Introduction
Acute myocardial infarction (AMI) complicated by cardiogenic shock is an emergency situation requiring immediate invasive therapeutic strategy [1]. Although early revascularization of the culprit lesion in the coronary artery yields significant survival gains, cardiogenic shock remains unresolved in many cases [2]. The application of extracorporeal membrane oxygenation (ECMO) can be considered in patients with AMI complicated by cardiogenic shock, who have not improved with medical treatment or intra-aortic balloon pump application. The 2020 European Society of Cardiology guidelines for patients without persistent ST-segment elevation recommended a short period of percutaneous mechanical circulatory support in selected patients with acute coronary syndrome complicated by cardiogenic shock [1]. Several reports on ECMO application in patients with AMI complicated by cardiogenic shock support this guideline. ECMO-assisted cardiopulmonary resuscitation (CPR) demonstrates better clinical outcomes than conventional CPR in patients with in-hospital cardiac arrest of cardiac origin [3]. Early application of ECMO has improved the survival among patients with AMI complicated by profound shock [4]. However, optimal application times and long-term clinical outcomes for ECMO remain unclear.
This study evaluated the 3-year clinical outcomes of patients with AMI complicated by cardiogenic shock according to the application and initiation time of ECMO.
Methods
This study was based on the Korean Acute Myocardial Infarction Registry – National Institutes of Health; a nationwide, prospective, observational multicenter registry including 20 large medical institutions/university hospitals. The collected clinical data were managed through the National Institute of Health’s Clinical Research and Trial Management System. All data were entered by research coordinators who have undergone professional training. The data input method of the coordinator, a regular progress check, and the registration status were thoroughly monitored. All patients provided written informed consent before enrollment in this study. This study was performed following the Declaration of Helsinki. Each institution gave ethical approval. The institutional review board approval number was CNUH-2011-172, Chonnam National University Hospital.
Among 13,104 patients with AMI registered in the Korean Acute Myocardial Infarction Registry – National Institutes of Health between November 2011 and December 2015, 949 with cardiogenic shock, who underwent successful percutaneous coronary intervention (PCI) were included in the study (Fig. 1). Cardiogenic shock is defined as systolic blood pressure < 90 mmHg for > 30 min even with adequate filling status with signs of hypoperfusion and at least one of the following: cold sweaty extremities, oliguria, mental confusion, metabolic acidosis, elevated serum lactate, and elevated serum creatinine [5–9]. Exclusion criteria were no cardiogenic shock, no PCI, and suboptimal/failed PCI.
The study population was divided into two groups depending on ECMO use: a no ECMO application group (n = 845) and an ECMO application group (n = 104). The ECMO application group was further divided into two groups according to whether or when they underwent CPR: an ECMO application after CPR group (n = 93) and an ECMO application without or before CPR group (n = 11). Only 1 patient underwent ECMO application before CPR among 11 patients. The interval between the two events was 38 days.
All medical treatments and procedures were conducted following the myocardial infarction guidelines. Dual antiplatelet therapy, a combination of acetylsalicylic acid and a P2Y12 inhibitor, was administered before the intervention. After coronary angiography, PCI was performed based on the decision of the individual operator. Successful PCI was defined as residual stenosis of the culprit lesion of < 30% and a Thrombolysis in Myocardial Infarction grade of III. The operator also determined the use of other equipment, including ECMO application. After the procedure, statins, beta-blockers, and renin–angiotensin system inhibitors were administered according to patient condition. In-hospital complications, such as acute heart failure, acute kidney injury, and major bleeding, were also investigated at admission. Major bleeding was defined according to the Thrombolysis in Myocardial Infarction Trial, as an intracranial hemorrhage or hemoglobin decrease of > 5 g/dL (or 15% in hematocrit) [10]. Follow-up for patients was conducted at 6 months and 1, 2, and 3 years from the discharge date. Follow-up examinations, including blood tests, echocardiography, and coronary angiography, were performed at the physician’s discretion.
The primary outcome was a major adverse cardiac event (MACE) (all-cause death [cardiac and non-cardiac], spontaneous myocardial infarction, repeat PCI, coronary artery bypass graft) at 3 years. The secondary endpoints were all-cause death, cardiac death, spontaneous myocardial infarction, and repeat revascularization at 3 years. Spontaneous myocardial infarction was defined as elevated levels of cardiac enzymes over the 99th percentile of the upper reference limit with typical chest pain or an electrocardiogram change. Repeat revascularization is considered ischemia-driven revascularization, involving repeat PCI and coronary artery bypass grafting. The definitions of all these cardiac events were based on the Academic Research Consortium [11].
Categorical data are expressed in counts and percentages. A chi-square test was used to evaluate the significance of the two variables. Fischer’s exact test was used when > 20% of cells had an expected count < 5. Continuous variables were represented by means and standard variances. Student’s t-test was used to evaluate the significance of the two variables. Normality distribution was determined with the Kolmogorov–Smirnov and Shapiro–Wilk tests. If the two variables were not normally distributed, the Mann–Whitney test was used. Kaplan–Meier curve analysis was performed to calculate cumulative event rates. The survival rates of the two groups were compared using the log-rank test. Univariable analysis was performed by inserting variables into the Cox proportional hazards model. In multivariable analysis, clinically relevant variables with a p-value < 0.05 in univariable analysis were inserted into the multivariable Cox model. The following variables included in the multivariable analysis had missing values: current smoker (n = 26), left ventricular ejection fraction (n = 156), and creatinine (n = 1). Statistical significance was determined with a 2-tailed test and was considered significant at p < 0.05. The 95% confidence intervals (CI) and hazard ratios (HR) were estimated by Cox regression. All statistical analyses were performed using IBM® SPSS® Statistics, version 25.0.
Results
All patients were monitored for 3 years; the median follow-up duration was 689 days. Baseline clinical characteristics of the patients, initial laboratory findings at admission, and medications administered during hospitalization are summarized in Table 1. Although patients in the ECMO application group were younger than those in the no ECMO application group, they had more Killip class ≥ 3 (72.1% vs. 46.6%; p < 0.001), ST-segment elevation myocardial infarction (80.8% vs. 71.6%; p < 0.048) at initial presentation, lower blood pressure, and lower left ventricular ejection fraction (34.0% vs. 48.2%; p < 0.001). Moreover, the ECMO application group showed higher myocardial enzyme levels and took fewer medicines, such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, beta-blockers, and statins. A comparison of the findings of the ECMO application without or before CPR group and ECMO application after CPR group revealed that they were similar, although the ECMO application without or before CPR group revealed higher heart rates, and the group members were administered more statins than those in the ECMO application after CPR group.
administered during admission.
Total |
No ECMO |
ECMO |
P |
Total |
ECMO |
ECMO |
P |
|
Demographics |
||||||||
Age [years] |
67.1 ± 12.4 |
67.6 ± 12.4 |
63.3 ± 11.8 |
0.001 |
63.3 ± 11.8 |
60.3 ± 13.2 |
63.6 ± 11.6 |
0.374 |
Age > 75 years |
310 (32.7%) |
290 (34.3%) |
20 (19.2%) |
0.002 |
20 (19.2%) |
3 (27.3%) |
17 (18.3%) |
0.439 |
Male |
684 (72.1%) |
603 (71.4%) |
81 (77.9%) |
0.162 |
81 (77.9%) |
8 (72.7%) |
73 (78.5%) |
0.704 |
Body mass index |
23.3 ± 3.3 |
23.2 ± 3.2 |
24.3 ± 3.9 |
0.004 |
24.3 ± 3.9 |
24.8 ± 3.1 |
24.2 ± 4.0 |
0.201 |
Initial presentation |
||||||||
Killip class ≥ 3 |
469 (49.4%) |
394 (46.6%) |
75 (72.1%) |
< 0.001 |
75 (72.1%) |
6 (54.5%) |
69 (74.2%) |
0.169 |
SBP [mmHg] |
100.5 ± 39.8 |
101.7 ± 39.9 |
90.5 ± 38.2 |
0.008 |
90.5 ± 38.2 |
102.8 ± 17.7 |
89.0 ± 39.8 |
0.140 |
DBP [mmHg] |
61.8 ± 26.5 |
62.5 ± 26.4 |
56.2 ± 26.8 |
0.024 |
56.2 ± 26.8 |
66.8 ± 13.5 |
54.9 ± 27.8 |
0.077 |
Heart rate [bpm] |
77.7 ± 30.7 |
77.4 ± 30.3 |
80.9 ± 33.8 |
0.272 |
80.9 ± 33.8 |
100.5 ± 28.3 |
78.5 ± 33.7 |
0.041 |
STEMI |
689 (72.6%) |
605 (71.6%) |
84 (80.8%) |
0.048 |
84 (80.8%) |
8 (72.7%) |
76 (81.7%) |
0.439 |
Process of care index |
||||||||
Symptom onset-to--door time [h] |
15.1 ± 61.2 |
15.6 ± 64.3 |
10.7 ± 25.6 |
0.439 |
10.7 ± 25.6 |
8.5 ± 13.1 |
11.0 ± 26.7 |
0.410 |
Door-to-balloon |
7.8 ± 27.6 |
8.0 ± 27.7 |
6.0 ± 27.0 |
0.488 |
6.0 ± 27.0 |
27.0 ± 77.3 |
3.6 ± 10.3 |
0.196 |
Cardiovascular risk factors |
||||||||
Family history |
49 (5.3%) |
42 (5.1%) |
7 (7.1%) |
0.406 |
7 (7.1%) |
1 (10.0%) |
6 (6.7%) |
0.537 |
Hypertension |
489 (51.5%) |
435 (51.5%) |
54 (51.9%) |
0.932 |
54 (51.9%) |
6 (54.5%) |
48 (51.6%) |
0.854 |
Diabetes mellitus |
311 (32.8%) |
274 (32.4%) |
37 (35.6%) |
0.518 |
37 (35.6%) |
7 (63.6%) |
30 (32.3%) |
0.051 |
Dyslipidemia |
82 (8.6%) |
75 (8.9%) |
7 (6.7%) |
0.463 |
7 (6.7%) |
0 (0.0%) |
7 (7.5%) |
1.000 |
Previous history of MI |
71 (7.5%) |
64 (7.6%) |
7 (6.7%) |
0.758 |
7 (6.7%) |
0 (0.0%) |
7 (7.5%) |
1.000 |
Previous history |
27 (2.9%) |
25 (3.0%) |
2 (2.0%) |
0.759 |
2 (2.0%) |
0 (0.0%) |
2 (2.2%) |
1.000 |
Previous history |
75 (8.0%) |
71 (8.5%) |
4 (3.8%) |
0.123 |
4 (3.8%) |
0 (0.0%) |
4 (4.3%) |
1.000 |
Current smoker |
353 (38.2%) |
312 (37.8%) |
41 (42.3%) |
0.389 |
41 (42.3%) |
5 (50.0%) |
36 (41.4%) |
0.601 |
LVEF [%] |
47.0 ± 13.1 |
48.2 ± 12.4 |
34.0 ± 14.0 |
< 0.001 |
34.0 ± 14.0 |
33.9 ± 8.9 |
34.1 ± 14.8 |
0.965 |
Laboratory findings |
||||||||
Creatinine [mg/dL] |
1.4 ± 1.4 |
1.3 ± 1.3 |
1.6 ± 1.9 |
0.076 |
1.6 ± 1.9 |
1.1 ± 0.3 |
1.6 ± 2.0 |
0.150 |
Peak troponin I |
88.3 ± 138.4 |
74.8 ± 112.8 |
190.8 ± 237.5 |
<0.001 |
190.8 ± 237.5 |
166.0 ± 172.0 |
193.2 ± 243.5 |
0.487 |
Peak CK-MB [ng/mL] |
196.9 ± 221.6 |
176.8 ± 173.0 |
363.2 ± 422.4 |
< 0.001 |
363.2 ± 422.4 |
247.5 ± 207.0 |
375.7 ± 438.3 |
0.283 |
Medications |
||||||||
ASA |
944 (99.5%) |
842 (99.6%) |
102 (98.1%) |
0.095 |
102 (98.1%) |
11 (100.0%) |
91 (97.8%) |
1.000 |
Clopidogrel |
745 (78.5%) |
670 (79.3%) |
75 (72.1%) |
0.093 |
75 (72.1%) |
7 (63.6%) |
68 (73.1%) |
0.495 |
Prasugrel |
127 (13.4%) |
108 (12.8%) |
19 (18.3%) |
0.121 |
19 (18.3%) |
3 (27.3%) |
16 (17.2%) |
0.418 |
Ticagrelor |
199 (21.0%) |
181 (21.4%) |
18 (17.3%) |
0.331 |
18 (17.3%) |
2 (18.2%) |
16 (17.2%) |
1.000 |
ACEI or ARB |
501 (52.8%) |
477 (56.4%) |
24 (23.1%) |
< 0.001 |
24 (23.1%) |
4 (36.4%) |
20 (21.5%) |
0.273 |
Beta-blocker |
535 (56.4%) |
508 (60.1%) |
27 (26.0%) |
< 0.001 |
27 (26.0%) |
4 (36.4%) |
23 (24.7%) |
0.470 |
Statin |
641 (67.5%) |
607 (71.8%) |
34 (32.7%) |
< 0.001 |
34 (32.7%) |
9 (81.8%) |
25 (26.9%) |
0.001 |
Oral anticoagulant |
38 (4.0%) |
35 (4.1%) |
3 (2.9%) |
0.790 |
3 (2.9%) |
0 (0.0%) |
3 (3.2%) |
1.000 |
Baseline procedural findings and the development of in-hospital complications are summarized in Table 2. The proportion of patients with the left main coronary artery as the culprit vessel was higher in the ECMO application group than in the no ECMO application group (25.0% vs. 4.4%; p < 0.001). The ECMO application group received smaller diameter stents (3.1 ± 0.4 mm vs. 3.2 ± 0.5 mm; p = 0.037) and more frequent intra-aortic balloon pump application (48.1% vs. 26.7%; p < 0.001) than the no ECMO application group. However, intravascular ultrasound-guided PCI was performed less in the ECMO application group (7.7% vs. 17.4%; p = 0.012). In-hospital complications were more common in the ECMO application group than in the no ECMO application group. A comparison of the ECMO application without or before CPR group and ECMO application after CPR group revealed that their procedural findings and development of in-hospital complications were similar. The ECMO without or before CPR group received everolimus-eluting stents (81.8% vs. 45.2%; p = 0.027) more frequently than the ECMO after CPR group; this was the only difference.
Total |
No ECMO |
ECMO |
P |
Total |
ECMO without or before CPR |
ECMO |
P |
|
Culprit lesion profiles |
||||||||
Location: |
||||||||
Left main artery |
63 (6.6%) |
37 (4.4%) |
26 (25.0%) |
< 0.001 |
26 (25.0%) |
2 (18.2%) |
24 (25.8%) |
0.727 |
LAD |
416 (43.8%) |
373 (44.1%) |
43 (41.3%) |
0.588 |
43 (41.3%) |
7 (63.6%) |
36 (38.7%) |
0.193 |
LCX |
119 (12.5%) |
101 (12.0%) |
18 (17.3%) |
0.120 |
18 (17.3%) |
1 (9.1%) |
17 (18.3%) |
0.685 |
RCA |
351 (37.0%) |
334 (39.5%) |
17 (16.3%) |
< 0.001 |
17 (16.3%) |
1 (9.1%) |
16 (17.2%) |
0.687 |
Type B2/C lesion* |
875 (92.2%) |
779 (92.2%) |
96 (92.3%) |
0.966 |
96 (92.3%) |
9 (81.8%) |
87 (93.5%) |
0.200 |
Overall lesion profiles |
||||||||
Left main artery disease |
92 (9.7%) |
60 (7.1%) |
32 (30.8%) |
< 0.001 |
32 (30.8%) |
3 (27.3%) |
29 (31.2%) |
1.000 |
3-vessel disease |
185 (19.5%) |
171 (20.2%) |
14 (13.5%) |
0.100 |
14 (13.5%) |
2 (18.2%) |
12 (12.9%) |
0.641 |
Procedural characteristics |
||||||||
Transradial approach |
119 (12.5%) |
108 (12.8%) |
11 (10.6%) |
0.522 |
11 (10.6%) |
2 (18.2%) |
9 (9.7%) |
0.328 |
Glycoprotein IIb/IIIa |
250 (26.3%) |
224 (26.5%) |
26 (25.0%) |
0.742 |
26 (25.0%) |
2 (18.2%) |
24 (25.8%) |
0.727 |
Thrombus aspiration |
297 (31.3%) |
270 (32.0%) |
27 (26.0%) |
0.214 |
27 (26.0%) |
5 (45.5%) |
22 (23.7%) |
0.119 |
IRA treatment |
||||||||
BMS |
72 (7.6%) |
60 (7.1%) |
12 (11.5%) |
0.107 |
12 (11.5%) |
0 (0.0%) |
12 (12.9%) |
0.355 |
EES |
452 (47.6%) |
401 (47.5%) |
51 (49.0%) |
0.760 |
51 (49.0%) |
9 (81.8%) |
42 (45.2%) |
0.027 |
ZES |
182 (19.2%) |
161 (19.1%) |
21 (20.2%) |
0.781 |
21 (20.2%) |
0 (0.0%) |
21 (22.6%) |
0.115 |
BES |
146 (15.4%) |
134 (15.9%) |
12 (11.5%) |
0.249 |
12 (11.5%) |
2 (18.2%) |
10 (10.8%) |
0.612 |
SES |
25 (2.6%) |
21 (2.5%) |
4 (3.8%) |
0.343 |
4 (3.8%) |
0 (0.0%) |
4 (4.3%) |
1.000 |
NES |
10 (1.1%) |
10 (1.2%) |
0 (0.0%) |
0.613 |
0 (0.0%) |
0 (0.0%) |
0 (0.0%) |
|
PES |
11 (1.2%) |
11 (1.3%) |
0 (0.0%) |
0.621 |
0 (0.0%) |
0 (0.0%) |
0 (0.0%) |
|
Other stents |
5 (0.5%) |
5 (0.6%) |
0 (0.0%) |
1.000 |
0 (0.0%) |
0 (0.0%) |
0 (0.0%) |
|
Plain balloon angioplasty |
59 (6.2%) |
53 (6.3%) |
6 (5.8%) |
0.841 |
6 (5.8%) |
1 (9.1%) |
5 (5.4%) |
0.498 |
Stent diameter [mm] |
03.1 ± 0.4 |
03.2 ± 0.5 |
03.1 ± 0.4 |
0.037 |
03.1 ± 0.4 |
03.0 ± 0.4 |
03.1 ± 0.4 |
0.635 |
Stent length [mm] |
24.8 ± 7.4 |
24.9 ± 7.3 |
24.1 ± 8.1 |
0.337 |
24.1 ± 8.1 |
24.6 ± 7.2 |
24.1 ± 8.2 |
0.734 |
Pre-PCI TIMI flow in culprit |
643 (67.8%) |
570 (67.5%) |
73 (70.2%) |
0.573 |
73 (70.2%) |
7 (63.6%) |
66 (71.0%) |
0.729 |
Post-PCI TIMI flow 3 |
949 (100.0%) |
845 (100.0%) |
104 (100.0%) |
104 (100.0%) |
11 (100.0%) |
93 (100.0%) |
||
IVUS during PCI |
155 (16.3%) |
147 (17.4%) |
8 (7.7%) |
0.012 |
8 (7.7%) |
0 (0.0%) |
8 (8.6%) |
0.595 |
OCT during PCI |
8 (0.8%) |
8 (0.9%) |
0 (0.0%) |
1.000 |
0 (0.0%) |
0 (0.0%) |
0 (0.0%) |
|
IABP use |
276 (29.1%) |
226 (26.7%) |
50 (48.1%) |
< 0.001 |
50 (48.1%) |
5 (45.5%) |
45 (48.4%) |
0.854 |
In-hospital complications |
||||||||
Acute heart failure |
149 (15.7%) |
123 (14.6%) |
26 (25.0%) |
0.006 |
26 (25.0%) |
3 (27.3%) |
23 (24.7%) |
1.000 |
Re-infarction |
16 (1.7%) |
12 (1.4%) |
4 (3.8%) |
0.088 |
4 (3.8%) |
0 (0.0%) |
4 (4.3%) |
1.000 |
Stent thrombosis |
14 (1.5%) |
11 (1.3%) |
3 (2.9%) |
0.191 |
3 (2.9%) |
0 (0.0%) |
3 (3.2%) |
1.000 |
Major bleeding |
||||||||
Intracranial hemorrhage |
65 (6.8%) |
35 (4.1%) |
30 (28.8%) |
< 0.001 |
30 (28.8%) |
2 (18.2%) |
28 (30.1%) |
0.505 |
Hb decrease† |
53 (5.6%) |
36 (4.3%) |
17 (16.3%) |
< 0.001 |
17 (16.3%) |
1 (9.1%) |
16 (17.2%) |
0.687 |
Hct decrease‡ |
5 (0.5%) |
2 (0.2%) |
3 (2.9%) |
0.011 |
3 (2.9%) |
0 (0.0%) |
3 (3.2%) |
1.000 |
Minor bleeding |
94 (9.9%) |
79 (9.3%) |
15 (14.4%) |
0.102 |
15 (14.4%) |
1 (9.1%) |
14 (15.1%) |
1.000 |
Atrial fibrillation |
147 (15.5%) |
134 (15.9%) |
13 (12.5%) |
0.372 |
13 (12.5%) |
2 (18.2%) |
11 (11.8%) |
0.625 |
Sepsis |
34 (3.6%) |
29 (3.4%) |
5 (4.8%) |
0.476 |
5 (4.8%) |
2 (18.2%) |
3 (3.2%) |
0.086 |
CPR |
458 (48.3%) |
364 (43.1%) |
94 (90.4%) |
< 0.001 |
94 (90.4%) |
1 (9.1%) |
93 (100.0%) |
< 0.001 |
MOF |
56 (5.9%) |
39 (4.6%) |
17 (16.3%) |
< 0.001 |
17 (16.3%) |
0 (0.0%) |
17 (18.3%) |
0.204 |
Defibrillation |
282 (29.7%) |
226 (26.7%) |
56 (53.8%) |
< 0.001 |
56 (53.8%) |
4 (36.4%) |
52 (55.9%) |
0.338 |
Acute kidney injury |
51 (5.4%) |
36 (4.3%) |
15 (14.4%) |
< 0.001 |
19 (14.4%) |
1 (9.1%) |
14 (15.1%) |
1.000 |
At 3 years, the ECMO application group had a higher risk of MACEs (80.8% vs. 41.5%; HR 2.49 [95% CI 1.74–3.56]; p < 0.001) than the no ECMO application group. The risks of all-cause death and cardiac death were also significantly higher in the ECMO application group. A comparison of the ECMO application without or before CPR group and ECMO application after CPR group showed that the risk of MACEs was lower in the ECMO application without or before CPR group (63.6% vs. 82.8%; HR 2.33 [95% CI 1.07–5.07]; p = 0.033). The all-cause death rate was also significantly lower in the ECMO application without or before CPR group. A comparison of the ECMO application without or before CPR group and no ECMO application group during the whole follow-up period revealed no significant differences in MACEs (Fig. 2, Table 3).
No ECMO |
ECMO |
Unadjusted |
Multivariable-adjusted |
|||
HR (95% CI) |
P |
HR (95% CI) |
P |
|||
3-year follow-up |
||||||
All-cause death |
281 (33.3) |
80 (76.9) |
3.72 (2.89–4.79) |
< 0.001 |
2.81 (1.91-4.14) |
< 0.001 |
Cardiac death |
218 (25.8) |
73 (70.2) |
4.08 (3.12–5.34) |
< 0.001 |
2.81 (1.84-4.30) |
< 0.001 |
Spontaneous MI |
24 (2.8) |
1 (1.0) |
0.91 (0.12–6.70) |
0.923 |
0.96 (0.11–8.62) |
0.973 |
Repeat revascularization |
71 (8.4) |
4 (3.8) |
1.25 (0.46–3.41) |
0.668 |
1.47 (0.49–4.46) |
0.496 |
All-cause death or MI |
298 (35.3) |
81 (77.9) |
3.62 (2.82–4.65) |
< 0.001 |
2.76 (1.89–4.03) |
< 0.001 |
MACE |
351 (41.5) |
84 (80.8) |
3.36 (2.64–4.28) |
< 0.001 |
2.49 (1.74–3.56) |
< 0.001 |
ECMO without |
ECMO after CPR |
Unadjusted |
Multivariable-adjusted |
|||
HR (95% CI) |
P |
HR (95% CI) |
P |
|||
3-year follow-up |
||||||
All-cause death |
6 (54.5) |
74 (79.6) |
2.55 (1.11–5.88) |
0.028 |
4.79 (1.42–16.13) |
0.011 |
Cardiac death |
6 (54.5) |
67 (72.0) |
2.26 (0.98–5.23) |
0.057 |
2.94 (0.95–9.16) |
0.062 |
All-cause death or MI |
7 (63.6) |
74 (79.6) |
2.19 (1.00–4.77) |
0.049 |
8.074 (2.08–31.29) |
0.003 |
MACE |
7 (63.6) |
77 (82.8) |
2.33 (1.07–5.07) |
0.033 |
5.94 (1.73–20.38) |
0.005 |
No ECMO |
ECMO without or before CPR |
Unadjusted |
Multivariable-adjusted |
|||
HR (95% CI) |
P |
HR (95% CI) |
P |
|||
3-year follow-up |
||||||
All-cause death |
281 (33.3) |
6 (54.5) |
1.71 (0.76–3.84) |
0.193 |
2.68 (1.05–6.81) |
0.039 |
Cardiac death |
218 (25.8) |
6 (54.5) |
2.17 (0.96–4.87) |
0.062 |
3.62 (1.38–9.54) |
0.009 |
Spontaneous MI |
24 (2.8) |
1 (9.1) |
3.91 (0.53–28.93) |
0.182 |
4.94 (0.66–36.85) |
0.119 |
Repeat revascularization |
71 (8.4) |
1 (9.1) |
1.28 (0.18–9.22) |
0.806 |
1.19 (0.13–11.42) |
0.878 |
All-cause death or MI |
298 (35.3) |
7 (63.6) |
1.92 (0.91–4.06) |
0.088 |
2.95 (1.25–6.97) |
0.013 |
MACE |
351 (41.5) |
7 (63.6) |
1.63 (0.77–3.44) |
0.201 |
2.28 (0.98–5.31) |
0.055 |
Independent predictors of the primary and secondary outcomes were identified using a multivariable Cox proportional hazard model. ECMO application was a significant and positive independent predictor of MACEs (HR 2.49 [95% CI 1.74–3.56]; p < 0.001) and all-cause death (HR 2.81 [95% CI 1.91–4.14]; p < 0.001) at 3 years (Table 4). CPR was also associated with a higher incidence of MACEs (HR 1.87 [95% CI 1.45–2.41]; p < 0.001) and all-cause death (HR 2.50 [95% CI 1.84–3.40]; p < 0.001). Age > 75 years, sex, serum creatinine level ≥ 2 mg/dL, left ventricular ejection fraction < 40%, sepsis, and multi-organ failure were also identified as independent predictors of MACEs (Suppl. Table 1).
Hazard ratio |
95% CI |
P |
|
All-cause death |
|||
Age > 75 years |
3.30 |
2.45–4.43 |
< 0.001 |
Sex |
1.44 |
1.07–1.95 |
0.017 |
Diabetes mellitus |
1.37 |
1.03–1.83 |
0.030 |
Creatinine ≥ 2 mg/dL |
2.13 |
1.47–3.09 |
< 0.001 |
LVEF < 40% |
2.04 |
1.53–2.72 |
< 0.001 |
Sepsis |
1.86 |
1.13–3.07 |
0.015 |
Multi-organ failure |
3.15 |
1.95–5.10 |
< 0.001 |
CPR |
2.50 |
1.84–3.40 |
< 0.001 |
ECMO |
2.81 |
1.91–4.14 |
< 0.001 |
MACE |
|||
Age > 75 years |
2.30 |
1.78–2.97 |
< 0.001 |
Sex |
1.33 |
1.02–1.73 |
0.034 |
Creatinine ≥ 2 mg/dL |
2.10 |
1.50–2.94 |
< 0.001 |
LVEF < 40% |
1.65 |
1.28–2.12 |
< 0.001 |
Sepsis |
1.81 |
1.13–2.89 |
0.013 |
MOF |
3.39 |
2.12–5.42 |
< 0.001 |
CPR |
1.87 |
1.45–2.41 |
< 0.001 |
ECMO |
2.49 |
1.74–3.56 |
< 0.001 |
Discussion
Herein, we compared 3-year clinical outcomes between the no ECMO application group and the ECMO application group with AMI complicated by cardiogenic shock. We found that the no ECMO application group showed significantly lower risks of all-cause death, cardiac death, and MACEs than the ECMO application group, which were consistently observed after multivariable analysis. Second, the ECMO application without or before CPR group showed significantly lower risks of all-cause death and MACEs than the ECMO application after CPR group, which were also consistently observed after multivariable analysis. Third, the ECMO application without or before CPR group showed similar outcomes of MACEs during a 3-year follow-up compared with the no ECMO application group.
Cardiogenic shock occurs in 5–10% of patients with AMI, and it is the leading cause of death after AMI [12]. The most common cause of AMI complicated by cardiogenic shock was predominant left ventricular failure (78.5%). Acute severe mitral regurgitation, ventricular septal rupture, and isolated right ventricular shock can also cause cardiogenic shock [13]. In the SHOCK trial, early revascularization showed a lower mortality rate at 6 months than medical treatment in patients with AMI complicated by cardiogenic shock due to left ventricular failure [2]. Consequently, the rate of PCI in cardiogenic shock continued to increase, and the mortality rate decreased accordingly. In the study by De Luca et al. [14], PCI in patients with AMI complicated by cardiogenic shock increased from 19% in 2001 to 60% in 2014, and accompanying in-hospital mortality decreased from 68% in 2001 to 38% in 2014. However, the clinical outcomes, including in-hospital mortality of AMI complicated by cardiogenic shock, remained high.
To overcome this problem, a mechanical circulatory support device can be considered. Venous arterial ECMO is a mechanical circulatory support device that draws blood from the venous system and passes it through a centrifugal pump, and then returns oxygenated blood to the arterial system [15, 16]. Consequently, venous arterial ECMO plays a role in earning time for myocardial recovery (bridge to recovery) or stabilizing the patient’s condition before the consideration of further strategies (bridge to bridge or bridge to transplant) [17]. Several studies support venous arterial ECMO application in patients with cardiac arrest. In the study by Chen et al. [3], extracorporeal CPR was compared with conventional CPR in patients with in-hospital cardiac arrest of cardiac origin, who underwent CPR for > 10 min. The extracorporeal CPR group showed long-term survival benefits over the conventional CPR group at the 1-year follow-up (HR 0.51; 95% CI 0.35–0.74; p < 0.001) [3]. In the study by Shin et al. [18], the extracorporeal CPR group showed higher survival rates with minimal neurologic impairments than the conventional CPR group in patients with in-hospital cardiac arrest (HR 0.17; 95% CI 0.04–0.68; p = 0.012). The 2020 European Society of Cardiology guidelines also recommend short-term mechanical circulatory support application in patients with AMI complicated by cardiogenic shock as Class IIb and Level C, depending on the patient’s characteristics such as age, underlying disease, neurological state, and long-term life expectancy [1]. However, few studies have reported on the optimal timing of ECMO application, and long-term clinical outcomes after ECMO application in patients with AMI complicated by cardiogenic shock.
In this study, 7.2% (n = 949) of patients with AMI complicated by cardiogenic shock among 13,104 patients with AMI underwent successful PCI. ECMO was applied in 11% (n = 104) of the enrolled patients with AMI complicated by cardiogenic shock, and ECMO without or before CPR was applied in only 10.6% (n = 11). Survival rates on discharge were 63.6% in the ECMO without or before CPR group, 22.6% in the ECMO after CPR group, and 26.9% in the total ECMO group (Fig. 3). In the study by Vallabhajosyula et al. [19], ECMO use with AMI in the United States increased 11.4-fold from 2000 to 2014. During this period, ECMO was used in approximately 0.5% of patients with AMI complicated by cardiogenic shock. Moreover, the average survival rate on discharge for those treated with ECMO was 40.8%, which had increased from 0% in 2000 to 54.9% in 2014. The rate of ECMO application is higher in patients with AMI complicated by cardiogenic shock in South Korea compared with the United States and other countries [20]. However, there are several limitations to comparing the results directly. First, the enrollment period was different between the two studies. ECMO application also changed rapidly. Second, mechanical circulatory support devices such as Impella® had not yet been introduced; thus, the tendency was to rely on ECMO to treat cardiogenic shock in South Korea. Third, the Korean Acute Myocardial Infarction Registry – National Institutes of Health data includes only patients with AMI who underwent PCI in large-scale hospitals. All patients with AMI were included based on the Healthcare Quality and Utilization Project National Inpatient Sample data in the United States.
Another specific finding of this study was that the mortality rate of the total ECMO group and ECMO after CPR group were significantly higher in South Korea compared with the United States and other studies. In a systematic review, the survival rate on discharge ranged from 30% to 79.2% in patients with AMI complicated by cardiogenic shock who underwent ECMO application [21–26]. In the Extracorporeal Life Organization registry, the survival rate on discharge was approximately 42% in patients with refractory cardiogenic shock treated with venous arterial ECMO [27]. In our study, the ECMO application group had more negative factors in their baseline characteristics and procedural characteristics than the no ECMO application group. Moreover, the rate of ECMO application without or before CPR was considerably smaller than the rate of ECMO application after CPR. These results suggest that ECMO tended to be applied later for patients in poor condition. Several studies support the benefit of early ECMO application. In the study by Sheu et al. [4], early ECMO-assisted primary PCI was compared with conventional primary PCI in patients with ST-segment elevation myocardial infarction complicated by profound cardiogenic shock. The early ECMO-assisted primary PCI group showed a lower mortality rate than the conventional primary PCI group at the 30-day follow-up (HR 0.223; 95% CI 0.062–0.801; p = 0.021). In the study by Choi et al. [28], the early ECMO application before revascularization group showed a lower risk of composite in-hospital mortality, left ventricular assist device implantation, and heart transplantation than the ECMO application after revascularization group (HR 0.360; 95% CI 0.152–0.853; p = 0.020) or the E-CPR before revascularization group in patients with AMI complicated by cardiogenic shock. Although there are many reasons for hesitating or not using ECMO, such as age, underlying disease, economic conditions, and psychological resistance due to expected complications and prognosis after ECMO application, it is necessary to consider earlier ECMO application, especially before a CPR situation, based on these studies.
Limitations of the study
This study has several limitations. First, selection bias should be considered because the medical treatments and procedure strategies, including ECMO application, were performed based on individual physicians’ decisions. Thus, multivariable analysis was performed to minimize selection bias. Second, although the date on which the event (CPR and ECMO application) occurred was recorded, the exact time (hour and minute) and duration were not recorded. Specific CPR data (location and presence or absence of early CPR) and the ECMO application method (cannulation techniques and with/without left ventricular unloading) were also not recorded. If CPR and ECMO application took place on the same day, the patient was classified as having undergone ECMO application after CPR. However, this assumption is acceptable because CPR is generally not performed after ECMO application. Third, the ECMO groups (especially ECMO without CPR) were relatively small. Further analysis will be needed by extending the research period to confirm the clinical effect of early ECMO application in patients with AMI complicated by cardiogenic shock. Furthermore, large-scale randomized controlled trials should be conducted to the extent that they would not pose an ethical or legal issue, such as in Society for Cardiovascular Angiography and Interventions stage B or C [29]. Fourth, lactate levels during hospitalization could not be checked in this registry, although these are part of the definition criteria for cardiogenic shock and robust tools for ECMO implantation and prognosis. Fifth, there are no data about left ventricular assist devices and heart transplantation, which can affect long-term clinical outcomes in patients with cardiogenic shock.
Conclusions
To date, ECMO has been used as salvage therapy for rescue, and it has not been used frequently before the patient’s condition has worsened. Herein, ECMO application without or before CPR showed good long-term clinical outcomes. Therefore, early application of ECMO can be considered a reasonable procedural strategy in patients with AMI complicated by cardiogenic shock, to improve clinical outcomes.
Acknowledgments
This research was funded by the Research of Korea Centers for Disease Control and Prevention (2016-ER6304-02) from Cheongju, South Korea. It was also supported by a grant from Chonnam National University Hospital Biomedical Research Institute (BCRI-21054). The authors thank the patients and investigators who participated in this registry.