An Early and Simple Predictor of Severe Left Main and/or

Three-Vessel Disease in Patients With Non–ST-Segment

Elevation Acute Coronary Syndrome
Masami Kosuge, MD*, Toshiaki Ebina, MD, Kiyoshi Hibi, MD, Satoshi Morita, PhD,
Mitsuaki Endo, MD, Nobuhiki Maejima, MD, Noriaki Iwahashi, MD, Kozo Okada, MD,
Toshiyuki Ishikawa, MD, Satoshi Umemura, MD, and Kazuo Kimura, MD
Clopidogrel should be initiated as soon as possible in patients with non–ST-segment
elevation acute coronary syndrome (NSTE-ACS) except those who urgently require coro-
nary artery bypass grafting (CABG). The present study assessed the ability to predict
severe left main coronary artery and/or 3-vessel disease (LM/3VD) that would most likely
require urgent CABG based on only clinical factors on admission in 572 patients with
NSTE-ACS undergoing coronary angiography. Severe LM/3VD was defined as >75%
stenosis of LM and/or 3VD with >90% stenosis in >2 proximal lesions of the left anterior
descending coronary artery and other major epicardial arteries. Patients were divided into
the 3 groups according to angiographic findings: no LM/3VD (n ⴝ 460), LM/3VD but not
severe LM/3VD (n ⴝ 57), and severe LM/3VD (n ⴝ 55). Severe LM/3VD was associated
with a higher rate of urgent CABG compared to no LM/3VD and LM/3VD but not severe
LM/3VD (46%, 2%, and 2%, p <0.001). On multivariate analysis, degree of ST-segment
elevation in lead aVR was the strongest predictor of severe LM/3VD (odds ratio 29.1,
p <0.001), followed by positive troponin T level (odds ratio 1.27, p ⴝ 0.044). ST-segment
elevation >1.0 mm in lead aVR best identified severe LM/3VD with 80% sensitivity, 93%
specificity, 56% positive predictive value, and 98% negative predictive value. In conclusion,
ST-segment elevation >1.0 mm in lead aVR on admission electrocardiogram is highly
suggestive of severe LM/3VD in patients with NSTE-ACS. Selected patients with this
finding might benefit from promptly undergoing angiography, withholding clopidogrel to
allow early CABG. © 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;107:
495–500)

Dual antiplatelet therapy with clopidogrel and aspirin require urgent CABG, using only clinical factors on admis-
should be initiated as soon as possible in patients with sion in patients with NSTE-ACS.
non–ST-segment elevation acute coronary syndrome
(NSTE-ACS).1,2 However, such combination therapy can
increase perioperative bleeding in patients undergoing early Methods
coronary artery bypass grafting (CABG).3–7 Therefore, one We studied 572 consecutive patients (mean age 67 ⫾ 11
might consider with-holding clopidogrel until coronary an- years, range 30 to 92, 397 men and 175 women) who were
giography and definition of the coronary anatomy.8 The admitted to Yokohama City University Medical Center
proportion of patients with NSTE-ACS who undergo (Yokohama, Japan) coronary care unit and fulfilled the
CABG during hospitalization is 9% to 21%.4,5,8 –12 CABG following criteria: (1) typical chest discomfort attributed to
can often be deferred for several days, and few patients cardiac ischemia, lasting ⱖ5 minutes, occurring within 24
require urgent CABG. Ideally, clopidogrel should be with- hours before hospital admission, and involving an unstable
held in the minority of patients who urgently require CABG pattern of pain including pain at rest, new onset, severe or
and should be given to the remaining majority of patients. frequent angina, or accelerating angina14; (2) no conditions
We previously examined clinical factors related to left main precluding evaluation ST-segment changes on electrocar-
coronary artery and/or 3-vessel disease (LM/3VD) that diogram (ECG) such as left or right bundle branch block,
would most likely lead to CABG in patients with NSTE- left ventricular hypertrophy, or ventricular pacing; (3) fully
ACS but did not evaluate severity of coronary lesions in that assessable ECGs on admission; and (4) fully assessable
study.13 In the present study, we assessed the ability to angiographic data during hospitalization. We excluded pa-
predict “severe” LM/3VD, which would most likely to tients with nonischemic or atypical pain, persistent new
ST-segment elevation in leads other than lead aVR, recent
Division of Cardiology, Yokohama City University Medical Center,
(⬍6 months) percutaneous coronary intervention, or previ-
Yokohama, Japan. Manuscript received August 28, 2010; revised manu- ous CABG. All patients gave informed consent. The study
script received and accepted October 1, 2010. protocol was approved by the internal review board of
*Corresponding author: Tel: 81-45-261-5656; fax: 81-45-261-9162. Yokohama City University Medical Center.
E-mail address: masami-kosuge@pop06.odn.ne.jp (M. Kosuge). Standard 12-lead ECGs were recorded on admission at a

0002-9149/11/$ – see front matter © 2011 Elsevier Inc. All rights reserved. www.ajconline.org
doi:10.1016/j.amjcard.2010.10.005
496 The American Journal of Cardiology (www.ajconline.org)

Table 1
Clinical characteristics
LM/3VD p
Value
No LM/3VD Nonsevere Severe
(n ⫽ 460) (n ⫽ 57) (n ⫽ 55)

Age (years) 66 ⫾ 11 69 ⫾ 10 68 ⫾ 11 0.06

Men 322 (70%) 39 (68%) 36 (66%) 0.78
Systolic blood pressure on admission (mm Hg) 150 ⫾ 25 150 ⫾ 32 141 ⫾ 26 0.07
Heart rate on admission (beats/min) 76 ⫾ 17 81 ⫾ 20 89 ⫾ 23 ⬍0.001
Killip class ⱖII on admission 26 (6%) 9 (16%) 17 (31%) ⬍0.001
Symptom onset ⱕ6 hours 356 (78%) 43 (75%) 49 (89%) 0.13
Previous myocardial infarction 86 (19%) 18 (32%) 12 (22%) 0.07
Previous percutaneous coronary intervention 90 (20%) 15 (26%) 5 (9%) 0.06
Risk factors
Hypertension 304 (66%) 42 (74%) 38 (69%) 0.49
Diabetes mellitus 136 (30%) 29 (51%) 30 (55%) ⬍0.001
Smoking 229 (50%) 22 (39%) 23 (42%) 0.18
Hyperlipidemia* 230 (50%) 25 (44%) 29 (53%) 0.61
Family history of coronary artery disease 120 (26%) 13 (23%) 16 (29%) 0.75
Hemoglobin on admission (g/dl) 14 ⫾ 2 13 ⫾ 2 13 ⫾ 2 0.033
High-sensitivity C-reactive protein on admission (mg/dl) 0.131 (0.061–0.323) 0.180 (0.079–0.453) 0.253 (0.099–0.801) 0.005
Positive troponin T on admission 135 (29%) 28 (49%) 33 (60%) ⬍0.001
Creatine kinase-MB on admission (IU/L) 14 ⫾ 16 18 ⫾ 24 27 ⫾ 36 ⬍0.001
Estimated glomerular filtration rate on admission (ml/min/1.73 m2) 68 ⫾ 25 58 ⫾ 28 58 ⫾ 26 0.004
Brain natriuretic peptide on admission (pg/ml)† 67 (26–179) 187 (81–429) 230 (67–571) ⬍0.001
(n ⫽ 297) (n ⫽ 32) (n ⫽ 31)
Cardiac procedures and outcomes at 30 days
Death 1 (0.2%) 1 (2%) 2 (4%) 0.010
Myocardial (re)infarction 14 (3%) 3 (5%) 5 (9%) 0.23
Death/myocardial (re)infarction 15 (3%) 4 (7%) 7 (13%) 0.004
Urgent percutaneous coronary intervention 29 (6%) 7 (12%) 5 (9%) 0.22
Urgent coronary artery bypass surgery 7 (2%) 1 (2%) 25 (46%) ⬍0.001
Urgent revascularization (percutaneous coronary intervention or 36 (8%) 8 (14%) 30 (55%) ⬍0.001
coronary artery bypass surgery)
Cardiac procedures
Percutaneous coronary intervention 272 (59%) 36 (63%) 14 (25%) ⬍0.001
Coronary artery bypass surgery 27 (6%) 13 (23%) 40 (73%) ⬍0.001
Any revascularization (percutaneous coronary intervention or 291 (63%) 49 (86%) 54 (98%) ⬍0.001
coronary artery bypass surgery)

Data are presented as mean ⫾ SD, median (interquartile range), or number of patients (percentage).
* Fasting total cholesterol concentration ⱖ220 mg/dl, fasting triglyceride concentration ⱖ150 mg/dl, or use of antihyperlipidemic therapy.
†
Available for 360 patients.

Table 2
Electrocardiographic findings
Variable LM/3VD p Value

No LM/3VD Nonsevere Severe

(n ⫽ 460) (n ⫽ 57) (n ⫽ 55)

ST-segment depression ⱖ0.5 mm 288 (63%) 53 (93%) 55 (100%) ⬍0.001

Maximal ST-segment depression (mm) 0.8 ⫾ 1.0 1.7 ⫾ 1.1 2.6 ⫾ 1.7 ⬍0.001
Sum of ST-segment depressions (mm) 2.6 ⫾ 3.6 6.7 ⫾ 5.1 10.5 ⫾ 7.3 ⬍0.001
Number of leads with ST-segment depression ⱖ0.5 mm 2.5 ⫾ 2.5 5.1 ⫾ 2.6 6.1 ⫾ 2.2 ⬍0.001
ST-segment elevation ⱖ0.5 mm in lead aVR 68 (15%) 39 (68%) 50 (91%) ⬍0.001
ST-segment elevation in lead aVR (mm) 0.1 ⫾ 0.3 0.6 ⫾ 0.5 1.2 ⫾ 0.7 ⬍0.001

Data are presented as mean ⫾ SD or number of patients (percentage).

paper speed of 25 mm/s and an amplification of 10 mm/mV. ms after this point for ST-segment elevation using the preced-
All ECGs were examined by a single investigator who was ing TP segment as a baseline.15 ST-segment deviation was
blinded to all other clinical data. ST-segment shifts were mea- considered present if deviation was ⱖ0.5 mm in any lead.14
sured 80 ms after the J-point for ST-segment depression and 20 A qualitative assay for cardiac-specific troponin T (de-
 Coronary Artery Disease/Prediction of Severe LM/3VD in NSTE-ACS 497

tection limit 0.1 ng/ml of cardiac-specific troponin T; Roche

Diagnostics, Tokyo, Japan) was performed on admission.
Troponin T ⱖ0.1 ng/ml was defined as positive. Blood
samples for measuring hemoglobin, plasma high-sensitivity
C-reactive protein levels, and estimated glomerular filtra-
tion rate were also taken on admission. Japanese equations
were used to calculate estimated glomerular filtration rate
from serum creatinine level.16 Brain natriuretic peptide was
simultaneously measured in 360 patients. Creatine ki-
nase-MB levels were measured on admission, at 3-hour
intervals during the first 24 hours, and in any patient with
suspected reinfarction.
All patients underwent cardiac catheterization a median
of 3 days after admission. Urgent cardiac catheterization
was performed in patients with unstable hemodynamics
from ischemic attacks or with ischemic attacks that could
not be controlled by intensive drug treatment. Type and
timing of revascularization were left to the discretion of the
treating physician. All coronary angiograms were evaluated
by a single investigator who was blinded to all other clinical
data. Stenosis ⱖ50% in the diameter of the LM or stenosis
of ⱖ75% in ⱖ1 major epicardial vessel or its main branches
was considered clinically significant. Severe LM/3VD was
defined as (1) ⱖ75% stenosis of the LM, (2) 3VD with
ⱖ90% stenosis of the proximal portion of the left anterior
descending coronary artery and ⱖ90% stenosis of the right
coronary artery and/or left circumflex coronary artery, and
(3) definitions 1 and 2. Patients were categorize according to
presence (n ⫽ 112) or absence (n ⫽ 460) of LM/3VD, and
the former group was subdivided according to severity of
coronary lesions: nonsevere LM/3VD (n ⫽ 57) and severe
LM/3VD (n ⫽ 55).
Demographic data, risk factors for coronary artery dis-
ease, and data from physical examination on admission
were collected. Major adverse events such as death, myo-
cardial (re)infarction, or urgent revascularization were also
recorded for all patients. Myocardial infarction was diag-
nosed according to cardiac enzyme levels or electrocardio-
graphic criteria. Enzymatic evidence of myocardial infarc-
tion was defined as an increase of creatine kinase-MB to
higher than the upper limit of normal if the previous creatine
kinase-MB level was in the normal range or 50% above the
previous level if the previous level was above the normal
range.17 Electrocardiographic evidence of myocardial in-
farction was defined as new clinically significant Q waves in
ⱖ2 contiguous leads distinct from the enrollment myocar-
dial infarction.17 Patients were followed for 30 days after
admission. Figure 1. Representative electrocardiogram of a patient with severe left
Results are expressed as mean ⫾ SD or as frequency main coronary artery and/or 3-vessel disease. Troponin T was positive on
(percentage), and high-sensitivity C-reactive protein and admission. ST-segment elevation in lead aVR was 4.5 mm on admission
brain natriuretic peptide levels are expressed as median and electrocardiogram. Urgent coronary angiography showed 90% stenosis of
interquartile range. Data were compared by 1-way analysis the left main trunk.
of variance, Kruskal-Wallis test, and chi-square analysis.
Differences were considered statistically significant at p tified on multivariate analysis were determined. SPSS sta-
value ⬍0.05. Multivariate logistic regression analysis was tistical software (SPSS, Inc., Chicago, Illinois) was used for
used to identify clinical predictors of severe LM/3VD all analyses.
among the variables associated (p ⬍0.05) with this diagno-
sis on univariate analysis. Odds ratios and 95% confidence Results
intervals were calculated. In addition, sensitivity, specific-
ity, positive predictive value, negative predictive value, and Baseline characteristics are listed in Table 1. Patients
predictive accuracy of predictors of severe LM/3VD iden- with LM/3VD, especially severe LM/3VD, had a more
498 The American Journal of Cardiology (www.ajconline.org)

Table 3
Univariate and multivariate predictors of severe left main coronary artery and/or three-vessel disease
Variable Odds Ratio (95% CI) p Value

Univariate Multivariate

Systolic blood pressure 0.020 0.07

Heart rate ⬍0.001 0.29
Killip class ⱖII ⬍0.001 0.29
Previous percutaneous coronary intervention 0.045 0.80
Diabetes mellitus 0.001 0.08
High-sensitivity C-reactive protein ⬍0.001 0.30
Positive troponin T 1.27 (1.10–2.78) ⬍0.001 0.044
Creatine kinase-MB ⬍0.001 0.33
Estimated glomerular filtration rate ⬍0.001 0.32
Maximal ST-segment depression ⬍0.001 0.053
Sum of ST-segment depressions ⬍0.001 0.055
Number of leads with ST-segment depression ⱖ0.5 mm ⬍0.001 0.24
Degree of ST-segment elevation in lead aVR 29.1 (9.54–49.8) ⬍0.001 ⬍0.001

CI ⫽ confidence interval.

Table 4 and predictive accuracy of ST-segment elevation in lead

Comparison of ST-segment elevation in lead aVR and positive troponin aVR and positive troponin T for severe LM/3VD are pre-
T for predicting severe left main coronary artery and/or three-vessel sented in Table 4. ST-segment elevation ⱖ1.0 mm in lead
disease
aVR best identified severe LM/3VD.
Sensitivity Specificity PPV NPV Predictive
Accuracy
Discussion
ST-segment elevation
in lead aVR Our study showed that ST-segment elevation ⱖ1.0 mm
ⱖ0.5 mm 91% 79%† 32%† 99% 80%† in lead aVR and positive troponin T on admission (espe-
ⱖ1.0 mm 80% 93% 56% 98% 92% cially the former) were highly suggestive of severe LM/
ⱖ1.5 mm 27%† 98%† 58% 93%† 91% 3VD, and the converse was also true, i.e., absence of these
Positive troponin T 60%* 69%† 17%† 94%† 68%† findings was rarely associated with severe LM/3VD. To our
NPV ⫽ negative predictive value; PPV ⫽ positive predictive value. knowledge, this is the first study to establish a reliable
* p ⬍0.05; † p ⬍0.01 versus ST-segment elevation ⱖ1.0 mm in lead technique for early identification of patients with severe
aVR. LM/3VD who are most likely to require urgent CABG in
patients with NSTE-ACS. Our findings have important im-
plications for identification of high-risk patients and selec-
rapid heart rate, higher prevalences of Killip class ⱖII, tion of optimal treatment strategy in the setting of NSTE-
diabetes mellitus, positive troponin T, and higher levels of ACS.
high-sensitivity C-reactive protein, creatine kinase-MB, and The standard 12-lead ECG, which is an inexpensive,
brain natriuretic peptide than did patients without LM/3VD. noninvasive, and readily available clinical tool, has a central
LM/3VD was associated with lower levels of hemoglobin role in diagnosis and immediate triage for NSTE-ACS and
and estimated glomerular filtration rate. There were no sig- provides important prognostic information. In particular,
nificant differences in other clinical variables among the 3 presence of ST-segment depression on admission ECG has
groups. been recognized to be a strong predictor of adverse out-
Urgent CABG was more frequently done in patients with comes in patients with NSTE-ACS.14,17–20 The Global Uti-
severe LM/3VD (46%). In contrast, urgent CABG was done lization of Strategies to Open Occluded Arteries in Acute
in only 2% of patients with LM/3VD but not severe LM/ Coronary Syndrome IV (GUSTO-IV ACS) trial of 7,800
3VD. patients with NSTE-ACS has highlighted the striking prog-
Electrocardiographic findings are presented in Table 2. nostic value of ST-segment depression on admission com-
Compared to patients without LM/3VD, those with LM/ pared to expanded biomarker profiles and traditional risk
3VD, especially severe LM/3VD, had a higher prevalence factors.18 However, most previous studies assessing the
and a larger amount of ST-segment depression, a larger clinical significance of admission ECG in patients with
number of leads other than lead aVR with ST-segment NSTE-ACS have focused on ST-segment deviation in leads
depression, and a higher prevalence and greater magnitude other than lead aVR; i.e., clinicians have used an “11-lead”
of ST-segment elevation in lead aVR. Figure 1 shows a ECG, neglecting lead aVR.
representative ECG of a patient with severe LM/3VD. Several studies have found that analysis of lead aVR is
In multivariate models, degree of ST-segment elevation useful for evaluation of NSTE-ACS.13,15,21,22 Gorgels et
in lead aVR was the strongest predictor of severe LM/3VD, al21 reported that ST-segment elevation in lead aVR accom-
followed by positive troponin T (Table 3). Sensitivity, spec- panied by ST-segment depression in leads I, II, and V4 to V6
ificity, positive predictive value, negative predictive value, during episodes of angina strongly suggests LM/3VD in
 Coronary Artery Disease/Prediction of Severe LM/3VD in NSTE-ACS 499

patients with angina at rest. Barrabés et al15 demonstrated ST-segment depression in other leads in patients with
that presence of ST-segment elevation in lead aVR predicts NSTE-ACS.
risk of in-hospital death in patients with a first non–ST- Recently approved antiplatelet agents such as prasugrel
segment elevation acute myocardial infarction. In that and ticagrelor, a new reversible agent, have been shown to
study, ST-segment elevation in lead aVR was also related to decrease ischemic events compared to clopidogrel, but the
LM/3VD; however, coronary angiography was performed former increased the risk of perioperative bleeding7 and the
in only 56% of subjects within 6 months after infarction. We latter did not decrease the risk of perioperative bleeding.26
previously demonstrated that presence of ST-segment ele- Until an antiplatelet agent that decreases ischemic events
vation ⱖ0.5 mm in lead aVR on admission ECG strongly and decreases perioperative bleeding compared to clopi-
suggested LM/3VD and had a higher prognostic value than dogrel becomes available, some patients will be exposed to
ST-segment depression in other leads in patients with a risk of urgent CABG-related bleeding caused by upstream
NSTE-ACS who underwent coronary angiography in the dual antiplatelet therapy.
acute phase.13,22 However, previous studies, including ours, This study was retrospective, performed at a single cen-
did not consider severity of LM/3VD, which has clinical ter, and included a small number of patients who underwent
implications for timing of CABG in relation to dual anti- coronary angiography during hospitalization. However, the
platelet therapy. An increased risk of perioperative bleeding proportion of patients undergoing CABG during hospital-
events due to early clopidogrel administration is clinically ization in this study (14%) was similar to that in previous
problematic in patients with LM/3VD who urgently require studies.4,10,12 Moreover, because our subjects underwent
CABG. In such patients, postponing CABG for several days cardiac catheterization a median of 3 days after admission,
might seriously compromise outcomes. Timing of CABG our data on clinical outcomes according to angiographic
depends on many factors including severity of coronary findings cannot be generalized to hospitals that provide
lesions, risk of ongoing ischemia, general condition of a early invasive strategies. Further studies in larger numbers
patient, bleeding risk associated with upstream antithrom- of patients are needed to verify our results.
botic therapies, and local logistic factors such as collocation
of cardiac surgical services and surgical waiting lists. The 1. Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey
present study examined predictors of patients with severe DE Jr, Chavey WE II, Fesmire FM, Hochman JS, Levin TN, Lincoff
AM, Peterson ED, Theroux P, Wenger NK, Wright RS, Smith SC Jr,
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