CLINICAL STUDY: CORONARY ARTERY DISEASE
Exercise performance-based outcomes of medically treated patients with coronary artery disease and profound ST segment depression
Craig A. Thompson, MD*,
Samer Jabbour, MD, MPH*,
Robert J. Goldberg, PhD ,
Renee Y. S. McClean, BS*,
Brian Z. Bilchik, MD, FACC*,
Charles M. Blatt, MD, FACC*,
Shmuel Ravid, MD, FACC* and
Thomas B. Graboys, MD, FACC*
* Lown Cardiovascular Research Foundation, Brigham and Women’s Hospital, Harvard Medical School, Boston, USA
Department of Medicine, Division of Cardiovascular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA
Manuscript received April 10, 2000;
revised manuscript received June 28, 2000,
accepted August 18, 2000.
Reprint requests and correspondence: Dr. Craig A. Thompson, Lown Cardiovascular Center, 21 Longwood Avenue, Brookline, Massachusetts 02446-5239
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Abstract
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OBJECTIVES
We sought to determine the relationship between exercise duration and cardiovascular outcomes in patients with profound ( 2 mm) ST segment depression during exercise treadmill testing (ETT).
BACKGROUND
Patients with stable symptoms but profound ST segment depression during ETT are often referred for a coronary intervention on the basis that presumed severe coronary artery disease (CAD) will lead to unfavorable cardiovascular outcomes, irrespective of symptomatic and functional status. We hypothesized that good exercise tolerance in such patients treated medically is associated with favorable long-term outcomes.
METHODS
We prospectively followed 203 consecutive patients (181 men; mean age 73 years) with known stable CAD and 2 mm ST segment depression who are performing ETT according to the Bruce protocol for an average of 41 months. The primary end point was occurrence of myocardial infarction (MI) or death.
RESULTS
Eight (20%) of 40 patients with an initial ETT exercise duration  6 min developed MI or died, as compared with five (6%) of 84 patients who exercised between 6 and 9 min and three (3.8%) of 79 patients who exercised 9 min (p = 0.01). Compared with patients who exercised 6 min, increased ETT duration was significantly associated with a reduced risk of MI/death (6 to 9 min: relative risk [RR] = 0.25, 95% confidence interval [CI] 0.08 to 0.76; >9 min: RR = 0.14, 95% CI 0.04 to 0.53). This protective effect persisted after adjustment for potentially confounding variables. We observed a 23% reduction in MI/death for each additional minute of exercise the patient was able to complete during the index ETT.
CONCLUSIONS
Optimal medical management in stable patients with CAD with profound exercise-induced ST segment depression but good ETT duration is an appropriate alternative to coronary revascularization and is associated with low rates of MI and death.
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Abbreviations and Acronyms
| | CAD | = coronary artery disease | | CHF | = congestive heart failure | | CI | = confidence interval | | ECG | = electrocardiographic or electrocardiogram | | ETT | = exercise treadmill test | | HMG-CoA | = hydroxymethyl glutaryl coenzyme A | | LBBB | = left bundle branch block | | MI | = myocardial infarction | | NYHA | = New York Heart Association | | PHR | = peak heart rate | | RR | = relative risk |
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Profound ST segment depression provoked by exercise treadmill testing is predictive of significant multivessel coronary artery disease (CAD) (1–6). These patients are often referred for coronary angiography and subsequent revascularization, irrespective of symptoms, on the basis that reducing the extent of ischemic burden may improve long-term outcomes. In the present longitudinal study, we have attempted to define the natural history of medically managed patients with stable CAD who exhibited profound ST segment depression during standard Bruce protocol exercise treadmill testing (ETT). Our hypothesis was that increased exercise duration was positively associated with improved outcomes in medically managed patients with significant CAD.
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Methods
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A total of 203 patients (181 men, average age 73 years) with CAD and 2 mm planar or downsloping ST segment depression who performed ETT according to the Bruce protocol were prospectively followed for an average of 41 months. Baseline data regarding medical history and the use of cardiac medications were obtained by questionnaire at the initial clinic visit. Coronary artery disease was defined by coronary angiography, documented previous myocardial infarction (MI) or the combination of typical ischemic symptoms and a positive noninvasive test for CAD or ischemia. Patients with New York Heart Association (NYHA) functional class III or IV congestive heart failure (CHF), unstable coronary syndromes or baseline electrocardiographic (ECG) abnormalities that would make the treadmill test nondiagnostic (i.e., left bundle branch block [LBBB], nonspecific intraventricular conduction abnormality, nonspecific ST segment abnormalities [resulting in ST segment shift 0.5 mm], 0.5 mm ST segment depression with hyperventilation and digoxin therapy before testing) were excluded.
All patients exercised on a motorized treadmill according to the standard Bruce protocol until the point of exhaustion, unless one of the following developed: 1) progressive angina (increasing, subjective, typical pain resulting in the patient’s desire to stop exercise); 2) signs of peripheral hypoperfusion (pallor, clammy skin, glazed look) and/or profound exertional hypotension (<10 mm Hg decrease in systolic blood pressure as compared with pretest standing, posthyperventilation blood pressure); 3) development of sustained ventricular arrhythmias (>10 consecutive beats or by physician’s discretion); or 4) the patient’s reluctance to continue. Profound (2 mm) shifts in ST segment depression, a calculated "peak heart rate" (PHR = 220 – age), and a predetermined time limit were not indications for stopping the test. The patient’s exercise duration and follow-up were based on the index treadmill test with profound ST segment depression. The study group was subclassified into three groups on the basis of their exercise duration (<6 min, 6 to 9 min and >9 min) to broadly identify patients with poor, moderate, and superior exercise tolerance, respectively.
Criteria for cardiac catheterization and consideration for revascularization included: 1) cardiac arrest/primary ventricular fibrillation; 2) pulmonary edema of potentially ischemic etiology; 3) intolerance of, or noncompliance with, medical therapy; 4) mandate of job description (e.g., pilot, bus driver); or 5) decreased left ventricular function by echocardiography with clinical evidence of ischemia.
The primary end point of this observational study was the development of MI or death. Secondary end points were the occurrence of unstable angina (accelerated chest pain [or equivalent] syndrome with rest or nocturnal symptoms or symptoms with very limited exertion), CHF (NYHA functional class IV requiring change in treatment or hospital admission), ventricular tachycardia (any repetitive ventricular rhythm >100 beats/min resulting in symptoms [e.g., syncope, presyncope, or chest pain, or lasting >30 s]) or coronary revascularization. "Optimal medical therapy" in this investigation was achieved by placing emphasis on the widespread use of beta-blockers, aspirin and hydroxymethyl glutaryl coenzyme A (HMG-CoA) reductase inhibitors in the study group, with supplementation of long-acting and sublingual nitrates and calcium channel blockers, as necessary to control symptoms. Beta-blockers in our practice setting were titrated to maintain the rest heart rate 60 beats/min and to attenuate the chronotropic response on subsequent exercise testing. Our statin therapeutic targets included total serum cholesterol 180 mg/dl and low density lipoprotein cholesterol 100 mg/dl. Long-acting nitrates and calcium channel blockers were used in patients with a greater frequency of angina. The long-acting nitrates were timed to be temporally effective with anticipated symptoms. Sublingual nitroglycerin was encouraged prophylactically for activities anticipated to precipitate angina in this cohort of patients.
Patients in this study were seen on follow-up visits every six months subsequent to the index ETT and were evaluated by history, physical examination and yearly echocardiograms. Hospital records were obtained for independent verification in patients who experienced primary or secondary study end points. At least one year of follow-up data were obtained in all patients included in this study (unless an end point occurred before one year).
Data analysis.
Demographic and clinical characteristics and the occurrence of study end points in patients with stable, medically managed CAD further categorized according to strata of exercise duration were evaluated by using the Fisher exact test to compare categoric variables and the Student t tests to compare continuous variables. All tests of statistical significance were two-tailed at p < 0.05. Multivariable Cox regression models were used to examine the association of the primary study end points to exercise duration, while controlling for potentially confounding demographic, historic and clinical variables. These variables included age, gender and a history of hypertension, diabetes, MI or revascularization.
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Results
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The study group consisted of a largely middle to upper socioeconomic class Caucasian population (average age 73 years) from the northeastern United States. Sixty-five percent of this study group was referred for second opinion regarding the need for coronary revascularization. Individuals who were able to exercise for a longer time on the index ETT included a greater proportion of men and individuals without a history of hypertension and diabetes (Table 1). The rates of coronary revascularization were 26%, 17% and 19%, respectively, for patients who were able to exercise for <6 min, 6 to 9 min and >9 min.
The mean PHR was 122 beats/min; the mean peak (systolic) blood pressure was 149 mm Hg; and the median ST segment depression was 2.5 mm Hg for the study group during ETT according to the Bruce protocol. Thirty-one of the patients (15.3%) stopped the exercise test because of angina pectoris. Of these 31 patients, 10 (33%) exercised for <6 min;15 (48.4%) for 6 to 9 min; and 6 (19.4%) for >9 min (p = 0.04). Use of beta-blockers, calcium channel blockers and nitroglycerin was declined with progressively higher levels of peak exercise performance at the time of baseline studies (Table 1).
The overall event rate of MI and/or death was low in the study group. The overall death rate was 3.9%, or an annualized mortality rate of 1.1%, for the entire study group. The incidence of the primary end point—death or nonfatal MI—was 20% in the 6-min group; 6% in the 6- to 9-min group; and 3.8% in the 9 min group (p = 0.01) (Fig. 1). Compared with the baseline 6-min group, increased ETT duration was significantly associated with a reduced risk of MI/death (6 to 9 min: relative risk [RR] = 0.24, 95% confidence interval [CI] 0.08 to 0.76; >9 min: RR = 0.14, 95% CI 0.04 to 0.53). After adjusting for varying durations of follow-up and previously described potential prognostic confounders in a Cox regression model, the protective effect of increased ETT duration persisted (Table 2). Patients who were able to exercise for 6 to 9 min and >9 min were at 68% and 72% reduced risk, respectively, of MI/death as compared with patients in the referent group (<6 min) (Table 2). Inclusion of second-opinion referral status as a baseline covariate in this regression model did not affect these findings. Furthermore, stopping ETT because of angina pectoris did not diminish the protective effect of exercise duration when included in the multivariate model.
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Table 2 Crude and Multivariable Adjusted Odds of Developing Myocardial Infarction or Death Based on Exercise Duration
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When exercise duration was considered as a continuous variable (after adjusting for varying durations of follow-up, revascularization and other potential prognostic confounders in a Cox regression model), a 22% reduction (95% CI 0.59 to 1.0) in MI/death was demonstrated for each additional minute of ETT duration attained (p = 0.06). In addition, patients with poorer exercise capacity were more likely to reach the primary end point earlier, as compared with those who could perform at a higher work load (Fig. 2). Further adjustments for a history of hypertension and beta- blocker use did not affect these results. Use of beta-blockers, calcium channel antagonists and nitrates was increased among all groups, according to peak exercise performance, as compared with use of these medications at baseline enrollment (Table 3).
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Figure 2 Event-free survival based on exercise duration. Solid line= <6 min; long-dashed line = 6 to 9 min; short-dashed line = >9 min.
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The incidence of the secondary end points of CHF, unstable angina and ventricular tachycardia also declined with increasing peak exercise capacity (Fig. 3).
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Discussion
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Exercise-induced ST segment depression during treadmill testing often results in referral for angiography and revascularization, even if the patient has no or minimal symptoms and a good hemodynamic response to exercise. However, considerable evidence exists to suggest that, while being a predictor of CAD, ST segment depression alone does not predict the long-term outcomes of patients with CAD.
This study demonstrates a 22% reduction in the rate of death or MI per 1-min increment in the duration of ETT (Bruce protocol). This finding, which suggests that increased levels of exercise performance are associated with an improved prognosis, is consistent with the results of previous investigations (6–16). A previous report from our group on a different cohort of 143 medically managed patients with stable symptoms but with profound ST segment depression on consecutive Bruce protocol exercise treadmill tests, demonstrated a low incidence of cardiac complications and a trend toward improved outcomes with increased exercise tolerance over a follow-up of 59 months (7).
Goraya et al. (8) recently reported that work load was the only treadmill characteristic associated with all-cause mortality in 514 elderly (65 years of age) and 2,593 younger (<65 years of age) patients included in an inception cohort followed for a mean duration of six years. Morris et al. (9), in a prospective study of 588 men (mean age 59 years) referred for evaluation of CAD and followed for an average of 30 months, failed to observe an association between exercise-induced ST segment depression and cardiovascular death or nonfatal MI. Factors associated with a poor outcome in their study included a history of CHF, the presence of ST segment depression on the rest ECG and exertional hypotension. Using these predictors to classify patients into low, moderate, and high risk subgroups, they found annual rates of cardiac mortality to be 1%, 7% and 12%, respectively (9). In a prospective study of 595 men who had undergone exercise treadmill testing and coronary arteriography and who were followed for an average of 60 months, ST segment depression was significantly associated with severity of CAD, but was not associated with impaired long-term survival. History of CHF, reduced left ventricular function and poor exercise capacity were strong predictors of long-term survival in this study (6). In a prospective study of 936 patients (mean age 59 years) between one and six months after their MI or unstable angina, an increased incidence of adverse outcomes was observed in patients with symptomatic ischemia and poor exercise tolerance over an average follow-up of nearly two years (10). Finally, in a prospective study of 2,546 male veterans (mean age 59 years) followed for 45 months, an association between peak exercise capacity and clinical cardiovascular outcomes was observed. In contrast to the previous studies, however, the degree of exercise-induced ST segment depression was independently related to poor long-term outcome. Differences between the results of this study and the previously described studies may relate, in part, to the inclusion of patients with clinical CHF or digoxin use, or both, in this study as compared with others (11).
Maximization of medical therapy is paramount to improving morbidity and mortality in patients with stable coronary disease. In our cohort, particular emphasis was given to the use of aspirin, beta-blockade and HMG-CoA reductase therapies, which have been shown to decrease the risk of nonfatal MI and death in patients with CAD (17–23). Long-acting nitrates and calcium channel blockers were used as supplemental therapy in patients with greater levels of angina. We emphasized the use of sublingual nitroglycerin prophylactically for activities anticipated to produce angina, as well as for pain. The antianginal therapies were individually tailored for the time of day and situations during which angina was likely to occur.
Study strengths.
This study’s strengths include a novel and contemporary perspective on the natural history of patients traditionally considered to be at high risk for CAD and adverse cardiac outcomes in the "modern" medical era in which aspirin, beta-blockers and statins are widely used. The prospective design and relatively long duration of follow-up diminish biases that may be encountered in retrospective or short-term studies. Other strengths include the inclusion of women, an older age group and use of regression analyses to control for potential confounding variables.
Study limitations.
Potential limitations of this study include the relatively small sample size and low absolute number of study end points, which is reflected by the relatively wide 95% CIs on the estimated risks of adverse outcomes associated with ETT duration. However, the low number of nonfatal MIs and deaths in the overall study group only further emphasizes that such patients may be safely managed medically, with decisions about revascularization being based on symptoms and clinical status, rather than on the degree of ischemia provoked by treadmill testing. A large percentage of the study group was referred for a second opinion on cardiac catheterization. This may reflect a selection bias that could limit the ability to generalize our findings. However, such referral biases often favor greater levels of disease rather than less. The variables in this study included only those tests that were interpretable by ECG criteria. Therefore, patients with rest LBBB or nonspecific intraventricular conduction abnormalities or those receiving digoxin therapy were excluded from the study.
Conclusions.
On the basis of our findings, patients with profound ST segment depression provoked by ETT, but with good exercise tolerance, hemodynamic response and well-controlled symptoms, can be safely managed medically with an expectation of low rates of death or nonfatal MI. The likelihood of these events is inversely proportional to increased exercise performance on treadmill testing. Revascularization procedures may be safely delayed and often deferred in such patients.
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Acknowledgments
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We are indebted to Christi Moore Thompson, MSc, for her assistance in the preparation of this manuscript.
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Footnotes
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All financial support for this investigation was provided by the Lown Cardiovascular Research Foundation.
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References
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Abstract
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