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J Am Coll Cardiol, 2003; 41:905-915, doi:10.1016/S0735-1097(02)02970-4 © 2003 by the American College of Cardiology Foundation |
* Heart Center, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
Department of Cardiology, Uppsala University Hospital, Uppsala, Sweden
Duke Clinical Research Institute, Durham, North Carolina, USA
Manuscript received August 7, 2002; revised manuscript received October 31, 2002, accepted November 11, 2002.
* Reprint requests and correspondence: Dr. Lene Holmvang, The Heart Center 2141, Copenhagen University Hospital, Blegdamsvej 9, 2100 Copenhagen Ø Denmark.
lene.holmvang{at}dadlnet.dk
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Abstract |
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 Top Abstract MethodsResultsDiscussionAPPENDIX AReferences |
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BACKGROUND: An early invasive treatment strategy has been shown to be the preferable treatment for non–ST-segment elevation acute coronary syndromes (ACS). The population of patients with unstable coronary artery disease is heterogeneous regarding both the underlying pathology and prognosis. Early risk stratification is important to select patient subgroups that will benefit the most from a given treatment.
METHODS: In 2,201 patients with non–ST-segment elevation ACS, the ischemic burden at hospital admission was determined by quantitative measurements of ST-T-segment deviations on the ECG. The patients were subsequently sub-grouped in tertiles based on the amount of ST-segment deviation. The primary end point for this analysis was death or myocardial infarction (MI) within one year after study inclusion.
RESULTS: The invasive treatment strategy produced a reduction of 
50% in death or MI among the patients with intermediate or major ST-segment deviation. The findings were independent of age, gender, or troponin T status. The patients with confounding factors precluding ST analysis had a poor outcome regardless of the treatment strategy.
CONCLUSIONS: Ischemic burden on the admission ECG identifies patients with ACS who benefit the most from an invasive treatment strategy. When the standard ECG is scrutinized with complete quantitative measurements, it provides independent information on prognosis and benefit of treatment.
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We and other investigators have previously found that admission electrocardiographic (ECG) variables carry similar or even better prognostic information than troponin measurements in patients with acute coronary syndromes (ACS) (4,5). In the Fast Revascularization during InStability in Coronary artery disease trial (FRISC-II) population, qualitative analysis of ECG data predicted the treatment outcome, either alone or in combination with TnT data (6,7). Although efforts have been made into finding the appropriate cut-off levels for troponin to predict prognosis and treatment success, the quantitative findings on the admission ECG have not yet been systematically investigated regarding their ability to identify treatment responders.
Accordingly, the aim of the present study was to test the hypothesis that quantitative analysis of the admission ECG can help identify patients with non–ST-segment elevation ACS who might benefit the most from an invasive treatment strategy. The hypothesis is that the patients with the highest ischemic burden, as determined by ST-segment deviation on the standard ECG, have the greatest benefit, defined as improvement in mortality and morbidity, from an aggressive treatment strategy.
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Methods |
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TopAbstractMethodsResultsDiscussionAPPENDIX AReferences |
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In the invasive arm, the target was to perform the revascularization procedures (where indicated) within seven days after admission to the hospital. Non-invasive treatment included coronary angiography only when a patient had refractory or recurrent symptoms or a positive exercise test before discharge.
End points. The primary outcome of the FRISC-II trial was death or myocardial infarction (MI) at six months, but the patients were followed up for at least one year. Secondary end points were angina, re-admission to the hospital, myocardial revascularization, and bleeding. Myocardial infarction was defined by the occurrence of two of three of the classic criteria: typical chest pain, diagnostic ECG, or elevation of biochemical markers of infarction (8). When the present sub-study was carried out, one-year follow-up data were available. Because these data confirmed the findings from the six-month analysis documenting a benefit of an invasive treatment strategy, one-year follow-up data were used in this sub-study.
ECG data. A 12-lead ECG was obtained at admission, at randomization, after the intervention, or at hospital discharge, and then at three-month and six-month visits, as well as when there was any suspicion of angina or MI. The admission ECGs were quantitatively analyzed in the ECG core laboratory at the Department of Medicine B, Rigshospitalet, Copenhagen University Hospital, before any other data, including end point data, were revealed. The Copenhagen ECG core laboratory was established post hoc, and ECG data originating in this core laboratory were not included in the FRISC-II main data base. The presence and amount of ST-segment deviation and T-wave amplitudes were measured in all leads except aVR, and the patients were subsequently sub-grouped in tertiles based on the amount of cumulative ST-segment deviation and number of leads with ST-segment deviation exceeding 0.5 mm on the admission ECG. A fourth subgroup included patients with confounding factors excluding reliable ST-segment analysis. Criteria used to define the confounding factors are shown in Appendix A.
Biochemical data. At randomization, blood samples were obtained from all patients and stored for central analysis of TnT. Quantitative TnT analysis was performed centrally at the biomarker core laboratory at Uppsala University Hospital, using the Elecsys TnT third-generation assay (Roche Diagnostics, Basel, Switzerland).
Angiographic data. The invasive strategy required coronary angiography within seven days after study inclusion. All angiograms were evaluated locally. An obstruction of at least 50% was considered significant. Revascularization was encouraged in all patients with an obstruction of 70% or more in any significant coronary artery. The study protocol recommended percutaneous coronary intervention (PCI) if there were one or two target lesions, and coronary artery bypass graft surgery (CABG) in the presence of three-vessel or left main CAD.
Statistics. Data analysis was performed based on the "intention-to-treat" principle. Relative risk ratios were calculated by univariate analysis, whereas odds ratios (ORs) were determined by multivariate logistic regression analysis. For risk and ORs, 95% confidence intervals for the combined end point of death and MI after one year of follow-up, in relation to treatment strategy, were calculated. The ORs were adjusted for the clinical variables of age, gender, smoking, previous MI, diabetes, hypertension, and admission TnT level, all pre-defined as important baseline characteristics in the main study (8). The timing of end points is illustrated by Kaplan-Meier plots.
To assess a possible interaction between ST-segment deviation and treatment, multiple logistic regression analysis was used. The following terms were included: ST-segment deviation x randomized treatment, age, previous MI, diabetes, smoking, hypertension, TnT, and randomized treatment in itself. The ST-segment variable was transformed to a dichotomous variable (summed ST-segment deviation <3 mm and 
3 mm at the 50th percentile) for a more simple interpretation.
A comparison of baseline characteristics, troponin values, and angiographic data between the three ST-segment deviation groups was done by using the Kruskall-Wallis analysis of variance median test (continuous variables) or the Pearson chi-square test (categorical variables), as appropriate. Comparisons between the ECG confounder group and any of the three ST-segment deviation groups were done by using the Mann-Whitney U test or chi-squared test.
The STATISTICA software program was used for data processing and statistical analysis, except for the logistic regression analysis and the test for interaction, which were performed using the SPSS program (version 9.0).
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Results |
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TopAbstractMethodsResultsDiscussionAPPENDIX AReferences |
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The patients were classified into subgroups according to the total amount of ST-segment deviation (the summated deviation in 11 leads and the total number of leads with ST-segment deviation 0.5 mm) at admission. Tertile values were used as cut-off limits to obtain three groups of almost equal size. Finally, 504 patients (23%) had confounding factors on the ECG excluding ST-segment analysis. Table 1 lists the presence of these confounding factors and the number of events occurring in this sub-population. Tables 2 and 3 present the benefit of an invasive treatment strategy when the patients are sub-grouped by cumulative ST-segment deviation and by the number of leads with >0.5-mm ST-segment deviation. There was a definite benefit of the invasive treatment strategy in reducing the risk of the combined end point death or MI among the patients with intermediate or major ST-segment deviation, defined either by the total amount of deviation or the number of leads with ST-segment deviation. Even when corrected for other baseline variables (gender, age, hypertension, smoking, diabetes, previous MI, and TnT >0.03 µmol/l) in multivariate logistic regression analysis, the risk reduction obtained by the invasive strategy was not affected. The invasive strategy reduced mortality among all the subgroups except for the patients with minor ST-segment changes defined by summed deviation. The numbers were too small, however, to obtain statistical significance. The patients with confounding ECG factors that precluded ST-segment analysis had a relatively poor outcome, regardless of the treatment strategy. The timing of the combined end point of death/MI is presented as Kaplan-Meier plots (Figs. 1A to 1D and Figs. 2A to 2C).
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Figure 3 illustrates the benefit of invasive treatment when the patients are classified into smaller subgroups according to admission ECG findings.
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Clinical course of patients randomized to a non-invasive strategy. Of the 1,109 patients randomized to a non-invasive strategy, 314 (28%) underwent coronary angiography within the first 30 days, because of either a positive exercise test or clinical symptoms. The patients who crossed over to an invasive strategy had significantly more ischemia on the admission ECG than the patients who continued to be managed conservatively (median ST-segment deviation 5 mm [range 2.5 to 7.5] vs. 4 mm [range 2.5 to 6.5], p = 0.001).
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Discussion |
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TopAbstractMethodsResultsDiscussionAPPENDIX AReferences |
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These previous findings were confirmed in the present study. The amount of ST-segment depression at admission was related to poor outcome among patients treated according to conventional principles. The rate of death or MI at one-year follow-up was doubled among the patients with major ST-segment deviation, compared with the patients with only minor or no ST-segment changes. ST-segment deviation was associated with a higher risk profile, higher TnT levels, and more extensive CAD determined by angiography.
Admittedly, risk and treatment stratification based solely on troponin measurement and the ECG might exclude some high-risk patients from beneficial therapies. Hence, in the Thrombolysis in Myocardial Infarction (TIMI) risk score system, age (>65 years), risk factors for CAD, known coronary artery stenosis >50%, ST-segment deviation at admission, at least two previous attacks of angina, use of aspirin within the last seven days, and elevated biomarkers have all been found to carry independent prognostic information (13). The Platelet IIb/IIIa Underpinning the Receptor for Suppression of Unstable Ischemia Trial (PURSUIT) found the most important baseline indicators of poor prognosis to be age, increased heart rate and blood pressure, ST-segment depression, signs of heart failure, and elevated cardiac markers (14). The present study confirms the findings from previous studies that ST-segment deviation on the admission ECG is an important risk indicator in patients admitted with an ACS. However, several of the other variables from the TIMI risk score seem to be associated with ST-segment deviation.
Benefit of invasive treatment. It has been shown that the mere presence of ST-segment depression at a threshold of 0.5 mm identifies patients at high risk of death on long-term follow-up after unstable angina/non–Q-wave MI (11). The present study suggests that invasive treatment is efficacious across wide ranges of extent and magnitude of ST-segment changes, but the magnitude of this effect does seem to increase with the quantity of the ST-segment deviation. Also, the extent of CAD increases substantially with an increasing amount of ST-segment deviation (i.e., patients with major ST-segment deviation had a threefold higher incidence of left main stenosis than the patients with only minor ST-segment changes).
We have previously shown that the inability to perform analysis of the ECG at discharge is associated with a poor outcome after an episode of unstable CAD (15). Because disqualifying ECG changes, such as bundle branch block and hypertrophy, will usually be present both at admission and discharge, the results of the present study are not surprising. The patients with ECG confounders resemble the patients with major ST-segment depression in terms of their TnT values, angiographic findings, and choice of revascularization procedure. Despite the fact that these "high-risk" patients seemed to benefit somewhat less from an invasive treatment strategy than did the patients with major ST-segment deviation, judged by the combined end point, mortality alone was reduced by 42% by the invasive strategy. The ECG confounders are probably indicators of several severe underlying conditions like advanced age, previous acute MI, and heart failure, leading to the same high risk as in patients with major ST-segment depression with similar TnT values.
The explanation for the apparent smaller benefit from invasive treatment among the patients with minor ST-segment deviation could hypothetically be sought in the pre-defined primary end point criteria. Peri-procedural MI was diagnosed based primarily on biomarker elevation after PCI, whereas the diagnosis of peri-operative MI during CABG required new Q-waves on the ECG. Because CABG was more common among the patients with major ST-segment depression (due to more severe CAD), the "risk" of a peri-procedural MI could paradoxically be lower. However, by counting the rate of procedure-related acute MI versus "spontaneous" acute MI, this was not the case. Thus, the higher rate of end points among the invasively treated patients in the minor ST-segment depression group could not be explained by a higher rate of PCI-related infarcts. Controversies still exist about the clinical relevance of PCI-related infarcts (16–18). A recent analysis of data from PURSUIT revealed that peri-procedural infarcts were associated with the same prognosis as spontaneous infarcts, as long as the infarcts were of similar size, as determined by biomarker levels (19). These findings were confirmed in the Treat Angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy–Thrombolysis In Myocardial Infarction-18 (TACTICS–TIMI-18) study, where larger infarcts (creatine kinase, MB isoenzyme >3x the upper limit of normal [ULN]) had the same prognosis, regardless of origin, whereas the smaller spontaneous infarcts (1 to 3x ULN) had a 10-fold increase in mortality within six months, compared with PCI-related infarcts of similar size (20). Whether small PTCA-related infarcts have a similar or better prognosis than conventional Q-wave infarcts associated with CABG remains to be shown.
Compared with the recently published TACTICS–TIMI-18 (21), in FRISC-II, only very few patients received treatment with a glycoprotein IIb/IIIa inhibitor outside the catheterization laboratory. The very early invasive treatment strategy used in TACTICS produced the lowest event rate ever in a trial of non–ST-segment elevation ACS. The results of previous trials of glycoprotein IIb/IIIa inhibitors (22), in combination with the low event rates in TACTICS, should lead to a recommendation of glycoprotein inhibitors for all patients with non–ST-segment elevation ACS. Whether this treatment would have further increased the benefit of the invasive treatment strategy in FRISC-II is speculative, however.
In the TACTICS–TIMI-18 trial, ST-segment changes on the standard ECG predicted a benefit from the early aggressive treatment strategy, and so did TnT. When stratified only according to the presence or absence of ST-segment changes at baseline, the patients without ST-segment changes had no benefit of an early invasive treatment strategy. Similarly, subgroup analysis showed that the 52% of patients in FRISC-II without ST-segment changes at baseline also had similar outcomes with the use of either strategy (8).
Within the last years of the past century, "the troponin hypothesis" gained support based on many trials on the ACS, although the potential information from standard ECG analysis has not been explored as extensively. Numerous studies have tried to determine the best cut-off levels for the various biochemical markers to identify high-risk patients with ACS. To do justice to the ECG, similar efforts must be put forth into identifying the ECG variables containing the most information.
Previous studies on the prognostic value of ECG analysis have mostly concentrated on ST-segment deviation analysis, and the results on prognostic information of isolated T-wave inversion are conflicting. A future sub-study on the FRISC-II population will hopefully reveal whether additional prognostic information can be extracted from careful analysis of the T wave.
Study limitations. The present study is based on a post hoc analysis of data from the FRISC-II trial. Subgroup analyses may be underpowered; hence, the results of post hoc analysis should be handled with care. The troponin cut-off level at 0.03 to 0.1 µg/l and the ST-segment thresholds were established based on a review of the data not tested prospectively. Also, the different rates of CABG and PCI in the subgroups are potential confounding factors that could have influenced the occurrence of end points. Even though the results of the present study indicate that an invasive treatment strategy is beneficial only in patients with a certain extent of ST-segment deviation on their admission ECG, such a conclusion cannot be made without a randomized trial aimed at this specific question. Based on the FRISC-II results, an invasive treatment strategy should be recommended for all patients with ACS who fulfill the original inclusion criteria of the trial.
Conclusions. The present study supports the fact that the standard ECG remains an easy available, inexpensive method of risk stratifying patients with acute chest pain. When ECG data are carefully handled, the ECG provides independent information on prognosis and benefit of treatment. Thus, the present study suggests that quantitative ECG data and troponin measurements should be considered as complementary; they constitute the two most useful non-invasive tests in patients with non–ST-segment elevation ACS. ST-segment depression should be included in the risk models for assessment of prognosis in ACS. Furthermore, when resources for early revascularization therapy are limited, careful analysis of the ECG could help identify patients who might benefit the most from an invasive treatment strategy and, just as important, which patients can initially be allocated to a less aggressive approach starting with antithrombic treatment and referred to elective cardiac catheterization based on stress testing and symptoms.
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APPENDIX A |
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TopAbstractMethodsResultsDiscussionAPPENDIX AReferences |
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RBBB = right bundle branch block
LAHB = left anterior hemi block
LPHB = left posterior hemi block
LVH = left ventricular hypertrophy
RVH = Right ventricular hypertrophy
WPW = Wolf-Parkinson-White syndrome
LBBB = left bundle branch block: QRS duration >120 ms and typical configuration
RBBB = right bundle branch block: QRS duration >120 ms and typical configuration
LAHB = left anterior hemi-block: QRS axis between –45° and –90° and rS configuration in leads II, III, and aVF
LPHB = left posterior hemi-block: QRS axis >120° and rS configuration in leads I and aVL
LVH = left ventricular hypertrophy: at least two of the following criteria (1,2):
35 mm 28 mm, women 20 mm) 25 mm = 3 points; R amplitude in leads V4 to V6 25 mm = 3 points; R or S amplitude in leads I, II, III, aVL, or aVF 20 mm = 3 points; terminal (downsloping) P-wave duration 40 ms = 3 points; left axis >–15° = 2 points; and QRS duration 90 ms = 1 point
RVH = right ventricular hypertrophy: R (lead V1 or V2) + S (lead V6 or I) – S (lead V1) 0.7 mV
WPW = Wolf-Parkinson-White syndrome: PR 
120 ms, wide QRS complex, delta wave
Low voltage: R + S amplitude 0.5 mV in leads I, II, III, aVL, and aVF and R + S amplitude 1.0 mV in the precordial leads
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Footnotes |
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References |
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TopAbstractMethodsResultsDiscussionAPPENDIX AReferences |
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