Abstract
Background:
Previous studies have reported that acute myocardial infarction (AMI) related to left anterior descending (LAD) lesion is associated with worse outcomes than left circumflex artery (LCX) or right coronary artery (RCA) lesions. However, it is unknown whether those relationships are still present in the contemporary era of primary percutaneous coronary intervention (PCI), using newer generation drug-eluting stents and potent antiplatelet agents.
Methods and Results:
This study is a sub-analysis of the Japan AMI Registry (JAMIR), a multicenter, prospective registry enrolling 3,411 AMI patients between December 2015 and May 2017. Among them, 2,780 patients undergoing primary PCI for only a culprit vessel were included and stratified based on infarction-related artery type (LAD, LCX, and RCA). The primary outcome was 1-year cardiovascular death. The overall incidence of cardiovascular death was 3.4%. Patients with LAD infarction had highest incidence of cardiovascular death compared to patients with LCX and RCA infarction (4.8%, 1.3%, and 2.4%, respectively); however, landmark analysis showed that culprit vessel had no significant effect on cardiovascular death if a patient survived 30 days after primary PCI. LAD lesion infarction was an independent risk factor for cardiovascular death in adjusted Cox regression analysis.
Conclusions:
The present sub-analysis of the JAMIR demonstrated that LAD infarction is still associated with worse outcomes, especially during the first 30 days, even in the contemporary era of PCI.
There has been a steady trend of decreasing in-hospital mortality, at approximately 5–8% for acute myocardial infarction (AMI) in the Japanese population, probably owing to the increased use of ambulance and primary percutaneous coronary intervention (PCI).1,2
Particularly, primary PCI for AMI has been shown to reduce cardiac adverse events, to convey earlier discharge and to lead to hemodynamic stabilization in cardiogenic shock, and subsequently to become a standard care in Japan.3
In addition, the introduction of second-generation and newer drug-eluting stents has markedly decreased the incidence of stent thrombosis even in patients with AMI.4
Furthermore, a recent introduction of a potent P2Y12
receptor inhibitor was found to have an adequate inhibitory effect on thrombotic events without an increase of bleeding risk after PCI in patients with AMI.5,6
The location of the culprit vessel is an important clinical predictor of outcomes in patients with AMI. Previous studies have demonstrated that the AMI related to the left anterior descending (LAD) lesion was associated with worse clinical outcomes due to the larger extent of myocardial damage, compared to the left circumflex artery (LCX) or right coronary artery (RCA) lesions.7–9
However, these studies were performed in the era of pre-reperfusion, thrombolysis, balloon angioplasty, and bare-metal stents. Therefore, it may not be applicable in the context of contemporary practice, including primary PCI using newer generation drug-eluting stents and potent antiplatelet therapies, and in the setting of overall improved AMI outcomes. In addition, it is unclear whether the effect of the infarction location on outcomes is seen in the short term as well as long term after primary PCI. Furthermore, there is ongoing uncertainty about whether LAD infarction predicts worse clinical outcome independently of infarct size.
The aim of this study was therefore to investigate the independent effect of the location of an infarction-related coronary artery, in particular the LAD, on the short-term as well as long-term clinical outcomes in a large population of Japanese AMI patients treated by contemporary primary PCI and medications, who were enrolled into the nationwide Japan AMI Registry (JAMIR).
Methods
Study Population
The design of the JAMIR has previously been described in detail.10
Briefly, JAMIR is a multicenter, nationwide, prospective registry enrolling consecutive patients with spontaneous onset of AMI at 50 institutions between December 2015 and May 2017. For diagnosing patients with AMI, either the universal definition of myocardial infarction criteria or the Monitoring Trends and Determinants in Cardiovascular disease (MONICA) criteria were used.11,12
We excluded patients who were admitted to the hospital ≥24 h after onset, those with no return of spontaneous circulation on admission after an out-of-hospital cardiopulmonary arrest, and those who had AMI as a complication of PCI or coronary artery bypass grafting (CABG). Management of patients was dependent on the discretion of the treating physician. Primary data were collected from the medical records of the patients. Information including patient demographics, medical history, ambulance use, details about coronary angiography and invasive therapy, cardiac medications, and outcomes were collected. The JAMIR registration system was used for data registration by investigators, clinical research coordinators, or local data managers at each study site. A follow-up data collection was performed 1 year after the onset of AMI based on the medical information available at each study site. When patients’ medical information was unavailable at the study sites after 1 year due to hospital transfer or other reasons, a letter requesting follow up was sent to the relevant patients.
This study was conducted in accordance with the ethical guidelines for medical research on humans laid out in the Declaration of Helsinki. This research protocol was approved by the Institutional Review Board of the National Cerebral and Cardiovascular Center and local ethics committees or local institutional review board at each study site. Although informed consent was not obtained, because of the observational nature of this registry, we applied an opt-out method using a website and at the study sites to show the subjects the content and timeline of the study, and to ensure that the subjects had the opportunity to refuse inclusion into this registry. In addition, the research secretariat confirmed compliance with opt-out procedures at each study site. This study was registered with the Japanese UMIN Clinical Trials Registry (UMIN000019479).
Study Endpoints
The primary endpoint of the study was a 1-year cardiovascular death. Secondary endpoints included 1-year all-cause death, MI, and stroke. Incidences of 1-year stent thrombosis and type 3 or type 5 bleeding based on Bleeding Academic Research Consortium (BARC) criteria were also evaluated. Definition of these clinical events was previously described in detail.10
A major adverse cardiac event (MACE) was defined as a composite of cardiovascular death, non-fatal MI, and non-fatal stroke.
Statistical Analysis
Baseline continuous variables are presented as mean with standard deviation (SD) for normally distributed variables or median with interquartile range for skewed variables. Categorical variables are presented as number (percentage). Comparisons of continuous variables with normal distribution were tested by an analysis of variance. Comparisons of continuous variables with a non-normal distribution were tested by using the Kruskal-Wallis test. Categorical variables were analyzed by using the chi-squared test as appropriate. The cumulative incidence of cardiovascular death was evaluated by using the Kaplan-Meier method, and its difference was assessed using log-rank tests. To distinguish early events after PCI from long-term events, landmark analysis was performed at 30 days. Those patients with the endpoint events before 30 days were excluded from the landmark analysis beyond 30 days. Multivariate Cox proportional hazard models were used to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of infarction-related arteries on the primary and secondary endpoints. Clinically relevant covariates including age (≥75 years), sex (male), clinical presentation (ST-elevation MI [STEMI] or non-STEMI), history of cerebrovascular disease, estimated glomerular filtration rate (eGFR) (<30 mL/min/1.73 m2), door-to-device time (<90 min), stent use, final Thrombolysis in Myocardial Infarction (TIMI) flow (≤2), peak creatine kinase (CK) (≥1,655 IU/L, its median value), history of previous myocardial infarction or CABG were included in the models as confounders. A 2-sided P<0.05 was considered statistically significant. All statistical analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA).
Results
Baseline Patient Characteristics
A total of 3,411 patients were registered to the JAMIR from the 50 sites. The current study excluded the following subjects: 104 patients who did not undergo emergent coronary angiography; 214 patients who were not treated with early reperfusion therapy; 26 patients who were treated with CABG; 173 patients who underwent PCI for culprit vessel related to infarction as well as non-culprit vessel; 78 patients who had culprit lesions in the left main coronary artery (LMCA), bypass graft, or undetermined; and 64 patients who were considered as having multiple culprit vessels. Finally, 2,780 patients were included in the current analysis (Figure 1). Of these, the distribution of the infarction-related artery location was the LAD in 1,353 patients (48.7%), the LCX in 386 patients (13.9%), and the RCA in 1,041 patients (37.5%).
Table 1
shows the baseline patient characteristics among patients with LAD, LCX and RCA infarction. Patients with LAD infarction had a significantly higher frequency of Killip class ≥2, increased peak CK and CK-MB level, reduced left ventricular ejection fraction (LVEF), and lower prevalence of previous CABG. Patients with LCX infarction presented to the hospital later after symptom onset and had lower prevalence of STEMI. Patients with RCA infarction had a higher rate of ambulance use and frequency of shock on arrival, lower rate of hypertension, and decreased level of eGFR and hemoglobin. The vast majority of patients received dual-antiplatelet therapy with aspirin plus P2Y12
receptor inhibitors and statins during hospitalization. Particularly, prasugrel was a most common P2Y12
receptor inhibitor. Concomitant medications during hospitalization including antiplatelet drugs, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, β-blockers and statins were comparable among the 3 groups, but the use of oral anticoagulants was more frequent in patients with LAD infarction. Duration of hospitalization was slightly but significantly different among the groups.
Table 1.
Baseline Patient Characteristics
| |
Overall
(n=2,780) |
LAD
(n=1,353) |
LCX
(n=386) |
RCA
(n=1,041) |
P value |
| Age (years) |
68±13 |
67±13 |
69±13 |
68±13 |
0.154 |
| Female |
623 (22.4) |
297 (22.0) |
84 (21.8) |
242 (23.3) |
0.713 |
| BMI (kg/m2) |
24.0±3.9 |
24.0±4.0 |
24.0±3.8 |
24.0±3.9 |
0.996 |
| Use of ambulance |
2,299 (82.7) |
1,105 (81.7) |
308 (79.8) |
886 (85.1) |
0.023 |
| Out-of-hospital cardiac arrest |
91 (3.3) |
52 (3.9) |
13 (3.4) |
26 (2.5) |
0.185 |
| Shock on arrival (SBP <90 mmHg) |
156 (5.8) |
45 (3.4) |
10 (2.7) |
101 (10.1) |
<0.001 |
| Time from onset to admission (min) |
138 [64–313] |
138 [63–305] |
188 [83–420] |
125 [60–270] |
<0.001 |
| STEMI |
2,264 (81.4) |
1,130 (83.5) |
216 (56.0) |
918 (88.2) |
<0.001 |
| Killip class ≥2 |
549 (19.8) |
295 (21.8) |
54 (14.0) |
200 (19.2) |
0.003 |
| Hypertension |
1,999 (71.9) |
993 (73.4) |
286 (74.1) |
720 (69.2) |
0.044 |
| Diabetes |
939 (33.8) |
452 (33.4) |
129 (33.4) |
358 (34.4) |
0.870 |
| Dyslipidemia |
1,931 (69.5) |
931 (68.8) |
281 (72.8) |
719 (69.1) |
0.305 |
| Previous myocardial infarction |
229 (8.2) |
97 (7.2) |
39 (10.1) |
93 (8.9) |
0.106 |
| Previous PCI |
289 (10.4) |
124 (9.2) |
42 (10.9) |
123 (11.8) |
0.103 |
| Previous CABG |
49 (1.8) |
11 (0.8) |
14 (3.6) |
24 (2.3) |
<0.001 |
| Previous cerebrovascular disease |
252 (9.1) |
116 (8.6) |
36 (9.3) |
100 (9.6) |
0.671 |
| Peripheral artery disease |
94 (3.4) |
45 (3.3) |
16 (4.2) |
33 (3.2) |
0.656 |
| Malignancy |
229 (8.2) |
110 (8.1) |
29 (7.5) |
90 (8.7) |
0.772 |
| Atrial fibrillation |
184 (6.6) |
99 (7.3) |
20 (5.2) |
65 (6.2) |
0.273 |
| Current smoking |
1,157 (41.6) |
553 (40.9) |
165 (42.8) |
439 (42.2) |
0.725 |
| eGFR (mL/min/1.73 m2) |
66.5±26.8 |
69.2±23.2 |
67.8±25.6 |
62.6±31.0 |
<0.001 |
| Hemoglobin (g/dL) |
13.9±2.1 |
14.2±2.2 |
14.0±2.1 |
13.6±2.1 |
<0.001 |
| Peak CK (IU/L) |
1,655 [650–3,404] |
1,859 [591–4,168] |
1,357 [519–2,812] |
1,598 [726–2,900] |
<0.001 |
| Peak CK-MB (IU/L) |
158 [60–329] |
185 [57–401] |
142 [54–289] |
145 [66–286] |
<0.001 |
| LVEF (%) |
52.2±11.9 |
49.6±12.4 |
55.2±10.2 |
54.6±11.1 |
<0.001 |
| Medication during hospitalization |
| Aspirin |
2,749 (98.9) |
1,335 (98.7) |
383 (99.2) |
1,031 (99.0) |
0.551 |
| Clopidogrel |
454 (16.3) |
222 (16.4) |
71 (18.4) |
161 (15.5) |
0.411 |
| Prasugrel |
2,400 (86.3) |
1,173 (86.7) |
322 (83.4) |
905 (86.9) |
0.197 |
| ACE inhibitors |
1,515 (54.5) |
752 (55.6) |
204 (52.9) |
559 (53.7) |
0.514 |
| ARBs |
770 (27.7) |
374 (27.6) |
113 (29.3) |
283 (27.2) |
0.734 |
| β-blockers |
1,831 (65.9) |
913 (67.5) |
239 (61.9) |
679 (65.2) |
0.109 |
| Statins |
2,562 (92.2) |
1,238 (91.5) |
354 (91.7) |
970 (93.2) |
0.298 |
| Oral anticoagulants |
346 (12.5) |
185 (13.7) |
35 (9.1) |
126 (12.1) |
0.049 |
| Mechanical complication |
| Cardiac rupture |
16 (0.58) |
12 (0.89) |
1 (0.26) |
3 (0.29) |
0.107 |
| Ventricular septal perforation |
2 (0.07) |
2 (0.15) |
0 (0) |
0 (0) |
0.348 |
| Papillary muscle rupture |
1 (0.04) |
0 (0) |
1 (0.26) |
0 (0) |
0.045 |
| Length of hospital stay (days) |
12 [8–16] |
12 [8–16] |
11 [8–14] |
12 [9–16] |
0.044 |
Data are presented as mean±standard deviation, median [interquartile range] or number (%). ACE, angiotensin-converting enzyme; ARBs, angiotensin II receptor blockers; BMI, body mass index; CABG, coronary artery bypass grafting; CK, creatinine kinase; eGFR, estimated glomerular filtration rate; LAD, left anterior descending artery; LCX, left circumflex artery; LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention; RCA, right coronary artery; SBP, systolic blood pressure; STEMI, ST-elevation myocardial infarction.
Table 2
shows the angiographic and interventional characteristics. A large proportion of patients were treated by newer-generation drug-eluting stents. Patients with LCX infarction were associated with longer door-to-device time, less frequent use of intra-aortic balloon pumping (IABP), and more frequent use of transradial access. Final TIMI flow was significantly decreased in patients with RCA infarction. Number of diseased vessels was significantly decreased in patients with LAD infarction.
Table 2.
Angiographic and Interventional Characteristics
| |
Overall
(n=2,780) |
LAD
(n=1,353) |
LCX
(n=386) |
RCA
(n=1,041) |
P value |
| Puncture site |
|
|
|
|
0.001 |
| Radial |
1,859 (66.9) |
923 (68.2) |
282 (73.1) |
654 (62.8) |
|
| Femoral |
871 (31.3) |
404 (29.9) |
96 (24.9) |
371 (35.6) |
|
| Brachial |
50 (1.8) |
26 (1.9) |
8 (2.1) |
16 (1.5) |
|
| Number of diseased vessels |
|
|
|
|
<0.001 |
| 0 |
4 (0.1) |
0 (0) |
2 (0.5) |
2 (0.2) |
|
| 1 |
1,685 (60.6) |
897 (66.3) |
206 (53.4) |
582 (55.9) |
|
| 2 |
691 (24.9) |
291 (21.5) |
119 (30.8) |
281 (27.0) |
|
| 3 |
400 (14.4) |
165 (12.2) |
59 (15.3) |
176 (16.9) |
|
| Mean number of diseased vessels |
1.5±0.7 |
1.5±0.7 |
1.6±0.8 |
1.6±0.8 |
<0.001 |
| Thrombolysis |
17 (0.6) |
5 (0.4) |
3 (0.8) |
9 (0.9) |
0.276 |
| Door-to-device time (min) |
69 [51–100] |
68 [50–100] |
82 [57–135] |
67 [51–91] |
<0.001 |
| Stent use |
2,538 (91.6) |
1,247 (92.3) |
340 (88.5) |
951 (91.8) |
0.061 |
| DES use |
2,467 (89.0) |
1,218 (90.2) |
330 (85.9) |
919 (88.7) |
0.060 |
| Type of DES |
| EES |
1,857 (75.3) |
921 (75.6) |
249 (75.5) |
687 (74.8) |
0.898 |
| BES |
20 (0.8) |
7 (0.6) |
1 (0.3) |
12 (1.3) |
0.095 |
| ZES |
165 (6.7) |
70 (5.8) |
27 (8.2) |
68 (7.4) |
0.161 |
| uSES |
439 (17.8) |
226 (18.6) |
54 (16.4) |
159 (17.3) |
0.578 |
| Final TIMI flow |
|
|
|
|
0.009 |
| 0 |
34 (1.2) |
10 (0.7) |
3 (0.8) |
21 (2.0) |
|
| 1 |
32 (1.2) |
12 (0.9) |
1 (0.3) |
19 (1.8) |
|
| 2 |
144 (5.2) |
73 (5.4) |
17 (4.4) |
54 (5.2) |
|
| 3 |
2,570 (92.5) |
1,258 (93.0) |
365 (94.6) |
947 (91.0) |
|
| Use of IABP |
259 (9.3) |
148 (10.9) |
17 (4.4) |
94 (9.0) |
0.001 |
| Use of V-A ECMO |
31 (1.1) |
19 (1.4) |
1 (0.3) |
11 (1.1) |
0.163 |
Data are presented as mean±standard deviation, median [interquartile range] or number (%). BES, biolimus-eluting stent; DES, drug-eluting stent; ECMO, extra-corporeal membrane oxygenation; EES, everolimus-eluting stent; IABP, intra-aortic balloon pumping; LAD, left anterior descending artery; LCX, left circumflex artery; RCA, right coronary artery; TIMI, Thrombolysis in Myocardial Infarction; uSES, ultimaster sirolimus-eluting stent; ZES, zotarolimus-eluting stent.
The median follow-up period was 11.7 months (interquartile range, 9.4–13.1 months).
Table 3
summarizes the unadjusted incidence of the primary, secondary endpoints, and other clinical outcomes. In the primary endpoint analysis, patients with LAD infarction showed the highest incidence of cardiovascular death compared to LCX and RCA infarction. In the secondary endpoint analysis, patients with LAD infarction showed a significantly higher incidence of all-cause death and a lower incidence of stroke. There were no significant differences in the incidence of myocardial infarction, stent thrombosis, and BARC type 3 or 5 bleeding. The Kaplan-Meier curves for the primary endpoint are presented in
Figure 2. Patients with LAD infarction carried the highest cumulative incidence of cardiovascular death compared to those with LCX and RCA infarctions (Log-rank P<0.001). In the 30-day landmark analysis, the cumulative incidence of cardiovascular death was higher in patients with LAD infarction than in those with LCX and RCA infarctions within 30 days (Log-rank P=0.012); however, it was no longer significant beyond 30 days (Log-rank P=0.141).
Table 3.
One-Year Clinical Outcomes
| |
Overall
(n=2,780) |
LAD
(n=1,353) |
LCX
(n=386) |
RCA
(n=1,041) |
P value |
| Cardiovascular death |
95 (3.4) |
65 (4.8) |
5 (1.3) |
25 (2.4) |
<0.001 |
| All-cause death |
170 (6.1) |
101 (7.5) |
15 (3.9) |
54 (5.2) |
0.010 |
| Myocardial infarction |
71 (2.6) |
33 (2.4) |
12 (3.1) |
26 (2.5) |
0.755 |
| Stroke |
28 (1.0) |
6 (0.4) |
6 (1.6) |
16 (1.5) |
0.015 |
| Stent thrombosis |
18 (0.7) |
11 (0.8) |
1 (0.3) |
6 (0.6) |
0.458 |
| BARC type 3 or 5 bleeding |
121 (4.4) |
63 (4.7) |
9 (2.3) |
49 (4.7) |
0.111 |
Data are presented as number (%). BARC, Bleeding Academic Research Consortium; LAD, left anterior descending artery; LCX, left circumflex artery; RCA, right coronary artery.
Table 4
lists the incidences of MACE and all-cause death before and after discharge. Incidences of in-hospital MACE, cardiovascular death, and all-cause death were significantly higher in patients with LAD infarction compared to those with non-LAD infarction. In contrast, the incidences of these events after discharge did not differ significantly among the groups. The incidence of cardiovascular death after discharge was relatively low compared to that before discharge. The most frequent causes of death after discharge were non-cardiovascular related in 72% of cases. There were no significant differences in the incidences of non-fatal myocardial infarction and non-fatal stroke among the groups before and after discharge.
Table 4.
Major Adverse Cardiac Events and All-Cause Death Before and After Discharge
| |
Overall |
LAD |
LCX |
RCA |
P value |
| In-hospital |
(n=2,780) |
(n=1,353) |
(n=386) |
(n=1,041) |
|
| Major adverse cardiac events |
102 (3.7) |
63 (4.7) |
7 (1.8) |
32 (3.1) |
0.014 |
| Cardiovascular death |
76 (2.7) |
53 (3.9) |
3 (0.8) |
20 (1.9) |
0.001 |
| Non-fatal myocardial infarction |
12 (0.4) |
7 (0.5) |
2 (0.5) |
3 (0.3) |
0.671 |
| Non-fatal stroke |
11 (0.4) |
2 (0.2) |
2 (0.5) |
7 (0.7) |
0.118 |
| All-cause death |
101 (3.6) |
64 (4.7) |
8 (2.1) |
29 (2.8) |
0.009 |
| After discharge |
(n=2,679) |
(n=1,289) |
(n=378) |
(n=1,012) |
|
| Major adverse cardiac events |
80 (3.0) |
35 (2.7) |
15 (4.0) |
30 (3.0) |
0.452 |
| Cardiovascular death |
19 (0.7) |
12 (0.9) |
2 (0.5) |
5 (0.5) |
0.419 |
| Non-fatal myocardial infarction |
47 (1.8) |
20 (1.6) |
9 (2.4) |
18 (1.8) |
0.557 |
| Non-fatal stroke |
15 (0.6) |
4 (0.3) |
4 (1.1) |
7 (0.7) |
0.179 |
| All-cause death |
69 (2.6) |
37 (2.9) |
7 (1.9) |
25 (2.5) |
0.527 |
Data are presented as number (%). Major adverse cardiac events were defined as a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. LAD, left anterior descending artery; LCX, left circumflex artery; RCA, right coronary artery.
The hazard ratios for primary and secondary endpoints are shown in
Table 5. LAD infarction had a significantly higher risk of cardiovascular death and all-cause death compared to RCA infarction in unadjusted as well as adjusted regression analyses. In contrast, unadjusted and adjusted risk of stroke was significantly lower in LAD infarction compared to RCA infarction patients. Those significant differences were not detected between LCX and RCA infarction.
Table 5.
Adjusted Hazard Ratios for Primary and Secondary Endpoints
| |
Unadjusted |
Multivariable† |
| HR |
95% CI |
P value |
HR |
95% CI |
P value |
| Cardiovascular death |
| LAD |
2.02 |
1.27–3.20 |
0.003 |
2.84 |
1.75–4.61 |
<0.001 |
| LCX |
0.53 |
0.20–1.39 |
0.200 |
0.62 |
0.23–1.67 |
0.345 |
| All-cause death |
| LAD |
1.45 |
1.04–2.02 |
0.028 |
1.94 |
1.38–2.74 |
<0.001 |
| LCX |
0.73 |
0.41–1.29 |
0.281 |
0.88 |
0.49–1.60 |
0.680 |
| Myocardial infarction |
| LAD |
0.98 |
0.58–1.63 |
0.927 |
1.06 |
0.63–1.79 |
0.827 |
| LCX |
1.21 |
0.61–2.40 |
0.587 |
1.22 |
0.60–2.50 |
0.589 |
| Stroke |
| LAD |
0.29 |
0.11–0.74 |
0.010 |
0.37 |
0.14–0.97 |
0.044 |
| LCX |
0.99 |
0.39–2.53 |
0.979 |
1.06 |
0.39–2.88 |
0.912 |
HRs were calculated for LAD and LCX compared with RCA infarctions. CI, confidence interval; HR, hazard ratio; LAD, left anterior descending artery; LCX, left circumflex artery; RCA, right coronary artery. †Multivariable Cox hazard modeling using clinically relevant covariates including age (≥75 years), sex (male), presence of ST-elevation myocardial infarction, history of cerebrovascular disease, estimated glomerular filtration rate (<30 mL/min/1.73 m2), door-to-device time (<90 min), stent use, final Thrombolysis in Myocardial Infarction (TIMI) flow (≤2), peak CK (≥1,655 IU/L, its median value), history of previous myocardial infarction or coronary artery bypass grafting.
Discussion
The main findings of this large nationwide study are that: (1) patients with LAD infarction had the highest incidence of cardiovascular death compared to those with LCX and RCA infarctions; (2) landmark analysis at 30 days showed that culprit vessel had no significant effect on cardiovascular death if a patient survived 30 days after primary PCI; and (3) LAD infarction was an independent risk factor for cardiovascular death after adjustment by infarction size assessed by peak CK. Our results highlight the prognostic relevance of LAD infarction, especially during the first 30 days, even in the setting of the contemporary era of PCI using newer-generation drug-eluting stents and potent antiplatelet agents.
In the present study, patients with LAD infarction had the highest cardiovascular mortality compared to patients with LCX and RCA infarctions, which is consistent with many previous studies comparing LAD with non-LAD infarctions.7–9
It has been speculated that the worse outcome in patients with a LAD infarction is related to a larger amount of damaged myocardium. A previous pathological study reported a mean infarct size of 40% of the LV for LAD infarction, compared with 18% for RCA and 20% for LCX infarctions.13
Indeed, in the present study, LAD infarction was significantly associated with increased levels of peak CK and CK-MB, and reduced LVEF, which implies larger infarct size compared to LCX and RCA infarction.
A notable finding of the present study was that the landmark analyses at 30 days showed no difference in long-term cardiovascular death between infarct vessels, indicating that early mortality explains the excess mortality as a result of LAD infarctions. We speculated that reasons for the higher relatively short-term mortality in patients with LAD infarction might be due to acute and subacute sequelae, including heart failure, as well as several potentially fatal complications such as ventricular arrythmia or mechanical complications including cardiac rupture, ventricular septum perforation, and papillary muscle rupture.14
In contrast, the attenuation of differences in the incidence of late-phase cardiovascular death stratified by infarct vessels may be explained by the previous findings from Pedersen et al,15
who demonstrated that patients who survive the 30 days after an AMI and were treated with primary PCI had an excellent prognosis, and that non-cardiac death was the main cause of later deaths. Indeed, in the present study, the incidence of cardiovascular death after discharge was relatively low (0.7%) compared to that before discharge (2.7%). The most frequent causes of death after discharge were non-cardiovascular in 72% of cases. Unfortunately, we could not collect enough data on the details of death and comorbidities including heart failure, arrhythmia, or sudden death after primary PCI. Particularly, heart failure complicating AMI is common and may be present at admission or develop during hospitalization, and is strongly related to mortality.16
Further studies are warranted to investigate the correlations between location of infarction and cause of death in the short as well as long term.
In the present study, patients with a LAD infarction had the highest mortality compared with patients with non-LAD infarction, independent of infarct size based on peak CK levels. However, it has been controversial whether infarct location predicts worse clinical outcomes independently of infarct size.9,17,18
This discordance can be primarily ascribed to the lack of a means to quantify the infarction size precisely. Conventionally, peak CK levels after AMI have been used to estimate infarct size. Recently, cardiac magnetic resonance (CMR) has been considered to allow an accurate assessment of infarct size by using the late-gadolinium enhancement technique.19
A more recent study has demonstrated that larger infarction size, as determined by CMR imaging, was associated with higher mortality after primary PCI independent of infarct location.20
In contrast, in the present study, LAD infarction might be more often accompanied by heart failure, ventricular arrhythmia or mechanical complications after primary PCI than non-LAD infarctions. Those comorbidities are most likely to affect the cardiovascular mortality independently of infarct size. However, as discussed already, we could not collect enough data on the details of cardiovascular death and comorbidities. Further studies are required to investigate the interrelationships between location and size of myocardial infarction as well as clinical outcomes.
In the present study, the incidence of stroke was 1.0% in patients, overall. AMI is a long-established risk factor for ischemic stroke and was associated with increasing mortality.21
The relationship seems to be causal because thrombi are often identified overlying areas of ventricular dyskinesis.22
A recent registry study demonstrated that both LAD and LCX infarctions were significantly associated with higher event rates of stroke within 1 year after AMI compared with RCA infarction (1.5%, 1.7%, and 1.2%, respectively).23
The higher relative risk of stroke in patients with LAD (and LCX) infarction could be explained by the anatomical myocardial supply, because LAD supplies the apex of the heart where apical dyskinesia may lead to increased risk for mural thrombi.24
In contrast, the incidences of stroke in the present study were significantly lower in patients with LAD infarction compared to LCX, RCA infarctions (0.4%, 1.6%, and 1.5%, respectively). Part of the reason for this discrepancy resides in the higher prescription rate of oral anticoagulants in patients with LAD infarction. The details of indications for oral anticoagulants were unknown in the present study. The prevalence of a previous history of atrial fibrillation did not differ significantly among the groups, whereas there were no data on the incidence of new-onset atrial fibrillation during hospitalization in this study; hence, we cannot deny the possibility that new-onset atrial fibrillation was more frequent in patients with LAD infarction. In addition, oral anticoagulants might had been more frequently prescribed in patients with LAD infarction to prevent mural thrombi in LV. In contrast, some previous trials showed a marginally increased risk of stroke in patients with AMI who underwent thrombus aspiration;25
however, we cannot address this issue in this study because we have no data on use of thrombus aspiration.
Previous studies suggested that the LAD infarction was associated with an increased risk of cardiogenic shock development compared with LCX and RCA infarctions.26
In contrast, a recent study has shown that cardiogenic shock on arrival is most common in patients with RCA infarction compared to those with LAD and LCX infarctions (3.0%, 2.2%, and 2.8%, respectively).23
This is in line with our finding of the highest incidence cardiogenic shock on arrival in patients with RCA infarction compared to LAD and LCX infarctions (10.1%, 3.4%, and 2.7%, respectively). These inconsistent results may be because of a diverse definition of cardiogenic shock. Low blood pressure on clinical presentation is a constituent of cardiogenic shock. We speculate that a large proportion of cardiogenic shock in patients with RCA infarction in the present study is possibly associated with so-called ‘rhythm shock’, which implied hypotension due to sinus bradycardia or second-degree type II (Mobitz II) atrioventricular (AV) block and complete AV block. Those brady-arrhythmia associated with inferior wall infarction usually resolve spontaneously or after reperfusion.27
In addition, cardiogenic shock in patients with RCA infarction might occur in part as a result of the Bezold-Jarisch reflex.28
Therefore, the higher incidence of cardiogenic shock is likely to not be associated with worse outcome in patients with RCA infarction in the present study. To clarify this hypothesis, further study is warranted to examine the incidence of brady-arrythmia, right ventricular infarction, and frequency of temporary pacemaker use.
The current study demonstrated that patients with LCX infarction had a significantly longer time from onset to admission, lower prevalence of STEMI, and longer door-to-device time. It is likely that some patients with LCX infarction are ‘‘missed’’ during the early phases of AMI. LCX infarction is known to be overseen in the STEMI population due to mirror imaging in the ECG and can be diagnosed as non-STEMI. Notably, those clinical delays in diagnosing LCX infarction did not lead to a worse outcome in the present study. In general, an area at risk and amount of myocardial damage in a patient with an LCX infarction depends on the coronary artery dominance. A recent study showed that 40% of patients with LCX infarction complicated with shock had left or co-dominant coronary arteries, which indicate an association between coronary artery dominance and LV damage in patients with LCX infarction.29
Therefore, we need further studies to assess the LCX dominancy to clarify the association between clinical delay and outcomes in patients with LCX infarction.
In the present study, we excluded patients who had culprit lesions in the LMCA based on the following reasons. First, the JAMIR retrospective cohort analysis has already reported the high in-hospital mortality (27.3%) in patients with AMI due to LMCA lesions.30
Second, in the present JAMIR prospective cohort, the incidence of LMCA culprit lesion only occurred in 62 of 3,411 (2.0%) AMI patients.5
Therefore, patients with LMCA culprit lesions were not evaluated in the current analysis.
Study Limitations
There are several limitations to the present study. First, residual or unmeasured confounding factors are likely to persist due to the observational nature of this study. Second, although the present study was conducted in 50 institutions in Japan and participation was nationwide, it may have a bias in terms of the selection of the hospital chosen to participate. Therefore, our results may not reflect the full picture of non-participating centers. Third, we did not assess STEMI or non-STEMI separately because the number of patients with non-STEMI was low (516 patients). Fourth, only AMI patients treated by early revascularization therapy, almost all of which was PCI, were included; hence, our findings may not be applicable to AMI patients who were not treated without it. Fifth, patients who underwent concurrent PCI in the non-culprit vessel or had multiple culprit vessels were excluded in the current analysis because it could be difficult to ascertain the effect of the infarction-related vessel in those cases. Finally, because the present study is observational, the timing of blood sampling to measure CK levels was not specified by the protocol and was instead performed according to local hospital standards. Therefore, peak CK levels might be underestimated in some cases.
Conclusions
Despite major changes in the past years in contemporary primary PCI strategies (including wider use of newer-generation drug-eluting stents, as well as more potent antithrombotic agents), LAD infarction was independently associated with worse outcomes after primary PCI, with a markedly higher risk within 30 days. However, the culprit vessel had limited effect on cardiovascular death if a patient survived 30 days after primary PCI. Patients with LAD infarction might warrant more intense monitoring, treatment and follow up, especially during the first 30 days, even in the contemporary era of PCI.
Acknowledgments
The authors wish to thank all the investigators, clinical research coordinators, and data managers involved in the JAMIR study for their contributions. The JAMIR study group consists of the following institutions and members:
Hokkaido Medical Center: Takashi Takenaka; Hirosaki University: Hirofumi Tomita, Hiroaki Yokoyama; Iwate Medical University: Tomonori Ito, Masaru Ishida, Yorihiko Koeda; Yamagata University: Masafumi Watanabe, Tetsu Watanabe, Taku Toshima; Tohoku University: Hiroaki Shimokawa, Yasuhiko Sakata, Jun Takahashi, Kiyotaka Hao; Sakakibara Heart Institute: Tetsuya Sumiyoshi, Masamori Takayama; Yokohama City University Hospital: Kazuo Kimura, Masami Kosuge, Toshiaki Ebina; Showa University Fujigaoka Hospital: Hiroshi Suzuki, Atsuo Maeda; Mie University Hospital: Masaaki Ito, Tairo Kurita, Jun Masuda; Matsuzaka Central General Hospital: Takashi Tanigawa; Ehime University Hospital: Jitsuo Higaki, Kazuhisa Nishimura; Oita University: Naohiko Takahashi, Hidefumi Akioka, Kyoko Kawano; Nagasaki University: Koji Maemura, Yuji Koide; Kumamoto University: Sunao Kojima, Kenichi Tsujita; National Cerebral And Cardiovascular Center: Hisao Ogawa, Satoshi Yasuda, Yasuhide Asaumi, Kensaku Nishihira, Yoshihiro Miyamoto, Misa Takegami, Satoshi Honda; Nagasaki Harbor Medical Center: Hiroshi Nakajima; Isahaya General Hospital: Kenji Yamaguchi; Sapporo City General Hospital: Takao Makino; Sapporo Cardiovascular Clinic: Daitarou Kannno; Teine Keijinkai Hospital: Yasuhiro Omoto; Hokkaido Cardiology Hospital: Daisuke Otta; Sapporo Kosei General Hospital: Toshiya Sato; Nippon Medical School Musashi Kosugi Hospital: Naoki Sato, Arifumi Kikuchi, Michiko Sone, Koji Takagi; Ayase Heart Hospital: Imun Tei; Tokyo Metropolitan Hiroo General Hospital: Takashi Shibui, Sho Nagamine; Nippon Medical School Hospital: Wataru Shimuzu, Takeshi Yamamoto; Tokyo Saiseikai Central Hospital: Toshiyuki Takahashi; Tokyo Medical Center: Yukihiko Momiyama; St. Luke’s International Hospital: Atsushi Mizuno; Edogawa Hospital: Hiroshi Ohira; Kyorin University Hospital: Hideaki Yoshino, Youhei Shigeta; Nihon University Itabashi Hospital: Atsushi Hirayama, Yasuo Okurmura, Daisuke Fukamachi, Tadateru Takayama; Toho University Omori Medical Center: Hiroki Niikura, Hiroki Takenaka; Mitsui Memorial Hospital: Shuzo Tanimoto, Kazuyuki Yahagi; Tokyo Metropolitan Tama Medical Center: Hiroyuki Tanaka; Disaster Medical Center: Yasuhiro Sato, Ohno Masakazu; Musashino Red Cross Hospital: Takamichi Miyamoto, Nobuhiro Hara; NTT Medical Center: Mikio Kishi; Oume Municipal General Hospital: Sigeo Shimizu, Ken Kurihara; Oghikubo Hospital: Yasuhiro Ishii; Teikyo University Hospital: Ken Kozuma, Yusuke Watanabe; Fraternity Memorial Hospital: Yasuhiro Takahashi; Jikei University Hospital: Michihiro Yoshimura, Satoshi Morimoto; Tokyo Women’s Medical University Hospital: Nobuhisa Hagiwara, Yuichiro Minami; Tokyo Medical University Hospital: Jun Yamashita; Osaki Citizen Hospital: Kaoru Iwabuchi, Takeshi Yamauchi; Sendai Open Hospital: Atsushi Kato, Shigeto Namiuchi; Sendai Medical Center: Tsuyoshi Shinozaki, and Kesennuma City Hospital: Kazunori Ogata, Ryuji Tsuburaya.
Source of Funding
This work was planned by the Japan Cardiovascular Research Foundation and is financially supported by Daiichi Sankyo Co., Ltd.
Disclosures
Dr. Maemura reports lecture fees from Daiichi Sankyo, Novartis, and Takeda, and scholarship donations from Daiichi Sankyo; Dr. Takayama reports lecture fees from Daiichi Sankyo; Dr. Ogawa reports lecture fees and research grants from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Pfizer, and Sanofi; Dr. Yasuda reports remuneration for lectures from Takeda, Daiichi Sankyo, and Bristol-Myers Squibb, and trust research/joint research funds from Takeda and Daiichi Sankyo; Dr. Maemura, Dr. Kosuge, Dr. Sakata, Dr. Ogawa, Dr. Kimura, and Dr. Yasuda are members of
Circulation Journal’s Editorial Team. The remaining authors have no conflicts of interest to declare.
IRB Information
The ethics committee of the National Cerebral and Cardiovascular Center (M27-019-12) approved this study.
Data Availability
Data sharing is not applicable to this article because it could compromise the privacy of research participants.
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