Hathaway WR, Peterson ED, Wagner GS, Granger CB, Zabel KM, Pieper KS, Clark KA, Woodlief LH, Califf RM, for the GUSTO-I Investigators . Prognostic Significance of the Initial Electrocardiogram in Patients With Acute Myocardial Infarction. JAMA. 1998;279(5):387-391. doi:10.1001/jama.279.5.387
From the Duke Clinical Research Institute, Duke University Medical Center, Durham, NC.
Clinical Cardiology section editors: Bruce
Brundage, MD, University of California, Los Angeles, School of Medicine; Margaret
A. Winker, MD, Senior Editor, JAMA .
Context.— Early risk stratification of patients with myocardial infarction is
critical to determine optimum treatment strategies and enhance outcomes, but
knowledge of the prognostic importance of the initial electrocardiogram (ECG)
Objective.— To assess the independent value of the initial ECG for short-term risk
stratification after acute myocardial infarction.
Design.— Retrospective analysis of the Global Utilization of Streptokinase and
t-PA (alteplase) for Occluded Coronary Arteries (GUSTO-I) clinical trial database.
Setting.— A total of 1081 hospitals in 15 countries.
Patients.— From the 41021 patients enrolled in the overall study, we selected those
who presented within 6 hours of chest pain onset with ST-segment elevation
and no confounding factors (paced rhythms, ventricular rhythms, or left bundle-branch
block) on the ECG performed before thrombolysis was administered (n=34166).
Main Outcome Measure.— Ability of initial ECG to predict all-cause mortality at 30 days.
Results.— Most ECG variables were associated with 30-day mortality in a univariable
analysis. In a multivariable analysis combining the initial ECG variables
and clinical predictors of mortality, the sum of the absolute ST-segment deviation
(both ST elevation and ST depression: odds ratio [OR], 1.53; 95% confidence
interval [CI], 1.38-1.69), ECG, heart rate (OR, 1.49; 95% CI, 1.41-1.59),
QRS duration (for anterior infarct: OR, 1.55; 95% CI, 1.43-1.68), and ECG
evidence of prior infarction (for new inferior infarct: OR, 2.47; 95% CI,
2.02-3.00) were the strongest ECG predictors of mortality. A nomogram based
on the multivariable model produced excellent discrimination of 30-day mortality
Conclusions.— In patients presenting with myocardial infarction accompanied by ST-segment
elevation, components of the initial ECG help predict 30-day mortality. This
information should be valuable in early risk stratification, when the opportunity
to reduce mortality is greatest, and may help in assessing outcomes adjusted
for patient risk.
THROMBOLYTIC THERAPY and direct angioplasty have significantly advanced
the treatment of acute myocardial infarction. Nonetheless, 30-day mortality
has ranged from 6% to 9% in recent clinical trials, and it is even higher
for those not enrolled.1 Risk assessment during
the initial patient evaluation is critical to facilitate optimal treatment
and the appropriate intensity of monitoring. The initial clinical variables
that most influence the 30-day prognosis after acute infarction include age,
systolic blood pressure, Killip class, and heart rate.2
The electrocardiogram (ECG), a critical component of the early assessment
and risk stratification of patients presenting with acute infarction, contains
valuable diagnostic and prognostic information. Despite the central role of
the ECG in patient evaluation, large studies have provided only limited qualitative
information about ECG variables most critical to the assessment of prognosis.
The aim of the present study was to determine the initial ECG predictors of
30-day mortality after thrombolysis for acute myocardial infarction and to
assess their incremental value when combined with known initial clinical prognostic
Te Global Utilization of Streptokinase and t-PA (alteplase) for Occluded
Coronary Arteries (GUSTO-I) trial enrolled 41021 patients with acute myocardial
infarction from December 1990 to February 1993 from 1081 hospitals in 15 countries.
Patients presented after 20 minutes but within 6 hours of the onset of chest
pain accompanied by ECG signs of 0.1 mV or greater ST-segment elevation in
2 or more limb leads or 0.2 mV or greater elevation in 2 or more contiguous
precordial leads. The full design and data collection methods of GUSTO-I have
been described.3 Patients were randomized by
telephone, with selected initial characteristics recorded to ensure eligibility.
Exclusion criteria included a history of stroke, active or recent bleeding
or major coagulation abnormality, recent trauma or major surgery, noncompressible
vascular punctures, and previous treatment with streptokinase or anistreplase.
There were no restrictions because of age, presentation in cardiogenic shock,
or prior bypass surgery or infarction.
Qualifying patients were randomly allocated to 1 of 4 treatment strategies:
streptokinase, 1.5 million U over 1 hour, with subcutaneous heparin, 12500
U twice daily, beginning 4 hours after the start of thrombolytic therapy;
streptokinase, 1.5 million U over 1 hour, with intravenous heparin in a bolus
dose of 5000 U then 1000 U per hour, with the infusion adjusted to maintain
an activated partial thromboplastin time of 60 to 85 seconds; accelerated
alteplase in a bolus dose of 15 mg, then an infusion of 0.75 mg/kg (up to
50 mg) over 30 minutes and 0.5 mg/kg (up to 35 mg) over the next hour, with
the same intravenous heparin regimen; or combined intravenous alteplase (1.0
mg/kg over 1 hour, up to 90 mg, with 10% given as a bolus) and streptokinase
(1.0 million U over 1 hour), given concurrently but through separate catheters,
with the same intravenous heparin regimen.
Initial clinical data were collected on all patients with a standard
data collection form. Definitions of the clinical variables in this trial
have been published.3,4 Extensive
quality control checks were used during data entry, and missing or questionable
answers were queried. A sample of 12% of the forms was audited by comparing
them with the hospital medical record.
The initial ECG was the one that fulfilled enrollment criteria and resulted
in randomization. First ECG tracings obtained after the start of thrombolytic
therapy were not considered to be initial tracings and resulted in patient
exclusion from this analysis. Patients who lacked an initial ECG or 30-day
mortality data were also excluded from analyses, as were those who failed
to meet entry criteria for ST-segment deviation and those who showed confounding
factors on the initial ECG (such as paced rhythms, ventricular rhythms, or
left bundle-branch block). All ECGs were analyzed by a central core laboratory
(Duke Clinical Research Institute, Durham, NC), whose personnel were blinded
to treatment assignment and patient information. The ECG variables included
heart rate per minute; heart rhythm (atrial flutter, atrial fibrillation);
conduction intervals (QRS interval in milliseconds); ST-segment measures (elevation
and depression for each lead in millimeters and the sum of each variable for
all leads, including the inferior leads [leads II, III, and aVF] and the precordial
leads [leads V1 to V4]; sum of absolute deviation [elevation
or depression] for all leads that measured 60 milliseconds after the J point
relative to the TP segment; maximum elevation in a single lead; number of
leads with ST-segment elevation ≥1 mm); conduction disturbances (first-degree
or second-degree atrioventricular block, right bundle-branch block, left anterior
hemiblock, left posterior hemiblock, complete heart block); location of infarction
(anterior, inferior, or other); left ventricular hypertrophy (Estes-Romholt
or Sokolow-Lyon criteria); and pathological Q waves (considered present if
they measured ≥20 milliseconds in lead V4; ≥30 milliseconds
in leads I, II, aVL, V5, or V6; or were present at any
width in leads V1 to V3).5,6
The primary end point of the trial was death from any cause within 30
days of randomization. The study coordinator at each site collected mortality
information on the main case report form for patients who died in the hospital.
Survival status after discharge but within 30 days was obtained by a postcard
returned by patients or their families. When no postcard was received, follow-up
status was determined by telephone. Thirty-day mortality status was known
for 40830 patients (99.5%) overall and for all 34166 patients in the substudy.
All categorical characteristics are described as percentages, and continuous
measures are summarized with medians and interquartile ranges. The univariable
relation of each factor to 30-day mortality was tested with the log-likelihood
ratio χ2 test. Logistic regression modeling techniques were
used to evaluate the univariable relations of continuous factors to 30-day
mortality and to estimate the joint relations of the ECG factors and the joint
relations of initial clinical2 and ECG factors
to 30-day mortality.
Several continuous variables were found to deviate from the key modeling
assumption of a linear relation between the variable and the logit of the
probability of death (Figure 1).
By comparing the model χ2 values and graphical relations of
the transformed and linear variables to outcome, appropriate spline transformations
of the variables were made.7 Linear splines
were determined to best fit QRS duration, number of leads with ST-segment
elevation, sum of ST-segment depression, heart rate on the ECG, maximum ST-segment
elevation in any lead, and sum of ST-segment elevation; linear splines were
used in all modeling procedures.
A stepwise variable selection technique was used to choose the best
multivariable model of initial ECG predictors of mortality. Variables remained
in the model if they contributed significant (P<.05)
additive or multiplicative prognostic information. The incremental value of
the ECG predictors above that of known clinical predictors of mortality2 was determined with a logistic regression model. Wald χ2 values are reported for the importance of each variable after adjusting
for all other factors in the model. The quality of the model was evaluated
by calculating the area under the receiver operating characteristic (ROC)
curve, also known as the C-index.8 The model
was then validated internally by means of the bootstrap method,9
using 40 replications.
Of the 41021 patients in the GUSTO-I trial, 3187 patients failed to
meet the entry ST-segment deviation criteria (maximum ST-segment elevation
<0.1 mV) or had confounding ECG factors on the initial tracing (paced rhythm,
left bundle-branch block, missing lead data). An additional 3526 were excluded
for lack of an initial ECG being forwarded to the core laboratory, and 142
patients were excluded for lack of 30-day mortality data, leaving 34166 patients
available for analysis. The clinical characteristics of this substudy population
were similar to those of the entire GUSTO-I study population3
and of patients not in the substudy (Table
1). Compared with those excluded from analysis, the substudy population
had a slightly higher proportion of patients who had anterior infarctions.
Most patients were male and white, and 16% had experienced a prior infarction.
Patients who were excluded from the ECG substudy had a 21% higher mortality
rate at 30 days than those included in the substudy (8.2% vs 6.8%).
Of the categorical initial ECG variables tested, only left ventricular
hypertrophy, first-degree or second-degree atrioventricular block, and complete
heart block were not significant univariable predictors of 30-day mortality
(Table 2). All the continuous
ECG variables showed significant univariable relations with 30-day mortality
(Figure 1). Both heart rate and
QRS duration were characterized by U-shaped curves, with increased mortality
at the extremes of the values recorded.
In a multivariable analysis of the ECG variables (Figure 2), faster heart rate, longer QRS duration, ECG evidence
of prior infarction, and sum of the absolute ST-segment deviation were most
highly associated with 30-day mortality. Other measures of ST-segment deviation
retained significance, including the absolute value of ST-segment elevation
in the inferior leads and the sum of ST-segment depression after adjustment
for other ECG measures. Two interaction terms were found to enter this model.
One indicated that increases in QRS duration were associated with a much greater
increase in risk with an anterior infarction than with an infarction in another
location. The other showed that patients with an inferior infarction who had
had a prior infarction had a higher risk of death than patients with other
locations of infarctions who had had a prior infarction, but inferior infarction
carried a lower risk of death than other infarct locations in the absence
of previous infarction.
In a multivariable model that combined the significant initial ECG and
clinical predictors of mortality, the sum of absolute ST-segment deviation,
QRS duration, and ECG evidence of prior infarction remained the strongest
of the ECG predictors (Table 3
and Figure 3). Overall, the clinical
variables age, systolic blood pressure, and Killip class were the strongest
independent predictors of 30-day mortality.
The model provided excellent discrimination between patients who died
and those who lived (C-index, 0.836). After correction for the bootstrap technique,
there was only a minimal alteration in this result (C-index, 0.833). Finally,
a nomogram created from the full model (Figure
3), which contained a reduced set of variables, also provided excellent
discrimination (C-index, 0.830).
In this large population of patients treated with thrombolytic therapy,
the initial ECG contained important prognostic information beyond that provided
by the medical history and physical examination. The most powerful independent
ECG predictor of 30-day mortality was heart rate, consistent with studies
that have shown sinus tachycardia to be correlated with adverse outcomes.10,11 The U-shaped nature of the curve
indicates that bradycardia is also associated with increased risk, perhaps
representing patients with large infarctions and various degrees of sinus
and atrioventricular nodal suppression. In the combined clinical and ECG model,
we used 2 measures of heart rate—that recorded on the initial ECG and
that recorded on the case report form by the nurse or study coordinator just
before thrombolytic therapy began. To further investigate this, we plotted
the difference between these 2 values against 30-day mortality and found that
patients with the greatest difference had the highest mortality. Thus, a change
in heart rate (increase or decrease) between the recording of the initial
ECG and thrombolysis was accompanied by increased mortality.
A variety of ST-segment indexes of infarct size or "myocardium at risk"
were investigated, and, not surprisingly, all showed univariable correlations
with mortality. The strongest of these was the sum of the absolute ST-segment
deviation in all leads (limb and precordial), which also added independent
information to the clinical model. Many investigations, in both the prethrombolytic
and thrombolytic eras, have shown a correlation between degree of ST-segment
elevation and final infarct size for both anterior and inferior infarctions.12- 14 The prognostic information
contained in the degree of elevation was not supplanted by information in
the other ECG variables, including infarct location, heart rate, and QRS duration,
or in the clinical variables of Killip class and systolic blood pressure,
all of which likely are indirect measures of infarct size.
Other investigators, as in this study, have found that mortality increases
progressively with the number of leads that show ST-segment elevation.15 Although our investigation found this to be a strong
univariable predictor, the number of leads with ST-segment elevation provided
no independent prognostic information in either of our models.
The prognostic significance and physiological implications of associated
ST-segment depression have been topics of considerable debate, particularly
for patients with inferior infarction.2,12,13,16- 19
In our study, the sum of ST-segment depression added major information to
the combined model, a concept that is perhaps not as well recognized by clinicians
as the importance of ST-segment elevation.
In this investigation, right bundle-branch block and both left anterior
and left posterior hemiblock showed univariable, but not multivariable, correlations
with mortality. This can be explained by the fact that QRS duration, which
retained independent significance, has correlated with mortality in other
studies of postinfarction patients. Although not in the setting of acute infarction,
the Cardiac Arrhythmia Suppression Trial investigators, examining placebo-treated
patients only, reported that an initial QRS duration of 100 milliseconds or
longer on the surface 12-lead ECG imparted a hazard ratio of 1.4 for new or
worsening congestive heart failure, for arrhythmic death or cardiac arrest,
and for all-cause mortality.20 The association
of longer QRS duration with increased mortality in our analysis may indicate
that when "late potentials" are of sufficient magnitude to affect the surface
ECG, they reflect extensive infarcts and involvement of the interventricular
conduction system. Prolonged QRS duration, therefore, might indicate slowed
and heterogeneous conduction in a large mass of ventricular myocardium with
increases in both the potential for heart failure and vulnerability to re-entrant
Although patients with inferior infarction had better survival than
the rest of the study population, the subpopulation that had inferior infarction
and ECG evidence of previous infarction had a higher risk of death. Previous
infarction was classified on the basis of "distant Q waves" (Q waves in leads
other than those related to the new infarction). Thus, patients with inferior
infarction by definition must have had previous anterior or lateral events;
conversely, those with acute infarction in the anterior leads must have had
previous inferior or lateral infarction. Because this interaction term would
identify patients with multivessel disease and poorer initial ventricular
function, we would expect a higher 30-day mortality in this population. In
contrast, a previous infarction in those with acute anterior wall infarction
carried no increased risk for 30-day mortality compared with patients with
no previous infarction.
As in all thrombolytic trials, this study is limited to patients eligible
for enrollment in GUSTO-I. Because trial populations have better outcomes
than do general, unselected populations with myocardial infarction, these
models should be validated in other, unselected populations. This prognostic
information applies only to the presenting ECG; serial ECGs were not analyzed
in this investigation. Because the ST segment fluctuates dynamically throughout
an infarction, and rhythm disturbances are often transient, analysis of the
"worst" tracing likely would have altered our results.
From the results of the multivariable analysis, a predictive nomogram
(Figure 3) was created to be used
in the initial risk estimation of patients who present with acute myocardial
infarction. A variety of clinical and ECG markers was selected, all of which
are readily assessable at presentation. A point score is assigned for the
given variable, and the points are summed to estimate the risk of mortality.
To increase its clinical applicability, it was necessary to limit the number
of variables in the nomogram. Despite reducing the number of variables, the
risk estimate from the nomogram was nearly identical to that from the entire
The initial ECG of patients who present with myocardial infarction and
ST-segment elevation contains valuable prognostic information mostly related
to heart rate, ST-segment deviations, QRS duration, and infarct location.
This information adds to that of known clinical predictors of mortality and
should be valuable in early risk stratification, when mortality is greatest.
It should facilitate the choice of optimal pharmacological and mechanical
treatments, helping physicians to target aggressive therapies to those likely
to benefit most. Such information will also enable risk-adjusted assessment
of both patient- and provider-specific outcomes.