(Circulation. 1998;98:2004-2009.)
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports |
Very Early Risk Stratification Using Combined ECG and Biochemical Assessment in Patients With Unstable Coronary Artery Disease (A Thrombin Inhibition in Myocardial Ischemia [TRIM] Substudy)
From the Heart Center, Rigshospitalet, Copenhagen (L.H., P.C., P.G.), and the Department of Cardiology, Aarhus Amtssygehus/Universitetshospital, Aarhus (M.S.L., K.T.), Denmark.
Correspondence to Lene Holmvang, MD, The Heart Center 2142, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen Ø, Denmark.
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Abstract |
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Background—The diagnostic capability of troponin T (TnT), troponin I (TnI), myoglobin, and creatine kinase (CK)-MB mass for detection of myocardial injury seems evident. Newer studies have found these sensitive markers to carry independent prognostic information in patients with unstable coronary artery disease as well. ST-segment depression in the admission ECG is known to be an important indicator of poor outcome in these patients. The present study investigates the prognostic capacities of the ECG in combination with biochemical admission measurements in 516 patients admitted to hospital with unstable coronary artery disease.
Methods and Results—Baseline ECG recordings and blood
samples were collected for central analysis. The patients were
followed up for 30 days, and predefined end points, ie, death,
myocardial infarction, and refractory angina, were registered as end
points. By univariate analysis, ST-segment
depression, inverted T waves in 
5 leads, TnT 0.1 µg/L, TnI 0.5
µg/L, myoglobin 40 µg/L, female sex, and age 65 years were
predictors of death and myocardial infarction at 30 days. By
multivariate analysis, female sex, ST-segment
depression at randomization, or inverted T-waves in 5 leads were the
only independent predictors of death or myocardial infarction. On the
basis of baseline ECG ST-T changes and CK-MB mass/TnT/TnI/myoglobin
levels, the patients were divided into 3 subgroups at high (14% event
rate), intermediate (6%), and low (3%) risk of early death/myocardial
infarction.
Conclusions—The present study found the combination of baseline values of TnT, TnI, CK-MB mass, and ST-T changes in the ECG to be effective for early risk stratification in patients with unstable coronary artery disease.
Key Words: prognosis • angina • electrocardiography • myoglobin • creatine kinase • troponin
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Introduction |
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It is generally accepted that unstable myocardial ischemia and infarction, registered as ECG ST-T–segment changes, are caused by an atherosclerotic plaque rupture, with concomitant platelet activation and thrombus formation.1 2 Despite optimal medical treatment, the group of patients with unstable coronary artery disease (ie, unstable angina and non–Q-wave myocardial infarction) carries a high risk of an adverse event within a few months of follow-up.3 4 5 Thus, it would be of importance to detect the individual patients at increased risk with intention to offer a more expedient treatment. In patients admitted with suspected acute myocardial infarction (AMI), ST-segment depression in the admission ECG has been shown to be an important indicator of high risk.6 7 The admission ECG, however, fails to identify many of the patients who experience a cardiac event during the early follow-up period. During the past years, novel sensitive biochemical markers for detecting minimal myocardial injury have been developed. Myoglobin has been shown to reach peak values early after onset of acute chest pain. Also, the new cardiospecific markers troponin T (TnT), troponin I (TnI), and creatine kinase (CK)-MB mass appear in blood relatively early after symptom onset8–12; in addition, new rapid bedside assays have been developed, making it possible to measure the release of cardiac enzymes within minutes after onset of symptoms. This information could facilitate decision-making in the emergency room and coronary care unit and expand the use of revascularization therapies to patients suspected of having AMI but without current ECG indications for use of thrombolysis or primary PTCA. In recent years, several studies have demonstrated that these sensitive biochemical markers are superior with regard to diagnostic and prognostic information in patients with unstable coronary artery disease,13 14 15 16 17 18 19 20 21 22 23 but none have explored the potential of combining the admission markers with the conventional ECG for early risk stratification. The aim of the present study is therefore to investigate the prognostic capabilities of a standard ECG combined with biochemical measurements obtained at admission in patients with unstable coronary artery disease.
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Methods |
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Population
Sixty centers (1209 patients) participated in the TRIM (Thrombin Inhibition in Myocardial Ischemia) study that randomized patients with unstable angina/non–Q-wave MI to 4 different treatment regimens of either heparin or a specific thrombin inhibitor (Inogatran). Many of these centers took part in substudies on biochemical markers, ECG, etc. The main study did not prove any superiority of the study drug (Inogatran) over heparin with regard to ischemic events24; thus, the patients in this substudy were considered as having received similarly effective treatment. From a total of 1209 patients, 516 patients from 22 centers were included in a predefined substudy of biochemical markers of myocardial damage and ECG.
Inclusion Criteria and Diagnosis
The entry criteria were either a clinical suspicion of unstable
angina pectoris or a non–Q-wave MI. The patients had to be included
within 24 hours after the qualifying episode of chest pain. The
clinical diagnosis had to be supported by either ECG changes compatible
with myocardial ischemia or a history of previous
coronary artery disease. Inclusion and exclusion criteria have
been described in detail elsewhere.24 The main
exclusion criteria were an indication for thrombolytic
treatment (decided by the attending cardiologist), heart failure,
ongoing arrhythmia, increased risk of hemorrhage, and
allergy to heparin or the study drug.
On the basis of the clinical course and plasma levels of biochemical markers obtained within 6 hours after inclusion, the patients were retrospectively categorized as having unstable angina pectoris (n=309), non–Q-wave MI (n=190), and other diseases (n=17).
Data
ECG Analysis
A standard 12-lead ECG was obtained in all patients at their
inclusion in the study. These ECGs were sent to and analyzed in
the ECG core laboratory at Rigshospitalet, Copenhagen, before any other
data on the patient were revealed. The ST-T changes were measured in
millimeters at 60 ms after the J point, and the changes had to appear
in at least 2 contiguous leads to be considered of significance.
ST-segment elevation had to be at least 2 mm in lead
V1-V2 and at least 1
mm in any other lead. ST-segment depression had to be a minimum of
1 mm in any lead. Inverted T waves had to be at least 1 mm as
well. Lead aVR was not evaluated. ECG data from the case report form
were not used in the present study.25
Blood Sampling and Biochemical Analysis
At randomization, blood samples were drawn and analyzed
for myoglobin, TnT, TnI, and CK-MB mass. The analysis was
performed centrally at the Core Laboratory at University Hospital,
Aarhus, Denmark. TnT was analyzed with an ES 300
analyzer (Boehringer Mannheim GmbH). The method is
based on a single-step sandwich principle with streptavidin-coated
tubes (solid phase) and 2 monoclonal anti-human TnT
antibodies.26 Based on previous
reports13 16 27 and the manufacturer's
recommendation, a cutoff value for TnT was set at 0.10 µg/L. The
chosen cutoff value was supported by our own receiver operating
characteristic (ROC) analysis (see below). TnI, CK-MB mass, and
myoglobin were measured with an Opus Magnum (Behring
Diagnostics Inc) based on the principle of 2-site
immunoassay using polyclonal antibodies to recognize epitopes unique to
TnI/myoglobin/CK-MB mass.28 29 The discriminator
value for TnI was set at 2.0 µg/L, also based on recommendation from
the manufacturer and previous studies.13 An
alternative cutoff value was set at 0.5 µg/L on the basis of ROC
analysis. Very little information is available regarding
recommended cutoff values for myoglobin for early risk stratification
in unstable coronary artery disease.30
The upper limit of normal is set by the manufacturer at 90 µg/L,
which is also the discrimination limit used for diagnosing MI in our
institution. However, the aim of the present study was not to
diagnose MI but rather to identify patients with minor myocardial
damage. Thus, a discrimination level at 40 µg/L was chosen and
further evaluated by ROC analysis. The prognostic capability of
CK-MB mass has previously been studied in patients with unstable
coronary artery disease.22 30 In those
studies, cutoff levels at 6.0 and 7.5 µg/L were used. In the
present study, a discrimination level at 7.0 µg/L was chosen.
End Points and Follow-Up
The following events were registered as end points: death,
MI/reinfarction, refractory angina (despite optimal treatment, leading
to any kind of intervention), and recurrent angina. MI was defined as a
diagnostic series of ECGs or at least 2 of the following:
(1) typical ischemic chest pain, (2) diagnostic
ECG, or (3) typical elevation of cardiac enzymes. Refractory angina was
defined as recurrence of chest pain lasting 5 minutes despite
maximal ongoing medical treatment, including intravenous
nitroglycerin and oral ß-blockers or calcium
antagonists. The pain episodes had to be associated with
transient ECG changes indicative of myocardial ischemia and
leading to coronary angiography. Recurrent angina was defined
as recurrent chest pain of 5 minutes' duration typical of myocardial
ischemia and responding to sublingual
nitroglycerin but not fulfilling the criteria for
refractory angina pectoris. After discharge, recurrent angina was
defined as readmission because of anginal chest pain. Further details
on end-point definition have been described
elsewhere.24
The patients were followed up for a period of 30 days after admission to hospital. After discharge, the patients returned to the outpatient clinic for a follow-up visit at 30 days after inclusion in the study. If a patient reached >1 end point during follow-up, the time of the first event was registered. The registration of end points was supervised by an independent end point committee that reviewed all end-point data and paid special attention to separating the index event from the predefined end points. In the present substudy, the composite of death and MI will be the main end points under discussion.
Statistical Analysis
All values are expressed as median (interquartile range).
Intergroup comparisons of biochemical concentrations were performed by
the Mann-Whitney U test. Event rates among subgroups were
compared by log-rank survival analysis, and the results were
presented as Kaplan-Meier plots. To evaluate independent
prognostic value of the variables, a Cox regression model was
constructed by use of backward elimination strategy. The Statsoft
program Statistica was used for computer analysis. Separate
analyses were performed for the composite of death and AMI and
for the composite of death, AMI, and refractory angina.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Baseline Characteristics
Table 1
presents the baseline characteristics for the study population. In
the 30-day follow-up period, 56 patients experienced 1 event(s).
There were 9 deaths (1.7%), 33 AMIs (6.3%), and 21 cases of
refractory angina (4.0%), and 242 patents (46.8%) experienced
recurrent angina. CABG or PTCA was performed in 102 patients
(19.5%).
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ECG Assessments
An ECG was collected for each patient at inclusion in the study.
Fourteen ECGs were either missing or of such poor quality that
ST-segment analysis could not be performed. Twenty-two ECGs
were nonevaluable because of bundle-branch block or left
ventricular hypertrophy that precluded reliable
ST-segment analysis. Thus, 9% of the ECGs were either missing
or uninterpretable. Of the 470 patients with evaluable ECGs, 92 (19%)
had minor ST elevations (median summed, 3.5 mm; range, 2 to 8
mm), 64 (14%) had ST-segment depression (median summed, 3.0 mm;
range, 2 to 12.5 mm), and 280 (59%) had inverted T waves. ECGs
without ST-T changes or confounding factors (n=150 [32%]) were
considered "normal."
Biochemical Results: Determination of Cutoff Values
The patients were divided into 2 subgroups based on whether or not
they reached a serious end point (death and AMI) within the 30-day
follow-up period. The median concentration of each biochemical marker
was calculated within each subgroup. Table 2 illustrates the
concentration of biochemical markers among the patients who died or had
an AMI within the follow-up period compared with the patients without
end points. All of the 4 biochemical markers were significantly
increased in the event group.
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Figure 1 illustrates the spectra of
sensitivities and specificities attained by the various cutoff levels
of the 4 biochemical markers for prediction of death and AMI. The
cutoff values with the best sensitivity and specificity were 0.10
µg/L for TnT, 0.5 µg/L for TnI, 40 µg/L for myoglobin, and 7.0
µg/L for CK-MB mass.
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Prognostic Value of Biochemical Markers, ECG Changes, and
Baseline Variables
Table 3 depicts the
prognostic values of various risk factors regarding death and AMI
during follow-up. All variables that were statistically significant
at the 10% level by univariate analysis were
entered into a Cox regression model using backward elimination
strategy. Female sex, ST-segment depression at admission, and T-wave
inversion in 5 leads were independent predictors of death/AMI by
multivariate analysis.
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Combined ECG and Biochemical Evaluation
TnT was the best of the 4 markers for prediction of risk by
univariate analysis. Figure 2 illustrates risk stratification of
patients based on initial ECG evaluation followed by a single blood
sample for biochemical analysis. Patients with ST-segment
depression at admission had a 14% risk of subsequent death or AMI
within the follow-up period. However, the patients without ST-segment
depression and/or inverted T waves in 5 leads or with nonevaluable
ECGs could, by a single blood test for TnT, be further subgrouped into
an intermediate-risk group (TnT 0.10 µg/L, event rate 6%,
P=0.01) and a low-risk group (TnT <0.10 µg/L, event rate
3%, P=0.07). Figure 3 depicts
the event rates among the 3 subgroups as Kaplan-Meier curves. Similar
analyses were performed regarding TnI, myoglobin, and CK-MB
mass, and the results are depicted in Table 4. All of the biochemical
markers managed to separate the patients without ST-segment depression
into a group at intermediate risk (6% event rate) and a group at low
risk (3% event rate). However, only by CK-MB mass did the difference
reach a significant level (P=0.05).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Risk stratification in patients with unstable coronary artery disease is a major clinical issue with important therapeutic implications. Very early identification of the high-risk patient is crucial, because a substantial number of cardiac events occur within the first few days after admission.4 23 Previous studies have proved the importance of the admission standard ECG in identifying patients at high risk for subsequent adverse events.6 7 However, the combination of the ECG and other indicators of myocardial ischemia might improve prognostic sensitivity and specificity.
In the present study of a population of patients admitted with
unstable coronary artery disease, the independent and combined
prognostic value of a single standard 12-lead ECG and a single blood
assessment of biochemical markers obtained at admission was evaluated.
ST-segment depression at admission, as well as T-wave inversion in 5
leads, was found to be a strong individual predictor of poor outcome.
New sensitive biochemical markers of ischemia have been found
to carry independent prognostic information in patients with unstable
coronary syndromes, and through recent years, new, rapid
methods of analyzing these markers have been introduced. Thus, a
biochemical assessment of a patient can be available within a very
short time after admission to hospital. In the present study, TnT,
TnI, myoglobin, and CK-MB mass were all markedly increased among the
patients who subsequently died or experienced an MI within a follow-up
period of 30 days after admission to hospital. By
univariate analysis, elevated admission levels of
TnT, TnI, and CK-MB mass were significant predictors of poor outcome,
together with other baseline variables. However, neither the
biochemical markers nor various baseline characteristics were found to
carry independent prognostic information when entered into a
multivariate regression model with ECG data.
Most of the newer studies of prognostic ability of biochemical markers have used serial blood sampling and peak values. However, in the GUSTO IIa population of patients with acute myocardial ischemia, Ohman et al14 found increased mortality within 30 days among patients with admission TnT values >0.10 µg/L. Compared with our population, the GUSTO IIa study population was a selected high-risk group, with 72% of the patients having Q-wave MI. The GUSTO IIa results are in concordance with a study by Stubbs et al,27 who found that elevated admission TnT values in patients with AMI defined a subgroup at increased risk of subsequent cardiac events. The only study of patients with MI ruled out in which the admission sample of TnT was used was reported by Wu et al,20 who evaluated the prognostic value of a single admission blood sample in a small population of 131 patients admitted with unstable angina pectoris. The study showed that TnT on admission could provide independent prognostic information, although it could be claimed that multivariate analysis including other variables was not performed. Although in the present study, elevated admission TnT did not carry independent prognostic information by multivariate analysis, it provided significant information regarding the patients without ST-segment depression in the standard 12-lead ECG or with noninterpretable ECGs. Previous reports based on the present study population13 found peak TnT values >0.10 µg/L within the first 6 hours to be independent predictors of death and MI. In that report, ECG changes were not found to be important by multivariate analysis. The ECG data in that study, however, were based on the local investigators' reports in the case report form and not on blinded analysis in an ECG core laboratory. Considerable differences between on-site evaluation of ECG data and the blinded evaluation performed in a core laboratory have recently been reported.25 Thus, the results from the present study must acknowledge the importance of baseline ECG ST-T changes.
In the present study, TnI levels were elevated among the patients
who died or had MI during the follow-up period, and by
univariate analysis, TnI levels 0.2 µg/L as
well as levels 0.5 µg/L were associated with an increased risk of
the composite of death and AMI. Antman and
coworkers18 found that TnI levels above a cutoff
value of 0.4 µg/L obtained in a single blood test at admission were
significantly associated with mortality in 1404 patients from the TIMI
IIIB trial. Galvani et al21 found increased
cardiac events among unstable angina patients with TnI values 3.1
µg/L at admission or 8 hours later. Except for the study by Antman,
serial blood sampling for the assessment of peak values seems to be
necessary for obtaining independent prognostic information from
TnI.13 22 A major problem in comparing the
various trials on TnI is the lack of standardization of assays and the
use of different discriminator levels.
Previous studies have proved myoglobin to be an early sensitive and specific marker of MI10,11; however, it has not yet been proved useful for risk stratification of patients with unstable angina pectoris.31 Even though the present study found elevated myoglobin concentrations among the patients who subsequently suffered a cardiac event, myoglobin was not found to carry independent prognostic information by univariate or multivariate analysis. These findings are in accordance with the results reported by de Winter and coworkers,30 who found elevated TnT but not myoglobin and CK-MB mass to predict future cardiac events in patients with acute chest pain in whom AMI had been ruled out.
In the present study, CK-MB mass values >7.0 µg/L were associated with an increased risk of death/AMI by univariate analysis. This is in accordance with the findings by Ravkilde et al,22 who found CK-MB mass values to be associated with poor outcome in serial analysis; however, once the ECG changes were considered, the biochemical markers did not add any additional information. The present study, however, revealed possibilities for baseline CK-MB mass measurements as a supplement to the admission ECG for early risk stratification.
Study Limitations
The present study is a substudy in a multicenter trial in
which the patients were selected on the basis of several inclusion and
exclusion criteria.18 The lack of standardization
of assays for determination of TnI and CK-MB mass and the use of
different discriminator levels is a major problem when results from
various trials are compared.
Conclusions
It can be concluded that the combination of admission values of
troponin T, troponin I, CK-MB mass, and ECG ST changes are advantageous
for early risk stratification in patients with unstable
coronary artery disease. By multivariate
analysis, only ST-segment depression in the baseline ECG
carried independent prognostic value; however, admission TnT, TnI, and
CK-MB mass added useful information.
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Acknowledgments |
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The TRIM study was funded by ASTRA. The present substudy was supported by grants from the Beckett Foundation, Asta Floridan Boldings Mindelegat, and Murermester Laurits Peter Christensen og hustru Kirsten Sigrid Christensens fond. Statistical support was financed through a grant from the Danish Medical Research Council. Astra Hässle AB has been very helpful in providing baseline and follow-up data. We gratefully appreciate the work of technician Hanne Høegh in data sampling. Without the enthusiastic work of all physicians and nurses at the TRIM study sites, the study could not have been completed.
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Footnotes |
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1 For a complete listing of all participating centers and investigators in the TRIM substudy of biochemical markers in unstable coronary artery disease, see Circulation. 1997;96:2578–2585.
Received March 25, 1998; revision received June 24, 1998; accepted July 1, 1998.
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