Abstract
Aims: Bleeding complications are often observed in patients with ST-segment elevation myocardial infarction (STEMI). Although the Japanese version of the high bleeding risk criteria (J-HBR) were established, it has not been sufficiently validated in patients with STEMI. This retrospective study aims to examine whether J-HBR is associated with cardiovascular and bleeding events in patients with STEMI.
Methods: We included 897 patients with STEMI and divided them into the J-HBR group (n=567) and the non-J-HBR group (n=330). The primary endpoint was the major adverse cardiovascular events (MACE), defined as the composite of all-cause death, non-fatal myocardial infarction, ischemic stroke, and systemic embolism. Another primary endpoint was total bleeding events defined as type 3 or 5 bleeding events as defined by the Bleeding Academic Research Consortium .
Results: During the median follow-up duration of 573 days, 187 MACE and 141 total bleeding events were observed. The Kaplan–Meier curves showed that MACE and total bleeding events were more frequently observed in the J-HBR group than in the non-J-HBR group (p＜0.001). Multivariate Cox hazard analysis revealed that after controlling for multiple confounding factors, the J-HBR group was significantly associated with MACE (hazard ratio [HR] 4.676, 95% confidence interval (CI) 2.936–7.448, p＜0.001) and total bleeding events (HR 6.325, 95% CI 3.376–11.851, p＜0.001).
Conclusions: J-HBR is significantly associated with MACE and total bleeding events in patients with STEMI. This study validated J-HBR as a risk marker for bleeding events and suggests J-HBR as a potential risk marker for MACE in patients with STEMI.
Introduction
Percutaneous coronary intervention (PCI) is a standard treatment for acute myocardial infarction (AMI), especially in patients with ST-segment elevation myocardial infarction (STEMI)1, 2). Several clinical trials have shown that the combination of aspirin and P2Y12 inhibitors such as clopidogrel was effective in preventing stent thrombosis3, 4). Since then, dual antiplatelet therapy (DAPT) has become the standard regimen after stent implantation5, 6). On the other hand, bleeding complications are often observed after PCI especially in the perioperative period of primary PCI since primary PCI requires not only DAPT but also anticoagulants such as heparin7). Furthermore, primary PCI may need mechanical circulatory support, requiring continuous anticoagulation8). The Academic Research Consortium for High Bleeding Risk (ARC-HBR) have defined the international criteria for patients with HBR who undergo PCI, which have been validated by various studies9, 10). Because the bleeding and the thrombotic risks are different between the Japanese population and the Western population11, 12), the Japanese Circulation Society issued the Japanese version of the HBR (J-HBR) criteria in 2020 13). There are several validation studies regarding J-HBR14-18). However, J-HBR has not been sufficiently studied in patients with STEMI who undergo primary PCI, in whom HBR is the most problematic. The purpose of this study is to examine whether J-HBR was associated with cardiovascular and bleeding events in patients with STEMI.
Methods
All patients with AMI treated at our institution (Saitama Medical Center, Jichi Medical University) between January 2015 and December 2021 were reviewed, with the inclusion criterion being those with AMI. The exclusion criteria were (1) patients with non-ST elevation myocardial infarction, (2) patients who did not undergo PCI to the culprit lesion, (3) patients who did not undergo PCI in our hospital, (4) the same patient with multiple occurrences during the study period, and (5) patients whose information regarding medication before admission were not available.
The J-HBR is composed of 14 major and 6 minor criteria13). Patients who had at least one major or two minor criteria were defined as J-HBR13). In this study, some J-HBR criteria were modified, as shown in Supplemental Table 1. The final study population was divided into the J-HBR group and the non-J-HBR group according to the presence of J-HBR. The primary endpoint was major cardiovascular events (MACE), defined as the composite of all-cause death, non-fatal myocardial infarction, ischemic stroke, and systemic embolism. Another primary endpoint was total bleeding events, defined as type 3 or 5 bleeding events by the Bleeding Academic Research Consortium19). Information regarding the above clinical outcomes were acquired from hospital records. The day of admission was defined as the index day (day 1). The patients were followed up until meeting MACE, total bleeding events, or the study end date (December 31, 2022). We calculated the PREdicting bleeding Complications In patients undergoing stent implantation and subsEquent Dual Anti Platelet Therapy (PRECISE-DAPT) score and the Pattern of non-Adherence to Antiplatelet Regimen in Stented Patients (PARIS) risk score as bleeding risk scores, and the Global Registry of Acute Coronary Events (GRACE) and the Age, Glomerular filtration rate, Ejection Fraction (AGEF) scores as ischemic risk scores13, 20-22). The independent variables are female sex23), number of narrowed coronary arteries24), infarct-related artery25), final thrombolysis in myocardial infarction (TIMI) flow grade26), chronic total occlusion (CTO) in non-culprit arteries27), approach site28), and J-HBR. This study was approved by the institutional review board of the Saitama Medical Center, Jichi Medical University (S22-161), and written informed consent was waived because of the retrospective study design. The data collection and storage were performed anonymously following the Japan Ministry of Health, Labor, and Welfare guidelines.
Supplemental Table 1.High bleeding risk definition
| J-HBR criteria |
Criteria in the present study |
Category |
Comments |
| Age ≥ 75 years |
Age ≥ 75 years |
Minor |
Identical |
| Low body weight, Frailty |
Low body weight (＜55 kg for men and ＜50 kg for women) or frailty (Clinical Frailty Score ＞4) |
Major |
Modified |
| Severe CKD (hemodialysis) |
eGFR ＜30 mL/min/1.73m2 or on hemodialysis
|
Major |
Identical |
| Moderate CKD |
Moderate CKD (eGFR 30- ＜60 mL/min/1.73m2) |
Minor |
Modified |
| Moderate to severe anemia |
Hemoglobin ＜11 g/dL |
Major |
Identical |
| Mild anemia |
Hemoglobin 11–12.9 g/dL for men and 11–11.9 g/dL for women |
Minor |
Identical |
| Heart failure |
Heart failure |
Major |
Identical |
| Anticipated use of long-term oral anticoagulation |
oral anticoagulation use on admission |
Major |
Modified |
| Long-term use of oral NSAIDs or steroids |
NSAIDs or steroids use on admission |
Minor |
Modified |
| Peripheral vascular disease |
Peripheral artery disease (ABI ＜0.9, post endovascular therapy, or post lower extremity bypass surgery) |
Major |
Modified |
| History of non-traumatic bleeding events |
History of non-traumatic bleeding events |
Major |
Identical |
| First non-traumatic bleeding event requiring hospitalization or transfusion in the past 6-12 months |
First non-traumatic bleeding event requiring hospitalization or transfusion in the past 6-12 months |
Minor |
Identical |
| Previous spontaneous ICH (at any time); Previous traumatic ICH within the past 12 months and presence of bAVM; Moderate or severe ischemic stroke within the past 6 months |
Previous spontaneous ICH (at any time); Previous traumatic ICH within the past 12 months and presence of bAVM; Ischemic stroke of NIHSS 5 or higher within the past 6 months |
Major |
Modified |
| Any ischemic stroke at any time not meeting the major criterion |
Any ischemic stroke at any time not meeting the major criterion |
Minor |
Identical |
| Thrombocytopenia (Platelets ＜100×109/L)
|
Thrombocytopenia (Platelets ＜100×109/L)
|
Major |
Identical |
| Active malignancy diagnosed within 12 months and/ or ongoing requirement for treatment |
Active malignancy diagnosed within 12 months and/or ongoing requirement for treatment |
Major |
Identical |
| Liver cirrhosis with portal hypertension |
Liver cirrhosis |
Major |
Modified |
| Chronic Bleeding Diatheses |
Chronic Bleeding Diatheses |
Major |
Identical |
| Nondeferrable major surgery on DAPT |
Nondeferrable major surgery on DAPT |
Major |
Identical |
| Recent major surgery or major trauma within 30 days before PCI |
Recent major surgery or major trauma within 30 days before PCI |
Major |
Identical |
Abbreviations: CKD = chronic kidney disease, NSAIDs = Non-Steroidal Anti-Inflammatory Drugs, ICH = intracranial hemorrhage, bAVMs = brain Arteriovenous Malformations, DAPT = dual antiplatelet therapy.
AMI was defined according to the universal definition29, 30). Diagnostic ST elevation was defined as a new ST elevation at the J point in at least two contiguous leads of 2 mm (0.2 mV), and AMI with ST elevation was defined as STEMI31, 32). The definitions of hypertension, diabetes mellitus, and dyslipidemia were described elsewhere33, 34). We used the laboratory data at admission. Since we could not measure some laboratory data such as HbA1c or low-density lipoprotein (LDL) cholesterol levels at off hours (night or holidays), we substituted the earliest HbA1c or LDL cholesterol levels since admission for the laboratory data at admission35). Left ventricular ejection fraction (LVEF) was measured using transthoracic echocardiography during the index hospitalization. LVEF was calculated through either the modified Simpson’s method, the Teichholz method, or eyeball estimation36). A Teichholz method was adopted only when a modified Simpson’s method was not available. An eyeball estimation was adopted only when both the modified Simpson’s method and the Teichholz method were not available37). We also calculated the estimated glomerular filtration rate (eGFR) using serum creatinine (Cr) level, age, weight, and gender according to the following formula: eGFR=194×Cr−1.094×age−0.287 (male), or eGFR=194×Cr−1.094×age−0.287×0.739 (female)38). The initial and final TIMI flow grades were recorded based on the coronary angiography results27).
Statistical Analysis
Data are presented as percentages for categorical variables, mean±standard deviation (SD) for normally distributed continuous variables, and median (quartile 1–quartile 3) for nonparametric variables. Categorical variables were presented as numbers (percentages) and were compared using the Chi-square test. The Kolmogorov–Smirnov test was performed to determine whether the continuous variables were normally distributed or not. Normally distributed continuous variables were compared using a student t-test. Otherwise, continuous variables were compared using a Mann–Whitney U test. Event-free survival curves were constructed using the Kaplan−Meier method, and statistical differences between curves were assessed using the log-lank test. We also performed a multivariate Cox hazard analysis to investigate the association between J-HBR and MACE and total bleeding events after controlling for confounding factors. Because J-HBR covers most of the patient clinical characteristics such as renal function, anemia, or presence of active malignancy, we selected confounding factors from the lesion and procedural characteristics to avoid multicollinearity. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. A p-value of ＜0.05 was considered statistically significant. All analyses were performed using statistical software, SPSS 28/Windows (SPSS, Chicago Illinois).
Results
A total of 1966 patients with AMI were admitted to our medical center from January 2015 to December 2021. After excluding 1069 patients based on the exclusion criteria, the final study population consisted of 897 patients with STEMI, which were divided into the J-HBR group (n=567) and the non-J-HBR group (n=330). The study flow chart is shown in Fig.1.
Table 1 shows the comparison of the patients’ characteristics between the two groups. The male sex prevalence was significantly lower in the J-HBR group than in the non-J-HBR group. The prevalence of shock at admission was higher in the J-HBR group than in the non-J-HBR group. LVEF was higher in the non-J-HBR group than in the J-HBR group. Supplemental Table 2 shows the comparison of the J-HBR major and minor criteria between the two groups. Table 2 shows the comparison of the lesion and procedural findings between the two groups. The prevalence of triple-vessel disease and CTO in non-culprit arteries were significantly higher in the J-HBR group than in the non-J-HBR group.
Table 1.The comparison of patient clinical characteristic between J-HBR group and non-J-HBR group
|
All (n = 897)
|
J-HBR (n = 567)
|
non-J-HBR (n = 330)
|
P value
|
| Age, years |
71.0 (61.0-79.0) |
77.0 (68.0-83.0) |
62.0 (53.0-69.0) |
＜0.001 |
| Male, n (%)
|
691 (77.0) |
398 (70.2) |
293 (88.8) |
＜0.001 |
| Body weight, kg |
62.90 (54.00-72.00) (n = 895)
|
58.00 (50.00-66.60) (n = 565)
|
69.50 (62.35-77.00) |
＜0.001 |
| Body mass index (kg/m2)
|
23.56 (21.40-25.90) (n = 895)
|
22.68 (20.40-25.09) (n = 565)
|
24.77 (23.17-27.15) |
＜0.001 |
| Comorbidities |
|
|
|
|
| Hypertension, n (%)
|
676 (75.4) |
428 (75.5) |
248 (75.2) |
0.911 |
| Hyperlipidemia, n (%)
|
470 (52.4) |
280 (49.4) |
190 (57.6) |
0.018 |
| Diabetes mellitus, n (%)
|
366 (40.9) (n = 895)
|
232 (41.1) (n = 565)
|
134 (40.6) |
0.894 |
| Current smoker, n (%)
|
328 (36.7) (n = 893)
|
155 (27.4) (n = 565)
|
173 (52.7) (n = 328)
|
＜0.001 |
| Chronic renal failure on hemodialysis, n (%)
|
38 (4.2) |
38 (6.7) |
0 (0.0) |
＜0.001 |
| History of previous PCI, n (%)
|
102 (11.4) (n = 896)
|
83 (14.7) (n = 566)
|
19 (5.8) |
＜0.001 |
| History of previous CABG, n (%)
|
13 (1.4) |
10 (1.8) |
3 (0.9) |
0.302 |
| History of previous myocardial infarction, n (%)
|
79 (8.8) |
61 (10.8) |
18 (5.5) |
0.007 |
| Cardiopulmonary arrest out of hospital, n (%)
|
65 (7.2) |
55 (9.7) |
10 (3.0) |
＜0.001 |
| Shock at admission, n (%)
|
133 (14.8) |
120 (21.2) |
13 (3.9) |
＜0.001 |
| Killip class |
|
|
|
＜0.001 |
| Killip class 1 or 2, n (%)
|
689 (76.8) |
372 (65.6) |
317 (96.1) |
|
| Killip class 3, n (%)
|
77 (8.6) |
77 (13.6) |
0 (0.0) |
|
| Killip class 4, n (%)
|
131 (14.6) |
118 (20.8) |
13 (3.9) |
|
| Region of infarction |
|
|
|
0.135 |
| Anterior, n (%)
|
479 (53.4) |
310 (54.7) |
169 (51.2) |
|
| Inferior, n (%)
|
348 (38.8) |
219 (38.6) |
129 (39.1) |
|
| Posterior, n (%)
|
67 (7.5) |
35 (6.2) |
32 (9.7) |
|
| Not determined, n (%)
|
3 (0.3) |
3 (0.5) |
0 (0.0) |
|
| Vital signs at admission |
|
|
|
|
| Systolic blood pressure, mmHg |
135.7±32.7 |
130.1±34.1 |
145.2±27.6 |
＜0.001 |
| Diastolic blood pressure, mmHg |
80.0 (68.0-94.0) |
77.0 (61.0-88.0) |
87.5 (76.0-100.0) |
＜0.001 |
| Pulse rate, bpm |
80.00 (65.50-95.50) |
80.00 (63.00-99.00) |
78.00 (67.00-90.00) |
0.098 |
| Laboratory data |
|
|
|
|
| Hemoglobin levels, g/dL |
13.7 (12.2-15.0) |
12.8 (11.4-14.1) |
14.7 (13.7-15.8) |
＜0.001 |
| Platelets, ×104/uL
|
22.10 (18.35-26.60) |
21.40 (17.50-26.40) |
22.85 (19.70-26.70) |
＜0.001 |
| Serum creatinine, mg/dL |
0.85 (0.69-1.10) |
0.94 (0.73-1.31) |
0.76 (0.64-0.89) |
＜0.001 |
| eGFR, mL/min/1.73 m2
|
65.30 (47.85-81.50) |
54.60 (38.20-72.90) |
77.20 (65.65-92.25) |
＜0.001 |
| Hemoglobin A1c, % |
6.10 (5.70-7.00) (n = 862)
|
6.10 (5.70-6.80) (n = 539)
|
6.10 (5.70-7.10) (n = 323)
|
0.650 |
| C-reactive protein, mg/dL |
0.25 (0.10-1.09) |
0.30 (0.11-1.77) |
0.20 (0.09-0.51) |
＜0.001 |
| Brain natriuretic peptide, pg/ml |
113.0 (33.0-382.4) (n = 865)
|
239.8 (60.0-634.8) (n = 548)
|
41.4 (12.8-115.4) (n = 317)
|
＜0.001 |
| Peak creatine kinase, U/L |
1562.0 (593.0-3283.0) |
1441.0 (546.0-3313.0) |
1765.0 (662.3-3201.0) |
0.561 |
| Peak creatine kinase-myocardial band, U/L |
141.0 (45.5-318.0) |
131.0 (43.0-317.0) |
153.0 (49.8-324.0) |
0.463 |
| Left ventricular ejection fraction, % |
51.00 (39.90-60.40) (n = 892)
|
47.45 (35.08-58.20) (n = 562)
|
55.70 (47.58-62.93) |
＜0.001 |
| Medication at admission |
|
|
|
|
| Aspirin, n (%)
|
151 (16.8) |
118 (20.8) |
33 (10.0) |
＜0.001 |
| Thienopyridine, n (%)
|
68 (7.6) |
56 (9.9) |
12 (3.6) |
＜0.001 |
| Statin, n (%)
|
219 (24.4) |
159 (28.0) |
60 (18.2) |
＜0.001 |
| ACE inhibitors or ARBs, n (%)
|
290 (32.3) |
215 (37.9) |
75 (22.7) |
＜0.001 |
| Beta-blocker, n (%)
|
127 (14.2) |
99 (17.5) |
28 (8.5) |
＜0.001 |
| Calcium channel blocker, n (%)
|
306 (34.1) |
218 (38.4) |
88 (26.7) |
＜0.001 |
| Diuretics, n (%)
|
87 (9.7) |
77 (13.6) |
10 (3.0) |
＜0.001 |
| Oral antidiabetic, n (%)
|
214 (23.9) |
138 (24.3) |
76 (23.0) |
0.658 |
| Insulin, n (%)
|
38 (4.2) |
26 (4.6) |
12 (3.6) |
0.496 |
| Direct oral anticoagulants., n (%)
|
19 (2.1) |
19 (3.4) |
0 (0.0) |
＜0.001 |
| Warfarin, n (%)
|
16 (1.8) |
16 (2.8) |
0 (0.0) |
0.002 |
Data were expressed as mean±SD, median (Q1-Q3) or numbers (percentages). A Student’s t test was used for normally distributed continuous variables and Mann–Whitney U test was used for abnormally distributed continuous variables. A Chi-square test was used for categorical variables. Abbreviations: J-HBR = Japanese version of the high bleeding risk, PCI = percutaneous coronary intervention, CABG = coronary artery-bypass grafting, eGFR = estimated glomerular filtration rate, ACE inhibitors = angiotensin-converting enzyme inhibitor, ARBs = angiotensin receptor blockers.
Supplemental Table 2.The comparison of the J-HBR major and minor criteria between J-HBR group and non-J-HBR group
|
All
(n= 897)
|
J-HBR
(n= 567)
|
non-J-HBR
(n= 330)
|
P value
|
| Major criteria |
|
|
|
|
| Low body weight, Frailty, n (%)
|
234 (26.1) |
192 (41.3) |
0 (0.0) |
＜0.001 |
| Severe CKD (hemodialysis), n (%)
|
95 (10.6) |
95 (16.8) |
0 (0.0) |
＜0.001 |
| Moderate to severe anemia, n (%)
|
101 (11.3) |
101 (17.8) |
0 (0.0) |
＜0.001 |
| Heart failure, n (%)
|
266 (29.7) |
266 (46.9) |
0 (0.0) |
＜0.001 |
| Anticipated use of long-term oral anticoagulation, n (%)
|
35 (3.9) |
35 (6.2) |
0 (0.0) |
＜0.001 |
| Peripheral vascular disease, n (%)
|
65 (7.2) |
65 (11.5) |
0 (0.0) |
＜0.001 |
| History of non-traumatic bleeding events, n (%)
|
10 (1.1) |
10 (1.8) |
0 (0.0) |
0.015 |
| Previous Ischemic Stroke or ICH, n (%)
|
18 (2.0) |
18 (3.2) |
0 (0.0) |
0.001 |
| Thrombocytopenia, n (%)
|
17 (1.9) |
17 (3.0) |
0 (0.0) |
0.001 |
| Active malignancy, n (%)
|
29 (3.2) |
29 (5.1) |
0 (0.0) |
＜0.001 |
| Liver cirrhosis, n (%)
|
3 (0.3) |
3 (0.5) |
0 (0.0) |
0.186 |
| Chronic bleeding diathesis, n (%)
|
0 (0.0) |
0 (0.0) |
0 (0.0) |
- |
| Nondeferrable major surgery on DAPT, n (%)
|
17 (1.9) |
17 (3.0) |
0 (0.0) |
0.001 |
| Recent major surgery or major trauma within 30 days before PCI, n (%)
|
13 (1.4) |
13 (2.3) |
0 (0.0) |
0.006 |
| Minor criteria |
|
|
|
|
| Age ≥ 75 years, n (%)
|
361 (40.2) |
330 (58.2) |
31 (9.4) |
＜0.001 |
| Moderate CKD, n (%)
|
279 (31.1) |
236 (41.6) |
43 (13.0) |
＜0.001 |
| Mild anemia, n (%)
|
185 (20.6) |
169 (29.8) |
16 (4.8) |
＜0.001 |
| Long-term use of oral NSAIDs or steroids, n (%)
|
51 (5.7) |
42 (7.4) |
9 (2.7) |
0.004 |
| First non-traumatic bleeding event requiring hospitalization or transfusion in the past 6-12 months, n (%)
|
0 (0.0) |
0 (0.0) |
0 (0.0) |
- |
| Any ischemic stroke at any time not meeting the major criterion, n (%)
|
65 (7.2) |
61 (10.8) |
4 (1.2) |
＜0.001 |
Data were expressed as numbers (percentages). A Chi-square test was used for categorical variables. Abbreviations: CKD = chronic kidney disease, ICH = intracranial hemorrhage, DAPT = dual antiplatelet therapy, PCI = percutaneous coronary intervention, NSAIDs = Non-Steroidal Anti- Inflammatory Drugs.
Table 2.The comparison of lesion and procedural characteristic between J-HBR group and non-J-HBR group
|
All (n = 897)
|
J-HBR (n = 567)
|
non-J-HBR (n = 330)
|
P value
|
| Number of narrowed coronary arteries |
|
|
|
＜0.001 |
| Single, n (%)
|
435 (48.5) |
244 (43.0) |
191 (57.9) |
|
| Double, n (%)
|
285 (31.8) |
200 (35.3) |
85 (25.8) |
|
| Triple, n (%)
|
177 (19.7) |
123 (21.7) |
54 (16.4) |
|
| Infarct-related artery |
|
|
|
0.170 |
| Left main-left anterior descending artery, n (%)
|
477 (53.2) |
307 (54.1) |
170 (51.5) |
|
| Right coronary artery, n (%)
|
338 (37.7) |
215 (38.1) |
123 (37.3) |
|
| Left circumflex artery, n (%)
|
78 (8.7) |
41 (7.2) |
37 (11.2) |
|
| Bypass graft, n (%)
|
2 (0.2) |
2 (0.4) |
0 (0.0) |
|
| Not determined, n (%)
|
2 (0.2) |
2 (0.4) |
0 (0.0) |
|
| 50% ≥ stenosis at left main, n (%)
|
76 (8.5) |
60 (10.6) |
16 (4.8) |
0.003 |
| First TIMI flow grade |
|
|
|
0.120 |
| 0, n (%)
|
494 (55.1) |
300 (52.9) |
194 (58.8) |
|
| 1, n (%)
|
81 (9.0) |
57 (10.1) |
24 (7.3) |
|
| 2, n (%)
|
165 (18.4) |
114 (20.1) |
51 (15.5) |
|
| 3, n (%)
|
157 (17.5) |
96 (16.9) |
61 (18.5) |
|
| Final TIMI flow grade |
|
|
|
0.119 |
| 0, n (%)
|
5 (0.6) |
5 (0.9) |
0 (0.0) |
|
| 1, n (%)
|
10 (1.1) |
8 (1.4) |
2 (0.6) |
|
| 2, n (%)
|
43 (4.8) |
31 (5.5) |
12 (3.6) |
|
| 3, n (%)
|
839 (93.5) |
523 (92.2) |
316 (95.8) |
|
| CTO in non-culprit arteries, n (%)
|
111 (12.4) |
91 (16.0) |
20 (6.1) |
＜0.001 |
| Use of aspiration catheter, n (%)
|
188 (21.0) |
116 (20.5) |
72 (21.8) |
0.629 |
| Final PCI Procedure |
|
|
|
0.003 |
| POBA only, n (%)
|
40 (4.5) |
34 (6.0) |
6 (1.8) |
|
| Aspiration only, n (%)
|
8 (0.9) |
6 (1.1) |
2 (0.6) |
|
| Drug coated balloon, n (%)
|
19 (2.1) |
14 (2.5) |
5 (1.5) |
|
| Bare metal stent, n (%)
|
18 (2.0) |
17 (3.0) |
1 (0.3) |
|
| Drug eluting stent, n (%)
|
794 (88.5) |
485 (85.5) |
309 (93.6) |
|
| POBA and aspiration, n (%)
|
13 (1.4) |
7 (1.2) |
6 (1.8) |
|
| Other, n (%)
|
5 (0.6) |
4 (0.7) |
1 (0.3) |
|
| Approach site |
|
|
|
＜0.001 |
| Radial artery, n (%)
|
605 (67.4) |
331 (58.4) |
274 (83.0) |
|
| Brachial artery, n (%)
|
10 (1.1) |
10 (1.8) |
0 (0.0) |
|
| Femoral artery, n (%)
|
282 (31.4) |
226 (39.9) |
56 (17.0) |
|
| Guide-Catheter size (Fr) |
|
|
|
＜0.001 |
| 6Fr, n (%)
|
660 (73.6) |
382 (67.4) |
278 (84.2) |
|
| 7Fr, n (%)
|
230 (25.6) |
178 (31.4) |
52 (15.8) |
|
| 8Fr, n (%)
|
7 (0.8) |
7 (1.2) |
0 (0.0) |
|
Data were expressed as numbers (percentages). A Chi-square test was used for categorical variables. Abbreviations: J-HBR = Japanese version of the high bleeding risk, TIMI = thrombolysis in myocardial infarction, CTO = chronic total occlusion, PCI = percutaneous coronary intervention, POBA = Plain old balloon angioplasty.
Table 3 shows the comparison of in-hospital outcomes between the two groups. It was found that the incidence of in-hospital death was significantly higher in the J-HBR group than in the non-J-HBR group, and in-hospital total bleeding events were more frequently observed in the J-HBR group than in the non-J-HBR group. Table 4 shows the comparison of long-term clinical outcomes between the two groups. Fig.2 shows the Kaplan–Meier curves for MACE and total bleeding events between the two groups. The median follow-up duration was 573 days (Q1: 195 days–Q3: 1326 days). MACE and total bleeding events were more frequently observed in the J-HBR group than in the non-J-HBR group. The J-HBR, PRECISE-DAPT score, and PARIS risk score were compared between the patients with and without major bleeding events (Supplemental Table 3-1). The J-HBR, GRACE score, and AGEF score were compared between the patients with and without MACE (Supplemental Table 3-2).
Table 3.In-hospital outcomes between J-HBR group and non-J-HBR group
|
All (n= 897)
|
J-HBR (n= 567)
|
non-J-HBR (n= 330)
|
P value
|
| In-hospital death, n (%)
|
60 (6.7) |
59 (10.4) |
1 (0.3) |
＜0.001 |
| Duration of CCU stays, days |
3.0 (2.0-4.0) |
3.0 (2.0-5.0) |
2.0 (2.0-3.0) |
＜0.001 |
| Duration of hospital stays, days |
8.0 (6.0-12.0) |
9.0 (7.0-13.0) |
7.0 (5.0-9.0) |
＜0.001 |
| In-hospital total bleeding event, n (%)
|
101 (11.3) |
95 (16.8) |
6 (1.8) |
＜0.001 |
| BARC type 3 bleeding, n (%)
|
37 (4.1) |
31 (5.5) |
6 (1.8) |
0.008 |
| BARC type 3a bleeding, n (%)
|
26 (2.9) |
21 (3.7) |
5 (1.5) |
0.06 |
| BARC type 3b bleeding, n (%)
|
10 (1.1) |
9 (1.6) |
1 (0.3) |
0.077 |
| BARC type 3c bleeding, n (%)
|
1 (0.1) |
1 (0.2) |
0 (0.0) |
0.445 |
| BARC type 5 bleeding, n (%)
|
64 (7.1) |
64 (11.3) |
0 (0.0) |
＜0.001 |
| BARC type 5a bleeding, n (%)
|
54 (6.0) |
54 (9.5) |
0 (0.0) |
＜0.001 |
| BARC type 5b bleeding, n (%)
|
10 (1.1) |
10 (1.8) |
0 (0.0) |
0.015 |
| Bleeding site |
|
|
|
|
| Gastrointestinal bleeding |
9 (1.0) |
9 (1.6) |
0 (0.0) |
|
| Access site-related bleeding |
20 (2.2) |
15 (2.6) |
5 (1.5) |
|
| Intracranial bleeding |
1 (0.1) |
1 (0.1) |
0 (0.0) |
|
| Required VA-ECMO |
60 (6.7) |
60 (10.6) |
0 (0.0) |
|
| Others |
11 (1.2) |
10 (1.8) |
1 (0.3) |
|
| Mechanical complications |
11 (1.2) |
11 (1.9) |
0 (0.0) |
0.011 |
| Free wall rapture, n (%)
|
5 (0.6) |
5 (0.9) |
0 (0.0) |
|
| Ventricular septal perforation, n (%)
|
2 (0.2) |
2 (0.4) |
0 (0.0) |
|
| Papillary muscle rupture, n (%)
|
4 (0.4) |
4 (0.7) |
0 (0.0) |
|
Data were expressed as median (Q1-Q3) or numbers (percentages). A Student’s t test was used for normally distributed continuous variables and Mann–Whitney U test was used for abnormally distributed continuous variables. A Chi-square test was used for categorical variables. Abbreviations: J-HBR = Japanese version of the high bleeding risk, CCU = coronary care unit, BARC = Bleeding Academic Research Consortium, VA-ECMO = Veno-Arterial Extracorporeal Membrane Oxygenation.
Table 4.Long-term outcomes between J-HBR group and non-J-HBR group
|
All (n= 897)
|
J-HBR (n= 567)
|
non-J-HBR (n= 330)
|
P value
|
| MACE, n (%)
|
187 (20.8) |
166 (29.3) |
21 (6.4) |
＜0.001 |
| All-cause death, n (%)
|
119 (13.3) |
113 (19.9) |
6 (1.8) |
＜0.001 |
| - Cardiac death, n (%)
|
72 (8.0) |
71 (12.5) |
1 (0.3) |
|
| - Non-cardiac death, n (%)
|
30 (3.3) |
26 (4.6) |
4 (1.2) |
|
| - Unknown death, n (%)
|
17 (1.9) |
16 (2.8) |
1 (0.3) |
|
| Non-fatal myocardial infarction, n (%)
|
48 (5.4) |
38 (6.7) |
10 (3.0) |
0.018 |
| Ischemic stroke, n (%)
|
29 (3.2) |
25 (4.4) |
4 (1.2) |
0.009 |
| Systemic embolism, n (%)
|
9 (1.0) |
8 (1.4) |
1 (0.3) |
0.108 |
| 1-year MACE, n (%)＊
|
76 (12.2) |
68 (17.8) |
8 (3.3) |
＜0.001 |
|
|
|
|
|
| Total bleeding event, n (%)
|
141 (15.7) |
130 (22.9) |
11 (3.3) |
＜0.001 |
| BARC type 3 bleeding, n (%)
|
71 (7.9) |
61 (10.8) |
10 (3.0) |
＜0.001 |
| - BARC type 3a bleeding, n (%)
|
31 (3.5) |
25 (4.4) |
6 (1.8) |
0.04 |
| - BARC type 3b bleeding, n (%)
|
29 (3.2) |
27 (4.8) |
2 (0.6) |
＜0.001 |
| - BARC type 3c bleeding, n (%)
|
11 (1.2) |
9 (1.6) |
2 (0.6) |
0.198 |
| BARC type 5 bleeding, n (%)
|
70 (7.8) |
69 (12.2) |
1 (0.3) |
＜0.001 |
| - BARC type 5a bleeding, n (%)
|
58 (6.5) |
58 (6.5) |
0 (0.0) |
＜0.001 |
| - BARC type 5b bleeding, n (%)
|
12 (1.3) |
11 (1.2) |
1 (0.1) |
0.04 |
| Bleeding site |
|
|
|
|
| Gastrointestinal bleeding |
25 (2.8) |
23 (4.1) |
2 (0.6) |
|
| Access site-related bleeding |
19 (2.1) |
14 (2.5) |
5 (1.5) |
|
| Intracranial bleeding |
12 (1.3) |
9 (1.6) |
3 (0.9) |
|
| Required VA-ECMO |
66 (7.4) |
66 (11.6) |
0 (0.0) |
|
| Others |
19 (2.1) |
18 (3.2) |
1 (0.3) |
|
| 1-year total bleeding event, n (%)¶
|
114 (18.3) |
106 (27.7) |
8 (3.3) |
＜0.001 |
Data were expressed as numbers (percentages). A Chi-square test was used for categorical variables. Abbreviations: J-HBR = Japanese version of the high bleeding risk, MACE = major cardiovascular events, BARC = Bleeding Academic Research Consortium, VA-ECMO = Veno-Arterial Extracorporeal Membrane Oxygenation. ＊The follow-up period was less than 1 year in 151 patients in the J-HBR group and 88 patients in the non-J-HBR group. ¶The follow-up period was less than 1 year in 181 patients in the J-HBR group and 91 patients in the non-J-HBR group.
Supplemental Table 3-1.Comparison of J-HBR, PRECISE-DAPT score, and PARIS risk score between patients with and without major bleeding
|
All (n= 897)
|
Major bleeding (n= 141)
|
No major bleeding (n= 756)
|
P value
|
| J-HBR, n (%)
|
567 (63.2) |
130 (92.2) |
437 (57.8) |
＜0.001 |
| PRECISE-DAPT Score |
24 (14-35) (n= 895)
|
34 (26-44) (n= 139)
|
22 (13-33) |
＜0.001 |
| PARIS Risk Score for Major Bleeding Events |
6 (5-7) |
6 (5-8) |
6 (5-7) |
0.708 |
Supplemental Table 3-2.Comparison of J-HBR, GRACE score, and AGEF score between patients with and without MACE
|
All (n= 897)
|
MACE (n= 187)
|
No MACE (n= 710)
|
P value
|
| J-HBR, n (%)
|
567 (63.2) |
166 (88.8) |
401 (56.5) |
＜0.001 |
| GRACE ACS Score |
167 (140-199) |
198 (163-249) |
161 (134-188) |
＜0.001 |
| AGEF Score |
1.81 (1.20-2.54) (n= 892)
|
2.49 (1.74-3.2) (n= 183)
|
1.58 (1.14-2.38) (n= 709)
|
＜0.001 |
Data were expressed as mean±SD, median (Q1-Q3) or numbers (percentages). A Student’s t test was used for normally distributed continuous variables and Mann–Whitney U test was used for abnormally distributed continuous variables. A Chi-square test was used for categorical variables. Abbreviations: J-HBR = Japanese version of the high bleeding risk, MACE = major cardiovascular events.
The results of the multivariate Cox hazard analysis are shown in Table 5. J-HBR was significantly associated with MACE (HR 4.676, 95% CI: 2.936–7.448, p＜0.001) and total bleeding events (HR 6.325, 95% CI 3.376–11.851, p＜0.001) after controlling for multiple confounding factors including sex, number of narrowed coronary arteries, infarct-related artery, final TIMI flow grade, CTO in non-culprit arteries, and approach site.
Table 5-1.Multivariate Cox Hazard Model to Predict MACE
| Composite endpoint |
Hazard ratio |
95% Confidence Interval |
P value
|
| MACE |
|
|
|
| Non-J-HBR group |
Reference |
|
|
| Unadjusted J-HBR group |
5.553 |
3.526-8.746 |
＜0.001 |
| Sex adjusted J-HBR group |
5.636 |
3.568-8.904 |
＜0.001 |
| Adjusted J-HBR group |
4.676 |
2.936-7.448 |
＜0.001 |
| Component endpoint |
Hazard ratio |
95% Confidence Interval |
P value
|
| All cause death |
|
|
|
| Non-J-HBR group |
Reference |
|
|
| Unadjusted J-HBR group |
12.728 |
5.599-28.935 |
＜0.001 |
| Sex adjusted J-HBR group |
12.385 |
5.431-28.245 |
＜0.001 |
| Adjusted J-HBR group |
9.255 |
4.025-21.280 |
＜0.001 |
| Non-fatal myocardial infarction |
|
|
|
| Non-J-HBR group |
Reference |
|
|
| Unadjusted J-HBR group |
2.756 |
1.373-5.532 |
0.004 |
| Sex adjusted J-HBR group |
3.063 |
1.520-6.173 |
0.002 |
| Adjusted J-HBR group |
2.931 |
1.432-5.997 |
0.003 |
| Ischemic stroke |
|
|
|
| Non-J-HBR group |
Reference |
|
|
| Unadjusted J-HBR group |
4.121 |
1.434-11.847 |
0.009 |
| Sex adjusted J-HBR group |
4.224 |
1.456-12.250 |
0.008 |
| Adjusted J-HBR group |
3.395 |
1.143-10.083 |
0.028 |
| Systemic embolism |
|
|
|
| Non-J-HBR group |
Reference |
|
|
| Unadjusted J-HBR group |
4.914 |
0.614-39.313 |
0.133 |
| Sex adjusted J-HBR group |
4.650 |
0.569-37.985 |
0.151 |
| Adjusted J-HBR group |
2.066 |
0.234-18.221 |
0.514 |
Table 5-2.Multivariate Cox Hazard Model to Predict Total Bleeding Events
| Composite endpoint |
Hazard ratio |
95% Confidence Interval |
P value
|
| Total bleeding events |
|
|
|
| Non-J-HBR group |
Reference |
|
|
| Unadjusted J-HBR group |
8.008 |
4.326-14.825 |
＜0.001 |
| Sex adjusted J-HBR group |
7.961 |
4.286-14.786 |
＜0.001 |
| Adjusted J-HBR group |
6.325 |
3.376-11.851 |
＜0.001 |
| Component endpoint |
Hazard ratio |
95% Confidence Interval |
P value
|
| BARC type 3 bleeding |
|
|
|
| Non-J-HBR group |
Reference |
|
|
| Unadjusted J-HBR group |
4.405 |
2.256-8.603 |
＜0.001 |
| Sex adjusted J-HBR group |
3.971 |
2.017-7.816 |
＜0.001 |
| Adjusted J-HBR group |
3.862 |
1.945-7.668 |
＜0.001 |
| BARC type 5 bleeding |
|
|
|
| Non-J-HBR group |
Reference |
|
|
| Unadjusted J-HBR group |
43.661 |
6.063-314.425 |
＜0.001 |
| Sex adjusted J-HBR group |
47.807 |
6.629-344.747 |
＜0.001 |
| Adjusted J-HBR group |
28.341 |
3.896-206.151 |
＜0.001 |
In the adjusted model, J-HBR group (vs. Non-J-HBR group) was adjusted for sex, number of narrowed coronary arteries, infarct-related artery, final TIMI flow grade, CTO in non-culprit arteries, approach site. Abbreviations: J-HBR = Japanese version of the high bleeding risk, MACE = major cardiovascular events, TIMI = thrombolysis in myocardial infarction, CTO = chronic total occlusion, BARC = Bleeding Academic Research Consortium.
Discussion
We included 897 patients with STEMI who underwent primary PCI and divided them into the J-HBR (n=567) and the non-J-HBR groups (n=330). We followed up with these patients after hospitalization with a median duration of 573 days. MACE and total bleeding events were more frequently observed in the J-HBR group than in the non-J-HBR group. The multivariate Cox hazard analysis revealed that after controlling for multiple confounding factors, J-HBR was significantly associated with MACE (HR 4.676, 95% CI: 2.936–7.448, p＜0.001) and total bleeding events (HR 6.325, 95% CI 3.376–11.851, p＜0.001).
The ARC-HBR criteria have been widely used as a standardized definition of HBR in post-PCI patients9, 10). The ARC-HBR criteria are independently associated with an increased risk of MACE in Japanese patients with acute coronary syndrome39). Several previous studies have found an association between J-HBR and total bleeding events in patients undergoing PCI15-18). Of note, Sotomi et al. reported that the J-HBR criteria showed better discriminative performance over the ARC-HBR criteria in patients with AMI14). The main difference between the present study and the above mentioned earlier studies was that the present study focused on patients with STEMI. Furthermore, the present study investigated not only the association between bleeding events and J-HBR but also the association between MACE and J-HBR. Because most patients with STEMI require primary PCI, the appropriate risk stratification regarding bleeding risk is most important in patients with STEMI among patients with coronary artery disease.
We should discuss why J-HBR was significantly associated with MACE in patients with STEMI. Among 14 major J-HBR criteria, 11 major criteria overlap with the ARC-HBR major criteria, whereas 3 major criteria (low body weight and frailty, heart failure, and peripheral vascular disease) are original J-HBR criteria9, 10, 13). A study from the Swedish Coronary Angiography and Angioplasty Registry revealed that patients who are underweight (body mass index ＜18.5 kg/m2) was significantly associated with the highest mortality among those with STEMI who underwent primary PCI40). A study using the US Nationwide Readmission Database showed that frailty was associated with increased readmissions in patients with STEMI41). Huang, et al. reported that in-hospital major adverse cardiovascular events were significantly associated with Killip class III/IV in patients with STEMI who underwent primary PCI42). Furthermore, a study from the Israel national registry revealed that peripheral vascular disease was associated with a higher 1-year mortality in patients with STEMI as well as in those with non-ST elevation myocardial infarction43). The abovementioned studies support the significant association between the 3 additional major criteria in J-HBR and MACE in patients with STEMI.
In this study, we found a significant association between J-HBR and increased total bleeding events. There are several works of literature regarding the association between ARC-HBR and increased bleeding events in patients with STEMI44, 45). Furthermore, frailty, which is one of 3 additional major criteria in J-HBR, was significantly associated with major bleeding events in patients with STEMI46). Mrdovic, et al. revealed the association between heart failure and serious bleeding events in patients with STEMI47). Mathews, et al. reported that the presence of peripheral artery disease was significantly associated with in-hospital major bleeding events after controlling for STEMI in patients with AMI48). These studies support the association between J-HBR and increased total bleeding events in our study.
The clinical implications of the present study should be noted. First, our results validated J-HBR as the predictor of major bleeding events in patients with STEMI. The Japanese Circulation Society recommends a short DAPT period, which ranges from 1 month to 3 months, for patients with HBR13). In the J-HBR group, a short DAPT period may contribute to a lower risk of bleeding in patients with STEMI. However, the present study shows the possibility of J-HBR as a potential predictor of MACE, including thrombotic events in patients with STEMI. A short DAPT period would reduce the incidence of bleeding events but would not reduce the incidence of thrombotic events. Because thrombotic events are more frequently observed in the culprit lesion of STEMI than in that of stable disease49), additional intervention, except for short DAPT, may be needed for J-HBR in patients with STEMI. Future studies regarding additional interventions are warranted for J-HBR in patients with STEMI.
This study has several limitations. Because this study is a single-center, retrospective study, there is a potential selection bias. Long-term bleeding events might be influenced by post-discharge medications. As our institution was a tertiary university hospital, patients were referred to their local clinic at discharge. Because most patients received medications from local clinics, information regarding post-discharge medications were not available in the present study. In addition, the patients’ inclusion period was from January 2015 to December 2021, and since the concept of J-HBR was published in the middle of the inclusion period (May 2020)13), some patients in the J-HBR group were not recognized as having high bleeding risks in clinical practice. Furthermore, in the multivariate Cox hazard analysis, we arbitrarily selected variables that included female sex, number of narrowed coronary arteries, infarct-related artery, final TIMI flow grade, CTO in non-culprit arteries, and the approach site.
Conclusions
In this study, we found that J-HBR is significantly associated with MACE and total bleeding events in patients with STEMI, suggesting that J-HBR may be a potential risk marker for MACE in patients with STEMI.
Acknowledgements
The authors acknowledge all staff in the catheter laboratory, cardiology units, and emergency and critical care units in Saitama Medical Center, Jichi Medical University for their technical support in this study.
Conflict of Interest
Dr. Sakakura has received speaking honoraria from Abbott Vascular, Boston Scientific, Medtronic Cardiovascular, Terumo, OrbusNeich, Japan Lifeline, Kaneka, NIPRO, and Daiichi-Sankyo. Dr. Jinnouchi has received speaking honoraria from Abbott Vascular. Prof. Fujita has served as a consultant for Mehergen Group Holdings, Inc.
References
- 1) Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet, 2003; 361: 13-20
- 2) Keeley EC, Boura JA, Grines CL. Comparison of primary and facilitated percutaneous coronary interventions for ST-elevation myocardial infarction: quantitative review of randomised trials. Lancet, 2006; 367: 579-588
- 3) Leon MB, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KK, Giambartolomei A, Diver DJ, Lasorda DM, Williams DO, Pocock SJ, Kuntz RE. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med, 1998; 339: 1665-1671
- 4) Sabatine MS, Cannon CP, Gibson CM, López-Sendón JL, Montalescot G, Theroux P, Lewis BS, Murphy SA, McCabe CH, Braunwald E; Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)-Thrombolysis in Myocardial Infarction (TIMI) 28 Investigators. Effect of clopidogrel pretreatment before percutaneous coronary intervention in patients with ST-elevation myocardial infarction treated with fibrinolytics: the PCI-CLARITY study. Jama, 2005; 294: 1224-1232
- 5) Lawton JS, Tamis-Holland JE, Bangalore S, Bates ER, Beckie TM, Bischoff JM, Bittl JA, Cohen MG, DiMaio JM, Don CW, Fremes SE, Gaudino MF, Goldberger ZD, Grant MC, Jaswal JB, Kurlansky PA, Mehran R, Metkus TS Jr, Nnacheta LC, Rao SV, Sellke FW, Sharma G, Yong CM, Zwischenberger BA. 2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation, 2022; 145: e18-e114
- 6) Neumann FJ, Sousa-Uva M, Ahlsson A, Alfonso F, Banning AP, Benedetto U, Byrne RA, Collet JP, Falk V, Head SJ, Jüni P, Kastrati A, Koller A, Kristensen SD, Niebauer J, Richter DJ, Seferovic PM, Sibbing D, Stefanini GG, Windecker S, Yadav R, Zembala MO; ESC Scientific Document Group. 2018 ESC/EACTS Guidelines on myocardial revascularization. Eur Heart J, 2019; 40: 87-165
- 7) Costa F, van Klaveren D, James S, Heg D, Räber L, Feres F, Pilgrim T, Hong MK, Kim HS, Colombo A, Steg PG, Zanchin T, Palmerini T, Wallentin L, Bhatt DL, Stone GW, Windecker S, Steyerberg EW, Valgimigli M; PRECISE-DAPT Study Investigators. Derivation and validation of the predicting bleeding complications in patients undergoing stent implantation and subsequent dual antiplatelet therapy (PRECISE-DAPT) score: a pooled analysis of individual-patient datasets from clinical trials. Lancet, 2017; 389: 1025-1034
- 8) Balthazar T, Vandenbriele C, Verbrugge FH, Den Uil C, Engström A, Janssens S, Rex S, Meyns B, Van Mieghem N, Price S, Adriaenssens T. Managing Patients With Short-Term Mechanical Circulatory Support: JACC Review Topic of the Week. J Am Coll Cardiol, 2021; 77: 1243-1256
- 9) Urban P, Mehran R, Colleran R, Angiolillo DJ, Byrne RA, Capodanno D, Cuisset T, Cutlip D, Eerdmans P, Eikelboom J, Farb A, Gibson CM, Gregson J, Haude M, James SK, Kim HS, Kimura T, Konishi A, Laschinger J, Leon MB, Magee PFA, Mitsutake Y, Mylotte D, Pocock S, Price MJ, Rao SV, Spitzer E, Stockbridge N, Valgimigli M, Varenne O, Windhoevel U, Yeh RW, Krucoff MW, Morice MC. Defining High Bleeding Risk in Patients Undergoing Percutaneous Coronary Intervention. Circulation, 2019; 140: 240-261
- 10) Urban P, Mehran R, Colleran R, Angiolillo DJ, Byrne RA, Capodanno D, Cuisset T, Cutlip D, Eerdmans P, Eikelboom J, Farb A, Gibson CM, Gregson J, Haude M, James SK, Kim HS, Kimura T, Konishi A, Laschinger J, Leon MB, Magee PFA, Mitsutake Y, Mylotte D, Pocock S, Price MJ, Rao SV, Spitzer E, Stockbridge N, Valgimigli M, Varenne O, Windhoevel U, Yeh RW, Krucoff MW, Morice MC. Defining high bleeding risk in patients undergoing percutaneous coronary intervention: a consensus document from the Academic Research Consortium for High Bleeding Risk. Eur Heart J, 2019; 40: 2632-2653
- 11) Kohsaka S, Miyata H, Ueda I, Masoudi FA, Peterson ED, Maekawa Y, Kawamura A, Fukuda K, Roe MT, Rumsfeld JS. An international comparison of patients undergoing percutaneous coronary intervention: A collaborative study of the National Cardiovascular Data Registry (NCDR) and Japan Cardiovascular Database-Keio interhospital Cardiovascular Studies (JCD-KiCS). Am Heart J, 2015; 170: 1077-1085
- 12) Kang J, Park KW, Palmerini T, Stone GW, Lee MS, Colombo A, Chieffo A, Feres F, Abizaid A, Bhatt DL, Valgimigli M, Hong MK, Jang Y, Gilard M, Morice MC, Park DW, Park SJ, Jeong YH, Park J, Koo BK, Kim HS. Racial Differences in Ischaemia/Bleeding Risk Trade-Off during Anti-Platelet Therapy: Individual Patient Level Landmark Meta-Analysis from Seven RCTs. Thromb Haemost, 2019; 119: 149-162
- 13) Nakamura M, Kimura K, Kimura T, Ishihara M, Otsuka F, Kozuma K, Kosuge M, Shinke T, Nakagawa Y, Natsuaki M, Yasuda S, Akasaka T, Kohsaka S, Haze K, Hirayama A. JCS 2020 Guideline Focused Update on Antithrombotic Therapy in Patients With Coronary Artery Disease. Circ J, 2020; 84: 831-865
- 14) Sotomi Y, Hikoso S, Nakatani D, Suna S, Dohi T, Mizuno H, Okada K, Kida H, Oeun B, Sunaga A, Sato T, Kitamura T, Sakata Y, Sato H, Hori M, Komuro I, Sakata Y; Osaka Acute Coronary Insufficiency Study (OACIS) Group. Prevalence of the Japanese high bleeding risk criteria and its prognostic significance for fatal bleeding in patients with acute myocardial infarction. Heart Vessels, 2021; 36: 1484-1495
- 15) Nakanishi N, Kaikita K, Ishii M, Kuyama N, Tabata N, Ito M, Yamanaga K, Fujisue K, Hoshiyama T, Kanazawa H, Hanatani S, Sueta D, Takashio S, Arima Y, Araki S, Usuku H, Nakamura T, Yamamoto E, Soejima H, Matsushita K, Tsujita K. Japanese high bleeding risk criteria status predicts low thrombogenicity and bleeding events in patients undergoing percutaneous coronary intervention. Cardiovasc Interv Ther, 2023; 38: 299-308
- 16) Kubota N, Ozaki K, Akiyama T, Washiyama Y, Yoneyama S, Okubo T, Ikegami R, Hoyano M, Yanagawa T, Tanabe N, Inomata T. Correlation Between the Japanese Version of the High Bleeding Risk (J-HBR) Criteria and the PRECISE-DAPT Score, and Optimal J-HBR Cut-Off Score to Predict Major Bleeding. Circ Rep, 2022; 4: 363-370
- 17) Matsumoto T, Saito Y, Sato T, Yamashita D, Suzuki S, Saito K, Wakabayashi S, Kitahara H, Sano K, Kobayashi Y. Validation of the Domestic High Bleeding Risk Criteria for Japanese Patients with Acute Myocardial Infarction. J Atheroscler Thromb, 2023; 30: 299-309
- 18) Natsuaki M, Morimoto T, Shiomi H, Ehara N, Taniguchi R, Tamura T, Tada T, Suwa S, Kaneda K, Watanabe H, Tazaki J, Watanabe S, Yamamoto E, Saito N, Fuki M, Takeda T, Eizawa H, Shinoda E, Mabuchi H, Shirotani M, Uegaito T, Matsuda M, Takahashi M, Inoko M, Tamura T, Ishii K, Onodera T, Sakamoto H, Aoyama T, Sato Y, Ando K, Furukawa Y, Nakagawa Y, Kadota K, Kimura T; CREDO-Kyoto PCI/CABG Registry Cohort-3 Investigators. Application of the Modified High Bleeding Risk Criteria for Japanese Patients in an All-Comers Registry of Percutaneous Coronary Intervention - From the CREDO-Kyoto Registry Cohort-3. Circ J, 2021; 85: 769-781
- 19) Mehran R, Rao SV, Bhatt DL, Gibson CM, Caixeta A, Eikelboom J, Kaul S, Wiviott SD, Menon V, Nikolsky E, Serebruany V, Valgimigli M, Vranckx P, Taggart D, Sabik JF, Cutlip DE, Krucoff MW, Ohman EM, Steg PG, White H. Standardized bleeding definitions for cardiovascular clinical trials: a consensus report from the Bleeding Academic Research Consortium. Circulation, 2011; 123: 2736-2747
- 20) Kimura K, Kimura T, Ishihara M, Nakagawa Y, Nakao K, Miyauchi K, Sakamoto T, Tsujita K, Hagiwara N, Miyazaki S, Ako J, Arai H, Ishii H, Origuchi H, Shimizu W, Takemura H, Tahara Y, Morino Y, Iino K, Itoh T, Iwanaga Y, Uchida K, Endo H, Kongoji K, Sakamoto K, Shiomi H, Shimohama T, Suzuki A, Takahashi J, Takeuchi I, Tanaka A, Tamura T, Nakashima T, Noguchi T, Fukamachi D, Mizuno T, Yamaguchi J, Yodogawa K, Kosuge M, Kohsaka S, Yoshino H, Yasuda S, Shimokawa H, Hirayama A, Akasaka T, Haze K, Ogawa H, Tsutsui H, Yamazaki T; Japanese Circulation Society Joint Working Group. JCS 2018 Guideline on Diagnosis and Treatment of Acute Coronary Syndrome. Circ J, 2019; 83: 1085-1196
- 21) Granger CB, Goldberg RJ, Dabbous O, Pieper KS, Eagle KA, Cannon CP, Van De Werf F, Avezum A, Goodman SG, Flather MD, Fox KA; Global Registry of Acute Coronary Events Investigators. Predictors of hospital mortality in the global registry of acute coronary events. Arch Intern Med, 2003; 163: 2345-2353
- 22) Andò G, Morabito G, de Gregorio C, Trio O, Saporito F, Oreto G. Age, glomerular filtration rate, ejection fraction, and the AGEF score predict contrast-induced nephropathy in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention. Catheter Cardiovasc Interv, 2013; 82: 878-885
- 23) Madan M, Abbott JD, Lennon R, So DYF, MacDougall AM, McLaughlin MA, Murthy V, Saw J, Rihal C, Farkouh ME, Pereira NL, Goodman SG; TAILOR‐PCI Investigators. Sex-Specific Differences in Clinical Outcomes After Percutaneous Coronary Intervention: Insights from the TAILOR-PCI Trial. J Am Heart Assoc, 2022; 11: e024709
- 24) Spirito A, Sharma A, Cao D, Sartori S, Zhang Z, Nicolas J, Pivato CA, Cohen R, Baber U, Sweeny J, Sharma SK, Dangas G, Kini A, Brener SJ, Mehran R. New Criteria to Identify Patients at Higher Risk for Cardiovascular Complications After Percutaneous Coronary Intervention. Am J Cardiol, 2023; 189: 22-30
- 25) Mennuni MG, Dangas GD, Mehran R, Ben-Gal Y, Xu K, Généreux P, Brener SJ, Feit F, Lincoff AM, Ohman EM, Hamon M, Stone GW. Coronary Artery Bypass Surgery Compared With Percutaneous Coronary Intervention for Proximal Left Anterior Descending Artery Treatment in Patients With Acute Coronary Syndrome: Analysis From the ACUITY Trial. J Invasive Cardiol, 2015; 27: 468-473
- 26) Brener SJ, Mehran R, Brodie BR, Guagliumi G, Witzenbichler B, Cristea E, Xu K, Lansky AJ, Stone GW. Predictors and implications of coronary infarct artery patency at initial angiography in patients with acute myocardial infarction (from the CADILLAC and HORIZONS-AMI Trials). Am J Cardiol, 2011; 108: 918-923
- 27) Fujimoto Y, Sakakura K, Jinnouchi H, Taniguchi Y, Tsukui T, Watanabe Y, Yamamoto K, Seguchi M, Wada H, Fujita H. Comparison of Outcomes of Patients With Acute Myocardial Infarction Between Chronic Total Occlusion Versus 90-99% Stenosis in Non-Culprit Arteries. Am J Cardiol, 2022; 170: 17-24
- 28) Rothenbühler M, Valgimigli M, Odutayo A, Frigoli E, Leonardi S, Vranckx P, Turturo M, Moretti L, Amico F, Uguccioni L, Contarini M, Gómez-Hospital JA, Mainar V, Creaco M, Petronio AS, Cremonesi A, Tamburino C, Fresco C, Bonmassari R, Díaz Fernández JF, Romagnoli E, Beyersmann J, Heg D, Jüni P. Association of acute kidney injury and bleeding events with mortality after radial or femoral access in patients with acute coronary syndrome undergoing invasive management: secondary analysis of a randomized clinical trial. Eur Heart J, 2019; 40: 1226-1232
- 29) Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, White HD; Executive Group on behalf of the Joint European Society of Cardiology (ESC)/American College of Cardiology (ACC)/American Heart Association (AHA)/World Heart Federation (WHF) Task Force for the Universal Definition of Myocardial Infarction. Fourth Universal Definition of Myocardial Infarction (2018). J Am Coll Cardiol, 2018; 72: 2231-2264
- 30) Sawano M, Yamaji K, Kohsaka S, Inohara T, Numasawa Y, Ando H, Iida O, Shinke T, Ishii H, Amano T. Contemporary use and trends in percutaneous coronary intervention in Japan: an outline of the J-PCI registry. Cardiovasc Interv Ther, 2020; 35: 218-226
- 31) Hori Y, Sakakura K, Jinnouchi H, Taniguchi Y, Tsukui T, Watanabe Y, Yamamoto K, Seguchi M, Wada H, Fujita H. Association of peak C-reactive protein with long-term clinical outcomes in patients with ST-segment elevation myocardial infarction. Heart Vessels, 2023; 38(6): 764-772
- 32) Kobayashi S, Sakakura K, Jinnouchi H, Taniguchi Y, Tsukui T, Watanabe Y, Yamamoto K, Seguchi M, Wada H, Fujita H. Influence of daily temperature on the occurrence of ST-elevation myocardial infarction. J Cardiol, 2023; 81: 544-552
- 33) Kasahara T, Sakakura K, Hori N, Jinnouchi H, Taniguchi Y, Tsukui T, Watanabe Y, Yamamoto K, Seguchi M, Wada H, Fujita H. Comparison of in-hospital outcomes of acute myocardial infarction between patients with cardiogenic shock and with cardiac arrest. Heart Vessels, 2023; 38: 139-146
- 34) Murakami T, Sakakura K, Jinnouchi H, Taniguchi Y, Tsukui T, Watanabe Y, Yamamoto K, Seguchi M, Wada H, Fujita H. Acute Ischemic Stroke and Transient Ischemic Attack in ST-Segment Elevation Myocardial Infarction Patients Who Underwent Primary Percutaneous Coronary Intervention. J Clin Med, 2023; 12
- 35) Aono-Setoguchi H, Sakakura K, Jinnouchi H, Taniguchi Y, Tsukui T, Watanabe Y, Yamamoto K, Seguchi M, Wada H, Fujita H. Factors associated with intensive care unit delirium in patients with acute myocardial infarction. Heart Vessels, 2023; 38: 478-487
- 36) Ban S, Sakakura K, Jinnouchi H, Taniguchi Y, Tsukui T, Watanabe Y, Yamamoto K, Seguchi M, Wada H, Fujita H. Association of Asymptomatic Low Ankle-Brachial Index with Long-Term Clinical Outcomes in Patients after Acute Myocardial Infarction. J Atheroscler Thromb, 2022; 29: 992-1000
- 37) Ban S, Sakakura K, Jinnouchi H, Taniguchi Y, Tsukui T, Watanabe Y, Yamamoto K, Seguchi M, Wada H, Fujita H. Association of Increased Pulse Wave Velocity With Long-Term Clinical Outcomes in Patients With Preserved Ankle-Brachial Index After Acute Myocardial Infarction. Heart Lung Circ, 2022; 31: 1360-1368
- 38) Ohashi J, Sakakura K, Jinnouchi H, Taniguchi Y, Tsukui T, Watanabe Y, Yamamoto K, Seguchi M, Wada H, Fujita H. Comparison of Long-Term Clinical Outcomes in Patients Stratified by a Novel Acute Myocardial Infarction Risk Stratification (nARS) System. Circ J, 2022; 86: 1519-1526
- 39) Shimono H, Tokushige A, Kanda D, Ohno A, Hayashi M, Fukuyado M, Akao M, Kawasoe M, Arikawa R, Otsuji H, Chaen H, Okui H, Oketani N, Ohishi M. Association between the number of Academic Research Consortium for High Bleeding Risk (ARC-HBR) criteria and clinical outcomes in patients with acute coronary syndrome. J Cardiol, 2023; 81: 553-563
- 40) Jamaly S, Redfors B, Omerovic E, Carlsson L, Karason K. Prognostic significance of BMI after PCI treatment in ST-elevation myocardial infarction: a cohort study from the Swedish Coronary Angiography and Angioplasty Registry. Open Heart, 2021; 8
- 41) Heaton J, Singh S, Nanavaty D, Okoh AK, Kesanakurthy S, Tayal R. Impact of frailty on outcomes in acute ST-elevated myocardial infarctions undergoing percutaneous coronary intervention. Catheter Cardiovasc Interv, 2023; 101: 773-786
- 42) Huang L, Zhang J, Huang Q, Cui R, Chen J. In-hospital major adverse cardiovascular events after primary percutaneous coronary intervention in patients with acute ST-segment elevation myocardial infarction: a retrospective study under the China chest pain center (standard center) treatment system. BMC Cardiovasc Disord, 2023; 23: 198
- 43) Matetzky S, Natanzon SS, Shlomo N, Atar S, Pollak A, Yosefy C, Zahger D, Fefer P, Iakobishvili Z, Mazin I, Beigel R. Peripheral Arterial Disease in Patients With Acute Coronary Syndrome: Results From a Large Real-World Registry. Heart Lung Circ, 2022; 31: 1093-1101
- 44) Inan D, Yumurtas AC, Simsek B, Palice A, Efendioglu EM, Yuksel G, Korkmaz B, Vatanoglu EG, Güngör B, Karabay CY. Performance of the Academic Research Consortium High Bleeding Risk Criteria in Patients With ST-Segment Elevation Myocardial Infarction: A Single Center Study. Angiology, 2022: 33197221135739
- 45) Fujii T, Ikari Y. Predictive Ability of Academic Research Consortium for High Bleeding Risk Criteria in ST-Elevation Myocardial Infarction Patients Undergoing Primary Coronary Intervention. Circ J, 2021; 85: 159-165
- 46) Borovac JA, Mohamed MO, Kontopantelis E, Alkhouli M, Alraies MC, Cheng RK, Elgendy IY, Velagapudi P, Paul TK, Van Spall HGC, Mamas MA. Frailty Among Patients With Acute ST-Elevation Myocardial Infarction in the United States: The Impact of the Primary Percutaneous Coronary Intervention on In-Hospital Outcomes. J Invasive Cardiol, 2022; 34: E55-e64
- 47) Mrdovic I, Savic L, Krljanac G, Asanin M, Lasica R, Djuricic N, Brdar N, Marinkovic J, Kocev N, Perunicic J. Simple risk algorithm to predict serious bleeding in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: RISK-PCI bleeding score. Circ J, 2013; 77: 1719-1727
- 48) Mathews R, Peterson ED, Chen AY, Wang TY, Chin CT, Fonarow GC, Cannon CP, Rumsfeld JS, Roe MT, Alexander KP. In-hospital major bleeding during ST-elevation and non-ST-elevation myocardial infarction care: derivation and validation of a model from the ACTION Registry®-GWTG™. Am J Cardiol, 2011; 107: 1136-1143
- 49) Iqbal J, Sumaya W, Tatman V, Parviz Y, Morton AC, Grech ED, Campbell S, Storey RF, Gunn J. Incidence and predictors of stent thrombosis: a single-centre study of 5,833 consecutive patients undergoing coronary artery stenting. EuroIntervention, 2013; 9: 62-69
