Relationship Between Platelet Aggregation and Clinical Events After Percutaneous Coronary Intervention for Dialysis Patients　― A PENDULUM Analysis Substudy ―

Abstract

Background: Patients with endstage kidney disease undergoing hemodialysis (HD) have higher risks of ischemic and bleeding events after percutaneous coronary intervention (PCI). However, the association between high platelet reactivity (HPR) and clinical events in dialysis patients remains unclear. This post hoc analysis of the PENDULUM registry examined the relationships of HPR with major adverse cardiac and cerebrovascular events (MACCE) and major bleeding in dialysis patients.

Methods and Results: Based on P2Y₁₂ reaction unit (PRU) levels, patients were stratified into HPR (PRU >208) and non-HPR (PRU ≤208) groups. Clinical events were assessed up to 30 months after the index PCI. A total of 6,266 patients were enrolled. Of the 5,907 patients with available PRU data, 357 were dialysis patients (HPR, n=199; Non-HPR, n=158), and 5,550 were non-dialysis patients (HPR, n=2,030; Non-HPR, n=3,520). Dialysis patients had significantly more frequent MACCE and major bleeding than non-dialysis patients. In non-dialysis patients, MACCE, but not bleeding events, were significantly more common in the HPR subgroup. However, in dialysis patients, no significant association was found between HPR and both MACCE and major bleeding.

Conclusions: HPR was not associated with increased risks of MACCE and major bleeding in dialysis patients.

Central Figure

Platelet function and reactivity are altered in patients with chronic kidney disease (CKD), characterized by changes in platelet count, receptor expression, bleeding time, and adhesion capacity.^1,2 In addition, previous studies have identified an association between CKD and high platelet reactivity (HPR).³ CKD is an independent risk factor for major adverse cardiovascular and cerebrovascular events (MACCE).^4,5 The Japanese Circulation Society (JCS) guidelines recommend a shorter duration of dual antiplatelet therapy (DAPT), typically 1–3 months, in patients with severe CKD undergoing drug-eluting stent (DES) implantation to reduce bleeding complications while maintaining efficacy in preventing thrombotic events.⁶ However, the applicability of shorter-duration DAPT in dialysis patients undergoing PCI remains uncertain due to their increased risk of both ischemic and bleeding events. Furthermore, information on the relationship between dialysis and HPR, as well as its impact on clinical outcomes, remains limited.⁷ This post hoc analysis of the PENDULUM registry evaluated the clinical impact of HPR on ischemic events and major bleeding in patients with dialysis.

Methods

The details of the PENDULUM registry (UMIN000020332) have been published previously.⁸ In brief, it was a multicenter, prospective study that investigated the relationship between platelet reactivity and ischemic and bleeding events after PCI with second-generation DES. Patients aged ≥20 years who underwent PCI with a DES were enrolled between December 2015 and June 2017 from 67 medical institutions across Japan. The choice of antiplatelet drug and the dosage administered to patients were left to the doctor’s discretion based on a pivotal study conducted in Japan.^9–13 All participants provided written informed consent prior to their involvement in the study.

This post hoc analysis compared the risk of MACCE and major bleeding between dialysis and non-dialysis patients who underwent PCI. Patients were categorized as dialysis or non-dialysis and stratified by platelet reactivity: HPR (P2Y₁₂ reaction unit [PRU] >208) or non-HPR (PRU ≤208) according to the recent consensus statement on platelet function and genetic testing for guiding P2Y₁₂ receptor inhibitor treatment in PCI.¹⁴ Clinical outcomes were assessed at discharge and 1, 12, 24, and 30 months after the index PCI. MACCE were defined as a composite endpoint including myocardial infarction (MI: new or recurrent), stroke (ischemic or non-ischemic), stent thrombosis (classified as definite, probable, or possible based on Academic Research Consortium criteria),¹⁵ and cardiovascular death. Stroke was defined by the presence of new neurological symptoms with confirmation of a corresponding lesion on imaging. Major bleeding was defined as Bleeding Academic Research Consortium (BARC) type 3 or higher, including bleeding events that affected hemodynamics or required surgical intervention.^16,17

In Japan, aspirin and clopidogrel or prasugrel are used as DAPT for the treatment of acute coronary syndrome (ACS), as well as stable coronary artery disease. The approved dosage of aspirin is 100 mg, of clopidogrel 75 mg, and of prasugrel 3.75 mg once daily as a maintenance dosage.¹⁸ The standard duration of DAPT according to the Japanese treatment guidelines is a minimum of 6 months for patients without ACS, and a minimum of 12 months for patients with ACS at the time of starting.^19–21

Statistical Analysis

Continuous variables are described by mean and standard deviation and compared by Student’s t-test. Discrete variables are described by numbers and percentages and compared by Fisher’s exact test. We constructed Kaplan-Meier curves to compare the dialysis and non-dialysis groups. Cumulative incidences were compared by Cox proportional hazards model. Differences of DAPT and PRU status between the dialysis and non-dialysis groups were compared by Fisher’s exact test. We used a Cox proportional hazards model to adjust confounding. The confounding factors to adjust were: age, sex, weight, diabetes, ACS, peripheral arterial disease (PAD), history of cerebral infarction or hemorrhage, CKD and anemia in MACCE; sex, weight, anemia, ACS, PAD, heart failure, malignant tumor, anticoagulation at discharge and CKD in major bleeding; sex, weight, ACS, PAD, CKD and anemia in the composite endpoints. We estimated the hazard ratios (HRs) and 95% confidence intervals (CIs) of all variables. The interaction between dialysis status and HPR status was examined using Cox proportional hazards models. A two-sided test was applied and P<0.05 was considered statistically significant. Subgroup analysis was made by HPR, which is classified as PRU >208. All statistical analyses were performed using SAS release 9.40.

Results

Patients’ Characteristics

Patients’ characteristics stratified by dialysis and non-dialysis patients are shown in Table 1 and Supplementary Table 1. Of the 5,907 patients with available PRU data, 357 were dialysis patients (HPR, n=199; Non-HPR, n=158), and 5,550 were non-dialysis patients (HPR, n=2,030; Non-HPR, n=3,520). Dialysis patients were more likely to have diabetes mellitus, heart failure, and PAD, and less likely to have ACS. PRU values measured 12–48 h after PCI are shown in Figure 1. The proportion of HPR patients was 35.6% overall, with 50.6% in the dialysis group and 34.6% in the non-dialysis group. The mean±SD PRU value was 214.0±75.6 in dialysis patients and 180.0±76.7 in non-dialysis patients; the difference was significant.

Table 1.

Patients’ Baseline Characteristics

	Total (n=6,266)	Dialysis (n=393)	Non-dialysis (n=5,873)
Age (years), mean (SD)	70.0 (10.7)	68.7 (10.5)	70.1 (10.7)
≥75 years	2,325 (37.1)	133 (33.8)	2,192 (37.3)
Body weight (kg), mean (SD)	63.9 (12.6)	61.1 (13.3)	64.1 (12.5)
≤50 kg	794 (12.7)	81 (20.6)	713 (12.1)
Body mass index (kg/m2), mean (SD)	24.21 (3.62)	23.20 (3.99)	24.28 (3.58)
Hypertension	5,188 (82.8)	349 (88.8)	4,839 (82.4)
Hyperlipidemia	4,926 (78.6)	258 (65.6)	4,668 (79.5)
Diabetes mellitus	2,771 (44.2)	264 (67.2)	2,507 (42.7)
Current cigarette smoking	1,327 (21.2)	61 (15.5)	1,266 (21.6)
Heart failure	865 (13.8)	102 (26.0)	763 (13.0)
Peripheral arterial disease	438 (7.0)	120 (30.5)	318 (5.4)
AF	539 (8.6)	52 (13.2)	487 (8.3)
Malignancy	389 (6.2)	24 (6.1)	365 (6.2)
Previous MI	1,575 (25.1)	105 (26.7)	1,470 (25.0)
Previous PCI	2,566 (41.0)	202 (51.4)	2,364 (40.3)
Previous CABG	265 (4.2)	30 (7.6)	235 (4.0)
History of ischemic stroke	657 (10.5)	64 (16.3)	593 (10.1)
History of cerebral hemorrhage	124 (2.0)	12 (3.1)	112 (1.9)
Clinical presentation
ACS	2,015 (32.2)	67 (17.0)	1,948 (33.2)
Unstable angina	790 (12.6)	42 (10.7)	748 (12.7)
Non-STEMI	323 (5.2)	10 (2.5)	313 (5.3)
STEMI	908 (14.5)	15 (3.8)	893 (15.2)
Hb (g/dL), mean (SD)	13.30 (2.04)	11.25 (1.81)	13.43 (1.98)
<11 g/dL (both)	727 (11.6)	173 (44.0)	554 (9.4)
eGFR (mL/min/1.73 m2), mean (SD)	61.25 (27.61)	7.94 (6.90)	64.73 (24.73)
Angiographic features
No. of diseased vessels
1	3,165 (50.5)	168 (42.7)	2,997 (51.0)
2	1,864 (29.7)	125 (31.8)	1,739 (29.6)
3	1,151 (18.4)	93 (23.7)	1,058 (18.0)
Left main disease	349 (5.6)	21 (5.3)	328 (5.6)
LVEF (%), mean, mean (SD)	56.7 (12.9)	51.7 (13.5)	57.1 (12.8)
≤40%	241 (12.7)	24 (19.5)	217 (12.2)
Procedural data
Puncture site
Radial access only	4,374 (69.8)	24 (6.1)	4,350 (74.1)
Femoral access	1,631 (26.0)	320 (81.4)	1,311 (22.3)
Brachial access	269 (4.3)	51 (13.0)	218 (3.7)
Radial access	4,517 (72.1)	24 (6.1)	4,493 (76.5)
Imaging guided	5,918 (94.4)	372 (94.7)	5,546 (94.4)
PCI for chronic total occlusion	428 (6.8)	29 (7.4)	399 (6.8)
Medications at discharge
Aspirin	6,148 (98.1)	380 (96.7)	5,768 (98.2)
P2Y12 inhibitor	6,209 (99.1)	383 (97.5)	5,826 (99.2)
Prasugrel	3,924 (62.6)	172 (43.8)	3,752 (63.9)
Clopidogrel	2,223 (35.5)	201 (51.1)	2,022 (34.4)
OAC	621 (9.9)	35 (8.9)	586 (10.0)
Proton pump inhibitor	5,302 (84.6)	336 (85.5)	4,966 (84.6)
NSAIDs	334 (5.3)	29 (7.4)	305 (5.2)
Steroids	249 (4.0)	30 (7.6)	219 (3.7)
Antihyperlipidemic agent	5,406 (86.3)	264 (67.2)	5,142 (87.6)
Modified ARC-HBR
HBR patients	3,192 (50.9)	383 (97.5)	2,809 (47.8)
Complex PCI	1,279 (20.4)	99 (25.2)	1,180 (20.1)
HPR (PRU >208)	2,229 (35.6)	199 (50.6)	2,030 (34.6)

Data are presented as mean (standard deviation) values or n (%). ACS, acute coronary syndrome; AF, atrial fibrillation; ARC-HBR, Academic Research Consortium for High Bleeding Risk; CABG, coronary artery bypass; eGFR, estimated glomerular filtration rate; Hb, hemoglobin; HF, heart failure; HPR, high platelet reactivity; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NSAIDs, non-steroidal anti-inflammatory drugs; OAC, oral anticoagulant; PCI, percutaneous coronary intervention; PRU, P2Y₁₂ reaction units; STEMI, ST-elevation myocardial infarction.

Figure 1.

P2Y₁₂ reaction unit (PRU) values 12–48 h after percutaneous coronary intervention (A) and their distribution (B) in the dialysis and non-dialysis groups. The box plot illustrates the 25th percentile (lower edge of the box), 50th percentile (median, marked by a line within the box), and 75th percentile (upper edge of the box). The whiskers extend to the most extreme values within 1.5-fold the interquartile range (IQR) from the median. Dialysis patients have higher PRU values than non-dialysis patients.

DAPT status is summarized in Table 2. No significant differences were observed between the dialysis and non-dialysis groups up to 6 months after PCI. However, the continuation rate of DAPT was significantly higher in the dialysis group at 12 months (65.0% vs. 58.0%, P=0.0074) and up to 30 months (37.5% vs. 26.7%, P=0.0002).

Table 2.

DAPT Status

	Total (n=6,266)	Dialysis (n=393)	Non-dialysis (n=5,873)	P value
At 3 months	92.6% (5,741/6,198)	90.9% (349/384)	92.7% (5,392/5,814)	0.1890
At 6 months	87.7% (5,403/6,161)	85.9% (323/376)	87.8% (5,080/5,785)	0.2917
At 12 months	58.4% (3,579/6,129)	65.0% (240/369)	58.0% (3,339/5,760)	0.0076
At 24 months	32.5% (1,919/5,899)	43.5% (138/317)	31.9% (1,781/5,582)	<0.001
At 30 months	27.2% (1,472/5,411)	37.5% (103/275)	26.7% (1,369/5,136)	0.0002

DAPT, dual antiplatelet therapy.

Clinical Outcomes of Patients With and Without Dialysis

Patients with dialysis had significantly more MACCE and major bleeding within 30 months after PCI (Table 3). The incidence of MACCE was approximately 4-fold higher in dialysis patients than in non-dialysis patients (HR: 3.96; 95% CI: 3.23–4.86; P<0.001). In dialysis patients, all-cause death occurred in 23.9%, with non-cardiac death in 20.1%, compared with 5.3% and 4.4%, respectively, in non-dialysis patients. The incidence of major bleeding was significantly higher in dialysis patients than in non-dialysis patients (HR: 3.49; 95% CI: 2.55–4.78; P<0.001).

Table 3.

Cumulative Incidence of Each Endpoint

	Event rate, n (%)		HR (95% CI) (Ref: Non-HF)	P value
	Dialysis (n=393)	Non-dialysis (n=5,873)
MACCEa	113 (28.8)	475 (8.1)	3.96 (3.23–4.86)	<0.001
All-cause death	94 (23.9)	309 (5.3)	5.03 (3.99–6.33)	<0.001
Cardiac death	15 (3.8)	49 (0.8)	4.97 (2.79–8.86)	<0.001
Non-cardiac death	79 (20.1)	260 (4.4)	5.04 (3.91–6.48)	<0.001
Non-fatal MI	15 (3.8)	86 (1.5)	2.80 (1.62–4.85)	<0.001
Non-fatal stroke	21 (5.3)	103 (1.8)	3.34 (2.09–5.34)	<0.001
Stent thrombosis	4 (1.0)	21 (0.4)	3.01 (1.03–8.76)	0.044
Major bleedingb	47 (12.0)	222 (3.8)	3.49 (2.55–4.78)	<0.001
TLR	73 (18.6)	280 (4.8)	4.625 (3.57–5.99)	<0.001
BARC 2+3+5	61 (15.5)	346 (5.9)	2.908 (2.22–3.82)	<0.001

^aIncludes all-cause death, non-fatal MI, non-fatal stroke, and stent thrombosis. ^bBARC 3 and 5. BARC, Bleeding Academic Research Consortium; CI, confidence interval; HF, heart failure; HR, hazard ratio; MACCE, major adverse cardiac and cerebrovascular event; MI, myocardial infarction; TLR, target lesion revascularization.

Clinical Outcomes in Dialysis Patients by HPR

The cumulative incidence of each endpoint by HPR in dialysis patients is shown in Table 4. MACCE occurred in 27.6% of the HPR group, and in 28.5% of the non-HPR group, with no significant difference between groups (P=0.978) (Figure 2). To further explore these outcomes, landmark analysis was conducted to evaluate the cumulative incidence of MACCE and major bleeding from 1 year after PCI (Figure 3). For dialysis patients, event rates are shown in Supplementary Table 2.

Table 4.

Cumulative Incidence of Each Endpoint by HPR in Dialysis Patients

	Event rate, n (%)		HR (95% CI)	P value
	HPR (n=199)	Non-HPR (n=158)
MACCEa	55 (27.6)	45 (28.5)	1.00 (0.67–1.48)	0.978
All-cause death	41 (20.6)	40 (25.3)	0.79 (0.51–1.23)	0.295
Cardiac death	6 (3.0)	6 (3.8)	0.78 (0.25–2.42)	0.665
Non-cardiac death	35 (17.6)	34 (21.5)	0.80 (0.50–1.27)	0.340
Non-fatal MI	12 (6.0)	3 (1.9)	3.18 (0.90–11.28)	0.073
Non-fatal stroke	11 (5.5)	9 (5.7)	0.956 (0.40–2.31)	0.921
Major bleedingb	27 (13.6)	16 (10.1)	1.34 (0.72–2.49)	0.350
TLR	44 (22.1)	26 (16.5)	1.36 (0.84–2.21)	0.212
BARC 2+3+5	34 (17.1)	22 (13.9)	1.22 (0.71–2.09)	0.465

^aIncludes all-cause death, non-fatal MI, non-fatal stroke, and stent thrombosis. ^bBARC 3 and 5. HPR, high platelet reactivity. Other abbreviations as in Table 3.

Figure 2.

Cumulative incidence of (A) MACCE and (B) major bleeding at 30 months after PCI by dialysis and HPR. For dialysis patients, event rates are shown in Table 4. No significant difference in event rates is observed in dialysis patients regardless of HPR status. CI, confidence interval; HPR, high platelet reactivity; HR, hazard ratio; PCI, percutaneous coronary intervention.

Figure 3.

Cumulative incidence of (A) MACCE and (B) major bleeding from 1 year after PCI by dialysis and HPR. Landmark analysis was conducted to evaluate the cumulative incidence of (A) MACCE and (B) major bleeding from 1 year after PCI. For dialysis patients, event rates are shown in Supplementary Table 1. No significant difference in event rates is observed in dialysis patients regardless of HPR status. CI, confidence interval; HPR, high platelet reactivity; HR, hazard ratio; PCI, percutaneous coronary intervention.

Landmark analyses of MACCE and major bleeding at 0–12 months and 12–30 months are shown in Figure 3. The cumulative incidence of MACCE was similar between the first year (HPR 16.6% vs. non-HPR 10.1%, P=0.09) and the subsequent year (HPR 13.3% vs. non-HPR 20.4%, P=0.089) between the 2 groups. The cumulative incidence of major bleeding was also similar between the first year (HPR 8.0% vs. non-HPR 5.7%, P=0.403) and the subsequent year (HPR 6.7% vs. non-HPR 5.1%, P=0.646), with no significant difference between the HPR and non-HPR groups (Table 4).

Clinical Outcomes in Non-Dialysis Patients by HPR

In non-dialysis patients, HPR was associated with an increased incidence of MACCE, although no significant association was found with major bleeding (Table 5, Figure 2).

Table 5.

Cumulative Incidence of Each Endpoint by HPR in Non-Dialysis Patients

	Event rate, n (%)		HR (95% CI)	P value
	HPR (n=2,030)	Non-HPR (n=3,520)
MACCEa	196 (9.7)	245 (7.0)	1.40 (1.16–1.70)	<0.001
All-cause death	132 (6.5)	157 (4.5)	1.47 (1.17–1.86)	0.001
Cardiac death	21 (1.0)	23 (0.7)	1.60 (0.88–2.88)	0.122
Non-cardiac death	111 (5.5)	134 (3.8)	1.45 (1.13–1.87)	0.004
Non-fatal MI	38 (1.9)	42 (1.2)	1.59 (1.02–2.46)	0.040
Non-fatal stroke	36 (1.8)	57 (1.6)	1.10 (0.73–1.68)	0.643
Stent thrombosis	12 (0.6)	7 (0.2)	2.99 (1.18–7.58)	0.021
Major bleedingb	87 (4.3)	125 (3.6)	1.22 (0.93–1.60)	0.156
TLR	111 (5.5)	152 (4.3)	1.29 (1.01–1.65)	0.041
BARC 2+3+5	138 (6.8)	193 (5.5)	1.26 (1.01–1.56)	0.041

^aIncludes all-cause death, non-fatal MI, non-fatal stroke, and stent thrombosis. ^bBARC 3 and 5. Abbreviations as in Tables 3,4.

Landmark analysis showed the cumulative incidences of MACCE and major bleeding from 1 year after PCI (Figure 3). For non-dialysis patients, event rates are shown in Supplementary Table 3.

Discussion

Compared with several previous studies,^22,23 the present study represents the largest registry-based investigation to date that incorporates PRU measurements in East Asian patients undergoing PCI. The major findings are presented. First, HPR was significantly associated with MACCE in non-dialysis patients. Conversely, no significant association was observed between HPR and MACCE in dialysis patients. The results of the multivariate analysis showed that the interaction between HPR and dialysis status did not reach statistical significance (HR: 1.115; 95% CI: 0.906–1.372; P=0.304). Second, the duration of DAPT was longer in dialysis patients than in non-dialysis patients. Third, the risks of ischemic and bleeding events in dialysis patients continued without attenuation after 12–30 months. This observation may be attributable to the substantially higher baseline risk of adverse events in dialysis patients than in non-dialysis patients, with dialysis itself exerting a stronger influence on event occurrence than HPR.

In dialysis patients, landmark analysis showed no significant difference in event rates regardless of HPR status. These findings reinforce the observation that, beyond the initial procedural period, the long-term risks of these events remain comparable between groups stratified by HPR status in the dialysis cohort. The impact of HPR appears to reflect antiplatelet efficacy in the early phase following PCI, whereas in the later phase, it is more likely affected by patient-related factors, including overall clinical status and comorbidities. Such data emphasize the unique interplay of hemodynamic and coagulative factors in dialysis patients, which could attenuate the conventional associations seen in non-dialysis populations.

Notably, when comparing the cumulative incidences of MACCE and major bleeding in dialysis patients, the overall trends suggest that the management of these patients should focus on balancing both thrombotic and bleeding risks. This is particularly critical in dialysis patients due to their inherently elevated baseline risks for both complications. The findings presented in Table 4 further corroborate these results, demonstrating no significant difference in event rates across different HPR statuses.

Data for HPR in HD patients were previously shown in the substudy of ADAPT-DES.²³ HD patients had 4-fold more ischemic and bleeding events, and HPR was associated with ischemic events in the overall cohort, but not in dialysis patients, similar to the results from the present study.²⁴

Clinical Implications

First, the findings highlight the need to individualize antiplatelet therapy in dialysis patients rather than adopting strategies derived from general population studies. Second, they underscore the importance of multidisciplinary care in the post-PCI period for dialysis patients, integrating nephrologists, cardiologists, and hematologists, to optimize treatment strategies tailored to this high-risk group. Finally, the lack of association between HPR status and event rates may prompt further research into alternative biomarkers or risk stratification tools that are more specific to dialysis patients. In conclusion, though prior studies have underscored the role of HPR status in predicting outcomes following PCI, its relevance appears diminished in dialysis patients. This finding highlights the complex interplay of factors in this unique population and underscores the importance of further research to better understand the determinants of long-term outcomes in these patients.

No significant differences were observed in DAPT status between the dialysis and non-dialysis groups up to 6 months after PCI. However, after 1 year, the DAPT rate was significantly higher in the dialysis group. Given the higher incidence of ischemic events in the dialysis group, there appears to be a tendency to continue DAPT for an extended period in this population.

As shown in Figure 3A, the incidence of MACCE in the dialysis group was higher in the HPR group during the first year, but became higher in the non-HPR group thereafter. This may be explained by the fact that most events in the dialysis group were non-cardiac deaths, suggesting a limited association between platelet reactivity and clinical outcomes in this population.

Study Limitations

This study has several notable limitations. First, due to the observational design, the findings must be interpreted with caution. Selection bias was unavoidable, because not all patients undergoing PCI at the participating institutions were included. Factors contributing to this exclusion included participation in other randomized controlled trials, challenges in obtaining informed consent in urgent PCI situations, and some patients refusing to provide consent. Second, this study lacked details on major bleeding. The incidence of major bleeding is higher in dialysis patients, but the underlying factors contributing to this remain insufficiently understood. If the number of dialysis patients had been larger, the results, particularly for major bleeding, might have been different.

Conclusions

HPR was not associated with increased risks of MACCE and major bleeding in dialysis patients.

Acknowledgments

The authors appreciate the support and collaboration of the coinvestigators participating in the PENDULUM registry.

Disclosures

Y.N. received remuneration and research funding from Daiichi Sankyo Co., Ltd. K.K. received a research grant from Abbott Medical Japan LLC., and research funding from Daiichi Sankyo Co., Ltd., as well as remuneration from Boston Scientific Japan K.K., Abbott Medical Japan LLC., Medtronic Japan Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Amgen Inc., Novartis Pharma K.K., Nippon Boehringer Ingelheim Co., Ltd., Bayer Yakuhin, Ltd., Mochida Pharmaceutical Co., Ltd., Novo Nordisk Pharma Ltd., and Shockwave Medical Inc. R.I. has received remuneration and research funding from Daiichi Sankyo Co., Ltd. A.T. has received research funding from Daiichi Sankyo Co., Ltd. Y.M. has received research funding from Daiichi Sankyo Co., Ltd. Y.M. is a member of Circulation Reports’ Editorial Team. M.F., S.A., and G.K. are employees of Daiichi Sankyo Co., Ltd. M.N. has received research funding from Daiichi Sankyo Co., Ltd. and remuneration from Daiichi Sankyo Co., Ltd. and Bayer Yakuhin, Ltd., as well as endowments from Boston Scientific Japan K.K., Kaneka Corporation, Terumo Corporation, Nipro Corporation, Otsuka Medical Devices Co., Ltd., Japan Lifeline Co., Ltd., Asahi Intecc Co., Ltd., and Biotronik Japan, Inc. K.T. has received research funding from Daiichi Sankyo Co., Ltd., as well as remuneration from Boston Scientific Japan K.K., Abbott Medical Japan LLC., Kaneka Corporation, Edwards Lifesciences Japan K.K., and Medis Medical Imaging B.V.

Funding

The present study was conducted under a collaborative research agreement with Daiichi Sankyo Co., Ltd.

Research Ethics

This study was registered in the University Hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN 000020332). The protocol and related documents for the PENDULUM registry were approved by the Ethics Committee at Toho University Ohashi Medical Centre on 14 December 2015 (Ref 15-71), and the post hoc analysis was approved by the Ethics Committee at Toho University Faculty of Medicine on 24 October 2022 (Ref A24019_A23039_A22037). The study adhered to the principles outlined in the Declaration of Helsinki and was approved by the appropriate institutional or regional ethics committee responsible for human research.

Author Contributions

Masato Nakamura conceived the article. Yoshitaka Murakami verified analytical methods. All authors discussed the results and contributed to the final article.

Data Availability

The deidentified participant data and the study protocol will be shared on a request basis for up to 36 months after the publication of this article. Researchers who make the request should include a methodologically sound proposal on how the data will be used; the proposal may be reviewed by the responsible personnel at Daiichi Sankyo Co., Ltd., and the data requestors will need to sign a data access agreement. Please contact the corresponding author directly to request data sharing. Once approved, the data will be shared in an appropriate way depending on the type of data requested.

Supplementary Files

Please find supplementary file(s);

https://doi.org/10.1253/circrep.CR-25-0148

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