Effects of Acute Coronary Syndrome and Stable Coronary Artery Disease on Bleeding and Ischemic Risk After Percutaneous Coronary Intervention

Masahiro Natsuaki; Takeshi Morimoto; Hiroki Shiomi; Kazushige Kadota; Tomohisa Tada; Yasuaki Takeji; Yukiko Matsumura-Nakano; Yusuke Yoshikawa; Hirotoshi Watanabe; Ko Yamamoto; Kazuaki Imada; Takenori Domei; Kyohei Yamaji; Kazuhisa Kaneda; Ryoji Taniguchi; Natsuhiko Ehara; Ryuzo Nawada; Mamoru Toyofuku; Eiji Shinoda; Satoru Suwa; Toshihiro Tamura; Tsukasa Inada; Mitsuo Matsuda; Takeshi Aoyama; Yukihito Sato; Yutaka Furukawa; Kenji Ando; Yoshihisa Nakagawa; Takeshi Kimura; for the CREDO-Kyoto PCI/CABG Registry Cohort-3 Investigators

doi:10.1253/circj.CJ-21-0016

Abstract

Background: Data evaluating the effects of acute coronary syndrome (ACS) relative to stable coronary artery disease (CAD) on bleeding risk after percutaneous coronary intervention (PCI) are scarce.

Methods and Results: From the CREDO-Kyoto Registry Cohort-3, 13,258 patients undergoing first PCI (5,521 ACS; 7,737 stable CAD) were identified. Patients were further stratified according to ACS presentation and Academic Research Consortium High Bleeding Risk (HBR): ACS/HBR: n=2,502; ACS/no-HBR: n=3,019; stable CAD/HBR: n=3,905; and stable CAD/no-HBR: n=3,832. The primary bleeding endpoint was Bleeding Academic Research Consortium 3/5 bleeding, whereas the primary ischemic endpoint was myocardial infarction (MI)/ischemic stroke. Compared with stable CAD, ACS was associated with a significantly higher adjusted risk for bleeding (hazard ratio [HR] 1.85; 95% confidence interval [CI] 1.68–2.03; P<0.0001), with a markedly higher risk within 30 days (HR 4.24; 95% CI 3.56–5.06; P<0.0001). Compared with the stable CAD/no-HBR group, the ACS/HBR, no-ACS/HBR, and ACS/no-HBR groups were associated with significantly higher adjusted risks for bleeding, with HRs of 3.05 (95% CI 2.64–3.54; P<0.0001), 1.89 (95% CI 1.66–2.15; P<0.0001), and 1.69 (95% CI 1.45–1.98; P<0.0001), respectively. There was no excess adjusted risk of the ACS relative to stable CAD group for MI/ischemic stroke (HR 1.07; 95% CI 0.94–1.22; P=0.33).

Conclusions: Bleeding risk after PCI depended on both ACS presentation and HBR, with a significant effect of ACS within 30 days.

Patients with acute coronary syndrome (ACS) are reportedly at a higher risk for ischemic events.¹ Therefore, in the current guidelines, newer and more potent P2Y₁₂ receptor inhibitors, such as ticagrelor and prasugrel, are recommended in patients with ACS, whereas clopidogrel is still recommended in patients with stable coronary artery disease (CAD).²^,³ In ACS patients, the current guidelines also recommend the use of anticoagulants before percutaneous coronary intervention (PCI), loading of antiplatelet agents, and longer-duration dual antiplatelet therapy (DAPT) if not at high bleeding risk (HBR).²^,³ Moreover, the transfemoral approach, which is reportedly associated with a higher risk for bleeding, is frequently selected in PCI for ACS.⁴ Therefore, patients with ACS may also have higher bleeding risk than patients with stable CAD. Nevertheless, the clinical presentation of ACS has not been included as a criterion in the Academic Research Consortium (ARC)-HBR, partly because there have been no previous studies comparing the bleeding risk after PCI between ACS and stable CAD patients.⁵

Editorial p 1942

New-generation drug-eluting stents (DES) were reported to reduce the long-term risks for stent thrombosis, myocardial infarction, and cardiac death compared with bare-metal stents in a meta-analysis of randomized trials including ACS patients.⁶ The balance between ischemic and bleeding risk after PCI in ACS patients may have changed substantially in the new-generation DES era.

Therefore, we sought to evaluate the effect of ACS compared with stable CAD on the bleeding and ischemic risk after PCI from a large observational database of patients undergoing first coronary revascularization in the new-generation DES era in Japan.

Methods

Study Design

The Coronary Revascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) PCI/coronary artery bypass grafting (CABG) Registry Cohort-3 is a physician-initiated, non-company-sponsored, multicenter registry enrolling consecutive patients who underwent their first coronary revascularization with PCI or isolated CABG without combined non-coronary surgery among 22 centers in Japan between January 2011 and December 2013, after approval of the new-generation DES in 2010 (Supplementary Appendix A).⁷ This study was conducted in accordance with the Declaration of Helsinki and the Ethical Guidelines for Medical and Health Research Involving Human Subjects in Japan. The relevant ethics committees in all participating centers approved the study protocol. Because of the retrospective enrollment, the need for written informed consent from patients was waived; however, we excluded those patients who refused participation in the study when contacted for follow-up. This strategy is concordant with the guidelines of the Japanese Ministry of Health, Labour and Welfare.

Between January 2011 and December 2013, 14,927 patients had first isolated coronary revascularization (PCI: 13,307 patients; isolated CABG: 1,620 patients) among 22 centers in Japan. After excluding 60 patients who refused study participation and 1,620 patients with CABG (11 CABG patients refused study participation), the study population of the present consisted of 13,258 patients who underwent their first PCI (Figure 1). Using retrospective registry data, we compared the clinical outcomes, focusing on major bleeding and ischemic events, between the 2 groups of patients with ACS and stable CAD.

Figure 1.

Flowchart showing study patient disposition. ACS, acute coronary syndrome; CABG, coronary artery bypass grafting; CAD, coronary artery disease; CREDO-Kyoto, Coronary Revascularization Demonstrating Outcome study in Kyoto; HBR, high bleeding risk; PCI, percutaneous coronary intervention.

Definitions and Outcome Measures

Patients with ST-elevation myocardial infarction (STEMI) were defined as those with an increase in cardiac biomarkers with persistent ST-segment elevation or new Q-wave on electrocardiograms. Patients with non-ST-elevation myocardial infarction (NSTEMI) were defined as those with an increase in cardiac biomarkers without electrocardiographic changes as seen for STEMI. Unstable angina (UA) was defined as Braunwald Class III with no increase in a cardiac biomarker.⁸

The ARC-HBR criteria have been described previously.⁵ Patients are considered to be at HBR if at least 1 major or 2 minor criteria are met. In the present analysis, several major and minor ARC-HBR criteria were not captured. Therefore, those patients with at least 1 major criterion, such as severe chronic kidney disease, thrombocytopenia, severe anemia, liver cirrhosis, prior hemorrhagic stroke, active malignancy or anticoagulation, and those with more than 2 minor criteria, such as age ≥75 years, mild anemia, prior ischemic stroke, prior bleeding or moderate chronic kidney disease, were classified as the HBR group. Patients with only 1 minor criterion or without any criterion were classified as the no-HBR group.

The primary bleeding outcome measure was major bleeding, defined as Bleeding Academic Research Consortium (BARC) Type 3 or 5 bleeding,⁹ whereas the primary ischemic outcome measure was defined as a composite of myocardial infarction or ischemic stroke. Death was regarded as cardiac in origin unless obvious non-cardiac causes could be identified. Death of unknown cause and any death during the index hospitalization for coronary revascularization were regarded as cardiac deaths. Cardiovascular deaths included cardiac death and other vascular deaths related to stroke, renal disease, and vascular disease. Myocardial infarction and stent thrombosis were adjudicated according to the ARC definition.¹⁰ To maintain consistency with CREDO-Kyoto PCI/CABG Registry Cohort-2,¹¹ myocardial infarction was also adjudicated according to the Arterial Revascularization Therapy Study (ARTS) definition,¹² in which only Q-wave myocardial infarction was regarded as myocardial infarction when it occurred within 7 days of the index procedure. Other definitions are provided in the Supplementary Methods.

Data Collection for Baseline Characteristics and Follow-up Events

Clinical, angiographic, and procedural data were collected from hospital charts or hospital databases according to the prespecified definitions by experienced clinical research coordinators from an independent clinical research organization (Research Institute for Production Development, Kyoto, Japan; see Supplementary Appendix B). Follow-up data were collected from hospital charts and/or obtained by contacting patients, their relatives, or referring physicians by mail with questions regarding vital status, subsequent hospitalizations, and status of antiplatelet therapy between January 2018 and December 2019. Follow-up was regarded as completed if follow-up data beyond July 1, 2017 were obtained. The clinical event committee adjudicated those events such as death, myocardial infarction, stent thrombosis, stroke, and major bleeding (see Supplementary Appendix C).

Statistical Analysis

Categorical variables are presented as numbers and percentages, were compared using Chi-squared tests. Continuous variables are expressed as the mean±SD or as the median with interquartile range (IQR). Based on their distribution, continuous variables were compared between 2 groups using Student’s t-test or the Wilcoxon rank-sum test, and among 4 groups using analysis of variance (ANOVA) or the Kruskal-Wallis test. The cumulative incidence of outcome measures was estimated by the Kaplan-Meier method, and differences were assessed using log-rank tests. To distinguish early events after PCI from long-term events, landmark analysis was performed at 30 days. Those patients with individual endpoint events before 1 month were excluded from the landmark analysis beyond 30 days. The effect of ACS relative to stable CAD for the outcome measures is expressed as a hazard ratio (HR) and 95% confidence intervals (CIs). The HRs were estimated by multivariable Cox proportional hazard models adjusting for the 36 clinically relevant factors listed in Table 1, as well as clinical presentation (ACS and stable CAD) as the primary variable. Continuous variables were dichotomized by clinically meaningful reference values to make proportional hazard assumptions robust and to be consistent with our previous report.¹⁰ Missing values for the risk-adjusting variables were imputed as “normal” in the binary classification, because data should have been available if abnormalities were suspected. Proportional hazard assumptions for the primary variable and the risk-adjusting variables were assessed on plots of log(time) vs. log[−log(survival)] stratified by the variable. The assumptions were verified to be acceptable for all variables.

Table 1. Baseline Characteristics and Medications

	ACS (n=5,521)	Stable CAD (n=7,737)	P value
Clinical characteristics
Age (years)	68.7±12.5	69.9±10.3	<0.0001
Age ≥75 years^A	1,947 (35)	2,734 (35)	0.93
Male sex^A	4,083 (74)	5,589 (72)	0.03
Body mass index (kg/m²)	23.7±3.6 (n=5,389)	23.9±3.6 (n=7,685)	0.0004
Body mass index <25.0 kg/m² ^A	3,819 (69)	5,082 (66)	<0.0001
Acute MI	5,316 (96)	0 (0)	<0.0001
STEMI	4,081 (74)	0 (0)	<0.0001
NSTEMI	1,235 (22)	0 (0)	<0.0001
Unstable angina	205 (3.7)	0 (0)	<0.0001
Hypertension^A	4,403 (80)	6,497 (84)	0.0001
Diabetes^A	1,886 (34)	3,153 (41)	<0.0001
On insulin therapy	281 (5.1)	810 (10)	<0.0001
Current smoker^A	2,004 (36)	1,668 (22)	<0.0001
Heart failure^A	1,679 (30)	1,438 (19)	<0.0001
Multivessel disease^A	3,090 (56)	4,511 (58)	0.007
LVEF (%)	55.2±12.4 (n=4,924)	61.1±12.9 (n=6,607)	<0.0001
LVEF ≤40%	581/4,924 (12)	556/6,607 (8.4)	<0.0001
Mitral regurgitation grade ≥3/4	449/5,060 (8.9)	445/6,640 (6.7)	<0.0001
Prior MI^A	148 (2.7)	1,312 (17)	<0.0001
Prior stroke^A	606 (11)	1,093 (14)	<0.0001
Prior hemorrhagic stroke	125 (2.3)	179 (2.3)	0.85
Prior ischemic stroke	507 (9.2)	959 (12)	<0.0001
Peripheral vascular disease^A	187 (3.4)	1,026 (13)	<0.0001
Atrial fibrillation^A	485 (8.8)	801 (10)	0.003
Chronic obstructive pulmonary disease^A	199 (3.6)	320 (4.1)	0.12
Liver cirrhosis^A	118 (2.1)	217 (2.8)	0.01
Malignancy	595 (11)	1,082 (14)	<0.0001
Active malignancy^A	89 (1.6)	181 (2.3)	0.004
Severe frailty^A,B	303 (5.5)	247 (3.2)	<0.0001
CKD
Moderate (eGFR 30–59 mL/min/1.73 m²)	1,666 (30)	2,509 (32)	0.006
Severe CKD	464 (8.4)	733 (9.5)	0.03
eGFR <30 mL/min/1.73 m²
Not on dialysis^A	322 (5.8)	264 (3.4)	<0.0001
On dialysis^A	142 (2.6)	469 (6.1)	<0.0001
Severe anemia (Hb <11 g/dL)^A	603 (11)	1,029 (13)	<0.0001
Mild anemia (Hb 11–12.9 g/dL for men, 11–11.9 g/dL for women)	883 (16)	1,814 (23)	<0.0001
Thrombocytopenia (platelets <100×10⁹/L)^A	111 (2.0)	151 (2.0)	0.81
ARC-HBR	2,502 (45)	3,905 (50)	<0.0001
Procedural characteristics
No. target lesions	1.45±0.78	1.5±0.79	0.002
Target of proximal LAD^A	3,161 (57)	4,838 (63)	<0.0001
Target of unprotected LMCA^A	250 (4.5)	341 (4.4)	0.74
Target of chronic total occlusion^A	226 (4.1)	1,105 (14)	<0.0001
Target of bifurcation^A	2,056 (37)	3,186 (41)	<0.0001
Side-branch stenting^A	167 (3.0)	357 (4.6)	<0.0001
Total number of stents
Median [IQR]	1 [1–2]	2 [1–2]	<0.0001
Mean±SD	1.80±1.26 (n=5,184)	1.99±1.38 (n=7,507)
Total stent length (mm)
Median [IQR]	28 [18–47]	32 [18–56]	<0.0001
Mean±SD	38.0±30.3 (n=5,182)	43.6±34.7 (n=7,507)
Total stent length >28 mm^A	2,292 (42)	3,931 (51)	<0.0001
Minimum stent size (mm)	2.92±0.46 (n=5,183)	2.82±0.42 (n=7,507)	<0.0001
Minimum stent size <3.0 mm^A	2,434 (44)	4,237 (55)	<0.0001
No stent	337 (6.1)	230 (3.0)	<0.0001
BMS only^A	1,681 (30)	676 (8.7)
DES used^A	3,503 (63)	6,831 (88)
New-generation DES used	3,472 (63)	6,711 (87)	<0.0001
IVUS or OCT used	3,548 (64)	6,190 (80)	<0.0001
IVUS used	3,524 (64)	6,105 (79)	<0.0001
OCT used	69 (1.3)	219 (2.8)	<0.0001
Transradial approach	1,100 (20)	3,873 (50)	<0.0001
Transfemoral approach^A	4,110 (74)	2,877 (37)	<0.0001
Staged PCI	1,256 (23)	1,394 (18)	<0.0001
Baseline medication
Antiplatelet therapy
Thienopyridine	5,366 (97.2)	7,677 (99.2)	<0.0001
Ticlopidine	117/5,366 (2.2)	241/7,677 (3.1)	<0.0001
Clopidogrel	5,167/5,366 (96.3)	7,404/7,677 (96.4)
Others	82/5,366 (1.5)	32/7,677 (0.4)
Aspirin	5,429 (98.3)	7,681 (99.3)	<0.0001
Cilostazol	132 (2.4)	225 (2.9)	0.07
Other medications
Statins^A	4,562 (83)	5,706 (74)	<0.0001
High-intensity statins^C	91 (1.7)	120 (1.6)	0.66
β-blockers^A	2,805 (51)	2,399 (31)	<0.0001
ACEI/ARB^A	4,124 (75)	4,403 (57)	<0.0001
Nitrates	972 (18)	1,591 (21)	<0.0001
Calcium channel blockers^A	1,287 (23)	3,933 (51)	<0.0001
Nicorandil	1,063 (19)	1,157 (15)	<0.0001
Oral anticoagulants^A	661 (12)	743 (9.6)	<0.0001
Warfarin	583 (11)	640 (8.3)	<0.0001
Direct oral anticoagulants	79 (1.4)	104 (1.3)	0.67
Proton pump inhibitors or H₂-blockers^A	4,689 (85)	5,545 (72)	<0.0001
Proton pump inhibitors	4,034 (73)	4,614 (60)	<0.0001
H₂-blockers	679 (12)	980 (13)	0.53

Continuous variables are expressed as the mean±SD or median [interquartile range]. Categorical variables are expressed as n (percentage). ^ARisk-adjusting variable selected for the Cox proportional hazard models. ^BSevere frailty was regarded as present when an inability to perform usual activities of daily living was documented in the hospital charts. ^CHigh-intensity statin therapy was defined as statin doses greater than or equal to atorvastatin 20 mg, pitavastatin 4 mg, or rosuvastatin 10 mg. ACEI, angiotensin-converting enzyme inhibitor; ACS, acute coronary syndrome; ARB, angiotensin II receptor blocker; ARC, Academic Research Consortium; CAD, coronary artery disease; CKD, chronic kidney disease; DES, drug-eluting stents; eGFR, estimated glomerular filtration rate; Hb, hemoglobin; HBR, high bleeding risk; IVUS, intravascular ultrasound; LAD, left anterior descending coronary artery; LMCA, left main coronary artery; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NSTEMI, non-ST-elevation myocardial infarction; OCT, optical coherence tomography; PCI, percutaneous coronary intervention; STEMI, ST-elevation myocardial infarction.

To compare outcome measures based on combinations of the clinical presentation and HBR, the effect of each category of interest (ACS/HBR, ACS/No-HBR, and stable CAD/HBR) relative to the reference category (stable CAD/No-HBR) was estimated with dummy variables and expressed as HRs and their 95% CIs. The adjusted risks were estimated using a multivariable Cox proportional hazard model by incorporating the dummy variables together with the 27 risk-adjusting variables, obtained by removing 9 variables related to ARC-HBR from the 36 risk-adjusting variables used for the comparison between ACS and stable CAD.

Statistical analyses were conducted by a physician (M.N.) and by a statistician (T.M.) in JMP 14.0 and SAS 9.2 (SAS Institute, Cary, NC, USA) software. All statistical analyses were 2-tailed, and P<0.05 was considered statistically significant.

Results

Study Population

Among 13,258 patients, there were 5,521 patients (42%) who presented with ACS (ACS group) and 7,737 patients (58%) who presented with stable CAD (stable CAD group). In the ACS group, there were 4,081 patients (74%) with STEMI and 1,440 patients (26%) with non-ST-elevation ACS (NSTEACS), including 1,235 patients (22%) with NSTEMI and 205 patients (3.7%) with UA. Patients were further divided into 4 groups of combinations based on the clinical presentation (ACS, stable CAD) and the presence of ARC-HBR (ACS/HBR: 2,502 patients; ACS/No-HBR: 3,019 patients; stable CAD/HBR: 3,905 patients; stable CAD/No-HBR: 3,832 patients; Figure 1).

Baseline Characteristics: ACS vs. Stable CAD

In the present study population, 48% of patients had ARC-HBR. Patients in the ACS group were younger, were more often men and current smokers, had a smaller body mass index, and more often had heart failure and severe frailty than those in the stable CAD group (Table 1).

In terms of procedural characteristics, the total number of stents was greater, total stent length was longer, and minimum stent size was smaller in the stable CAD than ACS group. The transfemoral approach was more often selected in the ACS than stable CAD group. Regarding baseline medications, patients in the ACS group more often received statins, β-blockers, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, oral anticoagulants, and proton pump inhibitors/H₂-blockers than those in the stable CAD group. The prevalence of high-intensity statins therapy was very low in both groups (Table 1).

Long-Term Clinical Outcomes: ACS vs. Stable CAD

The median follow-up duration for survivors was 6.0 years (IQR 5.1–6.8 years), and complete 1-, 3-, and 5-year clinical follow-up data were obtained for 96.9%, 93.4%, and 78.6% of patients, respectively. The cumulative incidence of persistent discontinuation of DAPT was significantly higher in the ACS than stable CAD group, indicating that DAPT duration was significantly shorter in the ACS than stable CAD group (Supplementary Figure 1).

The cumulative 5-year incidence of the primary bleeding outcome measure (BARC Type 3 or 5 bleeding) was significantly higher in the ACS than stable CAD group (Table 2; Figure 2A). In the 30-day landmark analysis, cumulative incidence of the primary bleeding outcome measure was much higher in the ACS than stable CAD group within 30 days (Table 3; Figure 2B). After adjusting confounders, the excess risk of ACS relative to stable CAD for the primary bleeding outcome measure remained significant during the entire follow-up period, and within 30-days, whereas it was no longer significant beyond 30 days (Tables 2,3). Regarding the types of bleeding, the cumulative incidence for each of access site bleeding, gastrointestinal bleeding, and other bleeding was significantly higher in the ACS than stable CAD group, whereas the cumulative incidence of intracranial bleeding did not differ between the 2 groups (Table 2). The cumulative incidence of the primary bleeding outcome measure did not differ between STEMI and NSTEACS (Supplementary Figure 2A).

Table 2. Clinical Outcomes

	No. patients with event (cumulative 5-year incidence; %)		Univariate		Multivariable
	ACS (n=5,521)	Stable CAD (n=7,737)	HR (95% CI)	P value	HR (95% CI)	P value
Major bleeding
BARC Type 3 or 5	1,153 (20.9)	1,200 (15.2)	1.5 (1.38–1.62)	<0.0001	1.65 (1.49–1.84)	<0.0001
Access site bleeding	287 (5.3)	121 (1.6)	3.47 (2.81–4.29)	<0.0001	NA
Gastrointestinal bleeding	295 (6.2)	397 (5.4)	1.18 (1.01–1.37)	0.03	NA
Intracranial bleeding	123 (2.4)	200 (2.7)	0.98 (0.79–1.23)	0.88	NA
Others	448 (8.6)	482 (6.4)	1.45 (1.28–1.65)	<0.0001	NA
BARC Type 5	52 (1.0)	70 (0.9)	1.12 (0.78–1.6)	0.54	1.48 (0.93–2.34)	0.1
GUSTO moderate/severe bleeding	934 (16.9)	1,066 (13.4)	1.34 (1.23–1.46)	<0.0001	1.51 (1.35–1.69)	<0.0001
GUSTO severe bleeding	423 (7.5)	530 (6.7)	1.2 (1.06–1.36)	0.005	1.34 (1.14–1.58)	0.0004
Hemorrhagic stroke	93 (1.6)	143 (1.7)	0.99 (0.76–1.28)	0.91	0.91 (0.65–1.28)	0.59
MI^A/Ischemic stroke	608 (10.9)	896 (10.8)	1.0 (0.91–1.11)	0.94	1.07 (0.94–1.22)	0.33
MI
ARC definition	338 (6.1)	566 (7.0)	0.87 (0.76–0.99)	0.048	0.83 (0.7–0.99)	0.04
ARTS definition	309 (5.5)	402 (4.9)	1.15 (0.99–1.34)	0.06	1.11 (0.91–1.34)	0.3
Ischemic stroke	293 (5.4)	377 (4.5)	1.18 (1.01–1.37)	0.04	1.49 (1.23–1.81)	<0.0001
CV death/MI/ischemic stroke	1,226 (21.1)	1,390 (16.2)	1.31 (1.21–1.41)	<0.0001	1.55 (1.41–1.71)	<0.0001
All-cause death	1,241 (20.3)	1,435 (15.4)	1.3 (1.21–1.41)	<0.0001	1.72 (1.56–1.89)	<0.0001
Cardiac death	680 (12.0)	526 (5.9)	1.93 (1.73–2.17)	<0.0001	2.43 (2.11–2.81)	<0.0001
CV death	749 (13.1)	671 (7.5)	1.67 (1.51–1.86)	<0.0001	2.16 (1.89–2.46)	<0.0001
Non-CV death	492 (8.3)	764 (8.6)	0.98 (0.87–1.1)	0.7	1.22 (1.06–1.41)	0.007
Definite stent thrombosis	78 (1.3)	37 (0.5)	3.13 (2.11–4.62)	<0.0001	2.66 (1.6–4.41)	0.0002
Target vessel revascularization	1,061 (20.6)	1,365 (17.6)	1.23 (1.13–1.33)	<0.0001	1.18 (1.06–1.31)	0.002
Any coronary revascularization	1,464 (28.6)	2,051 (26.5)	1.13 (1.06–1.21)	0.0003	1.08 (0.99–1.17)	0.1

The number of patients with an event was counted until the end of follow-up. Cumulative 5-year incidence was estimated by the Kaplan-Meier method. Hazard ratios (HRs) with 95% confidence intervals (CIs) of the ACS group relative to the stable CAD group for the outcome measures were estimated throughout the entire follow-up period using Cox proportional hazard models. ^AMI as a component of the composite outcome measure was adjudicated according to the ARC definition. ARTS, Arterial Revascularization Therapy Study; BARC, Bleeding Academic Research Consortium; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries; NA, multivariable HRs were not estimated due to the small number of events. Other abbreviations as in Table 1.

Figure 2.

Kaplan-Meier curves for the primary bleeding and ischemic outcome measures in the acute coronary syndrome (ACS) and stable coronary artery disease (CAD) groups. The primary bleeding outcome measure was major bleeding defined as Bleeding Academic Research Consortium (BARC) Type 3 or 5 bleeding, whereas the primary ischemic outcome measure was defined as a composite of myocardial infarction or ischemic stroke. (A) The primary bleeding outcome measure during the entire follow-up period. (B) Landmark analysis within and beyond 30 days for the primary bleeding outcome measure. (C) The primary ischemic outcome measure during the entire follow-up period. (D) Landmark analysis within and beyond 30 days for the primary ischemic outcome measure. PCI, percutaneous coronary intervention.

Table 3. Clinical Outcomes Within and Beyond 30 Days

	No. patients with event (cumulative 5-year incidence; %)		Univariate		Multivariable
	ACS (n=5,521)	Stable CAD (n=7,737)	HR (95% CI)	P value	HR (95% CI)	P value
Within 30 days
Major bleeding
BARC Type 3 or 5	607 (11.1)	230 (3.0)	3.87 (3.33–4.51)	<0.0001	3.35 (2.78–4.04)	<0.0001
Access site bleeding	269 (5.0)	90 (1.2)	4.32 (3.4–5.48)	<0.0001	NA
Gastrointestinal bleeding	88 (1.7)	44 (0.6)	3.0 (2.09–4.32)	<0.0001	NA
Intracranial bleeding	15 (0.3)	12 (0.2)	1.88 (0.88–4.01)	0.1	NA
Others	235 (4.4)	84 (1.1)	4.13 (3.22–5.3)	<0.0001	NA
BARC Type 5	16 (0.3)	3 (0.04)	7.57 (2.2–26.0)	0.0001	9.53 (2.04–44.6)	0.004
GUSTO moderate/severe bleeding	425 (7.8)	184 (2.4)	3.35 (2.82–3.99)	<0.0001	2.85 (2.3–3.53)	<0.0001
GUSTO severe bleeding	152 (2.8)	80 (1.0)	2.72 (2.07–3.56)	<0.0001	2.2 (1.56–3.09)	<0.0001
Hemorrhagic stroke	12 (0.2)	4 (0.05)	4.31 (1.39–13.4)	0.006	3.31 (0.8–13.7)	0.1
MI^A/ischemic stroke	187 (3.5)	302 (3.9)	0.87 (0.73–1.05)	0.15	0.77 (0.61–0.98)	0.03
MI
ARC definition	111 (2.1)	274 (3.5)	0.57 (0.46–0.71)	<0.0001	0.52 (0.39–0.68)	<0.0001
ARTS definition	78 (1.5)	98 (1.3)	1.14 (0.84–1.53)	0.4	0.86 (0.59–1.27)	0.46
Ischemic stroke	78 (1.5)	32 (0.4)	3.52 (2.33–5.3)	<0.0001	2.99 (1.79–5.0)	<0.0001
Cardiovascular death/MI/ ischemic stroke	446 (8.1)	323 (4.2)	1.95 (1.69–2.25)	<0.0001	1.79 (1.49–2.15)	<0.0001
All-cause death	287 (5.2)	32 (0.4)	12.9 (8.94–18.6)	<0.0001	8.55 (5.63–13.0)	<0.0001
Cardiac death	282 (5.1)	27 (0.4)	15.0 (10.0–22.2)	<0.0001	9.47 (6.06–14.8)	<0.0001
Cardiovascular death	282 (5.1)	28 (0.4)	14.45 (9.8–21.3)	<0.0001	9.19 (5.91–14.3)	<0.0001
Non-cardiovascular death	5 (0.1)	4 (0.05)	1.83 (0.49–6.81)	0.36	1.98 (0.37–10.7)	0.43
Definite stent thrombosis	42 (0.8)	14 (0.2)	4.31 (2.35–7.88)	<0.0001	2.88 (1.33–6.22)	0.007
Target vessel revascularization	159 (3.0)	72 (0.9)	3.22 (2.44–4.25)	<0.0001	2.85 (2.0–4.05)	<0.0001
Any coronary revascularization	196 (3.7)	85 (1.1)	3.37 (2.61–4.35)	<0.0001	3.03 (2.21–4.17)	<0.0001
Beyond 30 days
Major bleeding
BARC Type 3 or 5	546/4,703 (11.0)	970/7,452 (12.6)	0.9 (0.81–1.00)	0.06	1.06 (0.93–1.22)	0.33
Access site bleeding	18/4,703 (0.4)	31/7,452 (0.4)	0.93 (0.52–1.67)	0.81	NA
Gastrointestinal bleeding	207/4,703 (4.6)	353/7,452 (4.8)	0.94 (0.79–1.12)	0.5	NA
Intracranial bleeding	108/4,703 (2.1)	188/7,452 (2.5)	0.92 (0.73–1.17)	0.51	NA
Others	213/4,703 (4.4)	398/7,452 (5.4)	0.86 (0.73–1.02)	0.08	NA
BARC Type 5	36/5,182 (0.7)	67/7,674 (0.9)	0.82 (0.55–1.23)	0.33	1.0 (0.6–1.68)	0.99
GUSTO moderate/severe bleeding	509/4,884 (9.9)	882/7,498 (11.3)	0.9 (0.81–1.01)	0.06	1.04 (0.9–1.2)	0.58
GUSTO severe bleeding	271/5,096 (4.9)	450/7,602 (5.7)	0.92 (0.79–1.07)	0.29	1.04 (0.86–1.27)	0.66
Hemorrhagic stroke	81/5,175 (1.3)	139/7,670 (1.7)	0.89 (0.67–1.17)	0.39	0.81 (0.57–1.15)	0.24
MI^A/ischemic stroke	421/5,016 (7.7)	594/7,382 (7.2)	1.07 (0.95–1.21)	0.27	1.27 (1.08–1.49)	0.004
MI
ARC definition	227/5,081 (4.1)	292/7,408 (3.6)	1.17 (0.98–1.39)	0.08	1.2 (0.96–1.51)	0.11
ARTS definition	231/5,114 (4.1)	304/7,582 (3.6)	1.16 (0.98–1.38)	0.09	1.21 (0.97–1.51)	0.1
Ischemic stroke	215/5,115 (4.0)	345/7,644 (4.1)	0.95 (0.8–1.13)	0.57	1.3 (1.05–1.61)	0.02
Cardiovascular death/MI/ ischemic stroke	780/5,016 (14.1)	1,067/7,382 (12.5)	1.11 (1.01–1.21)	0.03	1.39 (1.24–1.57)	<0.0001
All-cause death	954/5,180 (15.9)	1,403/7,674 (15.1)	1.03 (0.95–1.12)	0.44	1.33 (1.2–1.48)	<0.0001
Cardiac death	398/5,180 (7.2)	499/7,674 (5.6)	1.21 (1.06–1.38)	0.004	1.61 (1.36–1.9)	<0.0001
Cardiovascular death	467/5,180 (8.4)	643/7,674 (7.2)	1.1 (0.98–1.24)	0.11	1.47 (1.26–1.7)	<0.0001
Non-cardiovascular death	487/5,180 (8.2)	760/7,674 (8.5)	0.97 (0.87–1.09)	0.65	1.22 (1.05–1.41)	0.009
Definite stent thrombosis	36/5,142 (0.5)	23/7,662 (0.3)	2.39 (1.42–4.04)	0.0007	2.53 (1.28–5.0)	0.007
Target vessel revascularization	902/5,033 (18.2)	1,293/7,604 (16.8)	1.11 (1.02–1.21)	0.01	1.07 (0.96–1.19)	0.24
Any coronary revascularization	1,268/5,002 (25.8)	1,966/7,591 (25.7)	1.03 (0.96–1.11)	0.41	0.98 (0.89–1.07)	0.62

In the landmark analysis beyond 30 days, the number of patients with an event was counted until the end of follow-up, whereas the cumulative incidence was estimated by the Kaplan-Meier method between 30 days and 5 years. HRs with 95% CIs of the ACS group relative to the stable CAD group for the outcome measures were estimated throughout the entire follow-up period using Cox proportional hazard models. AMI as a component of the composite outcome measure was adjudicated according to the ARC definition. Abbreviations as in Tables 1,2.

The cumulative 5-year incidence of the primary ischemic outcome measure was not significantly different between the 2 groups during the entire follow-up period, or within 30 days (Tables 2,3; Figure 2C,D). After adjusting for confounders, the excess risk of ACS relative to stable CAD for the primary ischemic outcome measure remained not significant (Table 2). The risk of ACS relative to stable CAD for the primary ischemic outcome measure was significantly lower within 30 days, but higher beyond 30 days (Table 3). The excess risk of ACS relative to stable CAD was significant for all-cause death, cardiac death, cardiovascular death, non-cardiovascular death, ischemic stroke, definite stent thrombosis, and target vessel revascularization, but not for myocardial infarction by the ARTS definition (Table 2). The cumulative incidence of the primary ischemic outcome measure did not differ between STEMI and NSTEACS (Supplementary Figure 2B).

Baseline Characteristics According to Clinical Presentation and HBR

Baseline characteristics and medications were significantly different across the 4 categories according to clinical presentation (ACS and stable CAD) and the presence of ARC-HBR (Table 4). Patients in the ACS/HBR group were older, had a lower body mass index, and more often had heart failure and severe frailty.

Table 4. Baseline Characteristics and Medications According to the Clinical Presentation and HBR

	ACS/HBR (n=2,502)	ACS/No-HBR (n=3,019)	Stable CAD/HBR (n=3,905)	Stable CAD/No-HBR (n=3,832)	P value
Clinical characteristics
Age (years)	75.3±11.0	63.3±10.9	74.3±9.3	65.5±9.3	<0.0001
Age ≥75 years	1,551 (62)	396 (13)	2,228 (57)	506 (13)	<0.0001
Male sex^A	1,633 (65)	2,450 (81)	2,654 (68)	2,935 (77)	<0.0001
Body mass index (kg/m²)	22.8±3.6 (2,419)	24.4±3.5 (2,970)	23.3±3.6 (3,868)	24.5±3.5 (3,817)	<0.0001
Body mass index <25.0 kg/m² ^A	1,931 (77)	1,888 (63)	2,818 (72)	2,264 (59)	<0.0001
Acute MI	2,419 (97)	2,897 (96)	0 (0)	0 (0)	<0.0001
STEMI	1,848 (74)	2,233 (74)	0 (0)	0 (0)	<0.0001
NSTEMI	571 (23)	664 (22)	0 (0)	0 (0)	<0.0001
Unstable angina	83 (3.3)	122 (4.0)	0 (0)	0 (0)	<0.0001
Hypertension^A	2,070 (83)	2,333 (77)	3,420 (88)	3,077 (80)	<0.0001
Diabetes^A	902 (36)	984 (33)	1,677 (43)	1,476 (39)	<0.0001
On insulin therapy	183 (7.3)	98 (3.3)	495 (13)	315 (8.2)	<0.0001
Current smoker^A	572 (23)	1,432 (47)	644 (16)	1,024 (27)	<0.0001
Heart failure^A	1,036 (41)	643 (21)	1,025 (26)	413 (11)	<0.0001
Multivessel disease^A	1,516 (61)	1,574 (52)	2,450 (63)	2,061 (54)	<0.0001
LVEF (%)	53.1±13.1 (2,171)	56.9±11.6 (2,753)	59.4±13.8 (3,343)	62.9±11.6 (3,264)	<0.0001
LVEF ≤40%	378/2,171 (17)	203/2,753 (7.4)	381/3,343 (11)	175/3,264 (5.4)	<0.0001
Mitral regurgitation grade 3/4	307/2,250 (14)	142/2,810 (5.1)	344/3,360 (10)	101/3,280 (3.1)	<0.0001
Prior MI^A	92 (3.7)	56 (1.9)	742 (19)	570 (15)	<0.0001
Prior stroke	546 (22)	60 (2.0)	945 (24)	148 (3.9)	<0.0001
Prior hemorrhagic stroke	125 (5.0)	0 (0)	179 (4.6)	0 (0)	<0.0001
Prior ischemic stroke	447 (18)	60 (2.0)	811 (21)	148 (3.9)	<0.0001
Peripheral vascular disease^A	135 (5.4)	52 (1.7)	720 (18)	306 (8.0)	<0.0001
Atrial fibrillation^A	394 (16)	91 (3.0)	708 (18)	93 (2.4)	<0.0001
Chronic obstructive pulmonary disease^A	117 (4.7)	82 (2.7)	190 (4.9)	130 (3.4)	<0.0001
Liver cirrhosis	118 (4.7)	0 (0)	217 (5.6)	0 (0)	<0.0001
Malignancy	415 (17)	180 (6.0)	774 (20)	308 (8.0)	<0.0001
Active malignancy	89 (3.6)	0 (0)	181 (4.6)	0 (0)	<0.0001
Severe frailty^A,B	276 (11)	27 (0.9)	216 (5.5)	31 (0.8)	<0.0001
Chronic kidney disease
Moderate (eGFR 30–59 mL/min/1.73 m²)	1,160 (46)	506 (17)	1,915 (49)	594 (16)	<0.0001
Severe CKD	464 (19)	0 (0)	733 (19)	0 (0)	<0.0001
eGFR <30 mL/min/1.73 m²
Not on dialysis	322 (13)	0 (0)	264 (6.8)	0 (0)	<0.0001
On dialysis	142 (5.7)	0 (0)	469 (12)	0 (0)	<0.0001
Severe anemia (Hb <11 g/dL)	603 (24)	0 (0)	1,029 (26)	0 (0)	<0.0001
Mild anemia (Hb 11–12.9 g/dL for men, 11–11.9 g/dL for women)	748 (30)	135 (4.5)	1,472 (38)	342 (8.9)	<0.0001
Thrombocytopenia (platelets <100×10⁹/L)	111 (4.4)	0 (0)	151 (3.9)	0 (0)	<0.0001
Procedural characteristics
No. target lesions	1.47±0.81	1.44±0.75	1.5±0.78	1.49±0.79	0.006
Target of proximal LAD^A	1,414 (57)	1,747 (58)	2,406 (62)	2,432 (63)	<0.0001
Target of unprotected LMCA^A	139 (5.6)	111 (3.7)	191 (4.9)	150 (3.9)	0.001
Target of chronic total occlusion^A	120 (4.8)	106 (3.5)	527 (14)	578 (15)	<0.0001
Target of bifurcation^A	908 (36)	1,148 (38)	1,577 (40)	1,609 (42)	<0.0001
Side-branch stenting^A	72 (2.9)	95 (3.2)	162 (4.2)	195 (5.1)	<0.0001
Total number of stents
Median [IQR]	1 [1–2]	1 [1–2]	2 [1–3]	1 [1–2]	<0.0001
Mean±SD	1.88±1.34 (n=2,276)	1.74±1.19 (n=2,908)	2.01±1.37 (n=3,769)	1.97±1.39 (n=3,738)
Total stent length (mm)
Median [IQR]	28 [18–51]	26 [18–45]	33 [18–56]	28 [18–56]	<0.0001
Mean±SD	40.1±32.5 (n=2,275)	36.4±28.4 (n=2,907)	44.2±34.3 (n=3,769)	43.0±35.2 (n=3,738)
Total stent length >28 mm^A	1,081 (43)	1,211 (40)	2,070 (53)	1,861 (49)	<0.0001
Minimum stent size (mm)	2.88±0.45 (n=2,275)	2.96±0.47 (n=2,908)	2.8±0.41 (n=3,769)	2.84±0.44 (n=3,738)	<0.0001
Minimum stent size <3.0 mm^A	1,154 (46)	1,280 (42)	2,191 (56)	2,046 (53)	<0.0001
No stent	226 (9.0)	111 (3.7)	136 (3.5)	94 (2.5)	<0.0001
BMS only^A	736 (29)	945 (31)	387 (9.9)	289 (7.5)
DES used^A	1,540 (62)	1,963 (65)	3,382 (87)	3,449 (90)
New-generation DES used	1,525 (61)	1,947 (64)	3,315 (85)	3,396 (89)	<0.0001
IVUS or OCT use	1,541 (62)	2,007 (66)	3,117 (80)	3,073 (80)	<0.0001
IVUS used	1,532 (61)	1,992 (66)	3,072 (79)	3,033 (79)	<0.0001
OCT used	20 (0.8)	49 (1.6)	110 (2.8)	109 (2.8)	<0.0001
Transradial approach	435 (17)	665 (22)	1,727 (44)	2,146 (56)	<0.0001
Transfemoral approach^A	1,901 (76)	2,209 (73)	1,597 (41)	1,280 (33)	<0.0001
Staged PCI	516 (21)	740 (25)	688 (18)	706 (18)	<0.0001
Baseline medication
Antiplatelet therapy
Thienopyridine	2,391 (95.6)	2,975 (98.5)	3,864 (99.0)	3,813 (99.5)	<0.0001
Ticlopidine	57/2,391 (2.4)	60/2,975 (2.0)	153/3,864 (4.0)	88/3,813 (2.3)	<0.0001
Clopidogrel	2,321/2,391 (97.1)	2,846/2,975 (95.7)	3,704/3,864 (95.9)	3,700/3,813 (97.0)
Others	13/2,391 (0.5)	69/2,975 (2.3)	7/3,864 (0.2)	25/3,813 (0.7)
Aspirin	2,438 (97.4)	2,991 (99.1)	3,865 (99.0)	3,816 (99.6)	<0.0001
Cilostazol	63 (2.5)	69 (2.3)	154 (3.9)	71 (1.9)	<0.0001
Other medications
Statins^A	1,864 (75)	2,698 (89)	2,548 (65)	3,158 (82)	<0.0001
High-intensity statins^C	32 (1.3)	59 (2.0)	45 (1.2)	75 (2.0)	0.006
β-blockers^A	1,270 (51)	1,535 (51)	1,393 (36)	1,006 (26)	<0.0001
ACEI/ARB^A	1,723 (69)	2,401 (80)	2,380 (61)	2,023 (53)	<0.0001
Nitrates	417 (17)	555 (18)	816 (21)	775 (20)	<0.0001
Calcium channel blockers^A	641 (26)	646 (21)	2,062 (53)	1,871 (49)	<0.0001
Nicorandil	542 (22)	521 (17)	645 (17)	512 (13)	<0.0001
Oral anticoagulants	661 (26)	0 (0)	743 (19)	0 (0)	<0.0001
Warfarin	583 (23)	0 (0)	640 (16)	0 (0)	<0.0001
Direct oral anticoagulants	79 (3.2)	0 (0)	104 (2.7)	0 (0)	<0.0001
Proton pump inhibitor or H₂-blockers^A	2,118 (85)	2,571 (85)	2,901 (74)	2,644 (69)	<0.0001
Proton pump inhibitor	1,852 (74)	2,182 (72)	2,434 (62)	2,180 (57)	<0.0001
H₂-blockers	279 (11)	400 (13)	496 (13)	484 (13)	0.12

Long-Term Clinical Outcomes According to Clinical Presentation and HBR

Across the 4 groups, the cumulative incidence of persistent discontinuation of DAPT was highest in the ACS/HBR group (Supplementary Figure 3).

The cumulative 5-year incidence of the primary bleeding outcome measure decreased in the order of ACS/HBR, stable CAD/HBR, and ACS/No-HBR, followed by the stable CAD/No-HBR group (Supplementary Table 1; Figure 3A). Within 30 days, the cumulative incidence of the primary bleeding outcome measure was higher in the 2 ACS groups with and without HBR than in the 2 stable CAD groups with and without HBR (Supplementary Table 1; Figures 3B,4). The adjusted risk for the primary bleeding outcome measure was much higher in the ACS/HBR group, and moderately higher in the ACS/No-HBR and stable CAD/HBR groups than in the stable CAD/No-HBR group (HR 3.05 [95% CI 2.64–3.54; P<0.0001], HR 1.69 [95% CI 1.45–1.98; P<0.0001], and HR 1.89 [95% CI 1.66–2.15; P<0.0001], respectively; Supplementary Table 2). Within 30 days, the adjusted risk for the primary bleeding outcome measure was much higher in the 2 ACS groups with and without HBR, and moderately higher in the stable CAD/HBR group than in the stable CAD/No-HBR group (Supplementary Table 2). Beyond 30 days, the adjusted risk for the primary bleeding outcome measure was significantly higher in the 2 HBR groups with and without ACS than in the stable CAD/No-HBR group (Supplementary Table 2).

Figure 3.

Kaplan-Meier curves for the primary bleeding and ischemic outcome measures according to the clinical presentation and high bleeding risk (HBR). The primary bleeding outcome measure was major bleeding defined as Bleeding Academic Research Consortium (BARC) Type 3 or 5 bleeding, whereas the primary ischemic outcome measure was defined as a composite of myocardial infarction or ischemic stroke. (A) The primary bleeding outcome measure during the entire follow-up period. (B) Landmark analysis within and beyond 30 days for the primary bleeding outcome measure. (C) The primary ischemic outcome measure during the entire follow-up period. (D) Landmark analysis within and beyond 30 days for the primary ischemic outcome measure. ACS, acute coronary syndrome; CAD, coronary artery disease; PCI, percutaneous coronary intervention.

Figure 4.

Number of patients with primary bleeding outcome measures within 30 days. The primary bleeding outcome measure was major bleeding defined as Bleeding Academic Research Consortium (BARC) Type 3 or 5 bleeding. ACS, acute coronary syndrome; CAD, coronary artery disease; HBR, high bleeding risk; PCI, percutaneous coronary intervention.

The cumulative 5-year incidence of the primary ischemic outcome measure was significantly higher in the 2 HBR groups than in the 2 No-HBR groups throughout the entire follow-up period (Supplementary Table 1; Figure 3C), as well as within and beyond 30 days (Figure 3D). The adjusted risk for the primary ischemic outcome measure was moderately higher in the 2 HBR groups than in the stable CAD/No-HBR group, whereas it was not significantly different between the ACS/No-HBR and stable CAD/No-HBR groups (Supplementary Table 2).

Primary Bleeding Outcome Measure at 30 Days According to Approach Site

The cumulative 30-day incidence of the primary bleeding outcome measure (BARC Type 3 or 5 bleeding) was significantly higher in patients with a femoral than radial approach (Supplementary Figure 4).

Discussion

The main findings of this study are that: (1) bleeding risk after PCI was dependent on both ACS presentation and HBR, with a significant effect of ACS within but not beyond 30 days; (2) the 30-day rate of major bleeding was very high in patients with ACS regardless of HBR; and (3) long-term ischemic risk after PCI was largely dependent on HBR.

Patients with ACS reportedly have a high risk for cardiovascular events after PCI. However, there are only a few large-scale studies comparing long-term outcomes after PCI between ACS and stable CAD. In the first-generation DES era, we reported that patients with acute myocardial infarction (AMI) had a higher risk of a composite of cardiac death or myocardial infarction, and definite stent thrombosis than patients without AMI, although the excess risk was limited to the early period within 3 months.¹ In the NOBORI-2 study, the risk for cardiac death was significantly higher in patients with NSTEMI than in those with stable CAD.¹³ In the present study, which enrolled patients in the new-generation DES era, comparing ACS and stable CAD patients revealed that the former were also associated with a higher risk of cardiac death or definite stent thrombosis. However, the higher risk of ACS patients for cardiac death was driven primarily by the excess cardiac death within 30 days. Conventional endpoints including mortality outcomes may be heavily biased for estimating the ischemic risk of ACS patients, because they would be highly influenced by the index ACS event, but not related to the new cardiovascular events after ACS. It is true that the risk for definite stent thrombosis was higher in ACS than stable CAD patients, but the absolute difference in event rate was very small. The excess risk of ACS patients relative to stable CAD patients was not demonstrated for the primary ischemic outcome measure of a composite of myocardial infarction or ischemic stroke in the present study. The current guidelines recommend DAPT for at least 1 year in patients with ACS, if not at HBR, based on the premise that ACS patients are associated with a much higher risk for ischemic events than stable CAD patients.² However, given the similar risk for the primary ischemic outcome measure of a composite of myocardial infarction or ischemic stroke in ACS patients compared with stable CAD patients, shorter-duration DAPT may be an option even in ACS patients to reduce bleeding events. The ShorT and OPtimal Duration of Dual AntiPlatelet Therapy-2 Study for the Patients With ACS (STOPDAPT-2 ACS) trial has just finished enrollment of 4,100 patients to evaluate the safety and efficacy of 1-month DAPT followed by clopidogrel monotherapy vs. 12-month DAPT with aspirin and clopidogrel in all-comer patients with ACS undergoing PCI with cobalt-chromium everolimus-eluting stent (XIENCE^TM; ClinicalTrials.gov ID: NCT03462498).

Previous studies in ACS patients have reported relatively high rates of major bleeding. The rate of Thrombolysis in Myocardial Infarction (TIMI) major/minor bleeding was 5.9% in the prasugurel group and 4.8% in the clopidogrel group at 15 months after PCI in STEMI patients in the TRITON-TIMI 38 trial.¹⁴ In the Platelet Inhibition and Patient Outcomes (PLATO) trial, the cumulative 1-year incidence of TIMI major/minor bleeding was 7.9% in the ticagrelor group and 7.7% in the clopidogrel group, which is higher than the cut-off value of 4%/year in the ARC-HBR definition.⁵^,¹⁵ In a meta-analysis of 3 randomized trials of patients with ACS undergoing PCI with bivalirudin or heparin plus a glycoprotein IIb/IIIa inhibitor, the rate of TIMI major/minor bleeding was high (5.3% at 30 days).¹⁶ However, no previous studies compared the bleeding risk between patients with ACS and patients with stable CAD after PCI. In the present study, ACS patients, compared with stable CAD patients, were associated with a substantially higher risk of major bleeding, particularly within 30 days after PCI. The 30-day rate of major bleeding was unacceptably high (11.1%) in patients with ACS. Furthermore, higher 30-day bleeding risk in patients with ACS was present regardless of the presence of the ARC-HBR criteria, although ACS patients with HBR had higher 30-day bleeding risk than ACS patients without HBR. In fact, the cumulative incidence of persistent discontinuation of DAPT was significantly higher in the ACS than stable CAD group, which was mainly seen within 30 days after PCI. Higher bleeding risk within 30 days could have affected the shorter DAPT in the ACS than stable CAD group. ARC-HBR did not include ACS as an HBR criterion, presumably, in part, because increased bleeding risk in ACS is attributable to the more aggressive antiplatelet therapy rather than the ACS per se, and partly because there is no previous study comparing the bleeding risk between patients with ACS and those with stable CAD after PCI.⁵ The periprocedural use of antithrombotic agents, such as heparin and a loading dose of antiplatelet therapy, as well as the high prevalence of the transfemoral approach, could have increased the risk of bleeding in ACS patients. Indeed, in the present study the transradial approach was selected in only 20% of patients in the ACS group, compared with 50% in the stable CAD group. Furthermore, patients with a transfemoral approach had a significantly higher incidence of 30-day bleeding than those with a transradial approach. Further efforts are needed to reduce early bleeding events in ACS patients by selecting the transradial approach, the prophylactic use of gastrointestinal mucosa-protective agents, and an appropriate intensity of antithrombotic therapy before and early after PCI. In the Acetyl Salicylic Elimination Trial: The ASET Pilot Study (ASET), prasugrel monotherapy without aspirin immediately after successful new-generation DES implantation was associated with a favorable outcome without any stent thrombosis.¹⁷ Therefore, a completely aspirin-free strategy may be an option to reduce bleeding events early after PCI, if not associated with increasing ischemic events. We are launching the STOPDAPT-3 trial, which randomizes 3,000 patients with HBR and/or ACS before PCI to either an experimental arm of prasugrel monotherapy or a control arm of DAPT with aspirin and prasugrel (ClinicalTrials.gov ID: NCT04609111). The coprimary endpoints are BARC 3 or 5 bleeding (superiority) and a composite of cardiovascular death, myocardial infarction, ischemic stroke, or definite stent thrombosis (non-inferiority) at 30 days after PCI.

Another important finding in the present study was that the long-term ischemic risk after PCI was largely dependent on HBR, regardless of ACS. This observation is basically in line with previous reports. In the CREDO-Kyoto Registry Cohort-2, 43% of patients had ARC-HBR and this was associated not only with a higher bleeding risk, but also a higher ischemic risk.¹⁸ The vast majority of patients with high ischemic risk also had high- or intermediate bleeding risk.¹⁹ In the present study, 48% of patients had ARC-HBR, with higher associated risks for both bleeding and ischemic events. In HBR patients, the rate for BARC Type 3 or 5 bleeding was higher than that for myocardial infarction/ischemic stroke. In several randomized trials, more intensive antithrombotic therapy was reported to reduce cardiovascular events in patients with high ischemic risk.²⁰^–²² However, in real-world clinical practice, given the higher bleeding risk in most patients with high ischemic risk, it would not be realistic to intensify antithrombotic therapy in these patients. Indeed, recent trials exploring a shorter duration of DAPT after DES implantation, such as 1 month in STOPDAPT-2 and GLOBAL LEADERS: and 3 months in Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention (TWILIGHT) and Ticagrelor Monotherapy After 3 Months in the Patients Treated With New Generation Sirolimus Stent for Acute Coronary Syndrome (TICO), have suggested the benefit of shorter-duration DAPT followed by P2Y₁₂ receptor blocker monotherapy in reducing bleeding events without increasing cardiovascular events.²³^–²⁶ Further studies would be warranted to confirm these seminal observations to incorporate shorter DAPT regimens after PCI into practice guidelines.

Study Limitations

Several study limitations should be considered. First, the CREDO-Kyoto PCI/CABG Registry Cohort-3 was not designed to investigate the performance of ARC-HBC criteria, and therefore data were not available for some ARC-HBR criteria. The prevalence of HBR patients would have been underestimated in this study. Moreover, the original definitions of some of the ARC-HBR criteria (i.e., for liver cirrhosis, ischemic stroke, and previous bleeding) were somewhat different from those in the current registry, and approximation was needed when they were implemented retrospectively. Third, the clinical practice in this study was much different from current practice, in which there is more widespread use of a transradial approach, a higher prevalence of high-intensity statins therapy, the use of a new P2Y₁₂ receptor blocker (prasugrel), more widespread use of direct oral anticoagulants, and a shorter duration of DAPT. In particular, the frequent use of a transfemoral approach could have affected the higher risk for bleeding events in patients with ACS. These limitations may significantly affect the external contemporary validity of the present study results. Fourth, information on the use of mechanical supports, which could contribute to major bleeding events after PCI, was not available in this study. Finally, the balance between ischemic and bleeding risk in Japanese patients may be different to that for patients outside of Japan. Furthermore, glycoprotein IIb/IIIa antagonist treatment is not available in Japan.

Conclusions

Bleeding risk after PCI was dependent on both ACS presentation and HBR with a significant effect of ACS within, but not beyond, 30 days. The 30-day rate of major bleeding was very high in patients with ACS regardless of HBR. Long-term ischemic risk after PCI was largely dependent on HBR.

Acknowledgment

The authors thank the clinical research coordinators of the Research Institute for Production Development.

Sources of Funding

This study was supported by an educational grant from the Research Institute for Production Development (Kyoto, Japan).

Disclosures

M.N. reports honoraria from Abbott Vascular, Amgen, Boehringer-Ingelheim, Boston Scientific, Daiichi-Sankyo, Medtronic, Sanofi, Takeda, and Terumo. T.M. reports honoraria from Bayer and Kowa, and has acted as an expert witness for Boston Scientific and Sanofi. N.E. reports honoraria from Abbott Vascular, Bayer, Boston Scientific, Daiichi-Sankyo, Edwards Scientific, Medtronic, Pfizer, and Terumo. Y.F. reports honoraria from Bayer, Kowa, and Sanofi. Y.N. reports research grants from Abbott Vascular and Boston Scientific, and honoraria from Abbott Vascular, Bayer, and Boston Scientific. T.K. reports honoraria from Abbott Vascular, Astellas, AstraZeneca, Bayer, Boston Scientific, Kowa, and Sanofi. T.K. is also a member of Circulation Journal’s Editorial Team. The remaining authors have nothing to disclose.

IRB Information

The research protocols of the CREDO-Kyoto Cohort-3 were approved by the Institutional Review Board of Kyoto University (E2400) and by the local ethics committees in all participating medical centers.

Data Availability

The deidentified participant data will not be shared.

Supplementary Files

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-21-0016

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