Abstract
Aim: Both recurrent myocardial infarction (ReMI) and bleeding events after acute myocardial infarction (AMI) were reportedly associated with increased mortality. To date, the prognostic impact of these events on subsequent outcomes in East Asians is still unclear. In this study, we aimed to investigate the impact of bleeding or thrombotic events during acute phase on subsequent mortality and time-dependent change of the impact in patients with AMI undergoing percutaneous coronary intervention (PCI).
Method: We conducted a prospective, multicenter, observational study of patients with AMI (n=12,093). The patients who did not undergo emergent PCI were excluded. In addition, the patients registered before 2003 were excluded because the data of bleeding severity was not obtained. Eligible patients were divided into two groups based on the occurrence of major bleeding within 7 days of PCI, and the same approach was performed for ReMI within 7 days of PCI. The endpoint of this study was all-cause death. We assessed the impact of major bleeding and ReMI, which occurred within 7 days of index PCI, on the subsequent clinical outcomes up to 5 years.
Results: A total of 6,769 patients were found to be eligible. All-cause death occurred in 898 (13.3%) patients during a median follow-up period of 1,726 [511–1,840] days. After adjustment for multiple confounders, major bleeding in 7 days from index PCI was independently associated with higher 30-day and 30-day to 1-year mortality (odds ratio [OR]: 2.06 [1.45–2.92] p＜0.001, OR: 2.03 [1.28–3.15] p=0.002), whereas ReMI was not (OR: 1.93 [0.92–3.80] p=0.07, OR: 0.81 [0.24–2.03] p=0.68). Major bleeding and ReMI did not affect mortality between 1 and 5 years (hazard ratio [HR]: 1.32 [0.77–2.26] p=0.31, HR: 0.48 [0.12–1.94] p=0.30).
Conclusion: Major bleeding in 7 days from admission was independently associated with higher 30-day and 1-year mortality but not during 1–5 years. ReMI did not affect mortality in all phases. We should be more concerned about bleeding event during acute phase after PCI.
Clinical Trial Registration Number: UMIN000004575
Introduction
Percutaneous coronary intervention (PCI) is an established treatment strategy for chronic and acute coronary syndrome1). Dual antiplatelet therapy (DAPT) is the current standard therapeutic strategy following PCI. DAPT reduces the risk of thrombotic events but in turn increases the risk of bleeding2, 3). Both thrombotic and bleeding events cluster during the very acute phase (within 1 week of PCI) and exponentially decrease thereafter4-6). Therefore, optimal strategy for the prevention of both events in this acute phase is important. Prognostic impacts of bleeding and thrombotic events ≥ 30 days after PCI were previously reported in a substudy of the Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome (TRACER) trial (n=12,944)7). However, because these events mainly occur within 30 days of PCI, it is interesting to investigate the impacts of earlier clinical events on subsequent outcomes. Furthermore, because bleeding and thrombotic risks in the East Asian population are substantially different from those in the USA and European countries8, 9), the prognostic impact of bleeding and thrombotic events on subsequent clinical outcomes in East Asian cohort remains to be investigated.
Aim
This study aimed to investigate the impact of bleeding or recurrent myocardial infarction (ReMI) during acute phase (within seven days of PCI) on subsequent mortality and its time-dependent change in patients with acute myocardial infarction (AMI) undergoing PCI.
Method
Study Population
We used the Osaka Acute Coronary Insufficiency Study (OACIS) database (n=12,093). The OACIS is a prospective, multicenter, observational study designed to collect and analyze demographic, procedural, and outcome data in patients with AMI at 25 collaborating hospitals with cardiac emergency units. In the OACIS, patients were enrolled from 1998 to 2014 and were followed up until 2019. Written informed consent was obtained from them. A diagnosis of myocardial infarction (MI) was made if the patient met at least two of the following three criteria: (1) history of central chest pressure, pain, or tightness lasting ≥ 30 min; (2) typical ECG changes (i.e., ST-segment elevation of ≥ 0.1 mV in one standard limb lead or two precordial leads, ST-segment depression of ≥ 0.1 mV in two leads, abnormal Q waves, or T-wave inversion in two leads); and (3) a rise in serum creatinine phosphokinase (CK) concentration to more than twice the normal laboratory value. All collaborating hospitals were encouraged to enroll consecutive patients with AMI. We prospectively collected data obtained by research cardiologists and trained research nurses using a specific reporting form. The study is registered with the University Hospital Medical Information Network Clinical Trials Registry in Japan (ID: UMIN000004575). The study protocol complied with the Helsinki Declaration. Furthermore, the study was approved by the ethical review board of Osaka University Hospital (reference number: 14360) and the institutional ethics committee of each participating institution.
In this study, we aimed to evaluate the impact of major bleeding and ReMI on mortality in patients undergoing PCI. The patients who did not undergo emergent PCI were excluded. In addition, the patients registered before 2003 were excluded because the data of bleeding severity was not obtained (Fig.1A).
Study Endpoint and Definition
The endpoint of this study was all-cause death. In this subanalysis of the prospective cohort study, we assessed the impact of major bleeding and ReMI, which occurred within 7 days of index PCI, on the subsequent clinical outcomes up to 5 years. Major bleeding was defined as follows: (1) hemoglobin drop of ≥ 4 g/dL, (2) intracranial hemorrhage, (3) requirement of surgical treatment, or (4) requirement of any transfusion. ReMI was defined as AMI recurrence regardless of the lesion derived from the first culprit site. The criteria for diagnosing ReMI were identical to those used at the time of registration. Information on the clinical event was collected by local investigators when visiting outpatient clinics or through verbal or written contact with patients or family members.
PCI Procedure and Post-PCI Medication
PCI treatment strategies, including thrombectomy, pre- or post-dilation, use of atherectomy device, use of intracoronary device (IVUS [intravascular ultrasound], OCT [optical coherence tomography]), use of cardiocirculatory support device (IABP [intra-aortic balloon pumping], PCPS [percutaneous cardiopulmonary support]), and stent type, length, and diameter were decided at the operators’ discretion10). Post-PCI medication followed the standard guideline for the treatment of MI11).
Statistical Analysis
All analyses were conducted using the R software (version 4.1.3; R Foundation for Statistical Computing, Vienna, Australia). A p-value of ＜0.05 was considered to indicate statistical significance. Categorical variables were expressed as counts (percentages) and compared using the chi-squared test. On the other hand, continuous variables were expressed as mean (standard deviation) or median (interquartile range) and compared using student’s t-test or Mann–Whitney U test as appropriate. Study follow-up started at the time of initial hospitalization. Difference in survival curves between the patient groups was estimated using the Kaplan–Meier method and analyzed using the log-rank test. We investigated the impact of 7-day major bleeding and ReMI on subsequent mortality. To investigate the differential impact by time course after index PCI, we separately assessed the impact during three periods; ＜30 days, 30 days to 1 year, and after 1 year up to 5 years from the index PCI. For each period, we used a logistic regression model and a Cox proportional-hazards model, both of which were constructed based on the assumption of proportional hazards. The assumption of proportional hazards was partially validated through analysis of Schoenfeld residuals, yielding the following results: within the 30-day period (for major bleeding, p=0.029; for recurrent MI, p=0.013), from 30 days to 1 year (for major bleeding, p=0.0011; for recurrent MI, p=0.289), and from 1 year to 5 years (for major bleeding, p=0.43; for recurrent MI, p=0.32). Consequently, we proceeded with calculating the odds ratios (OR) for major bleeding or recurrent MI in relation to mortality within the 30-day period and from 30 days to 1 year using logistic regression analysis. Furthermore, we computed the hazard ratios (HR) for these events occurring after 1 year to 5 years using Cox regression analysis. The variables of interest were major bleeding and ReMI. The covariates included in those models were age, female sex, diabetes mellitus, hypertension, anemia (hemoglobin level of ＜12 g/dL in women and ＜13 g/dL in men, as defined by the World Health Organization), creatinine clearance (CrCl) of ＜60 mL/min, previous MI or PCI, atrial fibrillation (AF) or atrial flutter (AFL), heart failure, IABP, PCPS, and peak CK, which were selected based on the clinical consensus. AF or AFL was defined as AF or AFL detected by electrocardiogram on hospital admission. Heart failure was defined as that diagnosed within 1 week of hospital admission. Because the exclusion of missing data cases can cause bias in this analysis and loss of power for statistical difference detection, we imputed missing data by using the MissForest algorithm. MissForest is a random forest imputation algorithm for missing data, implemented in R in the missForest package.
Result
Of the 12,093 patients enrolled in the OACIS registry, those registered before 2003 (no information of bleeding severity) were excluded (n=4272). Patients who did not receive emergent PCI within 24 hours of hospitalization were also excluded (n=1027). In our registry, 6,794 patients underwent emergent PCI from 2003 to 2014. In this population, those who lacked data of major bleeding or ReMI in 1 week were excluded (n=25). A total of 6,769 patients were included in the final analysis (Fig.1A). These eligible patients were divided into two groups based on the occurrence of major bleeding within 7 days of PCI (Fig.1B). The same approach was performed for ReMI within 7 days of PCI (Fig.1C). While 336 (5.0%) patients had major bleeding, 117 (1.7%) had ReMI in 7 days from hospital admission. The patients’ background, history, and physical findings on admission are summarized in Table 1. Patients with major bleeding were older; were more likely to be female; had lower body mass index; had higher prevalence of low body weight (defined as ＜55 kg for men and ＜50 kg for women); and had a history of chronic kidney disease, previous MI or PCI, AF or AFL on admission, and Killip 3 or 4 compared with those without major bleeding. Patients with ReMI had a higher prevalence of previous MI or PCI than those without ReMI. Laboratory data on admission showed that those with major bleeding had lower hemoglobin and platelet levels and a higher creatinine level than those without. Laboratory data on admission was similar between patients with and without ReMI (Table 2). The use of circulatory assist device was more frequent in patients with either event than those without, and the peak CK/CK-MB levels were higher in patients with either event than those without (Table 3). Medication within 7 days of index PCI and at discharge is presented in Supplemental Table 1 and Table 4. The data for oral anticoagulants within 7 days of index PCI was not available. At discharge, diuretics and anticoagulants were more frequently used in patients with either event than in those without.
Table 1.Patient background, past history and physical findings
|
Without Major Bleeding |
With Major Bleeding |
P value
|
Without ReMI |
With ReMI |
P value
|
| n
|
6433 |
336 |
|
6652 |
117 |
|
| Age |
67.00 [58.00, 75.00] |
72.00 [63.00, 80.00] |
＜0.001 |
67.00 [59.00, 75.00] |
67.00 [58.00, 76.00] |
0.713 |
| Age ≥ 75 |
1692 (26.3) |
146 (43.5) |
＜0.001 |
1803 (27.1) |
35 (29.9) |
0.57 |
| Male |
4960 (77.1) |
215 (64.0) |
＜0.001 |
5078 (76.3) |
97 (82.9) |
0.122 |
| Body mass index |
23.71 [21.63, 25.86] |
22.42 [20.41, 24.99] |
＜0.001 |
23.63 [21.51, 25.82] |
23.48 [21.44, 25.62] |
0.643 |
| Low Body weight＊
|
1366 (21.2) |
132 (39.3) |
＜0.001 |
1467 (22.1) |
31 (26.5) |
0.301 |
| Diabetes mellitus |
2098 (33.6) |
122 (38.9) |
0.063 |
2178 (33.8) |
42 (38.2) |
0.386 |
| Hypertension |
4016 (64.6) |
220 (69.0) |
0.124 |
4170 (64.9) |
66 (61.1) |
0.479 |
| Dyslipidemia |
2868 (46.6) |
101 (32.4) |
＜0.001 |
2915 (45.8) |
54 (50.5) |
0.392 |
| History of smoking |
3946 (63.4) |
157 (51.0) |
＜0.001 |
4027 (62.7) |
76 (67.9) |
0.308 |
| Previous myocardial infarction or percutaneous catheter intervention |
865 (13.8) |
59 (17.9) |
0.041 |
898 (13.8) |
26 (23.0) |
0.008 |
| History of cerebrovascular disease |
593 (9.6) |
33 (10.3) |
0.774 |
612 (9.6) |
14 (12.4) |
0.407 |
| History of chronic kidney disease |
428 (7.0) |
52 (16.2) |
＜0.001 |
473 (7.4) |
7 (6.2) |
0.752 |
| Liver disease |
290 (4.7) |
20 (6.2) |
0.267 |
303 (4.8) |
7 (6.2) |
0.627 |
| Cancer |
396 (6.4) |
34 (10.6) |
0.005 |
425 (6.7) |
5 (4.4) |
0.446 |
| Heart failure |
1213 (18.9) |
185 (55.1) |
＜0.001 |
1356 (20.4) |
42 (35.9) |
＜0.001 |
| Peripheral vascular disease |
131 (2.1) |
15 (4.7) |
0.005 |
145 (2.3) |
1 (0.9) |
0.503 |
| ST elevation |
5463 (86.1) |
257 (86.0) |
＞0.999 |
5619 (86.0) |
101 (89.4) |
0.372 |
| Abnormal Q wave |
2828 (44.8) |
144 (47.2) |
0.444 |
2920 (44.9) |
52 (45.2) |
＞0.999 |
| Atrial fibrillation / flutter on admission |
414 (6.5) |
37 (12.0) |
＜0.001 |
443 (6.8) |
8 (7.1) |
＞0.999 |
| Systolic blood pressure on admission (mmHg) |
136.00 [116.75, 156.00] |
124.00 [96.25, 150.00] |
＜0.001 |
136.00 [116.00, 156.00] |
139.00 [114.00, 160.75] |
0.628 |
| Diastolic blood pressure on admission (mmHg) |
80.00 [68.00, 92.00] |
74.00 [60.00, 88.00] |
＜0.001 |
80.00 [68.00, 92.00] |
81.00 [64.00, 95.00] |
0.516 |
| Heart rate on admission |
78.00 [64.00, 90.00] |
86.00 [70.00, 102.50] |
＜0.001 |
78.00 [65.00, 91.00] |
81.50 [66.00, 92.25] |
0.348 |
| Killip3or4 |
658 (10.2) |
161 (47.9) |
＜0.001 |
799 (12.0) |
20 (17.1) |
0.126 |
＊Low body weight was defined as ＜55kg for men and ＜50kg for women
Table 2.Laboratory data on admission
|
Without Major Bleeding |
With Major Bleeding |
P value
|
Without ReMI |
With ReMI |
P value
|
| n
|
6433 |
336 |
|
6652 |
117 |
|
| Hemoglobin (g/dL) |
14.00 [12.50, 15.20] |
12.20 [10.60, 14.05] |
＜0.001 |
13.90 [12.40, 15.20] |
14.50 [12.98, 15.40] |
0.041 |
| Anemia＊＊
|
1313 (27.2) |
139 (52.1) |
＜0.001 |
1436 (28.7) |
16 (19.5) |
0.09 |
| Platelet (10^5 /μL) |
21.30 [17.60, 25.40] |
19.40 [15.00, 24.60] |
＜0.001 |
21.20 [17.40, 25.40] |
22.60 [18.65, 27.05] |
0.058 |
| Creatinine (mg/dL) |
0.88 [0.70, 1.10] |
1.09 [0.84, 1.40] |
＜0.001 |
0.89 [0.70, 1.10] |
0.86 [0.70, 1.01] |
0.457 |
| CrCl ≦60 mL/min |
2228 (35.8) |
194 (63.6) |
＜0.001 |
2383 (37.2) |
39 (35.5) |
0.787 |
| High density lipoprotein cholesterol (mg/dL) |
44.00 [37.00, 52.00] |
40.00 [33.00, 50.00] |
＜0.001 |
44.00 [37.00, 52.00] |
43.00 [35.00, 54.00] |
0.78 |
| Low density lipoprotein cholesterol (mg/dL) |
121.00 [97.00, 146.00] |
106.00 [76.00, 134.00] |
＜0.001 |
120.00 [96.00, 145.00] |
127.00 [104.10, 159.00] |
0.114 |
| HbA1c (%) |
5.60 [5.20, 6.50] |
5.60 [5.20, 6.43] |
0.582 |
5.60 [5.20, 6.50] |
5.70 [5.30, 6.60] |
0.566 |
＊＊Anemia was defined as hemoglobin ＜13.0g/dL for men and ＜12.0g/dL for women Abbreviations: CrCl, creatinine clearance
Table 3.Procedure associated information
|
Without Major Bleeding |
With Major Bleeding |
P value
|
Without ReMI |
With ReMI |
P value
|
| n
|
6433 |
336 |
|
6652 |
117 |
|
| Time to coronary angiography (hour) |
4.00 [2.00, 9.70] |
3.00[1.50, 7.00] |
＜0.001 |
4.00 [2.00, 9.50] |
4.00 [2.00, 6.62] |
0.337 |
| Right coronary artery |
2243 (36.4) |
113 (35.0) |
0.637 |
2324 (36.5) |
32 (27.8) |
0.068 |
| Left anterior descending artery |
2928 (47.6) |
143 (44.3) |
0.271 |
3003 (47.2) |
68 (59.1) |
0.014 |
| Left circumflex artery |
999 (16.2) |
42 (13.0) |
0.144 |
1028 (16.2) |
13 (11.3) |
0.202 |
| Left main trunk |
137 (2.2) |
47 (14.6) |
＜0.001 |
180 (2.8) |
4 (3.5) |
0.895 |
| Pre TIMI 0 |
3019 (53.8) |
152 (52.2) |
0.65 |
3127 (53.9) |
44 (42.7) |
0.031 |
| Collateral |
1911 (30.6) |
87 (26.4) |
0.118 |
1961 (30.3) |
37 (32.7) |
0.653 |
| Thrombolysis |
208 (3.2) |
17 (5.1) |
0.096 |
211 (3.2) |
14 (12.0) |
＜0.001 |
| Distal protection |
684 (10.6) |
47 (14.0) |
0.066 |
720 (10.8) |
11 (9.4) |
0.733 |
| Aspiration |
4076 (63.4) |
196 (58.3) |
0.071 |
4199 (63.1) |
73 (62.4) |
0.948 |
| Stent |
5384 (83.7) |
286 (85.1) |
0.539 |
5568 (83.7) |
102 (87.2) |
0.377 |
| Post TIMI 0 or 1 |
158 (2.5) |
13 (3.9) |
0.154 |
167 (2.6) |
4 (3.4) |
0.762 |
| Post TIMI 3 |
5813 (92.2) |
287 (87.0) |
0.001 |
5993 (91.9) |
107 (92.2) |
＞0.999 |
| PCPS |
209 (3.2) |
137 (40.8) |
＜0.001 |
333 (5.0) |
13 (11.1) |
0.006 |
| IABP |
1192 (18.5) |
215 (64.0) |
＜0.001 |
1352 (20.3) |
55 (47.0) |
＜0.001 |
| Peak CK (IU/L) |
2092.00 [966.00, 3952.00] |
3660.00 [1426.00, 8230.00] |
＜0.001 |
2127.50 [978.00, 4061.75] |
2718.00 [1118.75, 5238.00] |
0.071 |
| Peak CK-MB (IU/L) |
188.10 [90.00, 363.00] |
317.00 [123.25, 603.25] |
＜0.001 |
193.00 [91.00, 371.00] |
255.00 [127.50, 498.40] |
0.01 |
Abbreviation: TIMI, Thrombolysis in Myocardial infarction Trial; PCPS, percutaneous cardiopulmonary support; IABP, intra-aortic balloon pumping; CK, creatine phosphokinase
Supplemental Table 1.Medication within 7 days of admission
|
Without Major Bleeding |
With Major bleeding |
P value
|
Without ReMI |
With ReMI |
P value
|
| n
|
6433 |
336 |
|
6652 |
117 |
|
| Acetylsalicylic acid |
6096 (94.8) |
298 (88.7) |
＜0.001 |
6282 (94.4) |
112 (95.7) |
0.689 |
| Clopidogrel |
2552 (39.7) |
128 (38.1) |
0.604 |
2636 (39.6) |
44 (37.6) |
0.728 |
| Ticlopidine |
3008 (46.8) |
139 (41.4) |
0.061 |
3090 (46.5) |
57 (48.7) |
0.694 |
| Angiotensin-converting enzyme inhibitor |
2645 (41.1) |
81 (24.1) |
＜0.001 |
2674 (40.2) |
52 (44.4) |
0.405 |
| Angiotensin II receptor blocker |
1949 (30.3) |
82 (24.4) |
0.025 |
2005 (30.1) |
26 (22.2) |
0.08 |
| Beta blocker |
2990 (46.5) |
105 (31.2) |
＜0.001 |
3042 (45.7) |
53 (45.3) |
＞0.999 |
| Statin |
2693 (41.9) |
109 (32.4) |
0.001 |
2754 (41.4) |
48 (41.0) |
＞0.999 |
| Diuretics |
2496 (38.8) |
196 (58.3) |
＜0.001 |
2633 (39.6) |
59 (50.4) |
0.023 |
Table 4.Medication at discharge (excluding patients who died before discharge)
|
Without Major Bleeding |
With Major bleeding |
P value
|
Without ReMI |
With ReMI |
P value
|
| n
|
6128 |
200 |
|
6228 |
100 |
|
| Acetylsalicylic acid |
5860 (95.6) |
188 (94.0) |
0.354 |
5949 (95.5) |
99 (99.0) |
0.152 |
| Clopidogrel |
2449 (40.0) |
73 (36.5) |
0.362 |
2482 (39.9) |
40 (40.0) |
＞0.999 |
| Ticlopidine |
2916 (47.6) |
94 (47.0) |
0.927 |
2958 (47.5) |
52 (52.0) |
0.427 |
| Angiotensin-converting enzyme inhibitor |
2723 (44.4) |
72 (36.0) |
0.022 |
2742 (44.0) |
53 (53.0) |
0.091 |
| Angiotensin II receptor blocker |
2255 (36.8) |
79 (39.5) |
0.481 |
2307 (37.0) |
27 (27.0) |
0.05 |
| Beta blocker |
3990 (65.1) |
132 (66.0) |
0.854 |
4049 (65.0) |
73 (73.0) |
0.119 |
| Statin |
3751 (61.2) |
96 (48.0) |
＜0.001 |
3784 (60.8) |
63 (63.0) |
0.725 |
| Diuretics |
1670 (27.3) |
96 (48.0) |
＜0.001 |
1725 (27.7) |
41 (41.0) |
0.005 |
| Anticoagulants |
915 (14.9) |
41 (20.5) |
0.039 |
933 (15.0) |
23 (23.0) |
0.037 |
All-cause death occurred in 898 (13.3%) patients during a median follow-up period of 1,726 [511–1,840] days. During follow-up, 166 (49.4%) patients with major bleeding and 22 (18.8%) patients with ReMI died. The content of all-cause death is presented in Supplemental Table 2. Cardiac death occurred more frequently in patients with major bleeding or ReMI than in those without the events. Kaplan–Meier analysis revealed that patients with major bleeding (log rank p＜0.001) or recurrence of MI (log rank p=0.037) had a higher mortality than those without these events (Fig.2). The landmark analysis revealed that the impact of bleeding or thrombotic events on mortality depended on the time from admission (Fig.3). Major bleeding within 7 days of PCI was independently associated with a higher 30-day mortality (OR: 2.06 [1.45–2.92], p＜0.001). ReMI within 7 days of PCI was not associated with a 30-day mortality (OR: 1.93 [0.92–3.80] p=0.07). From 30 days to 1 year, patients with major bleeding had a significantly higher mortality (OR: 2.03 [1.28–3.15] p=0.002), whereas those with ReMI did not (OR: 0.81 [0.24–2.03] p=0.68). After 1 year, both bleeding and ReMI events did not affect mortality (major bleeding, HR: 1.32 [0.77–2.26] p=0.31; ReMI, HR: 0.48 [0.12–1.94] p=0.30) (Fig.4).
Supplemental Table 2.The content of all-cause death
|
Without Major Bleeding |
With Major Bleeding |
P value
|
Without reMI |
With reMI |
P value
|
| n
|
6433 |
336 |
|
6652 |
117 |
|
| All-cause death |
732 (11.4%) |
166 (49.4%) |
＜0.001 |
876 (13.2%) |
22 (18.8%) |
0.10 |
| cardiac death |
285/732 (38.9%) |
94/166 (56.6%) |
＜0.001 |
364/876 (41.6%) |
15/22 (68.2%) |
0.02 |
| non-cardiac death |
317/732 (43.3%) |
53/166 (31.9%) |
0.009 |
363/876 (41.4%) |
7/22 (31.8%) |
0.49 |
| unknown death |
130/732 (17.8%) |
19/166 (11.4%) |
0.063 |
149/876 (17.0%) |
0/22 (0.0%) |
0.068 |
Discussion
The main findings of the present study are summarized as follows: 1) major bleeding was associated with a significantly higher 30-day mortality, whereas ReMI was not; 2) only major bleeding correlated with a prolonged mortality risk between 30 days and 1 year; 3) both events were not associated with long-term mortality (1–5 years after PCI).
Impact and Time Pattern of Bleeding and Thrombotic Events for Mortality
The association between bleeding or thrombotic events and mortality was previously reported from Western countries. Valgimigli M. et al. demonstrated the difference in the prognostic impact of recurrent MI and bleeding, which occurred 30 days after randomization in patients presenting with non-ST-elevation ACS. The prognostic impact of recurrent MI was higher than that of mild-to-moderate bleeding (estimate of relative risk: 3.15 [2.08–4.77]), similar to severe non-intracranial bleeding (RR: 1.37 [0.81–2.30]) and lower than intracranial or intraocular bleeding (RR: 0.22 [0.13–0.36]). MI and bleeding had similar time association with mortality. The impact of those events was greater early after the events; it rapidly dissipated in the subsequent days but remained for several months7). Mehran R. et al. also reported the association between major bleeding and recurrent MI within 30 days from index procedure and mortality in patients presenting with non-ST-elevation ACS and managed with an early invasive strategy. Both major bleeding and MI had important and similar associations with mortality in the first year after presentation with ACS. MI was associated with an early-phase skewed risk of mortality (days 0–1 HR: 17.6 [10.8–28.7], days 2–7 HR: 8.2 [5.0–13.6], days 8–30 HR: 2.9 [1.6–5.3], day 31＋HR: 1.4 [0.9–2.1]), whereas a major bleed correlated with a more prolonged mortality risk (days 0–1 HR: 5.5 [2.7–11.0], days 2–7 HR: 5.8 [3.5–9.7], days 8–30 HR: 5.6 [3.5–8.8], days 31＋HR: 2.4 [1.7–3.3])12). In our study, major bleeding was associated with higher early-term (0–30 days) and mid-term (30 days to 1 year) mortality. ReMI was not significantly associated but tended to be associated with higher 30-day mortality. These impacts declined over time from the index PCI.
Recurrent Myocardial Infarction and Subsequent Mortality
ReMI can result in fatal cardiac arrhythmia or reduced ventricular function. The substudy of the Acute Catheterization and Urgent Intervention Triage strategy (ACUITY) trial showed that ReMI within 30 days of PCI was associated with higher early-term mortality but did not affect long-term mortality in patients presenting with non-ST-elevation ACS12, 13). Similar to the previous study, early ReMI was not associated with long-term mortality in this study. ReMI tended to be associated with higher 30-day mortality, although the association was not statistically significant. All ReMIs within 7 days of index PCI occurred during hospitalization and were assumed to be immediately detected and treated. It might minimize damage to the myocardium and its impact on prognosis. Further large-scale pragmatic studies are needed to investigate the relationship between ReMI during the acute phase and prognosis.
Major Bleeding and Subsequent Mortality
Many studies have reported a strong association between major bleeding and mortality4, 7, 12, 14, 15). Major bleeding such as intracranial hemorrhage or severe blood loss as can occur in gastrointestinal hemorrhage also may directly result in mortality, although such bleeding events would not explain the prolonged mortality risk observed after a major bleeding event. It was reported as one of the reasons that major bleeding might necessitate the discontinuation of antiplatelet or antithrombotic medications that increase the risk of thrombotic events. The risk of thrombotic events was highest during the acute phase after cessation of antiplatelet treatment due to bleeding16). It may explain the reason why the impact of bleeding on mortality is higher during the acute phase. It was also reported that increased production of erythropoietin in response to anemia may contribute to a prothrombotic systemic state beyond the acute phase17, 18). Some studies demonstrated that blood transfusions can cause effects such as inflammatory cascade activation or vasoconstriction and be linked to adverse shorter- and longer-term mortality19, 20). According to previous studies using mice models, plasma cardiac troponin levels were significantly increased in mice of hemorrhagic shock model. It might reflect injury of cardiomyocytes with marked disruption of the cardiac gap junction21). Hemorrhagic shock also caused ventricular structural remodeling and induced ventricular arrhythmia in the presence of action potential duration dispersion22). These studies suggested that major bleeding after AMI can cause damage of the myocardium, increase cardiac events, and affect late mortality. The non-availability of data of drug discontinuation, blood transfusion, erythropoietin, and cardiac function in the present study does not allow us to investigate the precise mechanisms by which bleeding events adversely affect long-term prognosis. Further studies are required to elucidate the mechanisms of the association between bleeding and late mortality.
Clinical Implication
This study demonstrated that only major bleeding affected 30-day and 1-year mortality after adjustment for covariates. Improvements in the PCI technique, device technology, and medications may have also further reduced thrombotic risks23). The proportion of patients with high bleeding risk is expected to increase in the future24-26). We should be more concerned about bleeding event during the acute phase after PCI, particularly for these patients, and should appropriately select a bleeding-risk-oriented strategy to improve their prognosis.
Study Limitation
This study has several limitations that need to be acknowledged. First, we had no access to data on medication on admission and during the long-term follow-up. Medication on admission might affect in-hospital outcomes in the acute phase. Some medications may have changed during the follow-up period. The duration of DAPT could not be assessed, although most patients might have 1-year or longer DAPT based on the guidelines at the time of patient enrollment. Furthermore, the prescription for a proton pump inhibitor was not available in our database, which does not allow us to assess the influence of the drug on the event rate of gastrointestinal bleeding. Second, comprehensive information pertaining to the PCI procedure was unavailable for analysis. The specific access site used during primary PCI holds significance, particularly in relation to bleeding events. It is noteworthy that the radial approach has historically demonstrated a reduced risk of bleeding compared with the femoral approach19). Regrettably, the specific details regarding the access site of PCI were not accessible within our database. Recent advancement of these procedures and device technologies possibly provides differing results. Further studies are warranted to assess the impact of bleeding or thrombotic events with the latest device, techniques, and drug therapies. Third, the major bleeding criteria used in the OACIS registry are innovative and exhibit slight disparities compared with the criteria presently utilized in clinical practice, as no officially sanctioned bleeding criteria were available when the OACIS registry was initiated in 1998. Our criteria bear a striking resemblance to those utilized in the ACUTY trial, which was published in 2006 27). A comprehensive summary comparing the major bleeding criteria is presented in Supplemental Table 3. Fourth, our database unfortunately lacked comprehensive information pertaining to the contents of major bleeding events occurring within 7 days of PCI. This limitation hindered our ability to delve into the intricacies of major bleeding during the specified timeframe. Furthermore, data regarding the bleeding site was solely accessible for cases resulting in fatality (Supplemental Fig.1). Notably, intracranial bleeding emerged as the predominant cause of fatal bleeding. Fifth, albeit the relatively large-scale sample size, the event number might have been underpowered, resulting in type II error. Finally, the results of this study are based on the analyses using the database of the East Asian registry, which limits the generalizability of the current findings to other races.
Supplemental Table 3.Comparison of criteria for major bleeding in this and previous studies
|
Major bleeding criteria |
Reference |
| OACIS |
Hemoglobin drop ≥ 4 g/dL Intracranial hemorrhage Requirement of surgical treatment Requirement of any transfusion |
|
| ACUITY |
Intracranial or intraocular hemorrhage
Access-site hemorrhage requiring intervention ≥ 5cm hematoma
Retroperitoneal Reduction in hemoglobin concentration of ≥ 4 g/dL without an overt source of bleeding
Reduction in hemoglobin concentration of ≥ 3 g/dL with an overt source of bleeding Reoperation for bleeding
Use of any blood product transfusion
|
Stone GW, et al. N Engl J Med, 2006; 355: 2203-2216
|
|
BARC
(Type3 or 5)
|
Type 3 Type 3a
Overt bleeding plus hemoglobin drop of 3 to <5 g/dL Any transfusion with overt bleeding
Type 3b
Overt bleeding plus hemoglobin drop ≥5 g/dL
Cardiac tamponade Bleeding requiring surgical intervention for control Bleeding requiring intravenous vasoactive agents
Type 3c
Intracranial hemorrhage
Subcategories confirmed by autopsy or imaging or lumbar puncture Intraocular bleed compromising vision
Type 5: fatal bleeding Type 5a
Probable fatal bleeding; no autopsy or imaging confirmation but clinically suspicious Type 5b
Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation
|
|
| Mehran R, et al. Circulation, 2011; 123: 2736-2747
|
| ISTH |
Fatal bleeding
Symptomatic bleeding in a critical area or organ, such as intracranial, intraspinal, intraocular, retroperitoneal, intraarticular or pericardial, or intramuscular with compartment syndrome
Bleeding causing a fall in hemoglobin level of 20 g/L or more, or leading to transfusion of two or more units of whole blood or red cells.
|
Schulman S, et al. J Thromb Haemost, 2005; 3: 692-694
|
| TIMI |
Any intracranial bleeding
Clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥ 5 g/dL Fatal bleeding (bleeding that directly results in death within 7 days)
|
Wiviott SD, et al. N Engl J Med, 2007; 357: 2001-2015
|
Conclusions
This study showed the time-sensitive variation of bleeding and thrombotic events. Major bleeding within 7 days of PCI for AMI was independently associated with a higher 30-day and 1-year mortality but not that during 1–5 years. ReMI within 7 days of PCI was not associated with an incremental risk of mortality in all phases.
Acknowledgements
We thank Nagisa Yoshioka, Satomi Kishimoto, Kyoko Tatsumi, Noriko Murakami, Mariko Kishida, Rie Nagai, Sugako Mitsuoka, and all other OACIS research coordinators and nurses for their excellent assistance with data collection. This study was supported in part by a grant from the Health and Labor Sciences Research Grant (Comprehensive Research on Life-Style-Related Disease including Cardiovascular Diseases and Diabetes Mellitus, 20FA1018), and by JSPS KAKENHI Grant Number JP22K16073.
Conflict of Interest
Yohei Sotomi received research grants from Abbott Medical Japan and TOA EIYO, and speaker honoraria from Abbott Medical Japan, Boston Scientific Japan, and Bristol Myers Squibb, and is an endowed chair funded by TOA EIYO. Shungo Hikoso received speaker honoraria from Daiichi Sankyo, Bayer, and Nippon Boehringer Ingelheim Japan. Yasuhiko Sakata received speaker honoraria from AstraZeneca, Nippon Boehringer Ingelheim, Ono Pharmaceutical, and Eli Lilly Japan. Issei Komuro received speaker honoraria from AstraZeneca, Otsuka Pharmaceutical, Ono Pharmaceutical, Kowa company, Daiichi Sankyo, Nippon Boehringer Ingelheim, Novartis Pharma and Bayer, and research grants from Takeda Pharmaceutical and Mitsubishi Tanabe pharma corporation. Yasushi Sakata received research grants from Nippon Boehringer Ingelheim and Bayer, speaker honoraria from Nippon Boehringer Ingelheim, Bayer and Daiichi Sankyo, and research funding from Nippon Boehringer Ingelheim and Bristol Myers Squibb. The other authors have nothing to disclose.
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