Bleeding Outcomes After Percutaneous Coronary Intervention in the Past Two Decades in Japan　― From the CREDO-Kyoto Registry Cohort-2 and Cohort-3 ―

Abstract

Background: Optimal intensity is unclear for P2Y₁₂ receptor blocker therapy after percutaneous coronary intervention (PCI) in real-world clinical practice.

Methods and Results: From the CREDO-Kyoto Registry, the current study population consisted of 25,419 patients (Cohort-2: n=12,161 and Cohort-3: n=13,258) who underwent their first PCI. P2Y₁₂ receptor blocker therapies were reduced dose of ticlopidine (200 mg/day), and global dose of clopidogrel (75 mg/day) in 87.7% and 94.8% of patients in Cohort-2 and Cohort-3, respectively. Cumulative 3-year incidence of GUSTO moderate/severe bleeding was significantly higher in Cohort-3 than in Cohort-2 (12.1% and 9.0%, P<0.0001). After adjusting 17 demographic factors and 9 management factors potentially related to the bleeding events other than the type of P2Y₁₂ receptor blocker, the higher bleeding risk in Cohort-3 relative to Cohort-2 remained significant (hazard ratio (HR): 1.52 95% confidence interval (CI) 1.37–1.68, P<0.0001). Cohort-3 compared with Cohort-2 was not associated with lower adjusted risk for myocardial infarction/ischemic stroke (HR: 0.96, 95% CI: 0.87–1.06, P=0.44).

Conclusions: In this historical comparative study, Cohort-3 compared with Cohort-2 was associated with excess bleeding risk, which might be at least partly explained by the difference in P2Y₁₂ receptor blockers.

Practice changes introduced for percutaneous coronary intervention (PCI) in the past decade have included new-generation drug-eluting stents (DES), more widespread use of the transradial approach and intravascular imaging, use of potent P2Y₁₂ receptor blockers, more prolonged dual antiplatelet therapy (DAPT), and more prevalent use of optimal medical therapy.^1–4 The introduction of new-generation DES has certainly reduced stent-related adverse events such as stent thrombosis (ST) or target vessel revascularization (TVR).^1,2 However, it remains unclear whether the recent practice changes have brought about a reduction in ischemic events such as myocardial infarction (MI) and stroke in the real world. More importantly, some of the recent practice changes such as the use of more potent P2Y₁₂ receptor blockers and more prolonged DAPT might be associated with an increase in bleeding events.^5,6 However, there is a scarcity of previous studies evaluating the changes in the long-term risk of bleeding events associated with adoption of more intensive antithrombotic strategy in the real world.⁷ Therefore, we sought to make a historical comparison of the bleeding and ischemic outcomes in 2 Japanese registries that enrolled consecutive patients undergoing their first PCI before 2010 and beyond 2010.

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Methods

Study Population

The Coronary Revascularization Demonstrating Outcome Study in Kyoto (CREDO-Kyoto) PCI/coronary artery bypass grafting (CABG) registry Cohort-2 and Cohort-3 are a series of physician-initiated, non-company-sponsored, multicenter registries enrolling consecutive patients who underwent their first coronary revascularization with PCI or isolated CABG without combined non-coronary surgery.^8–10 Cohort-2 enrolled patients between January 2005 and December 2007 among 26 centers in Japan after the introduction of DES in 2004,⁸ while Cohort-3 enrolled patients between January 2011 and December 2013 among 22 centers in Japan after approval of the new-generation DES in 2010 (Supplementary Appendix 1).^9,10 We made a historical comparison between Cohort-2 and Cohort-3 for the demographics, clinical practices, and long-term clinical outcomes of patients who underwent PCI.

A total of 30,866 patients had their first isolated coronary revascularization in Cohort-2 (n=15,939) and Cohort-3 (n=14,927). In the present study, we excluded patients who refused study participation and those who underwent CABG. To make Cohort-2 and Cohort-3 comparable, we further excluded 897 patients in Cohort-2 who were enrolled from divisions not participating in Cohort-3. Finally, we retrieved 25,419 patients with PCI for the current study (Cohort-2: 12,161 patients; Cohort-3: 13,258 patients) from 22 centers (Figure 1).

Figure 1.

Study patient flow. CREDO-Kyoto, the Coronary Revascularization Demonstrating Outcome study in Kyoto; PCI, percutaneous coronary intervention; CABG, coronary artery bypass grafting.

The relevant institutional review boards at all participating hospitals approved the study protocol, and we performed the study in accordance with the Declaration of Helsinki. Written informed consent for both registries was waived because of the retrospective nature of the study; however, we excluded those patients who refused participation in the study when contacted at follow-up.

Definitions

The primary bleeding outcome measure was major bleeding defined as the global utilization of streptokinase and tissue plasminogen activator for occluded coronary arteries (GUSTO) moderate/severe bleeding,¹¹ and the primary ischemic outcome measure was a composite of MI or ischemic stroke.¹² Death was regarded as cardiac in origin unless obvious non-cardiac causes could be identified. Deaths of unknown cause and any death during the index hospitalization for coronary revascularization were regarded as cardiac death. Cardiovascular death included cardiac death, and other vascular death related to stroke, renal disease, and vascular disease. ST was adjudicated according to the Academic Research Consortium (ARC) definition.¹³ To keep consistency with the CREDO-Kyoto PCI/CABG registry Cohort-2,⁸ MI was adjudicated according to the Arterial Revascularization Therapy Study (ARTS) definition,¹⁴ in which only Q-wave MI is regarded as MI if it occurs within 7 days of the index procedure. Stroke was defined as ischemic or hemorrhagic stroke with neurological symptoms lasting >24 h. TVR was defined as either PCI or CABG related to the target vessel. Any coronary revascularization was defined as either PCI or CABG for any reason. Duration of DAPT was left to the discretion of each attending physician. Persistent discontinuation of DAPT was defined as withdrawal of either P2Y₁₂ receptor blockers or aspirin for at least 2 months. The doses of P2Y₁₂ receptor blockers were the approved doses in Japan, consisting of a reduced dose (200 mg/day) for ticlopidine, and a global dose (75 mg/day) for clopidogrel. We also assessed surgery during follow-up, because it could be related to discontinuation of antiplatelet agents and bleeding events. The definitions of surgery during follow-up excluding CABG were the same as reported previously (Supplementary File 2).¹⁵ In the present analysis, we included CABG as surgery during follow-up. Other definitions are described in Supplementary File 2.

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 the experienced clinical research coordinators from an independent clinical research organization (Research Institute for Production Development, Kyoto, Japan) (Supplementary Appendix 2).

Follow-up data were collected from the hospital charts and/or obtained by contacting the patients, their relatives or referring physicians by sending postal mails with questions regarding vital status, subsequent hospitalizations, and status of antiplatelet therapy. Follow-up was censored at 3 years after the index procedure to ensure >90% clinical follow-up rate in both Cohort-2 and Cohort-3, and to make the follow-up duration comparable between cohorts. Complete 3-year follow-up information was obtained for 96.5% of patients in Cohort-2, and 94.7% of patients in Cohort-3. The clinical event committee adjudicated events such as death, MI, ST, stroke, and major bleeding (Supplementary Appendix 3).

Statistical Analysis

Categorical variables are presented as number and percentage, and were compared with the chi-square test. Continuous variables are expressed as mean±standard deviation, or median and interquartile range. Based on their distributions, continuous variables were compared between groups with Student’s t-test or the Wilcoxon rank sum test.

Cumulative incidence was estimated by the Kaplan-Meier method and differences were assessed with the log-rank test. To distinguish periprocedural events at the index PCI from long-term events, we also performed a 30-day landmark analysis. Those patients with individual endpoint events before 30 days were excluded from the landmark analysis beyond 30 days. To estimate the adjusted hazard ratios (HR) and 95% confidence intervals (CI) of Cohort-3 relative to Cohort-2, we used multivariable Cox proportional hazard models by incorporating 17 clinically relevant factors (model 1; Table 1). The risk-adjusting variables included demographic factors, but not factors related to patient management, because differences in management converged into changes between Cohort-2 and Cohort-3. Continuous risk-adjusting variables were dichotomized according to the clinically meaningful reference values to make proportional hazard assumptions robust and to be consistent with previous reports.^8–10 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.

Table 1. Baseline Characteristics

	Cohort-3 (n=13,258)	Cohort-2 (n=12,161)	P value
(A) Clinical characteristics
Age (years)	69.4±11.3	68.1±11.1	<0.0001
Age ≥75 years*	4,681 (35%)	3,726 (31%)	<0.0001
Men*	9,672 (73%)	8,760 (72%)	0.1
BMI	23.8±3.6 (13,074)	23.7±3.5 (11,765)	0.18
BMI <25.0 kg/m2*	8,901 (67%)	8,302 (68%)	0.054
Acute coronary syndrome*	5,521 (42%)	5,257 (43%)	0.01
STEMI	4,081 (31%)	3,804 (31%)	0.39
NSTEMI	1,235 (9.3%)	630 (5.2%)	<0.0001
UA	205 (1.6%)	823 (6.8%)	<0.0001
Hypertension*	10,900 (82%)	9,980 (82%)	0.76
Diabetes mellitus*	5,039 (38%)	4,529 (37%)	0.21
On insulin therapy	1,091 (8.2%)	931 (7.7%)	0.09
Current smoking*	3,672 (28%)	3,901 (32%)	<0.0001
Heart failure*	3,117 (24%)	2,433 (20%)	<0.0001
Multivessel disease	7,601 (57%)	6,875 (57%)	0.2
Mitral regurgitation grade 3/4	894 (6.7%)	479 (3.9%)	<0.0001
LVEF (%)	58.6±13.0 (11,531)	58.3±13.2 (9,985)	0.12
Prior MI*	1,460 (11%)	1,280 (11%)	0.21
Prior stroke*	1,699 (13%)	1,282 (11%)	<0.0001
Prior hemorrhagic stroke	304 (2.3%)	189 (1.6%)	<0.0001
Prior ischemic stroke	1,466 (11%)	1,133 (9.3%)	<0.0001
Peripheral vascular disease*	1,213 (9.2%)	885 (7.3%)	<0.0001
Moderate CKD (eGFR 30–59mL/min/1.73 m2)	4,175 (31%)	3,649 (30%)	0.01
Severe CKD*	1,197 (9.0%)	939 (7.7%)	0.0002
eGFR <30 mL/min/1.73 m2, not on dialysis	586 (4.4%)	501 (4.1%)	0.24
Dialysis	611 (4.6%)	438 (3.6%)	<0.0001
Atrial fibrillation*	1,286 (9.7%)	1,037 (8.5%)	0.001
Severe anemia (Hb <11 g/dL)*	1,632 (12%)	1,383 (11%)	0.02
Mild anemia (Hb 11–12.9 g/dL for men and 11–12.9 g/dL for women)	2,697 (20%)	2,276 (19%)	0.001
Platelets <100*109/L*	262 (2.0%)	184 (1.5%)	0.005
COPD	519 (3.9%)	442 (3.6%)	0.24
Liver cirrhosis*	335 (2.5%)	303 (2.5%)	0.86
Malignancy*	1,677 (13%)	1,084 (8.9%)	<0.0001
ARC-HBR	6,255 (47%)	5,140 (42%)	<0.0001
(B) Procedural characteristics
No. of target lesions	1.48±0.78	1.46±0.76	0.09
Target of proximal LAD	7,999 (60%)	6,950 (57%)	<0.0001
Target of unprotected LMCA	591 (4.5%)	442 (3.6%)	0.0009
Target of CTO	1,331 (10%)	1,431 (12%)	<0.0001
Target of bifurcation	5,242 (40%)	3,987 (33%)	<0.0001
Side-branch stenting	524 (4.0%)	596 (4.9%)	0.0002
Total no. of stents	1 (1–2)	1 (1–2)	0.17
	1.91±1.33 (12,691)	1.87±1.25 (11,341)
Stent use	12,691 (96%)	11,341 (93%)	<0.0001
Bare-metal stent use	2,753 (21%)	5,871 (48%)	<0.0001
DES use	10,334 (78%)	6,513 (54%)	<0.0001
1 st-generation DES use	242 (1.8%)	6,513 (54%)	<0.0001
New-generation DES use	10,183 (77%)	0 (0%)	<0.0001
Total stent length (mm)	28 (18–52)	28 (18–51)	0.43
	41.3±33.1 (12,689)	39.8±29.6 (11,340)
Total stent length >28 mm	6,223/12,689 (49%)	5,562/11,340 (49%)	0.99
Minimum stent size (mm)	2.86±0.44 (12,690)	2.92±0.45 (11,339)	<0.0001
Minimum stent size <3.0 mm	6,671/12,690 (53%)	4,902/11,339 (43%)	<0.0001
Transradial approach	4,973/13,243 (38%)	3,019/12,085 (25%)	<0.0001
Transfemoral approach	6,987/13,243 (53%)	7,757/12,085 (64%)	<0.0001
IVUS/OCT use	9,738 (73%)	4,706 (39%)	<0.0001
(C) Baseline medication
Medication at hospital discharge
Antiplatelet therapy
P2Y12 receptor blocker	13,043 (98.4%)	11,831 (97.3%)	<0.0001
Ticlopidine	358 (2.7%)	10,659 (87.7%)	<0.0001
Clopidogrel	12,571 (94.8%)	1,147 (9.4%)	<0.0001
Others	114 (0.9%)	25 (0.2%)	<0.0001
Loading of P2Y12 receptor blocker	7,121 (54%)	2,213 (18%)	<0.0001
Aspirin	13,110 (98.9%)	11,987 (98.6%)	0.03
Aspirin dose
Low dose ≤100 mg/day	12,918 (98.5%)	8,637 (72.1%)	<0.0001
High dose ≥162 mg/day	180 (1.4%)	3,297 (27.5%)
Unknown	12 (0.1%)	53 (0.4%)
Cilostazol	357 (2.7%)	2,427 (20%)	<0.0001
Other medications
Statins	10,268 (77%)	6,303 (52%)	<0.0001
High-intensity statins‡	210 (1.6%)	173 (1.4%)	0.29
β-blockers	5,204 (39%)	3,726 (31%)	<0.0001
ACE-I/ARB	8,527 (64%)	7,099 (58%)	<0.0001
Nitrates	2,563 (19%)	4,356 (36%)	<0.0001
Calcium-channel blockers	5,220 (39%)	4,837 (40%)	0.51
Nicorandil	2,220 (17%)	2,847 (23%)	<0.0001
Oral anticoagulants	1,404 (11%)	991 (8.2%)	<0.0001
Warfarin	1,223 (9.2%)	991 (8.2%)	0.002
DOAC	183 (1.4%)	0 (0%)	<0.0001
PPI/H2-blockers	10,234 (77%)	6,227 (51%)	<0.0001
PPI	8,648 (65%)	3,164 (26%)	<0.0001
H2-blockers	1,659 (13%)	3,087 (25%)	<0.0001

Continuous variables expressed as mean±standard deviation, or median (interquartile range). Categorical variables expressed as number (percentage). *Risk-adjusting variables for the Cox proportional hazard models (model 1). ^‡High-intensity statin therapy defined as statin dose ≥ atorvastatin 20 mg, pitavastatin 4 mg, or rosuvastatin 10 mg.²⁷ ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; ARC-HBR, the Academic Research Consortium for high bleeding risk; BMI, body mass index; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CTO, chronic total occlusion; DES, drug-eluting stents; DOAC, direct oral anticoagulants; eGFR, estimated glomerular filtration rate; Hb, hemoglobin; 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-segment elevation myocardial infarction; OCT, optical coherence tomography; PPI, proton pump inhibitors; STEMI, ST-segment elevation myocardial infarction; UA, unstable angina.

To account for possible causes of differences in bleeding risk between Cohort-2 and Cohort-3, we constructed additional multivariable models for the primary bleeding outcome measure as an exploratory analysis incorporating 9 factors related to management and potentially related to the bleeding events such as transradial approach, bare-metal stent (BMS) use, aspirin dose (dummy code variables including high dose ≥162 mg/day and unknown dose with low dose ≤100 mg/day or initial aspirin-free as the reference), loading of P2Y₁₂ receptor blocker, oral anticoagulant use, cilostazol use, proton pump inhibitor (PPI)/H₂-blocker use, surgery during follow-up, and DAPT discontinuation during follow-up, together with the 17 demographic factors mentioned before, throughout the 3-year study period, within 30 days and beyond 30 days (model 2). In the multivariate models, we included surgery during follow-up and DAPT discontinuation during follow-up as the time-updated covariates. We did not include the type of P2Y₁₂ receptor blocker (ticlopidine or clopidogrel) in the multivariable models, because ticlopidine and clopidogrel were representative of Cohort-2 and Cohort-3, respectively. Therefore, we performed a sensitivity analysis including only those patients who used ticlopidine in Cohort-2, and who used clopidogrel in Cohort-3 after coronary stent implantation (Figure 1).

Statistical analyses were conducted by physicians (M. Natsuaki, and K. Yamamoto) and a statistician (T. Morimoto) with the use of JMP 15.0, SAS 9.2 (SAS Institute Inc., Cary, NC, USA) and EZR (Saitama Medical Center, Jichi Medical University, Saitama, Japan). All statistical analyses were 2-tailed. P values <0.05 were considered statistically significant.

Results

Baseline Characteristics

Patients in Cohort-3 as compared with those in Cohort-2 were older and more often had heart failure, prior stroke, peripheral vascular disease, chronic kidney disease, atrial fibrillation, anemia, thrombocytopenia, malignancy, and Academic Research Consortium-high bleeding risk (ARC-HBR) and less often were current smoking (Table 1). Regarding the procedural characteristics, the proximal left anterior descending artery, left main coronary artery, and bifurcation lesion were more often treated in Cohort-3 than in Cohort-2, while chronic total occlusion was less frequently treated in Cohort-3 than in Cohort-2. Prevalence of DES use was much higher in Cohort-3 than in Cohort-2, with new-generation DES use in the majority of DES cases in Cohort-3. Minimum stent size was significantly smaller in Cohort-3 than in Cohort-2. The transradial approach was more often used in Cohort-3 than in Cohort-2 (Table 1).

In terms of baseline medications, patients in Cohort-3 more often took P2Y₁₂ receptor blockers, statins, β-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, oral anticoagulants, and PPI than those in Cohort-2, but less often took cilostazol, nitrates and nicorandil than those in Cohort-2. The doses of aspirin were ≤100 mg/day and ≥162 mg/day in 72.1% and 27.5% of patients, respectively in Cohort-2, and 98.5% and 1.4% of patients, respectively in Cohort-3. Regarding the types of P2Y₁₂ receptor blocker, ticlopidine was used in 87.7% of patients in Cohort-2, and clopidogrel was used in 94.8% of patients in Cohort-3 (Table 1).

Long-Term Clinical Outcomes

Cumulative incidence of persistent discontinuation of DAPT was lower in Cohort-3 than in Cohort-2 at 1 year (32.6% and 51.6%), but was similar at 3 years (63.6% and 62.8%) (Figure 2). At the time of persistent DAPT discontinuation, P2Y₁₂ receptor blocker was discontinued in 95% of patients in Cohort-2 and 86% of patients in Cohort-3, while aspirin was discontinued in 13% of patients in Cohort-2 and 19% of patients in Cohort-3. Among 5,691 patients who had persistent discontinuation of ticlopidine in Cohort-2, 880 (15.5%) discontinued ticlopidine due to side effects, and ticlopidine was switched to clopidogrel in 256 patients (4.5%). In cohort-3, clopidogrel was not switched to ticlopidine in any patient. Cumulative 3-year incidence of surgery was significantly higher in Cohort-3 than in Cohort-2 (26.8% and 23.9%) (Supplementary Figure 1).

Figure 2.

Kaplan-Meier curves for persistent discontinuation of dual antiplatelet therapy (DAPT). PCI, percutaneous coronary intervention.

Cumulative 3-year incidences of the primary bleeding outcome measure and GUSTO severe bleeding were significantly higher in Cohort-3 than in Cohort-2 (12.1% and 9.0%, P<0.0001, and 5.4% and 3.5%, P<0.0001, respectively) (Figure 3A, Table 2). Even after adjusting the demographic factors, the excess risk of Cohort-3 relative to Cohort-2 remained significant for the primary bleeding outcome measure as well as for GUSTO severe bleeding (HR: 1.26, 95% CI: 1.16–1.36, P<0.0001, and HR: 1.42, 95% CI: 1.26–1.61, P<0.0001, respectively) (Table 2).

Figure 3.

Kaplan-Meier curves for the primary outcome measures. (A) Primary bleeding outcome measure, and (B) primary ischemic outcome measure. The primary bleeding outcome measure was major bleeding defined as GUSTO moderate/severe bleeding, and the primary ischemic outcome measure was a composite of myocardial infarction (MI) or ischemic stroke. MI was adjudicated according to the ARTS definition, in which only Q-wave MI was regarded as MI when it occurred within 7 days of the index procedure. Stroke was defined as ischemic or hemorrhagic stroke with neurological symptoms lasting >24 h. ARTS, Arterial Revascularization Therapy Study; GUSTO, global utilization of streptokinase and tissue plasminogen activator for occluded coronary arteries; PCI, percutaneous coronary intervention.

Table 2. Clinical Outcomes Through 3 Years

	Cohort-3 (n=13,258)	Cohort-2 (n=12,161)	Crude HR (95% CI)	P value	Adjusted HR (95% CI)	P value
	N of patients with event (cumulative 3-year incidence)
GUSTO moderate/severe bleeding	1,538 (12.1%)	1,054 (9.0%)	1.37 (1.26–1.48)	<0.0001	1.26 (1.16–1.36)	<0.0001
Gastrointestinal bleeding	448 (3.8%)	292 (2.6%)	1.44 (1.24–1.67)	<0.0001	1.32 (1.13–1.53)	0.0003
Access site bleeding	236 (1.8%)	155 (1.3%)	1.41 (1.15–1.72)	0.0009	1.33 (1.09–1.64)	0.006
Intracranial bleeding	195 (1.7%)	142 (1.3%)	1.3 (1.04–1.61)	0.02	1.21 (0.98–1.51)	0.08
Others	659 (5.4%)	465 (4.1%)	1.33 (1.18–1.49)	<0.0001	1.21 (1.07–1.36)	0.002
GUSTO severe bleeding	672 (5.4%)	404 (3.5%)	1.55 (1.37–1.75)	<0.0001	1.42 (1.26–1.61)	<0.0001
Hemorrhagic stroke	130 (1.1%)	112 (1.0%)	1.08 (0.84–1.39)	0.56	1.0 (0.77–1.29)	0.98
MI/ischemic stroke	862 (7.0%)	789 (6.9%)	1.01 (0.92–1.12)	0.8	0.96 (0.87–1.06)	0.44
MI	470 (3.8%)	391 (3.4%)	1.11 (0.97–1.27)	0.11	1.09 (0.95–1.25)	0.21
Ischemic stroke	414 (3.4%)	414 (3.7%)	0.93 (0.81–1.06)	0.27	0.85 (0.74–0.97)	0.02
All-cause death	1,486 (11.5%)	1,339 (11.2%)	1.03 (0.96–1.11)	0.43	0.89 (0.82–0.95)	0.001
Cardiovascular death	893 (7.0%)	843 (7.1%)	0.98 (0.89–1.08)	0.69	0.86 (0.78–0.94)	0.002
Cardiac death	782 (6.1%)	735 (6.2%)	0.98 (0.89–1.09)	0.76	0.87 (0.79–0.96)	0.007
Non-cardiovascular death	593 (4.9%)	496 (4.4%)	1.11 (0.99–1.25)	0.08	0.93 (0.83–1.05)	0.27
Non-cardiac death	704 (5.8%)	604 (5.3%)	1.09 (0.97–1.21)	0.14	0.91 (0.81–1.01)	0.08
Definite stent thrombosis	84 (0.66%)	144 (1.24%)	0.54 (0.41–0.7)	<0.0001	0.54 (0.42–0.71)	<0.0001
Hospitalization for heart failure	778 (6.4%)	679 (6.0%)	1.06 (0.96–1.18)	0.24	0.93 (0.84–1.03)	0.16
Target vessel revascularization	2,021 (16.4%)	2,736 (23.9%)	0.65 (0.61–0.68)	<0.0001	0.65 (0.61–0.68)	<0.0001
Any coronary revascularization	2,931 (23.8%)	3,523 (30.8%)	0.72 (0.69–0.76)	<0.0001	0.73 (0.69–0.76)	<0.0001

Cumulative 3-year incidences estimated by the Kaplan-Meier method. HRs with 95% CIs of the Cohort-3 relative to Cohort-2 for the outcome measures estimated by the Cox proportional hazard models. CI, confidence interval; GUSTO, Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries; HR, hazard ratio; MI, myocardial infarction.

Cumulative 3-year incidence of the primary ischemic outcome measure was similar between Cohort-3 and Cohort-2 (7.0% and 6.9%, P=0.8) (Figure 3B). Even after adjusting the demographic factors, the risk of Cohort-3 relative to Cohort-2 remained insignificant for the primary ischemic outcome measure (HR: 0.96, 95% CI: 0.87–1.06, P=0.44) (Table 2). Nevertheless, the lower risk of Cohort-3 relative to Cohort-2 was significant for ischemic stroke, but was not significant for MI (Table 2).

Cumulative 3-year incidence of all-cause death was not significantly different between the 2 cohorts (Supplementary Figure 2). However, after adjusting the demographic factors, the lower mortality risk of Cohort-3 relative to Cohort-2 turned out to be significant (Table 2). Cohort-3 as compared with Cohort-2 was associated with significantly lower unadjusted and adjusted risk for definite ST, TVR, and any coronary revascularization (Supplementary Figure 2, Table 2).

Landmark Analysis Within and Beyond 30 Days

In the 30-day landmark analysis, cumulative incidence of the primary bleeding outcome measure was significantly higher in Cohort-3 than in Cohort-2 both at 30 days (4.6% and 3.6%, P<0.0001), and beyond 30 days (7.9% and 5.6%, P<0.0001) (Figure 4A, Table 3). Even after adjusting the demographic factors, the excess risk of Cohort-3 relative to Cohort-2 remained significant for the primary bleeding outcome measure both at 30 days and beyond 30 days. The excess adjusted risk of Cohort-3 relative to Cohort-2 was significant for access site bleeding at 30 days, while the excess adjusted risk of Cohort-3 relative to Cohort-2 was significant for gastrointestinal bleeding beyond 30 days (Table 3).

Figure 4.

Kaplan-Meier curves for the landmark analysis within and beyond 30-day. (A) Primary bleeding outcome measure, and (B) primary ischemic outcome measure. The primary bleeding outcome measure was major bleeding defined as GUSTO moderate/severe bleeding, while the primary ischemic outcome measure was a composite of myocardial infarction (MI) or ischemic stroke. MI was adjudicated according to the ARTS definition, in which only Q-wave MI was regarded as MI when it occurred within 7 days of the index procedure. Stroke was defined as ischemic or hemorrhagic stroke with neurological symptoms lasting >24 h. ARTS, Arterial Revascularization Therapy Study; GUSTO, global utilization of streptokinase and tissue plasminogen activator for occluded coronary arteries; PCI, percutaneous coronary intervention.

Table 3. Clinical Outcomes Within and Beyond 30 Days

	Cohort-3 (n=13,258)	Cohort-2 (n=12,161)	Crude HR (95% CI)	P value	Adjusted HR (95% CI)	P value
	N of patients with event (cumulative incidence)
(A) Within 30 days	(n=13,258)	(n=12,161)
GUSTO moderate/severe bleeding	609 (4.6%)	436 (3.6%)	1.29 (1.14–1.46)	<0.0001	1.21 (1.07–1.37)	0.002
Gastrointestinal bleeding	119 (0.9%)	99 (0.8%)	1.11 (0.85–1.45)	0.44	1.02 (0.78–1.36)	0.88
Access site bleeding	205 (1.6%)	136 (1.1%)	1.39 (1.12–1.73)	0.003	1.31 (1.05–1.63)	0.02
Intracranial bleeding	27 (0.2%)	21 (0.2%)	1.19 (0.67–2.1)	0.55	1.05 (0.59–1.87)	0.87
Others	258 (2.0%)	180 (1.5%)	1.32 (1.1–1.6)	0.004	1.27 (1.05–1.53)	0.02
GUSTO severe bleeding	232 (1.8%)	169 (1.4%)	1.26 (1.04–1.54)	0.02	1.18 (0.97–1.44)	0.11
Hemorrhagic stroke	16 (0.1%)	13 (0.1%)	1.13 (0.54–2.35)	0.74	1.07 (0.51–2.23)	0.86
MI/ischemic stroke	283 (2.2%)	225 (1.9%)	1.16 (0.97–1.38)	0.1	1.13 (0.95–1.35)	0.17
MI	176 (1.3%)	134 (1.1%)	1.21 (0.96–1.51)	0.1	1.2 (0.96–1.51)	0.11
Ischemic stroke	110 (0.8%)	95 (0.8%)	1.06 (0.81–1.4)	0.66	1.02 (0.77–1.34)	0.89
All-cause death	319 (2.4%)	276 (2.3%)	1.06 (0.9–1.25)	0.46	0.99 (0.84–1.16)	0.89
Cardiovascular death	310 (2.3%)	270 (2.2%)	1.06 (0.9–1.24)	0.52	0.99 (0.84–1.16)	0.88
Cardiac death	309 (2.3%)	267 (2.2%)	1.06 (0.9–1.25)	0.46	1.0 (0.85–1.18)	0.97
Non-cardiovascular death	9 (0.07%)	6 (0.05%)	1.38 (0.49–3.88)	0.54	1.06 (0.37–3.02)	0.92
Non-cardiac death	10 (0.08%)	9 (0.08%)	1.02 (0.42–2.52)	0.96	0.76 (0.3–1.91)	0.56
Definite stent thrombosis	56 (0.4%)	70 (0.6%)	0.73 (0.52–1.04)	0.08	0.74 (0.52–1.06)	0.1
Hospitalization for heart failure	69 (0.5%)	44 (0.4%)	1.44 (0.99–2.11)	0.053	1.26 (0.86–1.84)	0.24
Target vessel revascularization	231 (1.8%)	294 (2.5%)	0.72 (0.61–0.86)	0.0002	0.73 (0.61–0.86)	0.0003
Any coronary revascularization	281 (2.2%)	355 (3.0%)	0.72 (0.62–0.85)	<0.0001	0.73 (0.62–0.86)	<0.0001
(B) Beyond 30 days and up to 3 years
GUSTO moderate/severe bleeding	929/12,382 (7.9%)	618/11,499 (5.6%)	1.42 (1.28–1.57)	<0.0001	1.3 (1.17–1.44)	<0.0001
Gastrointestinal bleeding	329/12,382 (2.9%)	193/11,499 (1.8%)	1.61 (1.35–1.92)	<0.0001	1.48 (1.23–1.77)	<0.0001
Access site bleeding	31/12,382 (0.3%)	19/11,499 (0.2%)	1.54 (0.87–2.72)	0.14	1.51 (0.85–2.68)	0.16
Intracranial bleeding	168/12,382 (1.5%)	121/11,499 (1.1%)	1.32 (1.04–1.66)	0.02	1.24 (0.98–1.57)	0.07
Others	401/12,382 (3.5%)	285/11,499 (2.6%)	1.33 (1.14–1.54)	0.0003	1.18 (1.02–1.38)	0.03
GUSTO severe bleeding	440/12,698 (3.7%)	235/11,719 (2.1%)	1.76 (1.5–2.06)	<0.0001	1.61 (1.37–1.89)	<0.0001
Hemorrhagic stroke	114/12,845 (1.0%)	99/11,828 (0.9%)	1.07 (0.82–1.4)	0.62	0.99 (0.76–1.3)	0.97
MI/ischemic stroke	579/12,602 (4.9%)	564/11,633 (5.1%)	0.95 (0.85–1.07)	0.44	0.9 (0.8–1.01)	0.07
MI	295/12,701 (2.5%)	258/11,717 (2.3%)	1.06 (0.9–1.26)	0.46	1.03 (0.87–1.22)	0.7
Ischemic stroke	304/12,759 (2.6%)	319/11,754 (2.9%)	0.88 (0.76–1.03)	0.12	0.8 (0.68–0.94)	0.006
All-cause death	1,167/12,854 (9.3%)	1,063/11,840 (9.1%)	1.02 (0.94–1.11)	0.62	0.86 (0.79–0.93)	0.0004
Cardiovascular death	583/12,854 (4.7%)	573/11,840 (5.0%)	0.95 (0.84–1.06)	0.34	0.8 (0.71–0.9)	0.0001
Cardiac death	473/12,854 (3.9%)	468/11,840 (4.1%)	0.94 (0.83–1.07)	0.33	0.8 (0.7–0.91)	0.0006
Non-cardiovascular death	584/12,854 (4.8%)	490/11,840 (4.3%)	1.11 (0.98–1.25)	0.09	0.93 (0.83–1.05)	0.26
Non-cardiac death	694/12,854 (5.7%)	595/11,840 (5.3%)	1.09 (0.97–1.21)	0.14	0.91 (0.81–1.01)	0.09
Definite stent thrombosis	28/12,804 (0.2%)	74/11,770 (0.7%)	0.35 (0.23–0.54)	<0.0001	0.36 (0.23–0.55)	<0.0001
Hospitalization for heart failure	709/12,788 (5.6%)	635/11,794 (5.6%)	1.04 (0.93–1.15)	0.51	0.9 (0.81–1.01)	0.07
Target vessel revascularization	1,790/12,637 (14.9%)	2,442/11,553 (22.0%)	0.64 (0.6–0.68)	<0.0001	0.64 (0.6–0.68)	<0.0001
Any coronary revascularization	2,650/12,593 (22.2%)	3,168/11,499 (28.7%)	0.72 (0.69–0.76)	<0.0001	0.73 (0.69–0.76)	<0.0001

Cumulative incidences estimated by the Kaplan-Meier method. Those patients with individual endpoint events before 30 days excluded in the landmark analysis beyond 30 days. HRs with 95% CIs of Cohort-3 relative to Cohort-2 for the outcome measures estimated by Cox proportional hazard models. Abbreviations as in Table 2.

Cumulative incidence of the primary ischemic outcome measure was similar between the 2 cohorts both at 30 days (2.2% and 1.9%, P=0.1), and beyond 30 days (4.9% and 5.1%, P=0.44) (Figure 4B, Table 3). Even after adjusting the demographic factors, the risk of Cohort-3 relative to Cohort-2 remained insignificant for the primary ischemic outcome measure both at 30 days and beyond 30 days (Table 3).

Exploratory Analysis for the Primary Bleeding Outcome Measure and Sensitivity Analysis

In the exploratory analysis with further adjustment for the 9 factors related to the management and potentially related to the bleeding events, the excess risk of Cohort-3 relative to Cohort-2 remained highly significant for the primary bleeding outcome measure throughout the entire 3-year follow-up (HR: 1.52, 95% CI: 1.37–1.68, P<0.0001), at 30 days (HR: 1.62, 95% CI: 1.37–1.9, P<0.0001), and beyond 30 days (HR: 1.43, 95% CI: 1.25–1.63, P<0.0001).

In the sensitivity analysis including only those patients with coronary stent implantation who used ticlopidine in Cohort-2, and who used clopidogrel in Cohort-3, the results were fully consistent with those in the main analysis. Clopidogrel users in Cohort-3 as compared with ticlopidine users in Cohort-2 were associated with significantly higher risk for the primary bleeding outcome measure both in multivariable model 1 (HR: 1.27, 95% CI: 1.16–1.38, P<0.0001), and model 2 (HR: 1.54, 95% CI: 1.37–1.74, P<0.0001) (Supplementary Table).

Primary Outcome Measures in Patients With or Without HBR

Cumulative 3-year incidences of the primary bleeding outcome measure were significantly higher in Cohort-3 than in Cohort-2 in patients with and without ARC-HBR (Supplementary Figure 3).

Cumulative 3-year incidences of the primary ischemic outcome measure were similar between Cohort-3 and Cohort-2 in patients with and without ARC-HBR (Supplementary Figure 4).

Discussion

The main findings of this study were the following. (1) Patients in Cohort-3 enrolled in 2011–2013 compared with those in Cohort-2 enrolled in 2005–2007 were older and more often had comorbidities with higher prevalence of ARC-HBR; (2) Cohort-3 compared with Cohort-2 was associated with higher early and long-term bleeding risk even after adjusting the demographic factors and those factors related to the management and potentially related to the bleeding events, which might be at least partly explained by the difference in the type of P2Y₁₂ receptor blockers (a global dose of clopidogrel in Cohort-3 and a reduced dose of ticlopidine in Cohort-2); (3) Cohort-3 compared with Cohort-2 was associated with significantly lower risk for death, ischemic stroke, definite ST, TVR, and any coronary revascularization, but not for the primary ischemic outcome measure (a composite of MI or ischemic stroke) and MI.

Regarding the cardiovascular outcomes, Cohort-3 compared with Cohort-2 was associated with significantly lower risk for death, ischemic stroke, definite ST, TVR, and any coronary revascularization. BMS and/or 1st-generation DES were used in Cohort-2 as coronary stents, while approximately 80% of patients were treated with new-generation DES in Cohort-3. In line with previous reports, more widespread use of DES, and the introduction of new-generation DES have been major drivers for the reduction of definite ST, TVR, and any coronary revascularization.^1,2 Higher prevalence of guideline-directed medical therapy in Cohort-3 than in Cohort-2 might have been one of the major drivers for the reduction of death and ischemic stroke, although we could not specify all the factors potentially related to improvement in these cardiovascular outcomes. Overall, we have been moving in the right direction in terms of reduction in cardiovascular events.

However, in the present study, we found more frequent occurrence of major bleeding in Cohort-3 than in Cohort-2. Both the present study and previous studies clearly demonstrated that patients undergoing PCI have become older, and have had more comorbidities over time, leading to a higher prevalence of patients with HBR.^16,17 Nevertheless, a few previous studies evaluating the temporal trend of PCI outcomes have suggested a reduction in procedural bleeding over time, which might be largely explained by the more prevalent use of transradial approach and PPI, and less prevalent use of glycoprotein IIb/IIIa inhibitors.^3,18,19 However, there was a scarcity of previous studies evaluating the changes in the long-term risk of bleeding events associated with adoption of more intensive antithrombotic strategy in the real world. In the present study, major bleeding occurred more frequently in Cohort-3 than in Cohort-2, which could be related to the higher prevalence of HBR in Cohort-3 than in Cohort-2. However, the higher bleeding risk in Cohort-3 relative to Cohort-2 remained significant even after adjusting the demographic factors related to HBR. Regarding the treatment strategy, the prevalence of transradial approach, low-dose aspirin use, PPI use, cilostazol use, and surgery during follow-up was higher in Cohort-3 than in Cohort-2, while the prevalence of DES use, and oral anticoagulants use was higher and DAPT duration was longer in Cohort-3 than in Cohort-2. However, the higher bleeding risk in Cohort-3 relative to Cohort-2 remained significant even after adjusting these 9 factors related to the management and potentially related to the bleeding events. One of the biggest differences in antithrombotic therapy between Cohort-2 and Cohort-3 was the type of P2Y₁₂ receptor blocker (global dose of clopidogrel in Cohort-3 and reduced dose of ticlopidine in Cohort-2). Therefore, we might argue that one of the reasons for the higher bleeding risk in Cohort-3 than in Cohort-2 was the use of more intensive antiplatelet therapy with global dose of clopidogrel in Cohort-3 as compared with reduced dose of ticlopidine in Cohort-2. Indeed, in the sensitivity analysis, clopidogrel users in Cohort-3 as compared with ticlopidine users in Cohort-2 were associated with significantly higher risk for the primary bleeding outcome measure. The global dose of P2Y₁₂ inhibitor might need to be adjusted for Japanese, such as ticlopidine or prasugrel.

There is accumulating evidence suggesting less intensive antithrombotic therapy might be better than more intensive antithrombotic therapy in real-world populations with a high prevalence of HBR. In the past decade, more potent antiplatelet agents such as ticagrelor and prasugrel, and longer DAPT duration have been adopted mainly in patients with acute coronary syndrome (ACS).^4,20 However, a recent observational study did not observe the apparent benefit of ticagrelor over clopidogrel, but ticagrelor compared with clopidogrel was associated with higher risk for non-CABG-related bleeding in the broader population encountered in clinical practice.⁷ Moreover, 2 randomized trials comparing ticagrelor with clopidogrel in ACS patients conducted in East Asia consistently demonstrated significantly higher rates of major bleeding events and numerically higher rates of cardiovascular events in the ticagrelor group than in the clopidogrel group.^21,22 Moreover, recent clinical trials exploring very short DAPT have consistently demonstrated significant reduction in major bleeding events without an increase in cardiovascular events with 1- to 3-month DAPT followed by monotherapy with P2Y₁₂ receptor blockers.^23–26 In the present study, use of less intensive antithrombotic therapy with a reduced dose of ticlopidine in Cohort-2 compared with the global dose of clopidogrel in Cohort-3 was associated with a significantly lower risk for bleeding events without apparent increase in the risk for ischemic events. The present study suggests that the sweet spot in the balance between bleeding and cardiovascular events in Japan might be in the direction of less intensive antithrombotic therapy. Further studies are warranted to define less intensive and optimal antithrombotic strategies after PCI. We have launched the STOPDAPT-3 (ShorT and OPtimal duration of Dual AntiPlatelet Therapy-3) trial to explore the role of completely aspirin-free strategy after PCI (ClinicalTrials.gov: NCT04609111).

Study Limitations

Some limitations to our study should be considered. First, this study was an observational study with historical comparison. Despite extensive statistical adjustment with clinically relevant factors, there could be residual unmeasured confounders. We adjusted 9 factors potentially related to bleeding events. Nevertheless, we cannot deny the presence of other factors leading to increased bleeding in Cohort-3 than in Cohort-2. Furthermore, historical comparison could result in systematic differences in the selection of patients and acquisition of outcome data, although we were careful in using data only from those centers that participated in both Cohort-2 and Cohort-3, standardizing the follow-up duration at 3 years, and adopting identical methodology for baseline and follow-up data collection, and for definitions of baseline characteristics and clinical outcome measures in Cohort-2 and Cohort-3. Actually, we cannot deny the possibility of ascertainment bias for major bleeding, although we adopted the identical definition of bleeding in both Cohort-2 and Cohort-3. It could be possible that more major bleeding events were recorded in the hospital charts due to the growing interest in bleeding events in the later time period. Moreover, there might be another ascertainment bias for MI during follow-up. Less widespread use of troponin measurement for the diagnosis of MI in Cohort-2 compared with Cohort-3 might have underestimated the incidence of MI during follow-up in Cohort-2. Second, we did not adjust the factors related to the management and potentially related to ischemic events such as new-generation DES use or statin use in comparing the primary ischemic outcome measure between the 2 Cohort-2 and Cohort-3. Therefore, we could not assess the influence of the 2 types of P2Y₁₂ receptor blockers on the risk of ischemic events. Finally, information on the antiplatelet activity was not available in this study which could be related to the effects of clopidogrel on clinical outcomes.

Conclusions

In this historical comparison study, Cohort-3 compared with Cohort-2 was associated with excess bleeding risk, which might be at least partly explained by the difference in the type of P2Y₁₂ receptor blockers.

Acknowledgment

We 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

T.K. is a member of Circulation Journal’s Editorial Team.

IRB Information

The research protocols of the CREDO-Kyoto Cohort-2 and Cohort-3 were approved by the Institutional Review Board, Kyoto University (E42 and 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-21-0526

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