 or hemodialysis). Values are missing for left ventricular ejection fraction in 40 patients, estimated glomerular filtration rate in 2 patients, and total stent length in 1 patient. Number of target lesions and total stent length are based on the first index PCI, as well as the staged PCI within 1 month. High-intensity statin therapy is defined as use of the maximum approved dose of strong statins in Japan (e.g., rosuvastatin 10 mg, atorvastatin 20 mg, or pitavastatin 4 mg). ARC-HBR, Academic Research Consortium for high bleeding risk; DAPT, dual-antiplatelet therapy; ECMO, extracorporeal membrane oxygenation; HBR, high bleeding risk; IABP, intra-aortic balloon pumping; NSTEMI, non-ST segment elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction.
In the study population, 92.8% of the patients had 1 staged PCI procedure, 6.9% of the patients had 2 staged PCI procedures, and 0.4% of the patients had 3 staged PCI procedures (Table 2). The median interval from randomization to the first staged PCI was 8 (interquartile range 5–13) days. The status of antiplatelet agents at the staged PCI is presented in Table 2. The prevalence of patients receiving assigned antiplatelet agents at all staged PCI procedures was 92.8% in the no-aspirin group and 99.3% in the DAPT group. During the study period of 1 month, the majority of the study patients received the assigned antiplatelet agents (Supplementary Figure 1).
Table 2.
Details of the Staged PCI
| |
Staged PCI
(n=814) |
No-aspirin group
(n=401) |
DAPT group
(n=413) |
| No. staged PCI |
| 1 |
755 (92.8) |
373 (93.0) |
382 (92.5) |
| 2 |
56 (6.9) |
27 (6.7) |
29 (7.0) |
| 3 |
3 (0.4) |
1 (0.2) |
2 (0.5) |
| Days from randomization to the first staged PCI |
8 [5–13] |
9 [5–14] |
8 [5–12] |
| Antiplatelet agents at the first staged PCI |
n=814 |
n=401 |
n=413 |
| Aspirin only |
1 (0.1) |
0 (0) |
1 (0.2) |
| P2Y12 inhibitors only |
375 (46.1) |
375 (93.5) |
1 (0.2) |
| Prasugrel only |
372 (45.7) |
372 (92.8) |
1 (0.2) |
| Clopidogrel only |
3 (0.4) |
3 (0.7) |
0 (0) |
| DAPT |
435 (53.4) |
25 (6.2) |
411 (99.5) |
| Aspirin/prasugrel |
431 (52.9) |
22 (5.5) |
410 (99.3) |
| Aspirin/clopidogrel |
4 (0.5) |
3 (0.7) |
1 (0.2) |
| No antiplatelet therapy† |
1 (0.1) |
1 (0.2) |
0 (0) |
| Antiplatelet agents at the second staged PCI |
n=59 |
n=28 |
n=31 |
| Aspirin only |
0 (0) |
0 (0) |
0 (0) |
| P2Y12 inhibitors only |
25 (42.4) |
25 (89.3) |
0 (0) |
| Prasugrel only |
25 (42.4) |
25 (89.3) |
0 (0) |
| Clopidogrel only |
0 (0) |
0 (0) |
0 (0) |
| DAPT |
34 (57.6) |
3 (10.7) |
31 (100) |
| Aspirin/prasugrel |
34 (57.6) |
3 (10.7) |
31 (100) |
| Aspirin/clopidogrel |
0 (0) |
0 (0) |
0 (0) |
| No antiplatelet therapy |
0 (0) |
0 (0) |
0 (0) |
| Antiplatelet agents at the third staged PCI |
n=3 |
n=1 |
n=2 |
| Aspirin only |
0 (0) |
0 (0) |
0 (0) |
| P2Y12 inhibitors only |
1 (33.3) |
1 (100) |
0 (0) |
| Prasugrel only |
1 (33.3) |
1 (100) |
0 (0) |
| Clopidogrel only |
0 (0) |
0 (0) |
0 (0) |
| DAPT |
2 (66.7) |
0 (0) |
2 (100) |
| Aspirin/prasugrel |
2 (66.7) |
0 (0) |
2 (100) |
| Aspirin/clopidogrel |
0 (0) |
0 (0) |
0 (0) |
| No antiplatelet therapy |
0 (0) |
0 (0) |
0 (0) |
| Patients receiving assigned antiplatelet agents at all staged PCI |
782 (96.1) |
372 (92.8) |
410 (99.3) |
Categorical variables are presented as n (%). Continuous variables are presented as median [interquartile range]. †One patient (no-aspirin group) did not receive any antiplatelet therapy at the first staged PCI. The patient could not complete the first index PCI procedure due to access-site bleeding and discontinued prasugrel. After healing of the access-site bleeding, staged PCI was performed without any antiplatelet therapy, and prasugrel monotherapy was re-initiated from the next day of the staged PCI. PCI, percutaneous coronary intervention.
Clinical Outcomes
The co-primary bleeding endpoint occurred in 15 (3.74%) patients in the no-aspirin group and 8 (1.94%) patients in the DAPT group at 1 month (HR 1.94; 95% CI 0.82–4.57; P=0.13) (Figure 2A). The co-primary bleeding endpoint after the first staged PCI occurred in 5 (1.25%) patients in the no-aspirin group and 3 (0.73%) patients in the DAPT group (HR 1.71; 95% CI 0.41–7.18; Table 3). The details of the co-primary bleeding endpoint are shown in Table 4A. Among 15 patients who had a co-primary bleeding endpoint in the no-aspirin group, 4 patients (numbers 3, 7, 11, and 14 in Table 4A) were considered to have a procedural complication (e.g., access-site bleeding, ischemic stroke with hemorrhagic conversion, or cardiac tamponade) due to the staged PCI. Among 8 patients who had a co-primary bleeding endpoint in the DAPT group, 1 patient (number 20 in Table 4A) was considered to have a procedural complication (e.g., access-site bleeding) due to the staged PCI.
Table 3.
Clinical Outcomes at 1 Month
| Outcome |
No-aspirin group
(n=401) |
DAPT group
(n=413) |
Hazard ratio
(95% CI) |
No. patients with event
(cumulative incidence %) |
| Co-primary bleeding endpoint |
| BARC 3 or 5 bleeding |
15 (3.74) |
8 (1.94) |
1.94 (0.82–4.57) |
| After the first staged PCI procedure |
5 (1.25) |
3 (0.73) |
1.71 (0.41–7.18) |
| Co-primary cardiovascular endpoint |
A composite of cardiovascular death, MI, definite stent thrombosis,
or ischemic stroke |
14 (3.49) |
10 (2.42) |
1.44 (0.64–3.25) |
| After the first staged PCI procedure |
10 (2.49) |
5 (1.21) |
2.07 (0.71–6.05) |
| Major secondary endpoint |
A composite of cardiovascular death, MI, definite stent thrombosis,
ischemic stroke, or BARC 3 or 5 bleeding |
25 (6.23) |
18 (4.36) |
1.44 (0.78–2.63) |
| Secondary endpoint |
| Death |
3 (0.75) |
1 (0.24) |
3.09 (0.32–29.69) |
| Cardiovascular causes |
3 (0.75) |
1 (0.24) |
3.09 (0.32–29.69) |
| Sudden death |
1 (0.25) |
0 (0.00) |
NA |
| Non-cardiovascular causes |
0 (0.00) |
0 (0.00) |
NA |
| Stroke |
4 (1.00) |
3 (0.73) |
1.37 (0.31–6.12) |
| Ischemic |
3 (0.75) |
3 (0.73) |
1.03 (0.21–5.09) |
| Hemorrhagic |
1 (0.25) |
0 (0.00) |
NA |
| MI |
8 (2.00) |
5 (1.21) |
1.65 (0.54–5.05) |
| Spontaneous |
4 (1.00) |
1 (0.25) |
4.13 (0.46–36.91) |
| Procedural |
4 (1.01) |
4 (0.97) |
1.03 (0.26–4.13) |
| Definite or probable stent thrombosis |
2 (0.50) |
4 (0.97) |
0.51 (0.09–2.81) |
| Acute |
1 (0.25) |
2 (0.48) |
0.51 (0.05–5.68) |
| Subacute |
1 (0.25) |
2 (0.49) |
0.51 (0.05–5.66) |
| Definite |
2 (0.50) |
4 (0.97) |
0.51 (0.09–2.81) |
| Acute |
1 (0.25) |
2 (0.48) |
0.51 (0.05–5.68) |
| Subacute |
1 (0.25) |
2 (0.49) |
0.51 (0.05–5.66) |
| Probable |
0 (0.00) |
0 (0.00) |
NA |
| Acute |
0 (0.00) |
0 (0.00) |
NA |
| Subacute |
0 (0.00) |
0 (0.00) |
NA |
| Any coronary revascularization (unplanned) |
7 (1.75) |
7 (1.70) |
1.03 (0.36–2.93) |
| Target lesion (unplanned) |
3 (0.75) |
6 (1.46) |
0.51 (0.13–2.05) |
| Non-target lesion (unplanned) |
4 (1.00) |
2 (0.49) |
2.06 (0.38–11.26) |
| Bleeding |
| BARC 2, 3 or 5 |
30 (7.48) |
19 (4.61) |
1.65 (0.93–2.93) |
| BARC 5 |
2 (0.50) |
0 (0.00) |
NA |
| BARC 4 |
0 (0.00) |
0 (0.00) |
NA |
| BARC 3 |
14 (3.50) |
8 (1.94) |
1.81 (0.76–4.31) |
| BARC 2 |
15 (3.74) |
12 (2.91) |
1.30 (0.61–2.78) |
| Location of bleeding: BARC 3 or 5† |
| Intracranial bleeding |
2 (0.50) |
0 (0.00) |
NA |
| Gastrointestinal bleeding |
2 (0.50) |
3 (0.73) |
0.68 (0.11–4.10) |
| Access-site bleeding |
7 (1.75) |
3 (0.73) |
2.40 (0.62–9.29) |
| PCI access |
4 (1.00) |
3 (0.73) |
1.37 (0.31–6.13) |
| Radial access |
1 (0.25) |
2 (0.48) |
0.51 (0.05–5.68) |
| Non-radial access |
3 (0.75) |
1 (0.24) |
3.09 (0.32–29.71) |
| Non-PCI access |
3 (0.75) |
0 (0.00) |
NA |
| Cardiac tamponade |
1 (0.25) |
0 (0.00) |
NA |
| PCI procedure-related bleeding |
1 (0.25) |
2 (0.48) |
0.51 (0.05–5.67) |
| Surgery procedure-related bleeding |
0 (0.00) |
0 (0.00) |
NA |
| Retroperitoneum bleeding |
0 (0.00) |
0 (0.00) |
NA |
| Pulmonary bleeding |
0 (0.00) |
0 (0.00) |
NA |
| Genitourinary bleeding |
0 (0.00) |
0 (0.00) |
NA |
| Intraocular bleeding |
0 (0.00) |
0 (0.00) |
NA |
| Other bleeding |
5 (1.25) |
0 (0.00) |
NA |
†Some patients had bleeding in multiple locations. Non-PCI access indicated arterial and venous access other than the access for PCI. Cumulative incidences of the endpoints were estimated using the Kaplan-Meier method. The hazard ratio and 95% CI for the no-aspirin group relative to the DAPT group were estimated with the Cox proportional hazard model. Acute stent thrombosis was defined as that occurring within 24 h of PCI, and subacute stent thrombosis was defined as that occurring beyond 24 h and up to 30 days after PCI. BARC, Bleeding Academic Research Consortium; CI, confidence interval; DAPT, dual antiplatelet therapy; MI, myocardial infarction; PCI, percutaneous coronary intervention.
Table 4.
Details of the Events Adjudicated as the Co-Primary Bleeding and Cardiovascular Endpoints, (A) Co-Primary Bleeding Endpoint of BARC 3 or 5 Bleeding, (B) Co-Primary Cardiovascular Endpoint of a Composite of Cardiovascular Death, MI, Definite Stent Thrombosis, or Ischemic Stroke
(A)
No. |
Assigned
group |
Age
(years),
sex |
Presentation |
Target
lesion in the
index PCI |
Target lesion
in the
first staged PCI |
Antiplatelet
agents at the
first staged PCI |
Details of the event |
| 1 |
No aspirin |
71, M |
STEMI
(Killip 1) |
Proximal
RCA |
Mid LCX at
Day 16 |
Prasugrel
monotherapy |
ECMO access-site bleeding at Day 3 (BARC3) |
| 2 |
No aspirin |
66, M |
STEMI
(Killip 1) |
Mid-RCA |
LMCA at
Day 5 |
Prasugrel
monotherapy |
Unknown-site bleeding at Day 1 (BARC3) |
| 3 |
No aspirin |
81, M |
STEMI
(Killip 1) |
Proximal
RCA |
Proximal LAD
at Day 9 |
Prasugrel
monotherapy |
Ischemic stroke with hemorrhagic conversion due to
first staged PCI at Day 9 (BARC3) |
| 4 |
No aspirin |
81, F |
STEMI
(Killip 1) |
Mid-LAD |
Proximal LAD
at Day 19 |
Prasugrel
monotherapy |
PCI procedure-related bleeding due to index PCI at Day
5 (BARC3) |
| 5 |
No aspirin |
74, F |
STEMI
(Killip 2) |
Proximal
RCA |
Proximal LAD
at Day 23 |
Prasugrel
monotherapy |
Gastrointestinal bleeding at Day 10 (BARC3) |
| 6 |
No aspirin |
82, F |
STEMI
(Killip 2) |
Proximal
RCA |
Proximal LAD
at Day 18 |
Prasugrel
monotherapy |
PCI access-site bleeding due to index PCI (femoral
approach) at Day 1 (BARC3) |
| 7 |
No aspirin |
58, M |
STEMI
(Killip 2) |
Proximal
RCA |
Proximal LAD
at Day 13 |
Prasugrel
monotherapy |
ECMO and impella access-site bleeding due to first staged
PCI at Day 13 (BARC3), intracranial bleeding at Day 15
(BARC3), and gastrointestinal bleeding at Day 26 (BARC5) |
| 8 |
No aspirin |
89, M |
STEMI
(Killip 3) |
Mid-RCA |
LMCA at
Day 22 |
Prasugrel
and aspirin |
Unknown-site bleeding at Day 3 (BARC3) |
| 9 |
No aspirin |
78, M |
STEMI
(Killip 4) |
Distal LCX |
Proximal LAD
and distal
LCX at Day 2 |
Prasugrel
monotherapy |
Pectoralis major bleeding due to chest compression at
Day 0 (BARC3) |
| 10 |
No aspirin |
79, M |
STEMI
(Killip 4) |
Proximal
RCA |
Proximal-mid
RCA at
Day 10 |
Prasugrel
monotherapy |
Unknown site bleeding at Day 1 (BARC3) |
| 11 |
No aspirin |
86, F |
NSTEMI
(Killip 1) |
Mid-distal
RCA |
Proximal LAD
at Day 10 |
Prasugrel
monotherapy |
PCI access-site bleeding due to first staged PCI
(brachial approach) at Day 10 (BARC3) |
| 12 |
No aspirin |
80, F |
NSTEMI
(Killip 1) |
Mid-RCA |
Mid LAD at
Day 15 |
Prasugrel
monotherapy |
PCI access-site bleeding due to index PCI (femoral
approach) at Day 2 (BARC3) |
| 13 |
No aspirin |
88, F |
NSTEMI
(Killip 3) |
Proximal
LAD |
Proximal and
distal RCA
and mid-LAD
at Day 3 |
Prasugrel
monotherapy |
PCI access-site bleeding due to index PCI (radial
approach) at Day 0 (BARC3) |
| 14 |
No aspirin |
80, M |
UAP
(class 3) |
Mid-LCX |
LMCA and
proximal LCX
at Day 2 |
Prasugrel
monotherapy |
Cardiac tamponade and IABP access-site bleeding due
to first staged PCI at Day 2 (BARC5) |
| 15 |
No aspirin |
87, F |
CCS |
Proximal
RCA |
Proximal LAD
and proximal
LCX at Day 4 |
Prasugrel
monotherapy |
Unknown-site bleeding at Day 16 (BARC3) |
| 16 |
DAPT |
64, M |
STEMI
(Killip 1) |
Mid-LCX |
Mid LAD at
Day 13 |
Prasugrel
and aspirin |
PCI procedure-related bleeding due to index PCI at Day
0 (BARC3) |
| 17 |
DAPT |
71, M |
STEMI
(Killip 1) |
Proximal
RCA |
Proximal LAD
at Day 18 |
Prasugrel
and aspirin |
PCI procedure-related bleeding due to index PCI at Day
0 (BARC3) |
| 18 |
DAPT |
85, M |
STEMI
(Killip 1) |
Proximal
LAD |
Mid LCX at
Day 4 |
Prasugrel
and aspirin |
PCI access-site bleeding due to index PCI (femoral
approach) at Day 1 (BARC3) |
| 19 |
DAPT |
84, F |
NSTEMI
(Killip 1) |
Proximal
LCX |
Proximal RCA
at Day 13 |
Prasugrel
and aspirin |
PCI access-site bleeding due to index PCI (radial
approach) at Day 0 (BARC3) |
| 20 |
DAPT |
64, F |
NSTEMI
(Killip 1) |
Diagonal
branch |
Proximal RCA
at Day 1 |
Prasugrel
and aspirin |
PCI access-site bleeding due to first staged PCI (radial
approach) at Day 1 (BARC3) |
| 21 |
DAPT |
62, F |
CCS |
Proximal
RCA |
Proximal LCX
at Day 4 |
Prasugrel
and aspirin |
Gastrointestinal bleeding at Day 9 (BARC3) |
| 22 |
DAPT |
73, M |
CCS |
Distal RCA |
Proximal LAD
at Day 8 |
Prasugrel
and aspirin |
Gastrointestinal bleeding at Day 27 (BARC3) |
| 23 |
DAPT |
82, F |
CCS |
LMCA |
Mid RCA at
Day 7 |
Prasugrel
and aspirin |
Gastrointestinal bleeding at Day 3 (BARC3) |
(B)
No. |
Assigned
group |
Age
(years),
sex |
Presentation |
Target
lesion in the
index PCI |
Target lesion
in the first
staged PCI |
Antiplatelet
agents at
the first
staged PCI |
Target
lesion in
the second
staged PCI |
Antiplatelet
agents at
the second
staged PCI |
Details of the event |
| 1 |
No aspirin |
71, M |
STEMI
(Killip 1) |
Mid-RCA |
Mid LAD at
Day 13 |
Prasugrel
monotherapy |
Mid LCX at
Day 21 |
Prasugrel
monotherapy |
Ischemic stroke at Day 28 |
| 2 |
No aspirin |
69, M |
STEMI
(Killip 1) |
Distal RCA |
Mid-distal LAD
at Day 11 |
Prasugrel
monotherapy |
– |
– |
Periprocedural MI due to
first staged PCI at Day 11 |
| 3 |
No aspirin |
65, M |
STEMI
(Killip 1) |
Mid-LAD |
Proximal RCA
at Day 20 |
Prasugrel
and aspirin |
– |
– |
Definite ST and spontaneous
MI due to index PCI at Day 4 |
| 4 |
No aspirin |
72, F |
STEMI
(Killip 1) |
Proximal
LAD |
Proximal LCX
at Day 8 |
Prasugrel
and aspirin |
– |
– |
Spontaneous MI (PCI for
diagonal branch) at Day 4 |
| 5 |
No aspirin |
81, M |
STEMI
(Killip 1) |
Proximal
RCA |
Proximal LAD
at Day 9 |
Prasugrel
monotherapy |
– |
– |
Ischemic stroke with
hemorrhagic conversion due
to first staged PCI at Day 9 |
| 6 |
No aspirin |
53, M |
STEMI
(Killip 1) |
Mid-RCA |
Proximal LAD
at Day 30 |
Prasugrel
and aspirin |
– |
– |
Definite ST due to index
PCI at Day 0 |
| 7 |
No aspirin |
87, F |
STEMI
(Killip 2) |
Mid-LAD |
Proximal LCX
at Day 7 |
Prasugrel
monotherapy |
– |
– |
Spontaneous MI (PCI for
proximal RCA) at Day 11 |
| 8 |
No aspirin |
58, M |
STEMI
(Killip 2) |
Proximal
RCA |
Proximal LAD
at Day 13 |
Prasugrel
monotherapy |
– |
– |
Periprocedural MI due to
first staged PCI at Day 13
and cardiac death (cause
of death: periprocedural MI
due to first staged PCI) at 26 |
| 9 |
No aspirin |
75, M |
NSTEMI
(Killip 1) |
Proximal
RCA |
Proximal LAD
at Day 9 |
Prasugrel
monotherapy |
– |
– |
Periprocedural MI due to
first staged PCI at Day 10 |
| 10 |
No aspirin |
75, M |
NSTEMI
(Killip 1) |
Proximal
LAD |
Mid LCX at
Day 4 |
Prasugrel
monotherapy |
– |
– |
Spontaneous MI at Day 4
(PCI for diagonal branch
due to spontaneous MI
and scheduled staged PCI
for mid-LCX on same day) |
| 11 |
No aspirin |
88, F |
NSTEMI
(Killip 3) |
Proximal
LAD |
Proximal and
distal RCA
and mid-LAD
at Day 3 |
Prasugrel
monotherapy |
– |
– |
Cardiac death (cause of
death: myocardial
infarction) at Day 12 |
| 12 |
No aspirin |
80, M |
UAP
(class 3) |
Mid-LCX |
LMCA and
proximal LCX
at Day 2 |
Prasugrel
monotherapy |
– |
– |
Cardiac death (cardiac
tamponade due to first
staged PCI) at Day 3 |
| 13 |
No aspirin |
80, M |
UAP
(class 3) |
Proximal and
distal RCA |
Proximal LAD
at Day 7 |
Prasugrel
and aspirin |
Distal LCX
at Day 29 |
Prasugrel
and aspirin |
Ischemic stroke due to first
staged PCI at Day 7 |
| 14 |
No aspirin |
76, M |
UAP
(class 3) |
LMCA and
proximal-
mid-LAD |
Proximal and
distal RCA at
Day 7 |
Prasugrel
and aspirin |
Mid-distal
LAD at
Day 13 |
Prasugrel
and aspirin |
Periprocedural MI due to
index PCI at Day 0 |
| 15 |
DAPT |
79, M |
NSTEMI
(Killip 4) |
Mid-LCX |
Proximal LAD
at Day 2 |
Prasugrel
and aspirin |
– |
– |
Cardiac death (cause of
death: myocardial
infarction) at Day 3 |
| 16 |
DAPT |
53, M |
STEMI
(Killip 1) |
Mid-RCA |
Distal LCX at
Day 13 |
Prasugrel
and aspirin |
– |
– |
Definite ST and
periprocedural MI due to
first staged PCI at Day 13 |
| 17 |
DAPT |
67, M |
STEMI
(Killip 1) |
Proximal
RCA |
Proximal LAD
at Day 19 |
Prasugrel
and aspirin |
Mid LCX at
Day 21 |
Prasugrel
and aspirin |
Ischemic stroke at Day 1 |
| 18 |
DAPT |
55, M |
STEMI
(Killip 1) |
Mid- and
distal RCA |
Proximal LAD
and distal
LCX at Day 9 |
Prasugrel
and aspirin |
– |
– |
Ischemic stroke at Day 10
(the association between
staged PCI and ischemic
stroke was unknown) |
| 19 |
DAPT |
56, M |
STEMI
(Killip 1) |
Proximal
LAD |
Proximal LCX
at Day 11 |
Prasugrel
and aspirin |
– |
– |
Spontaneous MI (PCI for
proximal RCA) at Day 22 |
| 20 |
DAPT |
80, M |
STEMI
(Killip 2) |
Proximal and
distal RCA |
Proximal LCX
at Day 6 |
Prasugrel
and aspirin |
– |
– |
Definite ST and
periprocedural MI due
to index PCI at Day 0 |
| 21 |
DAPT |
91, M |
STEMI
(Killip 4) |
LMCA |
Proximal and
distal RCA at
Day 13 |
Prasugrel
and aspirin |
– |
– |
Ischemic stroke at Day 2 |
| 22 |
DAPT |
55, M |
STEMI
(Killip 4) |
Proximal
LAD |
Distal LCX at
Day 4 |
Prasugrel
and aspirin |
– |
– |
Definite ST due to index
PCI at Day 1 |
| 23 |
DAPT |
54, M |
UAP
(class 1) |
Mid-distal
RCA |
Proximal LCA
at Day 9 |
Prasugrel
and aspirin |
– |
– |
Definite ST and
periprocedural MI due
to index PCI at Day 0 |
| 24 |
DAPT |
88, M |
CCS |
LMCA |
Mid-RCA at
Day 5 |
Prasugrel
and aspirin |
– |
– |
Periprocedural MI due to
first staged PCI at Day 5 |
CCS, chronic coronary syndrome; F, female; LAD, left anterior descending coronary artery; LCX, left circumflex coronary artery; LMCA, left main coronary artery; M, male; RCA, right coronary artery; UAP, unstable angina pectoris. Other abbreviations as in Tables 1,3.
The co-primary cardiovascular endpoint occurred in 14 (3.49%) patients in the no-aspirin group and 10 (2.42%) patients in the DAPT group at 1 month (HR 1.44; 95% CI 0.64–3.25; P=0.38; Figure 2B). The co-primary cardiovascular endpoint after the first staged PCI occurred in 10 (2.49%) patients in the no-aspirin group and 5 (1.21%) patients in the DAPT group (HR 2.07; 95% CI 0.71–6.05; Table 3). The details of the co-primary cardiovascular endpoint are shown in Table 4B. Among 14 patients who had a co-primary cardiovascular endpoint in the no-aspirin group, 7 patients (numbers 2, 5, 8, 9, 10, 12, and 13 in Table 4B) were considered to have a procedural complication (e.g., periprocedural myocardial infarction, ischemic stroke, or cardiac death caused by cardiac tamponade) due to the staged PCI. Among 10 patients who had a co-primary cardiovascular endpoint in the DAPT group, 2 patients (numbers 16 and 24 in Table 4B) were considered to have a procedural complication (e.g., definite stent thrombosis, or periprocedural myocardial infarction) due to the staged PCI.
Definite stent thrombosis occurred in 2 (0.50%) patients in the no-aspirin group and in 4 (0.97%) patients in the DAPT group (HR 0.51; 95% CI 0.09–2.81; Table 3). Results for the other secondary endpoints are presented in Table 3.
In the sensitivity analysis, after excluding patients who did not receive assigned antiplatelet agents at any staged PCI, the results were consistent with those in the main analysis (Supplementary Table).
In the subgroup analysis stratified by acute or non-acute coronary syndrome, the results were consistent with those in the main analysis (Supplementary Figure 2).
Discussion
The main findings of the present STOPDAPT-3 subgroup analysis are as follows: (1) an aspirin-free prasugrel monotherapy relative to DAPT failed to reduce major bleeding within 1 month in patients undergoing staged PCI; and (2) an aspirin-free prasugrel monotherapy relative to DAPT had a numerically higher incidence of cardiovascular events within 1 month in patients undergoing staged PCI.
There are some clinical reasons to perform staged PCI, which include high-contrast medium exposure especially in patients with chronic kidney disease, high radiation exposure, complex lesions such as calcified lesions requiring atherectomy device or chronic total occlusion, unexpected lengthy procedure, and procedural complications or patient instability.1 Non-clinical reasons to perform staged PCI include the issues related to operator fatigue, logistics in the catheterization laboratory, and reimbursement (economic reasons).1 Previous randomized clinical trials have demonstrated the benefit of staged PCI for a non-culprit lesion compared with culprit-only PCI in patients with acute coronary syndrome.14–16 In addition, several randomized clinical trials have suggested the benefit of immediate multivessel PCI compared with staged multivessel PCI in patients with acute coronary syndrome.17,18 In contrast, approximately 65–75% of patients with multivessel disease underwent staged PCI in real-world practice.2,3
P2Y12
inhibitor monotherapy after very short DAPT (1–3 months) compared with standard DAPT reduced major bleeding events without increasing cardiovascular events after PCI in several randomized clinical trials.19–23 However, if patients required staged PCI procedures, they were enrolled after the completion of the final staged PCI procedures, and therefore, those who experienced bleeding or ischemic complications at the staged PCI were often not enrolled in these trials. Therefore, data of the optimal duration of DAPT in patients requiring staged PCI were scarce. In patients undergoing staged PCI in the GLOBAL LEADERS trial, which compared ticagrelor monotherapy after 1-month DAPT to the 12-month DAPT, the duration of DAPT was prolonged by the interval between the first index PCI and the staged PCI according to the study protocol.4 The subgroup analyses in patients undergoing staged PCI in the GLOBAL LEADERS trial showed that ticagrelor monotherapy after 1-month DAPT compared with the 12-month DAPT was associated with a lower incidence of major bleeding in patients with acute coronary syndrome, although the incidence of major bleeding was not significantly different between the 2 groups in the overall results of the GLOBAL LEADERS trial.4,19 Patients requiring staged PCI had a periprocedural bleeding risk due to multiple procedures, and an aspirin-free strategy for patients undergoing staged PCI during the periprocedural period might reduce bleeding events. However, an aspirin-free strategy compared with the DAPT strategy failed to reduce major bleeding within 1 month in patients undergoing staged PCI in the present study, which was consistent with the main results of STOPDAPT-3.11 The major component of bleeding in the present study was procedure-related bleeding, such as access-site bleeding. The removal of aspirin might be ineffective in reducing procedure-related bleeding.
Several single-arm studies reported that an aspirin-free strategy immediately after PCI was not associated with any spontaneous myocardial infarction or stent thrombosis in selected low-risk patients.8–10 However, because patients requiring staged PCI were not enrolled in these studies, the safety of an aspirin-free strategy for patients undergoing staged PCI has not been evaluated so far. In the STOPDAPT-3 trial, patients undergoing staged PCI were recommended to take each assigned antiplatelet regimen without additional loading doses according to the study protocol, and more than 90% patients received the assigned antiplatelet regimen. The incidence of the co-primary cardiovascular endpoint was numerically higher in the no-aspirin group than in the DAPT group. In addition, the incidence of the co-primary cardiovascular endpoint, which occurred after the first staged PCI, was numerically higher in the no-aspirin group than in the DAPT group. Considering the similar risk of major bleeding between the no-aspirin and DAPT groups in patients undergoing staged PCI in the present study, DAPT should be continued up to at least 1 month after staged PCI.
Study Limitations
The original STOPDAPT-3 trial had limitations such as an open-label design, use of reduced doses of prasugrel that were only approved in Japan, enrollment of only Japanese patients who might have a different risk–benefit balance for bleeding and cardiovascular events compared with other races, and no stringent recommendations on antithrombotic therapy before randomization.11 Reduced doses of prasugrel (at loading/maintenance of 20/3.75 mg), which were only approved in Japan, could be a problem when extrapolating the present study results outside of Japan. Nevertheless, in the pivotal study of prasugrel in Japan, the magnitude of risk reduction for cardiovascular events with 20/3.75 mg of prasugrel compared with 300/75 mg of clopidogrel was similar to that in the global pivotal trial using 60/10 mg of prasugrel.24,25 The open-label trial design might have influenced the treatment after assignment. Indeed, the prescription rate of proton-pump inhibitors was higher in the DAPT group than in the no-aspirin group, which might affect the lack of large difference in the co-primary bleeding endpoint. There are other important limitations in this study. First, the primary hypothesis in the original STOPDAPT-3 trial was not met. Moreover, the present subgroup analysis was post hoc and underpowered. Therefore, the present study should be interpreted as exploratory and hypothesis generating, and no statistically significant difference in the co-primary endpoints in the present study would preclude any strong clinical conclusions. The wide CIs of HRs of outcomes should necessitate further investigation of this topic. Second, the present study did not include patients who underwent staged PCI beyond 1 month. The study protocol recommended staged PCI within 3 months after randomization. The actual execution and timing of staged PCI were left to the discretion of each attending physician. Therefore, the allocated group (no-aspirin or DAPT) might affect the execution and timing of staged PCI. However, the number of patients who underwent staged PCI within 1 month was not different between the no-aspirin and DAPT groups. Third, the present study could not consider patients in whom staged PCI was planned, but not performed, due to unexpected clinical events. Last, we did not collect data on the reasons why the operator decided to perform the staged PCI.
Conclusions
An aspirin-free prasugrel monotherapy relative to DAPT had numerically higher risks of cardiovascular and major bleeding events in patients undergoing staged PCI at 1 month. The findings of the present study should be considered as hypothesis generating because of the post hoc and underpowered subgroup analyses of the overall STOPDAPT-3 trial, which was negative for the co-primary bleeding endpoint. Further investigations of an aspirin-free prasugrel monotherapy relative to DAPT should be mandatory for these patients.
Acknowledgments
We appreciate the study investigators for their efforts in enrolling patients and collecting data. We also appreciate the members of the Research Institute for Production Development for coordinating the study.
Sources of Funding
Abbott Medical Japan.
Disclosures
K.Y. reports honoraria 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 of the submitted work. T.M. reports lecturer’s fees from Abbott, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Japan Lifeline, Pfizer, Tsumura and UCB, a manuscript fee from Pfizer, and being on the advisory board for GlaxoSmithKline, Novartis and Teijin. Y.O. reports honoraria from Abbott Medical Japan. S.S. reports personal fees from Abbott Medical Japan and Daiichi Sankyo outside of the submitted work. K.K. reports honorarium for lecture from Boston Scientific, Abbott Medical, Medtronic, Otsuka, Daiichi-Sankyo, Amgen, Novartis, Behringer, Bayer, Life Science Institute, Mochida, and Novo Nordisk, and a scholarship fund from Abbott Medical. Ta. Kimura reports grants from Abbott Medical Japan and Boston Scientific, and being an advisory board member of Abbott Medical Japan and Terumo Japan. K.O. is a member of Circulation Reports’ Editorial Team. No other disclosures are reported.
IRB Information
The present study was approved by the Kyoto University Certified Review Board and Ethics Committee (Reference no. CRB5180002).
Data Availability
The deidentified participant data will not be shared.
Supplementary Files
Please find supplementary file(s);
https://doi.org/10.1253/circrep.CR-25-0026
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