Hung et al.

Critical Care (2018) 22:34

DOI 10.1186/s13054-018-1944-x

RESEARCH Open Access

Prevalence and outcome of patients with

non-ST segment elevation myocardial
infarction with occluded “culprit” artery – a
systemic review and meta-analysis
Chi-Sheng Hung†, Ying-Hsien Chen†, Ching-Chang Huang, Mao-Shin Lin, Chih-Fan Yeh, Hung-Yuan Li
and Hsien-Li Kao*

Abstract
Background: The aim was to determine the prevalence and impact of an occluded “culprit” artery (OCA) in
patients with non-ST segment elevation myocardial infarction (NSTEMI).
Methods: We searched PubMed, EMBASE, and Web of Science, with no language restrictions, up to 1 Jul. 2016.
Observational cohorts or clinical trials of adult NSTEMI were eligible for inclusion to determine the prevalence if the
proportion of OCA on coronary angiography was reported. Studies were further eligible for inclusion to determine
the outcome if the association between OCA and clinical endpoints was reported.
Results: Among the 60,898 patients with NSTEMI enrolled in 25 studies, 17,212 were found to have OCA. The
average proportion of OCA in NSTEMI was 34% (95% CI 30–37%). Patients with OCA were more likely to have left
circumflex artery as their culprit artery (odds ratio (OR) 1.65, 95% CI 1.15–2.37, p = 0.007), and this was associated
with lower left ventricular ejection fraction (standard mean difference -0.29, 95% CI -0.34 to -0.34, p < 0.001), higher
peak enzyme level (standard mean difference 0.43, 95% CI 0.27–0.58, p < 0.001), and higher risk for cardiogenic
shock (OR 1.66, 95% CI 1.35–2.04, p < 0.001), compared with patients with a non-occlusive culprit artery. Death rate
(OR 1.72, 95% CI 1.49–1.98, p < 0.001) and recurrent myocardial infarction (OR 1.7, 95% CI 1.06–2.75, p = 0.029) were
also higher in patients with OCA, compared with patients with a non-occlusive culprit artery.
Conclusions: Patients with OCA comprised a substantial portion of the NSTEMI population. These patients present
with more severe symptoms and worse clinical outcome. Whether these patients should be treated with more
aggressive strategy warrants further study.
Keywords: Non-ST segment elevation myocardial infarction, Coronary occlusion, Electrocardiography

Background syndromes, ranging from unstable angina (without cardio-

Acute coronary syndrome (ACS) has been categorized into myocyte loss) to NSTEMI (with cardiomyocyte necrosis).
ST segment elevation myocardial infarction (STEMI) and The management of NSTEACS is guided by risk stratifica-
non-ST segment elevation ACS (NSTEACS) based on the tion, with an early invasive strategy favoured in high-risk
results of initial 12-lead electrocardiography (ECG). In pa- patients [2], especially for patients with positive cardiac ne-
tients with STEMI, early reperfusion therapy of the culprit crosis biomarkers [3].
artery is a class I indication in current guidelines [1]. In STEMI results from acute total or nearly total occlusion
contrast, NSTEACS represent a wide spectrum of clinical of a coronary artery [4]. However, totally occluded culprit
artery (OCA) has also been observed among patients with
* Correspondence: [email protected] NSTEACS. According to recent large retrospective stud-
†
Equal contributors ies, up to 30% of patients with NSTEACS had OCA [5, 6].
Department of Internal Medicine, National Taiwan University Hospital, 7 One of the reasons for OCA to present as NSTEACS,
Chung-Shan South Road, Taipei, Taiwan

© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Hung et al. Critical Care (2018) 22:34 Page 2 of 11

instead of STEMI, is that ECG is not sensitive enough to artery disease (CAD), or STEMI; (4) studies selecting pa-
detect acute ischaemia or infarction over posterior or lat- tients by angiography results (for example, limited to
eral walls, when the left circumflex artery (LCx) is usually single-vessel disease, left main disease, or chronic total
the culprit artery. Indeed, the inferolateral territory was occlusion); (5) studies that did not specify the result of
more frequently involved among patients with NSTEACS cardiac necrosis biomarkers; (6) animal studies; and (7)
with OCA, compared with those with a non-occlusive cul- duplicate reports.
prit artery [6].
The clinical implication of OCA in NSTE-acute cor- Patients
onary syndrome (ACS) is still controversial, and how The inclusion criteria were (1) adults aged 18 or above;
patients with NSTEACS with OCA should be treated (2) patients with chest pain; and (3) patients with ele-
is also unknown. Some studies report worse outcome vated cardiac necrosis biomarkers (troponin or creatine
for patients with OCA [5, 7–9], while other studies kinase-MB isoenzyme (CK-MB)) according to the cri-
report otherwise [6, 10–12]. As unstable angina with- teria specified in individual studies. Patients with STEMI
out positive cardiac markers was also included in or patients with NSTEACS and negative cardiac necrosis
some of these studies [6, 9], the observations on out- markers were excluded from analyses.
comes were inevitably variable. Given the high inci-
dence of NSTEACS worldwide [13], and the potential Proportion of totally occluded culprit artery
impact of OCA on outcome, it is necessary to analyse The determination of the culprit artery and the defin-
in detail the currently available data. To decrease am- ition of OCA were based on the protocol of the individ-
biguity, we limited our analysis to patients with posi- ual study. Sensitivity analysis will be performed to
tive cardiac necrosis biomarkers, i.e. NSTEMI. The include only studies defining OCA as Thrombolysis In
goals of this meta-analysis were (1) to determine the Myocardial Infarction (TIMI)-flow grade 0 or 1 in the
proportion of patients with OCA in NSTEMI and (2) culprit artery (the most commonly used definition in
to determine the impact of OCA on the clinical se- these studies).
verity and outcomes including death and recurrent
myocardial infarction (MI) following NSTEMI. Outcome
Outcomes were assessed as all-cause mortality and re-
Methods current MI. Endpoints were taken at 1 year or the lon-
Data sources and search strategies gest follow up available (if the follow-up period was less
This systemic review and meta-analysis was performed than 1 year) in each study.
according to the preferred reporting items for systematic
reviews and meta-analyses (PRISMA) guidelines [14]. A Data extraction
literature search was performed using PubMed, Extraction of data on study characteristics and out-
EMBASE, and Web of Science without restriction on comes was performed independently by two re-
language and year of publication. The following search viewers (CSH and YHC). Discrepancies between
terms were used in PubMed: (ACS or acute coronary reviewers were resolved by consensus. The following
syndrome[MeSH Terms] or (acute AND coronary AND data were extracted from each study enrolled in our
syndrome) or “acute coronary syndrome” or NON-ST or analysis: the first author’s last name, year of publica-
NSTEMI or N-STEMI or NON-STEMI or NON STEMI tion, country of study performed, biomarkers mea-
or NSTEACS or angina, unstable[MeSH Terms]) AND sured, total number of patients, numbers of patients
((“total occlusion” or “totally occluded” or (occluded with OCA, mean age, gender, conventional risk fac-
AND culprit)) or “TIMI flow” or “TIMI-flow” or “(TIMI) tors for CAD (diabetes mellitus, hypertension, hyper-
flow”). Similar expressions were used in EMBASE and lipidaemia, smoking) and outcome (recurrent MI or
Web of Science. death). The study quality was judged using the
Newcast-Ottawa scale (NOS) for observational stud-
Eligibility criteria ies [15]. This scale assesses the quality of the study
Study design based on patient selection, comparability and out-
Studies included in the analysis were prospective or come. Studies controlled for age and sex were given
retrospective cohorts or randomized controlled trials. one star for comparability; studies controlled for
The exclusion criteria were (1) abstracts, review articles, conventional risk factors for CAD were given an-
case-control studies and case series with the number of other star for comparability. Studies with follow up
patients fewer than 20; (2) studies on myocardial infarc- of 1 year or longer were considered as long enough
tion that only reported Q wave or non-Q wave MI; (3) for outcome to occur. Studies with an NOS scale >
studies on patients with unstable angina, stable coronary =7 were considered of high quality.
Hung et al. Critical Care (2018) 22:34 Page 3 of 11

Data analysis varied from 42 to 30,386, with mean age from 58 to

We use the random-effects method because of its conser- 69 years, and 60 to 78.6% were male. Presence of hyper-
vative summary estimate and because it incorporates tension was reported in 35 to 85.5% of patients, diabetes
between-study and within-study variance. We used the I2 in 11.5 to 53.9%, hyperlipidaemia in 13 to 69.2%, and
statistic to assess heterogeneity of the event rates across smoking in 21.3 to 80.3% of patients. Coronary artery
studies [16]. A funnel plot with a linear regression ap- bypass grafting (CABG) was excluded in five studies [5,
proach to measure asymmetry was used to assess for the 8, 18–20]. The definitions of OCA and exclusion criteria
presence of publication bias [17]. Subgroup analyses were of the studies are summarised in Table 1. Among these
performed in different geographical regions (Asia-Pacific, 25 studies, 10 [5, 7–12, 21–23] reported distribution of
European, North American, and multinational). Sensitivity the culprit artery, presence of cardiogenic shock, peak
analyses using the leave-one-out method were performed creatine kinase (CK) level, and outcome by the status of
to identify key studies with major influence on between- the culprit artery. These 10 studies were used for the
study heterogeneity. Meta-regression was used to assess analysis of the impact of OCA on presentation, death,
the influence of study characteristics on outcome. All stat- and recurrent MI. The details of NOS for these 10 stud-
istical analyses were performed using Stata Version 13 ies are presented in Table 2. The total scores of NOS for
software (Stata Corporation, Collage Station, TX, USA). the other 15 studies (not included in outcome analysis)
All p values were two-sided, and those below 0.05 were are presented in Fig. 2.
regarded as statistically significant.
Prevalence of OCA in NSTEMI
Results All 25 studies provided data to be used for analysis of the
Results of the search proportion of OCA in patients with NSTEMI. A total of
The initial search identified 1432 citations. After critical 17,212 patients had OCA among the 60,898 patients in-
assessment of these papers, 25 studies fulfilled the inclu- cluded. The average proportion of OCA in NSTEMI was
sion criteria and were used to estimate the pooled pro- therefore 0.34 (95% confidence interval (CI) 0.30–0.38)
portion of OCA among NSTEMI patients. Ten of these (Fig. 2). However, there was evidence of substantial het-
25 papers fulfilled the criteria and were used to analyse erogeneity in the proportion rate (X2 = 1644.9, degrees of
the impact of OCA on outcome (Fig. 1). freedom (df) = 24, p < 0.001, I2 = 98.54%). After excluding
studies with OCA definition other than TIMI flow of 0 or
Study characteristics 1, the average proportion of OCA in the remaining 20
Characteristics of the 25 included studies are presented studies was 0.35 (95% CI 0.30–0.41; X2 = 1067.58, df = 19,
in Table 1. The studies were conducted in North I2 = 98.22%, p < 0.001) (Additional file 1: Figure S1). After
American (n = 5), European (n = 8), Asia-Pacific (n = 10), further excluding studies with time to diagnostic angiog-
or multinational regions (n = 2). The number of patients raphy more than 1 week or unknown, the average propor-
tion of OCA in the remaining 14 studies was 0.35 (95% CI
0.28–0.41; X2 = 797.04, df = 13, p < 0.001, I2 = 98.37%)
(Additional file 1: Figure S2).
The median proportion of patients with multivessel dis-
ease in all 25 studies was 57.6% (interquartile range 45.9–
62.1%). Two studies reported a substantially lower propor-
tion of patients with multivessel disease compared with
other studies (13.6% in Pride 2010 [9] and 11.7% in Daly
2012 [23]). After excluding these two studies with lower
proportions of patients with multivessel disease, the aver-
age proportion of OCA in the remaining 23 studies was
0.33 (95% CI 0.29–0.36; X2 = 1245.98, df = 22, p < 0.001, I2
= 98.23%) (Additional file 1: Figure S3).
Analysis by different locations showed possible hetero-
geneity among studies (Additional file 1: Figure S4). The
average proportion of OCA was 0.42 (0.31–0.52) in Europe,
0.21 (0.18–0.24) in North America, 0.34 (0.31–0.38) in the
Asia-Pacific area, and 0.24 (0.23–0.26) in multinational
Fig. 1 Searching strategy and number of studies at each stage of this studies. We further divided the 25 studies into low (NOS =
meta-analysis. STEMI ST segment elevation myocardial infarction, CAD
<5), moderate (NOS = 6), and high NOS (NOS > =7) stud-
coronary artery disease, TIMI Thrombolysis In Myocardial Infarction
ies. The average proportion of OCA was 0.30 (0.27–0.34, I2
Table 1 Characteristics of 25 studies included in the pooled estimation of the proportion of occluded culprit arteries among patients with non-ST segment elevation myocardial
infarction
References Year Area Designa Definition of Number of Age Male, n (%) Multivessel disease, OCA, n (%) Major exclusion criteria Follow-up Outcome
OCAb patients (years) n (%) duration
Wong et al. [33] 2002 North 1 1 194 62 138 (71.1%) 96 (49.5%) 32 (16.5%) Increased risk of bleeding, LBBB
America
Koyama et al. [34] 2002 Asia 2 1 125 61 93 (74.4%) - 64 (51.2%)
Bolognese et al. [35] 2004 Europe 2 1 42 63 33 (78.6%) 15 (35.7%) 8 (19%) Cardiogenic shock
Abbas et al. [36] 2004 North 2 2 61 60 46 (75.4%) 28 (45.9%) 29 (47.5%)
America
Hung et al. Critical Care (2018) 22:34

Yazici et al. [18] 2007 Asia 2 1 97 60 67 (69.1%) - 42 (43.3%) Heart failure, renal failure, prior CABG
Abbott et al. [19] 2007 North 2 1 583 62 363 (62.3%) 429 (73.6%) 111 (19%) Prior CABG
America
Jung et al. [10] 2008 Asia 3 1 205 63 123 (60%) 89 (43.4%) 62 (30.2%) LBBB, Q wave formation 6 months Death, MI
Dixon et al. [5] 2008 North 2 1 30386 69 - - 7199 (23.7%) Prior CABG, prior MI N/A Death
America
Pride et al. [9] 2010 Multinational 1 1 955 63 646 (67.6%) 130 (13.6%) 314 (32.9%) TIMI score <3, increased risk of bleeding 1 month Death, MI
Bahrmann et al. [11] 2011 Europe 2 1 448 67 301 (67.2%) 276 (61.6%) 130 (29%) Cardiogenic shock, increased risk of bleeding 6 months Death, MI
Mazurek et al. [37] 2011 Europe 2 1 554 63 380 (68.6%) - 333 (60.1%)
Kastrati et al. [38] 2011 Europe 1 1 1721 68 661 (38.4%) 1377 (80%) 444 (25.8%) Cardiogenic shock, malignancy, increased risk
of bleeding
Daly et al. [23] 2012 Europe 3 1 320 62 233 (72.8%) 38 (11.9%) 240 (75%) LBBB 1 month MACE
Kim et al. [7] 2012 Asia 2 2 2094 62 1467 (70.1%) 1298 (62%) 665 (31.8%) 1 year Death
Widimsky et al. [39] 2012 Europe 3 1 2577 67 1735 (67.3%) 1708 (66.3%) 711 (27.6%)
Park et al. [40] 2013 Asia 2 2 11814 65 7856 (66.5%) (0%) 3674 (31.1%)
Soon et al. [21] 2014 Pacific 3 4 143 64 97 (67.8%) 79 (55.2%) 34 (23.8%) LBBB 1 year Death, MI
Shin et al. [8] 2014 Asia 3 1 2878 64 1953 (67.9%) 1644 (57.1%) 1070 (37.2%) LBBB, prior CABG 1 year Death, MI
Zhang et al. [41] 2014 Asia 1 1 151 58 109 (72.2%) - 39 (25.8%) Increased risk of bleeding
Guerra et al. [42] 2014 Europe 4 1 190 65 139 (73.2%) - 94 (49.5%) Crdiogenic shock, pericarditis, pacemaker
Warren et al. [12] 2015 Multinational 1 1 1319 60 876 (66.4%) - 262 (19.9%) Cardiogenic shock, increased risk of bleeding 1 year Death, MI
Liu et al. [43] 2015 Asia 2 1 90 - - - 34 (37.8%)
Misumida et al. [44] 2015 North 3 1 481 66 298 (62%) 253 (52.6%) 115 (23.9%)
America
Aijaz et al. [22] 2016 Asia 4 1 703 58 565 (80.4%) 420 (59.7%) 277 (39.4%) In-hospital stay Death, MI
Karwowski et al. 2016 Europe 2 1 2767 64 1796 (64.9%) 1330 (48.1%) 1229 (44.4%) Prior MI, prior PCI, prior CABG
[20]
CABG coronary artery bypass grafting, LBBB left bundle branch block, MACE major adverse cardiac events, MI myocardial infarction, OCA totally occluded culprit artery, PCI percutaneous coronary intervention, N/A
not analysed
a
Design: 1, randomized controlled trial; 2, prospective cohort; 3, retrospective cohort; 4, cross-sectional
b
Definition of OCA: 1, Thrombolysis In Myocardial Infarction (TIMI) flow 0 or 1; 2, TIMI 0 only; 3, TIMI 1 only; 4,TIMI 0, TIMI 1, and TIMI 2
Page 4 of 11
Table 2 Newcastle-Ottawa Scale (NOS) for assessing quality of observational studies
Selection Comparability Outcome Total
References Representativeness Selection of the Ascertainment Demonstration that outcome of Control Control for Assessment Was follow up long Adequacy of NOS
Hung et al. Critical Care (2018) 22:34

of the exposed non-exposed of exposure interest was not present at start for age conventional CAD of outcome enough for outcomes follow up of quality
cohort cohort of study and sex risk factors to occur cohorts scale
Jung et al. ★ ★ ★ ★ ★ ★ ★ 7
2008 [10]
Dixon et al. ★ ★ ★ ★ 4
2008 [5]
Pride et al. ★ ★ ★ ★ ★ ★ ★ 7
2010 [9]
Bahrmann ★ ★ ★ ★ ★ ★ ★ 7
et al. 2011
[11]
Daly et al. ★ ★ ★ ★ ★ ★ ★ 7
2012 [23]
Kim et al. ★ ★ ★ ★ ★ ★ ★ ★ 8
2012 [7]
Soon et al. ★ ★ ★ ★ ★ ★ 6
2014 [21]
Shin et al. ★ ★ ★ ★ ★ ★ ★ ★ 8
2014 [8]
Warren ★ ★ ★ ★ ★ ★ ★ ★ 8
et al. 2015
[12]
Aijaz et al. ★ ★ ★ ★ ★ ★ 6
2016 [22]
CAD coronary artery disease
Page 5 of 11
Hung et al. Critical Care (2018) 22:34 Page 6 of 11

Fig. 2 The pooled proportion of occluded culprit artery among patients with non-ST elevation myocardial infarction (number of studies = 25).
NOS Newcastle-Ottawa scale, OCA occluded culprit artery, ES effect size

= 92.3%) in low NOS studies, 0.35 (0.28–0.42, I2 = 98.2%) in three studies [10, 11, 21] that reported peak CK level, the
moderate NOS studies, 0.36 (0.27–0.46, I2 = 98.7%) in high standard mean difference in CK was 0.43 (95% CI 0.27–
NOS studies. These results showed that subgroup analysis 0.58, p < 0.001; X2 = 1.36, df = 2, p = 0.506) in patients with
by different NOS did not reduce the heterogeneity OCA, compared with patients with a non-occlusive culprit
(Additional file 1: Figure S5). artery (Additional file 1: Figure S8).
The leave-one-out sensitivity analyses could not iden-
tify studies with major impact on the between-study het- Angiographic characteristics
erogeneity. The univariate meta-regression with the Among the 10 studies used for analysis of outcome, the dis-
covariate of NOS, year of publication, age, proportion of tribution of the culprit artery was reported in 6 studies [7,
patients with diabetes mellitus, hypertension, hyperlipid- 8, 10–12, 21]. The pooled OR for LCx as the culprit artery
aemia and single-vessel disease, showed no significant was 1.65 (95% CI 1.15–2.37, p = 0.007; X2 = 38.5, df = 5, p <
impact on between-study heterogeneity (all p > 0.05). 0.001) (Additional file 1: Figure S9) in patients with OCA,
compared with patients with a non-occlusive culprit artery.
Severity and infarct size The distribution of infarct location was reported in 7 stud-
Among the 10 studies used for analysis of outcome, severity ies [5, 7, 8, 10–12, 21] among the 10 studied used for ana-
scores (TIMI score or Global Registry of Acute Coronary lysis of outcome. The pooled OR for infarct location in the
Events (GRACE) score) were reported in 3 studies [7, 11, posterior or lateral area was 2.24 (95% CI 1.63–3.09, p <
12]. There was no difference in risk scores between patients 0.001; X2 = 75.45, df = 6, p < 0.001) for patients with OCA,
with or without OCA. In five studies [5, 7, 10, 11, 21] that compared with patients with a non-occlusive culprit artery
reported the occurrence of cardiogenic shock, the pooled (Additional file 1: Figure S10). The presence of collaterals
odds ratio (OR) for cardiogenic shock was higher for pa- on angiography had been reported in only one study [11],
tients with OCA (pooled OR 1.66, 95% CI 1.35–2.04, p < and well-developed collaterals were significantly more fre-
0.001; X2 = 2.35, df = 4, p = 0.671) (Additional file 1: Figure quent among patients with OCA.
S6). In six studies [7, 8, 10–12, 22] that reported the base- Among the 10 studies used for analysis of out-
line left ventricular ejection fraction (LVEF) on admission, come, the information about revascularization was
the standard mean difference in LVEF was -0.29 (95% CI reported in 6 studies [5, 7, 8, 11, 21, 22] (Additional
-0.34 to -0.34, p < 0.001; X2 = 79.97, df = 5, p < 0.001) file 1: Table S1). In the three studies that reported
(Additional file 1: Figure S7) in patients with OCA, com- the rate of successful percutaneous coronary inter-
pared with patients with a non-occlusive culprit artery. In vention (PCI), the pooled OR for PCI success was
Hung et al. Critical Care (2018) 22:34 Page 7 of 11

0.63 (95% CI 0.44–0.90, p = 0.011; X2 = 3.27, df = 2, p Outcome

= 0.195) (Additional file 1: Figure S11) for patients Among the 10 studies used for analysis of outcome,
with OCA, compared with patients with a non- mortality was reported in 8 studies [5, 7–12, 22]. The
occlusive culprit artery. In the three studies that re- pooled OR for mortality was 1.72 (95% CI 1.49–1.98,
ported stent length, the standard mean difference in p < 0.001; X2 = 6.34, df = 7, p = 0.501) for patients with
stent length was 0.16 mm (95% CI 0.10–0.21, p < OCA compared with patients with a non-occlusive
0.001; X2 = 9.63, df = 2, p = 0.008) (Additional file 1: culprit artery (Fig. 3). After excluding studies without
Figure S12) longer in patients with OCA, compared clear OCA definition, the pooled OR from the
with patients with a non-occlusive culprit artery. In remaining six studies was 1.46 (95% CI 1.12–1.90, p
the three studies that reported stent length and the = 0.006; X2 = 4.07, df = 5, p = 0.539) (Additional file 1:
use of a drug-eluting stent, there was no significant Figure S15). Further excluding studies with time to
difference between patients with OCA and patients diagnostic angiography more than 28 days or un-
with a non-occlusive culprit artery (Additional file 1: known, the pooled OR from the remaining four stud-
Figure S13 and S14). ies was 1.52 (95% CI 1.15–2.01, p = 0.003; X2 = 1.67,
df = 3, p = 0.644) (Additional file 1: Figure S16).
Predictors for NSTEMI with OCA The recurrence of MI was reported in seven studies
Among the 10 studies used for analysis of outcome, 5 [8–12, 21, 22]. The pooled OR for recurrent MI was 1.7
[7, 9–11, 23] reported the predictors of the presence (95% CI 1.06–2.75, p = 0.029; X2 = 16.43, df = 6, p =
of OCA among patients with NSTEMI. Possible pre- 0.012) for patients with OCA compared with patients
dictors included number of ST depression leads on with a non-occlusive culprit artery (Fig. 4). Further ex-
12-lead ECG [10], total ST depression score on 12- cluding studies without a clear OCA definition, the
lead ECG [23], 80-lead body surface potential map- pooled OR from the remaining six studies was 1.77 (95%
ping [23], ECG abnormalities on inferolateral leads CI 1.06–2.95, p = 0.03; X2 = 16.16, df = 5, p = 0.006)
[7], peak CK-MB concentration [9, 10], fibrinogen at (Additional file 1: Figure S17). Further excluding studies
admission [10], dyslipidaemia [7], duration of continu- with time to diagnostic angiography more than 28 days
ous chest pain [10], and collateral supply [11]. The or unknown, the pooled OR from the remaining four
prediction of NSTEMI with OCA had only been eval- studies was 1.67 (95% CI 0.94–2.95, p = 0.079; X2 =
uated by total ST depression score on 12-lead ECG (c 12.95, df = 3, p = 0.005) (Additional file 1: Figure S18).
statistic 0.693; 95% CI 0.521–0.771, p = 0.058) and 80-
lead body surface potential mapping (c statistic 0.906; Test for publication bias
95% CI 0.838–0.983, p < 0.001) among these possible The funnel plots for studies reporting the proportion of
predictors [23]. OCA (by sample size vs. proportion) were asymmetrical
Risk stratification scores had been reported in four (Fig. 5a). The Egger test confirmed the presence of
studies, with TIMI score reported in three [7, 10, 21] small-study effects (p < 0.001). The small-study effect
and GRACE score reported in one study [11]. There was persisted even when excluding studies with a less strict
no significant difference between patients with and with- OCA flow definition and studies with time to angiog-
out OCA using these two risk scores. raphy more than 1 week (Egger test p < 0.001). The

Fig. 3 Pooled odds ratio for all-cause mortality among patients with non-ST segment elevation myocardial infarction and an occluded culprit
artery (OCA) compared to with those with a non-occluded culprit artery (Non-OCA)
Hung et al. Critical Care (2018) 22:34 Page 8 of 11

Fig. 4 The pooled odds ratio for recurrent myocardial infarction among patients with non-ST segment elevation myocardial infarction and an
occluded culprit artery (OCA) compared to with those with a non-occluded culprit artery (Non-OCA)

funnel plot for studies reporting on outcome suggested with OCA was associated with more LCx as the culprit ar-
publication bias (Egger p < 0.001) (Fig. 5b). tery, higher peak enzyme level, lower LVEF, and more car-
diogenic shock; and (3) NSTEMI with OCA was associated
Discussion with a higher rate of recurrent MI and death. These im-
This meta-analysis showed that (1) the overall estimated portant findings remained the same if we limited our ana-
proportion of OCA in NSTEMI was 34%; (2) NSTEMI lysis to studies using TIMI flow 0–1 as the definition of
OCA and timely diagnostic angiography after onset.
There is substantial heterogeneity in our analysis, with a
wide range of proportion of OCA reported in the studies in-
cluded (0.15–0.75). The explanations for this variation in-
clude differences in the study geographic region, study
design and OCA definition, patient population, and timing
of angiography. The standard initial ECG evaluation proto-
col is often unavailable in retrospective studies, and subtle
ST change, especially in the posterior leads, may be missed.
Some of the studies excluded patients with prior coronary
artery bypass grafting (CABG) [5, 8, 18–20]. This difference
in enrolment criteria may also influence the proportion of
patients with OCA. The angiographic finding may change
with time after symptom onset [24], but the estimated OCA
proportion and outcome did not change after excluding
studies with angiography performed more than 7 days after
onset. Meta-regression did not identify the conventional risk
factors as the source of the heterogeneity in the pooled esti-
mation of OCA proportion. We did find different propor-
tions among studies in different geographic regions. Ethnic
difference has been reported in the prevalence of coronary
artery disease [25, 26] and in the distribution of coronary le-
sions [27]. However, whether the difference between geo-
graphic regions reflected a real difference in the ethnicity or
a combination of different design, inclusion criteria, and
timing of angiography, is not clear.
Our analysis suggested that OCA represents a substantial
portion of NSTEMI, and carries a worse clinical outcome.
Some researchers proposed that this condition should be
Fig. 5 Funnel plot. (a) Pooled proportion. (b) Outcome. OCA occluded
considered as “STEMI equivalent” and treated as such [6,
culprit artery, OR odds ratio
7]. However, whether OCA mandates a more aggressive
Hung et al. Critical Care (2018) 22:34 Page 9 of 11

treatment strategy or simply reflects worse disease severity all be helpful, but again mandating future research to
cannot be determined from the current analysis. There are establish their clinical significance.
several possible causes of OCA in NSTEMI: (1) acute total Our analysis has several strengths. First, we enrolled
occlusion of vessel suppling some part of myocardium (esp only patients with elevated cardiac necrosis markers.
lateral wall) which does not consistently lead to ST eleva- Focusing our biomarker-positive NSTEACS popula-
tion in conventional 12-lead ECG, probably due to the ab- tion helps us to decrease the ambiguity, targeting only
sence of corresponding leads; (2) acute total occlusion of patients with objective myocardial injury. More im-
vessels with good collaterals; (3) acute total occlusion in the portantly, patients with biomarker-positive NSTEACS
territory with dual blood supply [28]; (4) acute total occlu- may benefit from an early invasive strategy, compared
sion with a small infarction area; or (5) chronic total occlu- with biomarker-negative patients [3]. Second, the po-
sion misclassified as acute occlusion. In the first condition, tential influence of OCA definition and angiography
timely reperfusion by primary percutaneous coronary inter- timing were well-considered and controlled. By con-
vention may improve the outcome as in STEMI. Although ducting sensitivity analyses, we showed that there was
our analysis cannot provide evidence for any of the afore- no major impact of these two factors on the hetero-
mentioned hypotheses, the higher percentage of LCx as the geneity of OCA incidence.
culprit artery suggests that acute total occlusion not de- Our analysis does have several limitations. First, the
tected by standard 12-lead ECG may be the most possible ECG protocol used was not reported in detail in most of
cause. Acute LCx occlusion can result in isolated posterior the studies. Whether posterior leads have been applied
infarction with ST elevation only detected in leads V7–V9 in individual studies was unclear. Second, patients with
[29]. The isolated posterior infarction due to LCx occlusion contraindication for angiography or percutaneous coron-
is not uncommonly missed by medical personnel [30], and ary intervention were excluded by the analysis design.
is associated with longer time to reperfusion [31] and is less Therefore our results cannot be generalized in this
likely to be treated by primary percutaneous coronary inter- population. Third, angiography in the included studies
vention [32]. These factors are possibly associated with less was done within one week after symptom onset. Hence
favourable outcome, as in our analyses. Collateral artery the true OCA incidence at the time of onset could not
status was described in only one study, reporting higher in- be deducted from the present analysis. Fourth, a certain
cidence of angiographic collaterals in NSTEMI with OCA proportion of patients with posterior STEMI may be
[11]. The authors also identified better outcome in these classified as having NSTEMI. This misclassification may
patients with OCA with collaterals, compared with those be improved in the future by including routine posterior
without. Further study on the impact of collateral in pa- leads to detect posterior STEMI in patients with chest
tients with NSTEMI with OCA is needed. Finally, deter- pain. Fifth, because the outcomes reported in the studies
mination of the culprit artery is sometimes difficult in had not been stratified by some important moderators
NSTEMI without diagnostic ECG. Hence, misclassifying a including the procedures and the number of diseased
chronic total occlusion as the culprit is possible clinically, vessels, further analysis on the impact of OCA according
and the true incidence of misclassified chronic total occlu- to these moderators cannot be performed. Finally, given
sion cannot be determined by our analysis. the asymmetry of funnel plot, we cannot exclude the po-
Considering the large number of patients with tential publication bias against studies finding no signifi-
NSTEMI worldwide [13], it is imperative to explore cant difference in the outcomes of NSTEMI with or
methods to identify patients with NSTEMI with without OCA.
OCA. Three studies included in the present meta-
analysis reported the TIMI or GRACE risk score, but Conclusion
these scores cannot differentiate the outcomes of pa- Approximately one third of patients with NSTEMI
tients with OCA or those with a non-occlusive culprit have OCA. These patients present with more severe
artery. Body surface potential mapping using 80 chest clinical symptoms and have a worse outcome, com-
leads may improve detection of ST segment elevation pared with those with a non-occlusive culprit artery.
[23], but its clinical practicality needs further investi- There is as yet no reliable tool to identify this group
gation. The LVEF assessed by echocardiography was of patients before performing angiography. Whether
significantly lower in patients with NSTEMI with timely reperfusion will benefit this group of patients
OCA than in patients with a non-occlusive culprit ar- warrants further studies.
tery according to our analysis. Whether LVEF helps
to identify patients with NSTEMI with OCA should
be validated prospectively. Other practices incorporat- Additional file
ing coronary computed tomography angiography,
Additional file 1: Supplementary figures and table. (DOCX 3836 kb)
echocardiography, or routine posterior-leads ECG may
Hung et al. Critical Care (2018) 22:34 Page 10 of 11

Abbreviations 7. Kim MC, Ahn Y, Rhew SH, Jeong MH, Kim JH, Hong YJ, Chae SC, Kim YJ, Hur SH,
ACS: Acute coronary syndrome; CABG: Coronary artery bypass grafting; Seong IW, et al. Impact of total occlusion of an infarct-related artery on long-term
CAD: Coronary artery disease; CK: Creatine kinase; CK-MB: Creatine kinase-MB mortality in acute non-ST-elevation myocardial infarction patients who underwent
isoenzyme; ECG: Electrocardiography; GRACE: Global Registry of Acute Coronary early percutaneous coronary intervention. Int Heart J. 2012;53(3):160–4.
Events; LCx: Left circumflex artery; LVEF: Left ventricular ejection fraction; 8. Shin DI, Chang K, Ahn Y, Hwang BH, Park HJ, Seo SM, Koh YS, Kim PJ, Seung
MI: Myocardial infarction; NOS: Newcastle–Ottawa scale; NSTEACS: Non-ST KB, Jeong MH. Impact of occluded culprit arteries on long-term clinical
segment elevation acute coronary syndrome; NSTEMI: Non-ST segment outcome in patients with non-ST-elevation myocardial infarction: 48-month
elevation myocardial infarction; OCA: Occluded culprit artery; OR: Odds ratio; follow-up results in the COREA-AMI Registry. J Interv Cardiol. 2014;27(1):12–20.
PCI: Percutaneous coronary intervention; STEMI: ST segment elevation 9. Pride YB, Tung P, Mohanavelu S, Zorkun C, Wiviott SD, Antman EM,
myocardial infarction; TIMI: Thrombolysis In Myocardial Infarction Giugliano R, Braunwald E, Gibson CM, Group TS. Angiographic and clinical
outcomes among patients with acute coronary syndromes presenting with
Acknowledgements isolated anterior ST-segment depression: a TRITON-TIMI 38 (Trial to Assess
None. Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition
With Prasugrel-Thrombolysis In Myocardial Infarction 38) substudy. J Am
Funding Coll Cardiol Intv. 2010;3(8):806–11.
No external funding was acquired for this research. 10. Jung DH, Jeong MH, Kim KH, Lee WS, Lee KH, Yoon HJ, Yoon NS, Moon JY,
Hong YJ, Park HW, Kim JH, Ahn YK, et al. Predictors of total occlusion of the
Availability of data and materials infarct-related artery in patients with acute Non-ST elevation myocardial
All data analysed during this research are included in this published article. infarction. Korean J Med. 2008;74:271–80.
11. Bahrmann P, Rach J, Desch S, Schuler GC, Thiele H. Incidence and distribution
Authors’ contributions of occluded culprit arteries and impact of coronary collaterals on outcome in
CSH, YHC, and CCH searched the literature, collected the data, performed patients with non-ST-segment elevation myocardial infarction and early
the statistical analyses, and wrote the manuscript; MSL, CFY, HYL, and HLK invasive treatment strategy. Clin Res Cardiol. 2011;100(5):457–67.
contributed to conception, design, data interpretation, and supervision of 12. Warren J, Mehran R, Yu J, Xu K, Bertrand ME, Cox DA, Lincoff AM,
the study. All authors read and approved the final manuscript. Manoukian SV, Ohman EM, Pocock SJ, et al. Incidence and impact of totally
occluded culprit coronary arteries in patients presenting with non-ST-
Ethics approval and consent to participate segment elevation myocardial infarction. Am J Cardiol. 2015;115(4):428–33.
Not applicable. 13. Vedanthan R, Seligman B, Fuster V. Global perspective on acute coronary
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Consent for publication 14. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting
Not applicable (no individual personal data are included in the study). items for systematic reviews and meta-analyses: the PRISMA statement.
PLoS Med. 2009;6(7), e1000097.
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