Extent of ST-segment depression and cardiac events in non-ST-segment elevation acute coronary syndromes

Stefano Savonitto1,*, Mauricio G. Cohen2, Alessandro Politi3, Michael P. Hudson4,5, David F. Kong4,5, Yao Huang5, Karen S. Pieper5, Francesco Mauri1, Galen S. Wagner4,5, Robert M. Califf4,5, Eric J. Topol6 and Christopher B. Granger4,5

1Dipartimento Cardio-toraco-vascolare, ‘A. De Gasperis’, Ospedale Niguarda Ca' Granda, Piazza Ospedale Maggiore 3, 20162 Milan, Italy
2Division of Cardiology, University of North Carolina, Chapel Hill, NC, USA
3Department of Cardiology, Ospedale Sant' Anna, Como, Italy
4Department of Medicine, Duke University Medical Center, Durham, NC, USA
5Duke Clinical Research Institute, Durham, NC, USA
6Department of Cardiology, Cleveland Clinic, Cleveland, OH, USA

Received 20 February 2005; revised 23 May 2005; accepted 9 June 2005; online publish-ahead-of-print 29 June 2005.

* Corresponding author. Tel: +39 335 605 6565; fax: +39 02 688 3804. E-mail address: stefano.savonitto{at}fastwebnet.it


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Clinical implications: risk...
 References
 
Aims We sought to determine whether the extent of myocardial ischaemia on the admission electrocardiogram (ECG) has independent predictive value for short-term risk stratification of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS). Although the presence of ischaemic ECG changes on admission has been shown to predict outcome, the relationship between the extent of ECG changes and the risk of cardiac events is still ill defined.

Methods and results We analysed the admission ECGs of 5192 ACS patients enrolled in the GUSTO-IIb trial, without an ECG indication for thrombolysis. ECG tracings showing one or more of the following were eligible: ST-segment depression >0.5 mm, T-wave inversion >1 mm, and ST-segment elevation >0.5 mm but <1 mm. ECG variables associated with unfavourable 30 day outcomes in a univariable analysis were further assessed in a multivariable logistic regression model including independent clinical predictors. In the multivariable clinical, enzymatic, and ECG model, the sum of ST-segment depression (in millimetres) in all leads was a powerful independent predictor of 30 day death (P<0.0001), with a continuous increase in risk with the extent of ST-segment depression. The sum of ST-segment depression (P<0.0001) and the presence of minimal inferior ST-segment elevation (P<0.0001) or anterior ST-segment elevation (P=0.0182) were also independent predictors of the composite of death and myocardial infarction or reinfarction. The extent of ST-segment depression showed a highly significant correlation with the prevalence of three-vessel (P<0.0001) or left main coronary disease (P<0.0001), and also with the peak levels of creatine kinase (P<0.0001) during the index episode of ACS.

Conclusion In patients with NSTE ACS, the sum of ST-segment depression in all ECG leads is a powerful predictor of all-cause mortality at 30 days, independent of clinical variables and correlates with the extent and severity of coronary artery disease. The presence of even minimal (<1 mm) ST-segment elevation in anterior or inferior leads is independently associated with adverse outcomes.

Key Words: Non-ST-segment elevation acute coronary syndromes • Electrocardiogram • Logistic regression analysis • Myocardial infarction • Prognosis


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Clinical implications: risk...
 References
 
Non-ST-segment elevation acute coronary syndromes (NSTE ACS) account for approximately 2–2.5 million hospital admissions annually worldwide1 and represent the majority of admissions to coronary care units.2 These syndromes affect a broad spectrum of patients with symptoms suggestive of acute myocardial ischaemia, with varying risks for death and cardiac ischaemic complications.3,4 Rapid risk stratification is crucial for appropriate management of these patients and for targeting more potent and invasive therapies for higher-risk patients.58 The admission electrocardiogram (ECG) may identify high-risk patients who will benefit most from more aggressive treatments. A qualitative analysis of the ECG has been shown to provide prognostic information in NSTE ACS.912 More specifically, the presence of ST-segment depression during an acute episode has been shown to be a powerful and independent predictor of long-term mortality.1012 However, it is still not well understood whether a quantitative analysis of ST-segment depression and other ECG ischaemic variables may allow further prognostic discrimination. Taking advantage of the large ECG core lab database of the Global Use of Strategies To Open occluded coronary arteries in acute coronary syndromes-IIb (GUSTO-IIb) study,13 Kaul et al.14 found that a categorical quantification of the amount (1 mm or ≥2 mm) and distribution (less than or two or more ECG regions) of ST-segment depression can identify a gradient in risk independently of clinical variables.14 By using the clinical, ECG, and angiographic data from the same trial, the present study investigated the relationship between the global extent of ST-segment depression and the 30 day outcome and evaluated the relationship between the severity of coronary artery disease at angiography and the amount of enzymatic release during the index episode of ACS. We also investigated whether, besides ST-segment depression, other qualitative and quantitative ECG variables may predict outcome in NSTE ACS.


    Methods
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 Methods
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 Discussion
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Patients
The methods, results, and patient population of the GUSTO-IIb trial have been described in detail.13 Briefly, between May 1994 and October 1995 GUSTO-IIb recruited 12 142 patients with ACS at 373 hospitals in 13 countries. Patients were required to have had ischaemic symptoms at rest within the previous 12 h and to show signs of myocardial ischaemia on the admission ECG. Exclusion criteria were active bleeding, prior stroke, a contraindication to heparin, a serum creatinine level >2.0 mg/dL, systolic blood pressure (SBP) >200 mmHg or diastolic blood pressure (DBP) >110 mmHg, warfarin therapy, or childbearing potential. Patients were randomly assigned to 72 h of therapy with either intravenous unfractionated heparin or hirudin. Standard medical care included aspirin, thrombolytic therapy (if not contraindicated) for patients with ST-segment elevation ≥1 mm in two or more ECG leads, and anti-ischaemic therapy with ß-blockers, nitrates, and calcium channel blockers. The patient population of the present study was composed of GUSTO-IIb patients without ECG indication for thrombolytic therapy.

Electrocardiographic variables
To be enrolled in the GUSTO-IIb trial, patients were required to demonstrate ECG signs of myocardial ischaemia, consisting of either transient or persistent ST-segment elevation or depression >0.5 mm, or persistent and definite T-wave inversion >1 mm, including the pseudonormalization of a previously negative T-wave, in two or more contiguous leads. Patients with ST-segment elevation ≥1 mm in two or more contiguous leads on the admission ECG were classified as ST-segment elevation ACS (4131 patients), whereas all other patients were classified as NSTE ACS (8011 patients). This classification, made by the attending physician at admission, was the basis of previous reports on the GUSTO-IIb trial.3,11,13

A copy of the standard 12-lead ECG recorded on admission (at a paper speed of 25 mm/s) was sent to the trial co-ordinating centre at Duke Clinical Research Institute, Durham, NC, where all ECG data were read manually and classified by expert cardiologists blinded to treatment assignment and patient information. ST-segment depression was judged to be present if the J-point was depressed >0.5 mm. The present analysis included those patients with at least one of the following ECG characteristics: ST-segment depression >0.5 mm (with or without concomitant T-wave inversion), isolated T-wave inversion ≥1 mm, and ST-segment elevation >0.5 mm but <1 mm in two or more contiguous leads. Patients with factors potentially confounding the ECG interpretation, such as ventricular hypertrophy, bundle branch block, paced rhythm, ventricular rhythm, Wolf–Parkinson–White Syndrome, low voltage, poor quality, and incomplete ECG tracings were excluded. Most of those excluded had at least one of the following: 32% had left ventricular hypertrophy by Romhilt–Estes criteria, 24% had left ventricular hypertrophy by Sokolow–Lyon criteria, 31% had left anterior hemi-fascicular block, and 28% had right bundle branch block.

The ECG variables analysed by the core laboratory were cumulative sum of ST-segment depression (the sum of the ST-segment depression, in millimetres, in all leads showing ST-segment depression >0.5 mm), number of leads showing ST-segment depression >0.5 mm, isolated T-wave inversion ≥1 mm, maximal T-wave inversion amplitude, number of leads showing T-wave inversion ≥1 mm, heart rate, number of leads showing Q-wave ≥30 ms, QRS duration (up to 120 ms, because bundle branch block was excluded), and minimal ST-segment elevation (anterior or inferior) >0.5 mm but <1.0 mm.

Outcome measures
The primary endpoint of the GUSTO-IIb study was the composite of 30 day death, myocardial infarction (MI), or reinfarction. For the present analysis, we considered mortality as a separate endpoint. MI was defined by cardiac enzymes or ECG criteria. Enzymatic evidence of MI was defined as an elevation of creatine kinase-MB (CK-MB) fraction to higher than the upper limit of normal if the prior level was in the normal range, or 50% above the prior level if the prior level was above normal range. If CK-MB was not available, then total CK must have been greater than two times above the upper limit of normal and increased by at least 25% or 200 U/mL more than the previous value. ECG evidence of MI was defined as new significant Q-waves in at least two leads and distinct from the enrolment MI. All clinical endpoints were centrally adjudicated by a clinical events committee at the GUSTO-IIb co-ordinating centre. The committee made its determinations after reviewing all source documents relating to in-hospital death and MI.

Statistical analysis
All categorical variables are summarized as per cents. Continuous measures are summarized as medians with 25th and 75th percentiles. Logistic regression analysis determined the univariable relationships between the ECG characteristics and the death as well as the relationships between the ECG characteristics and death/MI within 30 days. The association between the sum of the ST-segment depression and the two outcomes was illustrated using SAS/PROC LOESS (SAS Institute, Cary, NC, USA) software smoothing techniques. These curves, with associated 95% confidence intervals (CIs), illustrate the nature of the associations. Logistic regression analysis was also used to determine the effect of ECG variables in combination with other clinical predictors. As previously reported,3,11 age, heart rate, Killip class, SBP and DBP, smoking status, sex, weight, prior MI, prior percutaneous transluminal coronary angioplasty, peripheral vascular disease, family history of coronary artery disease, renal insufficiency, hypertension, hyperlipidaemia, height, diabetes, and elevated CK levels on admission were associated with 30 day death; age, heart rate, Killip class, SBP and DBP, sex, prior MI, peripheral vascular disease, renal insufficiency, hypertension, previous angina, height, diabetes, and elevated CK levels on admission were associated with 30 day death/MI. These baseline clinical factors, as well as the ECG factors found in Tables 2 and 3 were entered into a logistic regression model using stepwise variable selection technique for final model selection. For the continuous variables considered in the model selection process, the linearity assumption is tested by fitting both the linear and non-linear (cubic) logistic models. A likelihood ratio test, with linearity as the null hypothesis, is then performed to determine whether the linearity assumption is valid. If the linearity assumption does not hold, then the appropriate transformation on the continuous variable is made.


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Table 2 Univariable associations between electrocardiographic variables and 30-day mortality
 

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Table 3 Univariable associations between electrocardiographic variables and 30-day death or MI
 
Factors that remained significant at the 0.05 level in the multivariable models comprised the final models. The estimates of the association between predictors and endpoints are presented as odds ratios (ORs) with 95% CIs. The Wald {chi}2 for all factors in the models are summed. The per cent for each {chi}2 relative to this total is used as an estimate of the per cent of the predictive information in the model accounted for by that variable.

The ability of the model to discriminate was assessed using the c-index or the area under the receiver operating characteristic curve. To validate these models, 1000 bootstrapped samples were generated and the degree of optimism estimated. Corrected c-indices were then obtained by subtracting this optimism from the original.15 All statistical tests were two-sided with a critical value of 0.05 for statistical significance. No adjustments were made for multiple testing and interpretation of the results should be made accordingly. SAS statistical software was used for all analyses (SAS Institute, Cary, NC, USA).


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Clinical implications: risk...
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Univariable associations of ECG variables and outcome
Of the 12 142 patients enrolled in the GUSTO-IIb study, 11 161 (4800 with ST-segment elevation and 6361 with no ST-segment elevation or confounding factors) were considered to have an analysable admission ECG. Confounding factors were present in 1169 patients with no ST-segment elevation. Thus, 5192 patients met the inclusion criteria for this study (Figure 1) and Table 1 summarizes their baseline characteristics. By day 30, 160 patients were dead (3.08%) and 416 had experienced the composite outcome of death or MI (8.01%) (Tables 2 and 3). Among the categorical variables, isolated T-wave inversion was associated with a benign outcome, whereas the combination of ST-segment depression plus T-wave inversion, minimal ST-segment elevation, and prolonged QRS signified increased risk. Among the numerical variables, the global or regional amount of ST-segment depression and the number of leads showing ST-segment depression or T-wave inversion were associated with higher risk.



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Figure 1 Detailed description of the inclusion and exclusion criteria for the study.

 

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Table 1 Baseline characteristics
 
Multivariable predictors of 30 day outcome including clinical and electrocardiographic variables
In the multivariable logistic regression model including the clinical and ECG variables, only the cumulative sum of ST-segment depression in all leads was a significant ECG predictor of 30 day mortality, with a predictive value second only to age (Table 4). Table 5 shows the unadjusted mortality rates at 30 days according to quartiles of sum of ST-segment depression. There was an incremental and continuous association between cumulative ST-segment depression and mortality (Figure 2, upper panel). The model has good discrimination (c-index=0.791), which remains after internal validation with bootstrapping (c-index=0.786).


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Table 4 Independent clinical and ECG predictors of death and of death or MI at 30 days
 

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Table 5 Unadjusted event rates, extent of coronary artery disease, per cent of admission MI, and peak levels of CK, by quartiles of sum of ST-segment depression in all ECG leads
 



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Figure 2 Unadjusted relation of the sum of ST-segment depression (mm) in all of the standard electrocardiographic leads (excluding aVR) with 30 day mortality (upper panel) and 30 day death or MI (lower panel).

 
The sum of ST-segment depression, and also minimal ST-segment elevation in inferior or anterior leads were powerful independent predictors for the composite endpoint of death or MI (Table 4). This model has a poor c-index discrimination (c-index=0.629) which is similar after internal validation with bootstrapping (c-index=0.624).

Table 5 shows the unadjusted rates of death or MI at 30 days according to quartiles of sum of ST-segment depression. The unadjusted relation between the sum of ST-segment depression and the probability of 30 day death or MI is shown in Figure 2 (lower panel).

Relationship between extent of ST-segment depression and coronary artery disease
The extent of ST-segment depression was also associated with the severity of coronary artery disease and the amount of CK release, as shown in Table 5, greater ST-segment depression was associated with an increased likelihood of three-vessel coronary artery disease or left main coronary stenosis as well as greater elevation in CK levels during the index episode (all P<0.0001).


    Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Clinical implications: risk...
 References
 
NSTE ACS encompass a wide spectrum of clinical presentations with different baseline risk and extent of coronary disease. Because early aggressive medical and interventional treatment has been shown to substantially reduce cardiac events, particularly in high-risk patients, current practice guidelines emphasize risk stratification upon hospital admission based on clinical history, physical examination, biochemical markers of myocardial damage and 12-lead ECG.5,6,16 The present paper adds two important pieces of information for improving risk stratification. First, even a minimal amount of transient ST-segment elevation is prognostically important. Secondly, significant prognostic information may be obtained by taking into account the amount of ST-segment depression across all 12 leads. This bedside analysis may allow a clinician to identify patients with a 30 day mortality risk of between 2 and 20%. According to the present study, the burden of ST-segment depression on the admission ECG reflects the severity of the underlying coronary artery disease.

Prognostic value of the qualitative assessment of the ECG in ACS
Over the last 15 years, we have learned that qualitative features of a standard 12-lead ECG taken upon hospital admission identify a gradient of risk across the spectrum of ACS. The Fibrinolytic Therapy Trialists' analysis distinguished outcomes for patients with anterior, inferior, and other ST-segment elevation as well as for patients presenting with left bundle branch block.17 ECG signs of prior MI18 and associated ST-segment depression11 have also been shown to predict a worse prognosis in this group. Among patients without ST-segment elevation, those with insignificant ECG changes have been shown to be at lower risk for adverse events9 than, progressively, those with isolated negative T-waves911 and those with any ST-segment depression.1012,14,19 The less-favourable outcomes of patients with ST-segment depression have been attributed to more extensive coronary artery disease, often associated with prior MI or heart failure and previous coronary revascularization procedures.11,20,21

Only patients showing some ECG signs of acute myocardial ischaemia on hospital admission were enrolled in GUSTO-IIb. Our analysis was performed in the largest cohort of ACS patients with ischaemic ECG changes at hospital presentation, as assessed by an independent core laboratory. The presence of isolated T-wave inversion was confirmed as a marker of relatively benign outcome, whereas the combination of ST-segment depression and T-wave inversion was associated with worse outcomes. This latter ECG pattern, particularly when recorded in leads V4 and V5 in patients without tachycardia and with concomitant ST-segment elevation in lead aVR, has been shown to represent ‘circumferential ischaemia’,22,23 often associated with left main or three-vessel disease, with sudden and severe increase of the left ventricular end-diastolic pressure and severe ischaemia of the subendocardial layer.24,25 In addition, the combination of abnormal ST-segments (either elevation or depression) with profound T-waves in leads V2 and V3 has been known for long time as the ECG pattern indicating critical narrowing of the proximal left anterior descending coronary artery.26 However, these qualitative ECG features did not remain significant independent predictors in our logistic regression analysis and were probably obscured by clinical markers of severe left ventricular dysfunction, such as hypotension, tachycardia, and high Killip class.

Another important qualitative finding of the present study is the observation that minimal ST-segment elevation, of a level insufficient to warrant fibrinolytic therapy, predicts poor outcomes, particularly MI or reinfarction, in patients with ACS. This finding is in disagreement with the observation that thrombolytic-treated patients showing a modest amount of ST-segment elevation have a good prognosis.16,17 However, according to the present study, when patients presenting with minimal ST-segment elevation are not considered for thrombolysis and are treated with anti-thrombotic therapy only, they are at increased risk. We suspect that these patients could have had more extensive coronary disease with either transient epicardial artery occlusion followed by spontaneous reperfusion or subepicardial ischaemia of a territory poorly represented in the conventional 12-lead ECG,26 which may explain their less-favourable outcomes.

Quantitative analysis of the ECG in ACS
In patients with ST-segment elevation MI, the number of leads with ST-segment elevation27,28 and the sum of absolute ST-segment deviation18 provide additional prognostic information. Moreover, the extent of ST-segment elevation has been shown to correlate with final infarct size2932 and is considered a reliable marker of risk when designing clinical trials in acute MI.

The most important finding of the present study is that the amount of ST-segment depression is a powerful, independent, and incremental predictor of mortality in patients without ST-segment elevation. As shown by logistic regression analysis, the sum of ST-segment depression provides much more information than the simple qualitative assessment of ST-segment depression >0.5 mm. A first step towards using the quantitative information included in the amount of ST-segment depression was made by Kaul et al.14 Using Platelet IIb/IIIa Antagonism for the Reduction of Acute coronary syndrome events in a Global Organization Network (PARAGON-A) and GUSTO IIb data, the authors quantified the amount of ST-segment depression as (i) no ST-segment depression; (ii) 1 mm ST-segment depression in two contiguous leads; or (iii) ST-segment depression >2 mm in two contiguous leads. This approach allowed the researchers to identify a gradient in risk for 1 year mortality that was independent of clinical variables. In their model, patients with ST-segment depression >2 mm, and those with ST-segment depression >2 mm in more than one region were, respectively, six times and almost 10 times more likely to die within 1 year than those with no ST-segment depression. The present analysis expands this important information by showing that the predictive power of ST-segment depression is higher, particularly in terms of mortality, when its quantification is made as a continuum. This consideration is of practical importance because, as reported in Table 5, 25% of the present study population showed >6 mm of total ST-segment depression and, as shown in Figure 2, the CI of the risk estimate remains rather tight at least up to 15 mm, indicating a sizeable patient population. Within this range of ST-segment depression, the increase in risk is still considerable.

The present study also provides the likely pathophysiological explanation for these findings, showing that the higher amount of ST-segment depression correlates with more severe and extensive coronary artery disease. A meta-analysis of 12 030 patients with stable coronary disease enrolled in 60 consecutive publications found that the amount of ST-segment depression during exercise stress testing has been found among the correlates of three-vessel or left main disease;33 our data extend these findings to patients with ACS. In patients with angina at rest, a sum of ST-segment deviation of 18 mm has been shown to be 90% sensitive for left main coronary artery disease.34 An additional contribution to increased mortality in patients with a higher burden of ST-segment depression might be in the correlation between the extent of ST-segment depression and the amount of enzyme release, which in turn might be responsible for the worse outcomes.

Study limitations
The present data set has been derived from a selected population of ACS patients presenting with acute ECG changes. In addition, patients with confounding ECG factors were excluded from the present analysis. Patients with ECG confounders represent a significant proportion of ACS patients (10% of the total GUSTO-IIb population) and have relatively higher mortality, as demonstrated in different trial databases and registries.35 However, in the analysis by Kaul et al.14 of the GUSTO-IIb database, the extent and distribution of ST-segment status dominated the presence of confounders in predicting 1 year mortality, because patients with ST-segment depression >2 mm in more than one region showed the worst outcomes, irrespective of the presence of confounders.14 Finally, the GUSTO-IIb trial was conducted in 1994–95 before the assessment of more sensitive cardiac markers, such as troponins, became standard practice.


    Clinical implications: risk stratification in ACS as a continuum
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Clinical implications: risk...
 References
 
The most powerful independent predictors of mortality in NSTE ACS (old age, elevated cardiac markers, and ST-segment depression) are commonly referred to as dichotomous variables in defining high-risk patient subsets.57 Although this approach may facilitate decision-making, particularly in the emergency room, significantly more information may be gained by considering age, cardiac marker levels, and the amount of ST-segment depression as continuous variables, because mortality increases continuously with the levels of these risk factors. This concept, which is obvious in the case of age, has been shown with biochemical markers of myocardial damage3639 and also applies to baseline ST-segment changes on the admission ECG. The stratification of risk as a continuum may assist decision-making when weighing the benefit and cost of complex issues such as patient transfer to a tertiary care centre, the timing of coronary angiography, or the use of expensive medications or devices. In addition, knowledge of the relationship between the extent of ST-segment depression and the severity of coronary disease may suggest that drugs with possible unfavourable effects in the case of emergency cardiac surgery should be withheld prior to coronary angiography. Thus, although novel biochemical markers continue to emerge for risk stratification in ACS, our data show that common clinical variables and systematic and quantitative ECG assessment continue to offer potent tools for risk stratification. The cumulative amount of ST-segment depression should be considered in future multivariate analyses of the incremental prognostic value of novel biomarkers.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Clinical implications: risk...
 References
 

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