(Circulation. 1997;96:2899-2904.)
© 1997 American Heart Association, Inc.
Articles |
Heart Rate Adjustment of Exercise-Induced ST-Segment Depression Identifies Men Who Benefit From a Risk Factor Reduction Program
From the Division of Cardiology (P.M.O., P.K.), Department of Medicine, The New York Hospital–Cornell Medical Center, New York; Division of Biostatistics (G.G.), School of Public Health, University of Minnesota, Minneapolis; EPICARE Center (P.M.R.), Bowman Gray University, Winston Salem, NC; Department of Epidemiology and Public Health (R.J.P.), University of Miami School of Medicine (Florida); Saint Louis University (J.D.C.), Saint Louis, Mo; Laboratory of Physiological Hygiene (R.S.C.), School of Public Health, University of Minnesota, Minneapolis.
Correspondence to Peter M. Okin, MD, The New York Hospital–Cornell Medical Center, 525 E 68th St, New York, NY 10021. E-mail pokin{at}mail.med.cornell.edu
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Abstract |
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Background Whether subjects identified as being at increased risk of coronary heart disease (CHD) death by heart rate adjustment of exercise-induced ST-segment depression will benefit from therapy aimed at reducing risk factors has not been examined.
Methods and Results Exercise ECGs were performed in 11 880 men
from the Usual Care (UC) and Special Intervention (SI) groups of the
Multiple Risk Factor Intervention Trial. UC men were referred to
customary sources of care in the community; SI men received counseling
on smoking cessation and dietary reduction of cholesterol,
and stepped-care therapy for hypertension. An abnormal ST-segment
response to exercise was defined according to standard criteria as
100 µV of additional horizontal or downsloping ST-segment
depression and by an ST-segment/heart rate (ST/HR) index >1.60
µV/bpm. After 7 years of follow-up, CHD mortality was significantly
lower in SI than UC men with an abnormal ST/HR index (2.4%, 19/786
versus 5.3%, 39/729, P=.005) but was comparable in SI and
UC men with a normal ST/HR index (1.6%, 84/5154 versus 1.3%, 70/5211,
P=NS). Risk reduction in SI men with an abnormal ST/HR index
was independent of age and other cardiac risk factors. In contrast,
there was no significant difference in CHD death rate between the
smaller groups of SI and UC men with an abnormal test by standard
criteria (3.6%, 7/192 versus 2.7%, 5/186, P=NS).
Conclusions An abnormal ST/HR index identifies men in whom therapy aimed at reducing CHD risk factors reduces the risk of CHD death by 61%. These findings support the application of heart rate adjustment of ST depression for screening of asymptomatic subjects at increased risk of CHD to identify those who will benefit most from risk factor–reduction programs.
Key Words: coronary disease • electrocardiography • exercise • heart rate • risk factors
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Introduction |
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Optimal identification of patients who will benefit most from risk reduction therapy by cholesterol- and blood pressure–lowering drugs remains a clinical priority.1 2 3 4 5 6 7 8 9 10 11 Although the exercise ECG has been widely used for risk stratification in patients with known or suspected coronary artery disease, standard ST-segment depression criteria based on achievement of a fixed magnitude of horizontal or downsloping ST-segment depression have demonstrated only limited predictive utility for this purpose.12 13 14 15 16 17 18 19 HR adjustment of ST-segment depression improves sensitivity of the exercise ECG for the detection of coronary disease,20 21 22 23 24 25 26 27 28 improves the prediction of nonfatal CHD events in low-risk cohort men and women from Framingham,18 and improves the prediction of death from CHD in relatively high-risk, asymptomatic men from the UC group of the MRFIT.19 An earlier study from MRFIT demonstrated that an abnormal exercise test by the ST integral method was associated with a lower risk of CHD death in SI group men who were exposed to a systematic risk factor–reduction program.29 However, the ST integral method has not been widely applied in clinical practice, while methods of HR adjustment of ST depression have become increasingly popular for the assessment of occult coronary disease and its severity.18 24 26 Thus, the present study was performed to determine whether the ST/HR index can identify a subgroup of men who will derive the greatest benefit from therapy aimed at reducing CHD risk factors and lowering blood pressure.
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Methods |
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Study Population
MRFIT was a randomized clinical trial in which 12 866 men between the ages of 35 and 57 years, without evidence of CHD by history, physical exam, or abnormal Q wave on the resting ECG, were enrolled and randomly assigned to either the SI or UC group.30 The eligibility criteria, statistical design considerations, and study methods have been previously described in detail.16 29 30 31 32 Selection criteria included use of a multiple logistic risk function, based on Framingham study data, to select subjects in the upper 15% (later changed to 10%) of risk of death from coronary disease on the basis of serum cholesterol concentration, diastolic blood pressure, and cigarette smoking. Men with clinically evident CHD, diastolic blood pressure
115 mm Hg, serum
cholesterol 350 mg/dL, or serious life-limiting
conditions were excluded from the trial. Participants in the SI group
received counseling for cessation of cigarette smoking, advice on
dietary practices to lower cholesterol, and stepped-care
therapy for hypertension. Men in the UC group were referred back to
their customary sources of health care in the community. Both study
groups were called back for annual examinations. Physicians of the UC
group participants were informed of the baseline and annual examination
results if the participant so requested, including a clinical
interpretation of the ECG exercise test by the supervising study
physician. The present report deals exclusively with the 5940 men
in the UC group and 5940 men in the SI group who underwent treadmill
exercise ECG at baseline and had technically adequate ECG tracings and
data to allow calculation of HR-adjusted ST depression criteria.
Exercise ECG
The Mason-Likar modification of the limb electrode
positions33 was used to record both rest and exercise
ECGs. Submaximal ECG exercise testing was performed on a treadmill with
a stepwise increase of the slope and speed of the treadmill.
Age-adjusted target HRs, based on 85% of predicted maximal
response,16 were sought as the exercise end point, but
exercise was terminated when necessary for clinical reasons, including
the development of limiting fatigue, significant symptoms, observed
ST-segment depression of 0.1 mV or greater at 80 ms after the J-point,
systolic blood pressure exceeding 250 mm Hg, a
decrease in systolic blood pressure with exercise, or technical
problems.16 ECGs, including leads aVL, aVF,
V4, V5, V6, bipolar
CS5, and orthogonal leads X, Y, and Z were recorded in
the sitting position immediately preceding exercise, at peak exercise,
and in the immediate recovery period in the sitting position.
ECG data recorded on FM cassettes were analyzed by computer at the ECG center in Halifax as previously described.16 19 ST-segment depression was measured by computer to the nearest microvolt at a point 75 milliseconds after the J-point, and exercise tests were evaluated by standard ECG criteria measured from the peak exercise tracings.26 34 The test was considered positive in the presence of an additional 100 µV (0.1 mV) of horizontal or downsloping ST-segment depression at the end of exercise, correcting for any resting ST depression in that lead on the preexercise ECG.18 19 26 28
The ST/HR index was calculated by dividing the maximal, additional ST-segment depression in any single lead at end exercise, corrected for any resting ST-segment depression in that lead on the sitting preexercise control ECG, by the exercise-induced change in HR.18 26 On the basis of previous studies,18 19 26 a positive ST/HR index was defined as a value of 1.60 µV/bpm or more. Calculation of the maximal ST/HR slope was not performed in this study because the intermediate-stage exercise HR and ST depression measurements necessary for calculation of the linear regression–based ST/HR slope26 were not among the variables originally selected for computer analysis.16
Definition and Determination of Coronary Deaths
Vital status was determined for a total period of 16 years,
including the 7 years of the trial and an additional 9 years of
follow-up of the randomized cohort after the end of the trial. Six- to
8-year follow-up vital status during the period of the trial was
ascertained using previously reported methods.31 Cause of
death was determined by a panel of three cardiologists who were
otherwise unaffiliated with the MRFIT clinical centers and who were
blinded to study group assignment. After the end of the trial, vital
status was determined by use of the National Death Index and
information from the Social Security Administration with ascertainment
of cause of death as previously described.31 Therefore,
16-year mortality is based on death certificate information.
Statistical Methods and Data Analysis
Cumulative CHD death rates for positive and negative exercise
test variables are initially reported as raw event rates, with
relative risk of a positive test and its 95% CI.35 Raw
event rates were compared statistically using 
2
analysis. Event-free survival rates were plotted according to
the method of Kaplan and Meier,36 with comparisons of
event-free survival between positive and negative tests and between
groups performed with the log-rank test.37 The relation
between a positive test by standard criteria and an abnormal ST/HR
index and subsequent occurrence of coronary mortality was
further analyzed by fitting a Cox proportional-hazards model to
the data.38 Age, diastolic blood pressure,
serum cholesterol concentration, and the number of
cigarettes smoked daily at study entry were used as covariates in each
model in addition to the presence of a normal or abnormal standard
exercise ECG or ST/HR index. With the proportional-hazards models, the
estimated relative risk of the incidence of CHD death for a positive
test outcome, compared with a negative test outcome, was computed as
the antilog of the estimated coefficient corresponding to the
dichotomous variable.39 The 95% CIs for the increased
risk associated with a positive test outcome were then calculated from
the estimated coefficient for a positive test and its standard
error.40 CHD death rates and relative risk estimates were
also computed by quintile of ST/HR index to determine the pattern of
risk across levels of ST/HR index.
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Results |
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MRFIT Trial Period Mortality
After a mean follow-up of 7 years there was no significant difference in the 1.8% (109/5940) CHD death rate in UC men and the 1.7% (103/5940) death rate in SI men (P=NS). The value of the ST/HR index and standard test criteria for prediction of CHD mortality in UC men alone has been previously reported.19 Cumulative 7-year mortality rates in each group according to exercise test response are compared in Table 1
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Comparison of SI and UC groups revealed a significant difference in CHD
death rates between SI and UC men with an abnormal ST/HR index (2.4%
versus 5.3%, P=.005) but no difference in CHD mortality
between SI and UC men with a normal ST/HR index (1.6% versus 1.3%,
P=NS). In contrast, there was no significant difference in
CHD mortality between the smaller groups of SI and UC men with an
abnormal exercise test defined by standard ST depression criteria
(3.6% versus 2.7%, P=NS) or among men with negative tests
according to standard criteria (1.7% versus 1.8%, P=NS).
Thus, an abnormal ST/HR index, but not an abnormal test by standard
criteria, identifies a subgroup of men in whom a risk factor–reduction
program reduced the 7-year rate of CHD death by 55%.
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Risk stratification in SI and UC men according to ST/HR index criteria
was further compared using Kaplan-Meier survival curves
(Figure). When adjusted for time to
occurrence of CHD death, comparison of SI and UC men confirmed the
significant reduction in CHD mortality associated with a positive ST/HR
index at baseline in men exposed to a risk factor–reduction program
(P=.003) and demonstrated no significant difference in
mortality between SI and UC men with negative ST/HR indexes after 7
years of follow-up.
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The predictive value of the ST/HR index and standard test criteria in
UC and SI men was further examined after control for risk factors known
to be potential predictors of cardiac mortality16 (Table 2). After multivariate
adjustment for age, diastolic blood pressure, serum
cholesterol, and cigarettes smoked per day at baseline, the
ST/HR index remained a significant predictor of CHD death in UC men,
with a relative risk of 3.6, but did not significantly concentrate risk
in SI men, with a relative risk of only 1.4. In contrast, an abnormal
exercise test by standard ECG criteria did not significantly predict
cardiac death in UC men after adjustment for these baseline risk
factors, with a relative risk of 1.4, and remained weakly predictive of
CHD death in SI men, with a relative risk of 2.0. Thus, even after
adjustment for potential baseline differences in known cardiac risk
factors, the risk factor–reduction program provided to SI men resulted
in a 61% reduction ([3.6-1.4]/3.6) in the relative risk of CHD
death in men with a positive ST/HR index compared with men in the UC
group (P=.003). In contrast, the smaller group of SI men
with a positive test by standard ECG criteria experienced a
nonstatistically significant 42% higher relative risk of CHD death
compared with UC men with abnormal exercise tests.
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Because previous analyses in UC men had shown that the
increased risk of future CHD death was directly related to the
magnitude of ST/HR index response above the partition value of 1.6
µV/bpm,19 CHD event rates in SI and UC men and the
relative risk of death in SI versus UC men were compared across
quintiles of ST/HR index values (Table 3). Analysis by quintile of ST/HR
index showed that reduction of risk of CHD death in SI men was confined
to the upper quintile of ST/HR index values and that, within this
quintile, the extent of absolute risk reduction was directly related to
test magnitude and present only at ST/HR index values greater than
the partition value of 1.6 µV/bpm. An ST/HR index between 1.2 and 1.6
µV/bpm was associated with a 3.5% mortality rate in SI men, a 3.3%
rate in UC men, and a relative risk of 1.1 for SI compared with UC men.
An ST/HR index between 1.6 and 3.3 was associated with a CHD mortality
of 1.9% in SI men and 4.3% in UC men, a relative risk of 0.45, and an
absolute risk reduction of 2.4% in SI compared with UC men. Last,
although based on relatively small numbers of men, an ST/HR index
greater than the 3.3 µV/bpm partition used to define the presence of
anatomically extensive disease at angiography24 identified
a subset of asymptomatic men with a 10% cumulative
incidence of CHD death in the UC group but only a 5.1% risk in the SI
group, a 0.5-fold risk relative to men in the UC group and an absolute
risk reduction of 4.9%. In contrast, there was no significant decrease
in mortality associated with the SI group across the first four
quintiles of men with ST/HR index values between 0 and 1.2
µV/bpm.
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Post-Trial Mortality
After approximately 7 years, the formal intervention ended and
participants in both the SI and UC groups returned to their usual
source of health care. Because ascertainment of vital status was
continued for an additional 9 years, the long-term impact of the SI on
relative CHD mortality rates and the long-term predictive value of the
ST/HR index could be examined. Cumulative 16-year mortality rates in
each group according to ST/HR index response are examined in Table 4 and the Figure
. After 16 years of
follow-up, there was a nonsignificant trend toward a lower CHD death
rate in SI men compared with UC men with an abnormal ST/HR index (8.4%
versus 11.0%, P=.09). In contrast, the absence of a
significant difference in CHD mortality between SI and UC men with a
normal ST/HR index at baseline persisted out to 16 years (5.1% versus
5.5%, P=NS).
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Examination of Kaplan-Meier survival curves provides additional insight
into the absence of a significant survival benefit after 16 years of
follow-up among men in the SI group who had an abnormal ST/HR index.
The difference in CHD mortality between SI and UC men with abnormal
ST/HR indexes at study enrollment narrowed substantially due to a
greater increase in mortality in the SI group after the end of the
formal intervention. In contrast, the similar mortality rates for SI
and UC men with negative ST/HR indexes persisted throughout the
follow-up period. Of note, after 16 years of follow-up, an abnormal
ST/HR index remained predictive of adverse outcome in both UC and SI
men, with significantly higher CHD mortality rates among subjects with
positive than those with negative tests (Table 4 and the Figure).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This study demonstrates that an abnormal ST/HR index, previously shown to stratify the risk of CHD death in UC men,19 identifies men in whom therapy aimed at reducing CHD risk factors decreases the 7-year relative risk of CHD death by 61%. These findings support the application of exercise ECG using heart rate–adjusted indexes of ST depression in the screening of asymptomatic subjects at increased risk of CHD for more accurate identification of those who will benefit most from risk factor–reduction programs.
Previous population studies of cholesterol lowering have documented a reduction in mortality in men with known or a high likelihood of coronary disease,1 2 3 even in the absence of multiple risk factors for CHD.3 However, some studies of primary prevention have failed to demonstrate a significant effect on mortality in middle-aged men with elevated cholesterol and no clinically apparent coronary disease.4 5 6 7 8 Similarly, antihypertensive therapy in the large group of middle-aged patients with mild to moderate hypertension appears to reduce all-cause mortality and the risk of fatal coronary events only when treatment is initiated in subjects with an increased baseline mortality risk.11 The current study further underscores the point that the greatest benefit of cholesterol lowering and antihypertensive therapy may be observed in patients with known or suspected coronary disease. Among asymptomatic men already considered to be at high risk of developing coronary disease by virtue of their risk factor profile, only those with possible asymptomatic coronary disease at baseline as evidenced by an abnormal ST/HR index experienced a significant mortality benefit from the SI program.
The 16-year mortality data provide additional support for the value of
a structured risk factor–reduction program in men with an abnormal
ST/HR index. As illustrated in the Figure, by approximately 3 years
after the end of formal intervention, the difference in mortality
between SI and UC men with abnormal ST/HR indexes at baseline study
entry had narrowed due to a greater increase in mortality among SI men,
and that by the end of the 16-year follow-up period there was no
significant difference in CHD mortality between the two groups. This
finding could reflect a gradual erosion of the mortality benefit once
the structured intervention program was discontinued or could reflect
the progression of disease despite therapy.
This study further highlights the importance of using heart rate–adjusted indexes of ST depression rather than standard ST depression criteria in the clinical interpretation of the exercise ECG. First, these methods improve accuracy for the detection of CHD and for the identification of anatomically or functionally severe CHD.20 21 22 23 24 25 26 27 28 Second, the ST/HR index but not an abnormal ECG by standard test criteria significantly concentrated the risk of CHD mortality in the UC group of MRFIT19 and predicted primarily nonfatal CHD events in very-low-risk men and women from Framingham.18
Previous reports from MRFIT demonstrated that an abnormal ST integral response to exercise also identified men in the SI group who would benefit from the risk factor–reduction program.29 The ST integral method is a technically more complex approach to analysis of the ST-segment response to exercise in which the time-voltage area between the ST segment and the isoelectric baseline is measured.15 16 41 However, in most applications, the ST integral has systematically underestimated the presence and severity of coronary disease compared with simple ST depression criteria, even after HR adjustment.41 Similar accuracy of the ST integral to the ST/HR index in MRFIT but not in other studies19 41 is most likely due to the precise technique used to calculate the ST integral for MRFIT. In MRFIT,29 the ST integral was calculated as 7/16 the area between the J-point and the point at which the ST segment crosses the isoelectric baseline. Because this area will decrease in subjects with upsloping ST depression as HR increases, this approach in effect provides a form of HR adjustment of ST integral measurements, which does not occur with standard ST integral methodology that examines the fixed interval between the J-point and the point at which the ST segment crosses the isoelectric baseline. Nonetheless, the ST integral has never achieved widespread clinical use beyond application in MRFIT16 29 and in the Lipid Research Clinics Study.15
There are several potential limitations to the current findings. First, this study represents a post hoc analysis of MRFIT data as opposed to a prospective study designed to address the value of HR adjustment in identifying subjects who will benefit from risk factor–reduction therapies. Second, the advent of more efficacious antihypertensive and lipid-lowering drugs could affect the conclusions of this study, which are based on a trial that was performed before the use of these agents. However, the findings from more recent studies1 2 3 11 suggest that these therapies might be even more effective in reducing CHD mortality in subjects identified as being at risk by virtue of an abnormal ST/HR index.
These findings suggest that the combination of an abnormal ST/HR index and standard risk factors should be used for the identification of asymptomatic patients in whom the most aggressive risk factor–reduction therapy should be targeted. The increased mortality associated with left ventricular hypertrophy, independent of blood pressure findings,42 43 suggests that the presence of both hypertrophy and an abnormal ST/HR index may further concentrate the risk of CHD mortality and more precisely target patients for an aggressive treatment approach. These findings highlight the potential use of HR-adjusted ST depression criteria for identification of subjects at high risk for inclusion in future clinical trials of risk reduction therapies.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by a grant from The Michael Wolk Heart Foundation, Inc, New York, NY.
Received April 14, 1997; revision received June 4, 1997; accepted June 6, 1997.
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