Author + information
- Received March 13, 2003
- Revision received July 2, 2003
- Accepted July 15, 2003
- Published online February 18, 2004.
- Steve Lai, MD†,* (, )
- Amir Kaykha, MD*,
- Takuya Yamazaki, MD*,
- Mary Goldstein, MD†,
- Joshua M Spin, MD, PhD*,
- Jonathan Myers, PhD* and
- Victor F Froelicher, MD†
- ↵*Reprint requests and correspondence:
Dr. Steve Lai, VA Medical Center Building 1, Box 181G, 4150 Clement Street, San Francisco, California 94121, USA.
Objectives This study seeks to further characterize the role of exercise testing in the elderly for prognosis and diagnosis of coronary artery disease.
Background Recent exercise testing guidelines have recognized that statements regarding the elderly do not have an adequate evidence-based quality because the studies they are based on have limitations in sample size and design. The Duke Treadmill Score has been recommended for risk stratification, but recent evidence has suggested that it does not function in the elderly.
Methods The study population consisted of male veterans (1,872 patients ≥65 years; 3,798 patients <65 years) who underwent routine clinical exercise testing with a mean follow-up of six years. A subset who underwent coronary angiography as clinically indicated (elderly, n = 405; younger, n= 809) were included. The primary outcome for all subjects was cardiovascular mortality with coronary angiographic findings as the outcome in those selected for angiography.
Results In survival analysis, exercise-induced ST depression was prognostic in both age groups only when cardiovascular death was considered as the end point. Peak metabolic equivalents were the most significant predictor for both age groups only when all-cause death was considered as the end point. New age-specific prognostic scores were developed and found to be predictive for cardiovascular mortality in the elderly. Moreover, in the angiographic subset of the elderly, a specific diagnostic score provided significantly better discrimination than exercise ST measurements alone. For any new score, there is a need for validation in another elderly population.
Conclusions The mortality end point affected the choice of prognostic variables. This study demonstrates that exercise test scores can be helpful for the diagnosis and prognosis of coronary disease in the elderly.
With aging of the population, heart disease continues to be the leading cause of mortality in the U.S. The standard exercise test is widely used to evaluate heart disease in the elderly. However, the value of exercise testing has not been fully characterized for elderly patients. Elderly persons exhibit a greater prevalence and severity of coronary disease and comorbid conditions, which may alter the ability of exercise testing to predict outcomes (1). In addition, differences in physiological responses to exercise may appear with aging (2–4). A recent study by Kwok et al. (5)concluded that the widely recommended Duke Treadmill Score (DTS) was limited in predicting cardiovascular mortality in the elderly.
In accordance with exercise testing guideline recommendations (6,7), we sought to obtain more data by examining the utility of exercise testing in male veterans and the DTS. We recently confirmed (8)a prior study of 514 elderly patients that found that exercise-induced ST depression did not independently predict prognosis in the elderly (9). However, the two studies (8,9)only considered all-cause mortality and did not include angiographic data. In this analysis, a larger population is considered, including those with established heart disease, and both angiographic results and cardiovascular death are included as outcomes.
After exclusion of patients with a history and/or findings of congestive heart failure, use of digoxin, or more than 1 mm of resting ST depression, the population consisted of 5,625 consecutive patients referred to two clinical exercise laboratories (Long Beach Veterans Affairs 1987 to 1991; Palo Alto Veterans Affairs 1992 to 2000). These labs were directed in consistent fashion by two of the authors (V.F.F. and J.M.), and patients already enrolled in research protocols were not considered in the analyses. This study included a subset of the population free of established coronary disease (prior myocardial infarction [MI] or coronary intervention) that had been selected for clinical indications for coronary angiography (≥65 years, n = 405; ≤65 years, n = 809) within four months of testing. The study protocol was approved by the hospital review committee at each Veterans Affairs institution. Written informed consent was obtained from all patients.
Both labs were affiliated with universities and had academic medical staffs with rotating house officers and fellows. Tests were directly supervised by these physicians or by nurse practitioners; all tests were read by two of the investigators (V.F.F. and J.M.). No imaging modality was performed in conjunction with exercise testing. A thorough clinical history, a list of medications, and cardiac risk factors were recorded prospectively at the time of testing using computerized forms (10,11). The forms included standard definitions of clinical conditions and exercise responses.
Patients underwent symptom-limited treadmill testing using the United States Air Force School of Aerospace Medicine (USAFSAM) protocol (12)or an individualized ramp treadmill protocol (13,14). Heart rate targets were not used as an end point or to judge the adequacy of the test. Patients were placed supine immediately after exercise (15). No medications were changed or stopped before testing, and no test was classified as indeterminate (16). After maximal heart rate was regressed on age in our male veteran population, the linear regression equation of 210 − 0.8 × (age) was derived for age-predicted maximal heart rate. Trained physicians or nurses were always in direct attendance of the test, and the senior authors were always available for consultation.
Visual ST-segment depression was measured at the J junction and corrected for pre-exercise ST-segment depression while standing; ST slope was measured over the following 60 ms and classified as upsloping, horizontal, or downsloping. The ST response considered was the most horizontal or downsloping ST-segment depression in any lead except aVR during exercise or recovery. An abnormal response was defined as 1 mm or more of horizontal or downsloping ST-segment depression. Ventricular tachycardia was defined as a run of three or more consecutive premature ventricular contractions as previously described (17). Blood pressure was taken manually. Estimated metabolic equivalents (METs) were calculated from treadmill speed and grade. The same equation used by the DTS group was applied to convert from Bruce minutes to METs: (Bruce minutes) = (METs + 2.2)/1.3. Pressure rate product (PRP or double product) pre-test and at maximal exercise were calculated as the product of systolic blood pressure and heart rate. Delta PRP was calculated as follows: PRP at maximal exercise minus PRP at rest/1,000. A previously validated treadmill angiographic score was calculated in each patient (18).
Coronary artery narrowing was visually estimated and expressed as percent lumen diameter stenosis. Patients with a 50% narrowing in one or more of the following were considered to have significant angiographic coronary artery disease (CAD): the left main coronary artery, the left anterior descending artery (LAD), the left circumflex, the right coronary artery, or major branches of these vessels. Severe disease consisted of either three-vessel disease, or two vessels with 50% narrowing or greater (requiring inclusion of either the proximal LAD or the left main). The 50% lesion criterion was chosen to be consistent with the cooperative trialists choice (19), and because we found little discriminatory difference between 50% to 75% lesions (20). Decisions regarding the need for cardiac catheterization were consistent with clinical practice (i.e., no attempt was made to limit work up bias).
The California death registry was used to match all of the patients using name and social security number. The index is updated yearly, and current information was used. Mean follow-up was six years. Data on subsequent interventions or nonfatal cardiovascular events were not available. Death status was determined as of July 2000. Cardiovascular death was differentiated from all-cause death in the California death registry by death certificates.
The population was divided into patients ≥65 years of age (elderly) and those <65 years of age. Comparisons were performed between these groups, and between survivors and nonsurvivors within each age group. Number Cruncher Statistical Systems Software (Salt Lake City, Utah) was used for all statistical analyses after transferring the data from an ACCESS (Microsoft) database. All relevant clinical and the exercise variables were selected for analysis. Unpaired ttesting was used to compare mean values for historical and demographic electrocardiogram (ECG) and exercise test data between those in the younger versus elderly group and for survivors versus nonsurvivors. Chi-square tests were used for differences between proportions. All-cause and cardiovascular mortality were used as the end point for follow-up for survival analysis. Patients were not removed from observation for interventions or infarction because this information was not available. Survival analysis was performed using Kaplan-Meier curves to compare variables and cut points. Cox hazard function was used for survival analysis to demonstrate which variables were independently associated with survival.
The scores were compared to the DTS by the use of the Cox hazard function, receiver operating characteristic (ROC) curves analysis, and Kaplan-Meier survival curves. For the Kaplan-Meier comparisons, the populations were divided into tertiles such that one-third of the population was in each score group associated with low, intermediate, and high risk.
In the subset clinically chosen for angiography, subjects were separated into those with and without significant angiographic disease. How well ST-segment depression and the scores separated patients with and without a given outcome (CAD) was assessed in the age groups by means of standard 2 × 2 tables and the area under ROC curve. A Z-score was calculated to determine if the differences between the areas under the curve (AUCs) were statistically significant (Z > 1.96 = p value <0.001).
The DTS was calculated as exercise time (converted to Bruce minutes from METs) − 5 × (amount ST depression) − 4 × (treadmill angina index). Variables found to be univariately significantly different between those who died and those who survived were considered in the Cox model. Variables then found to be significantly and independently associated with time to cardiovascular death were selected for predictive scores. Their coefficients were divided by the smallest coefficient to determine a relative weight with the weight of the smallest variable being unity. These weights were then multiplied by the variable and all products summed to provide new prognostic scores specific for the age groups. The previously validated simplified Veterans Affairs/University of West Virginia angiographic diagnostic score (VA/UWV score) (Fig. 1) was calculated as 6 × maximal heart rate code + 5 × ST depression code + 4 × age code + angina pectoris code + hypercholesterolemia code + diabetes code + treadmill angina index code (18). The treadmill angina index has a value of 0 if the patient had no angina during exercise, 1 if the patient had non-limiting angina, and 2 if angina was the reason the patient stopped exercising.
Average resting heart rate was ∼3 beats/min lower in the elderly, with a corresponding mean systolic blood pressure 7 mm Hg higher. Elderly subjects had a mean body mass index 1.6 kg/m2lower than the younger subjects. There were no significant differences in age between the different ethnicities. Overall, 74% were Caucasian, 9% were Hispanic, and 12% were African American. The relevant variables for elderly and younger patients are in Table 1. There were no significant differences in beta-blocker (19%, elderly; 19%, younger), anticoagulant, or antiarrhythmic usage between the age groups, but the elderly were more commonly on other cardiovascular medications, such as calcium channel blockers and nitrates. The elderly were significantly more likely to have a history of pulmonary disease, atrial fibrillation, claudication, and stroke. Elderly patients were also more likely to have a history of MI and coronary interventions such as coronary artery bypass graft surgery (CABG) or percutaneous coronary intervention. The only cardiac risk factor more common in the elderly was hypertension (55% vs. 44%). In fact, smoking (50% vs. 60%) and obesity (44% vs. 57%) were less prevalent in the elderly. Diabetes (11% vs. 10%) and hypercholesterolemia (29% vs. 31%) did not differ significantly between the age groups. Resting ECG abnormalities, including Q waves, atrial fibrillation, prolonged QRS duration, ST depression, and left ventricular hypertrophy were more common in the elderly (Table 2).
Exercise test responses
No major complications were encountered during testing, although there were six incidents of nonsustained ventricular tachycardia. Exercise test responses for the elderly and the younger veterans are presented in Table 2. Angina occurred during testing in 12% of the population, and it was the reason for stopping in 6%. All of the major exercise ECG abnormalities were significantly more prevalent in the elderly. Abnormal exercise-induced ST depression, the most common ECG abnormality, was more prevalent in the elderly (31.5% vs. 19.2%, p < 0.001). Silent ischemia (i.e., ST depression without chest pain) was nearly twice as common in the elderly. The next most prevalent ECG abnormality was frequent premature ventricular contractions and/or ventricular tachycardia (three beats in a row or more), and this combined response was twice as common in the elderly (11% vs. 5%, p < 0.001). ST elevation was rare (<1.5%). Both age groups gave a similar effort as reflected in the mean Borg scale rating of 17 for “very hard.”
Average maximal heart rate and METs achieved were significantly lower in the elderly. Failure to reach age-predicted heart rate target occurred in almost half of those tested, and was slightly, but significantly, more common in the elderly. The maximal PRP and delta PRP were significantly lower in the elderly.
The elderly age group experienced 28.5% all-cause mortality (44.9% cardiac deaths) versus 14.3% all-cause mortality (43.8% cardiac deaths) in the younger age group. The average annual cardiovascular mortality was 1.4% in the elderly and 0.7% in the younger veterans. Nonsurvivors in both age groups were significantly more likely to be taking cardiovascular medications. Also, patients with a history of MI or previous coronary interventions were less likely to survive, regardless of age group. Resting ECG abnormalities were associated with increased cardiovascular mortality in all groups. ST depression during exercise was significantly more prevalent in those who died compared with those who survived in both age groups (33% vs. 18%, younger age group; 45% vs. 30%, elderly). All measured exercise hemodynamic variables were significantly different, that is, lower in nonsurvivors versus survivors in both age groups.
Using stepwise selection, the proportional hazards model was allowed to build on each variable group. The clinical variables and exercise variables were considered univariately, and those that were significant (p < 0.001) were analyzed multivariately. Table 3shows the significant clinical and exercise variables that were independently associated with cardiovascular and all-cause mortality. In the elderly group, resting ST depression, delta PRP, history of CABG, MI history/Q waves, and abnormal ST depression during exercise were the most significant clinical and exercise test variables associated with cardiovascular death. In the younger age group, the maximal METs, history of CABG, prior history of MI/Q waves, and abnormal ST depression during exercise were most significant. For all-cause mortality analysis, the most important exercise test variable was maximal METs in both age groups, and exercise-induced ST depression was no longer chosen. Anti-ischemic medications such as calcium channel blockers and beta-blockers can produce false negative tests on treadmill testing. After adjusting for calcium channel blockers and beta-blockers, there were no differences in the clinical and exercise test variables in the hazard model. An age-specific prognostic score was created for patients ≥65 years as: [Δ PRP (10−3) − 10 (rest ST depression yes/no + history of MI or Q-wave yes/no + CABG yes/no) − 4 (exercise ST depression in mm)]. For patients <65 years, the score was: [peak METs − 5 (CABG yes/no + history of MI or Q-wave yes/no) − 2 (exercise ST depression in mm)].
Age-specific prognostic scores compared with the Duke score
Table 4shows the comparison of AUC for our >65 and <65 age-specific scores versus the DTS. Comparing our scores with the DTS for the total population, the ROC scores were significantly different and demonstrated the increased discriminatory power of the specific age scores in both age groups. For the >65 group, the AUC (± standard error) of the ROC plot for the DTS and Veterans Administration score was 0.59 ± 0.008 and 0.69 ± 0.007 (Fig. 2). For the <65 group, the AUC of the ROC plot for the DTS and Veterans Administration score was 0.67 ± 0.007 and 0.73 ± 0.006. When patients with previous MI and CABG/percutaneous coronary intervention were excluded, the Veterans Administration and DTS ROC curves were still significantly different in the >65 years group (0.65 ± 0.011 vs. 0.60 ± 0.012). However, the ROC curves for the Veterans Administration and DTS scores were not significantly different in the <65 year group (Fig. 3). In Figure 4, we show Kaplan-Meier survival curves of DTS using original cut points and the age-specific score for >65 using tertile cut points. In our age-specific score, the low-risk and high-risk group had more separation than that of the DTS.
Diagnostic characteristics of the scores in those with angiograms
In the angiographic subset (elderly, n = 405; younger, n = 809), the prevalence of angiographic disease was significantly higher in the elderly (72% vs. 53%, p < 0.001). Patients with CAD in both age groups had a significantly higher prevalence of hypercholesterolemia, typical angina, and abnormal exercise testing. Patients <65 years with CAD had ∼1.7 MET lower exercise tolerance than those without CAD (p < 0.001). Of those <65, 33% had abnormal exercise tests, and in those >65, 49% had abnormal exercise tests compared with 21% and 33%, respectively, in the total population consistent with workup bias.
There were no significant differences in test characteristics for the standard criterion of 1 mm of ST depression (predictive accuracy of 59% for the elderly and 65% for the younger group, sensitivity of 55% for the elderly and 47% for the younger group). The AUC of the ROC curves for ST depression, DTS, and a previously validated diagnostic score (VA/UWV score) (Fig. 1) (18)are presented in Table 5for the two age groups. The Z-score was calculated to compare the ability to discriminate between the age groups and then for the scores compared with the ST measurements alone. For the younger group, the AUC (± standard error) of the ROC plot for the ST response alone, DTS, and VA/UWV score were 0.67 ± 0.019, 0.72 ± 0.018, and 0.79 ± 0.016, respectively. For the elderly population, the AUC of the ROC plot for the ST response alone, DTS, and VA/UWV score were 0.66 ± 0.029, 0.72 ± 0.026, and 0.75 ± 0.025, respectively, and are shown in Figure 5. These were not significantly different between the age groups. In patients <65 years, AUC for VA/UWV score was significantly greater than the ST response alone and DTS, but both scores were significantly better than the ST measurements alone. For the elderly, only the AUC for VA/UWV score was significantly greater than that of ST response alone.
Clinical guidelines regarding ischemic heart disease have recommended the standard exercise test as the first choice for the evaluation of the elderly patient without confounding resting ECG abnormalities and that the DTS be used for prognostication (21,22). A recent study by Kwok et al. (5)comparing 247 patients 75 years or older to younger patients demonstrated that the prognostic value of the DTS in the elderly was limited. This could be explained by the fact that they have a higher prevalence of CAD, more severe CAD, and/or a lower exercise capacity. We included patients with minor resting ST depression (<1 mm) consistent with the guidelines and with the following two studies. Kwok et al. (23)validated the prognostic accuracy of the DTS in patients with nonspecific ST-depression, and Fearon et al. (24)also demonstrated that minor degrees of resting ST-segment depression did not affect the diagnostic characteristics of the treadmill test. Both demonstrated that those with resting ST depression have a higher mortality, making them important to evaluate further. While the DTS was designed to provide survival estimates, Shaw et al. (25)verified its diagnostic usefulness for angiographic CAD. However, in a similar mixed-age population with angiographic CAD as the outcome, we compared the diagnostic characteristics of the ST response alone, the DTS, and three other scores and found that the DTS was less accurate than other treadmill scores (26).
Our study showed that the mortality end point affected the choice of prognostic variables. In addition, the above 65 age group had different clinical and exercise variables of prognostic utility. The DTS has previously been validated for prognostication. The DTS was developed in a referral population that was younger (mean age, 49 years) (27). In addition, the DTS did not incorporate cardiac risk factors and comorbid conditions that we used in our multivariate analysis. The Veterans Administration is the largest health care system in the world with an older population, and, if the DTS is not appropriate for the elderly, there must be a search for a more predictive score. In this Veterans Administration cohort, a new prognostic score for age above 65 is proposed. This is adequate to provide an initial evaluation of the score. However, validation in another geographically distinct group is required to assess the transportability or generalizability.
The differences in the hemodynamic responses likely reflect physiological changes with aging, and their validity is supported by the similarly perceived exertion in both groups. The ability of the coronary circulation to respond to myocardial metabolic demand is estimated by the product of systolic blood pressure and heart rate, generally called PRP or double product (28,29). Generally, peak exercise systolic and delta systolic blood pressure increase with advancing age while PRP decreases, similar to our results (30). Prognostic studies demonstrating the prognostic value of delta PRP have largely centered on post-MI patients (31,32). The only prior study to consider and find PRP significantly associated with time to death in non-MI patients was from the Seattle Veterans Administration (33).
Comparison with younger patients
As expected, the elderly group experienced a higher cardiovascular mortality. The notable finding in the elderly group was that resting ST depression and delta PRP were the most significant exercise test variables associated with cardiovascular death, as opposed to maximal METs being the most powerful in the younger population. It is important to note that maximal METs had similar risk ratios in both groups, but, in the elderly, other clinical and exercise variables became more significant. Table 2indicates the standard deviation of METs is smaller for the elderly when compared with the younger group. This is expected as the METs achieved decreases with age. However, we have previously found that the percent age-adjusted METs did not function better than absolute METs achieved (32).
Resting ST depression is more prevalent in the elderly, and our findings are consistent with previous studies that revealed that patients with resting ST abnormalities have a worse prognosis (23,24). It is interesting to note that our derived score for the younger group looked very similar to the DTS when used in patients without CAD. The Duke treadmill angina index was evaluated as a potential predictor in all of our prognostic models and was not chosen as significantly and independently associated with time to death.
Comparison of cardiovascular mortality and all-cause mortality
In the all-cause mortality analysis, maximal METs was the most significant predictor in both age groups. Exercise capacity is a reflection of the integrity of the cardiopulmonary system and a marker of a physically active lifestyle. In the elderly, patients with lower maximal METs achieved often have other comorbid conditions that limit their exercise capacity and likely lead to increased mortality. In the all-cause mortality data, resting ST depression decreases in significance. Thus, the findings reveal that the end points determine which variables will be most significantly predictive. Previous studies that used all-cause mortality as an end point have found METs to be the most significant predictor (9,34). When using an end point of cardiovascular mortality, resting ST depression and delta PRP are more prognostic. Lauer et al. (35)have pointed out the inaccuracy of death certificates in regards to attributing death to cardiovascular causes. While cardiovascular death is weaker to use than all-cause mortality in outcome studies evaluating an intervention, we believe the goal of the exercise test is to predict cardiovascular disease, not cancer, accident, suicide, or pulmonary disease.
Comparison with prior studies
The largest previous study among the elderly came from the Rochester Epidemiology Project (9). They used the records of the doctor's offices performing treadmill testing to identify a retrospective cohort of Olmsted County residents tested between 1987 and 1989. During the study period, initial treadmill tests were performed in 2,593 persons <65 years of age and 514 persons ≥65 years of age. Peak METs were the only exercise-testing variable associated with all-cause mortality in both age groups, and the strength of association was similar. Metabolic equivalents and angina with exercise testing were associated with cardiac events in both age groups, whereas exercise-induced ST depression was associated with cardiac events only in younger persons. With consideration of clinical variables, peak METs was the only additional exercise variable that was predictive of death (p < 0.001) and cardiac events (p < 0.05); the strength of the association was similar in both age groups. Our study used cardiovascular death as the primary outcome to focus on the exercise treadmill test and included angiographic data.
Comparison of diagnostic characteristics of the scores/angiographic data
In the elderly, compared with the DTS, only the AUC of the VA/UWV angiographic diagnostic score was significantly greater than that of the ST response alone. Thus, although the DTS has been shown to have diagnostic utility for angiographic coronary disease, it is likely to be limited in the elderly. This is the first study to evaluate the diagnostic characteristics of the DTS in the elderly.
This study defines more clearly the diagnostic and prognostic utility of exercise testing in elderly men. Strengths include a long follow-up, the inclusion of all consecutive referrals of elderly patients to two similar academically aligned Veterans Administration medical centers spanning over 12 years, an angiographic subset, and the application of standardized methodology. This study is the largest to date that documents the safety of “symptom- and sign-” limited maximal exercise testing in the elderly.
Our survival analysis is limited because we did not remove patients from observation based on whether they had a cardiovascular procedure during follow-up, because that information was not available. While the DTS was generated using the end point of cardiovascular death like this study (27,36), patients with interventions such as bypass surgery or catheter procedures had their follow-up ended when interventions occurred in the Duke study. Censoring for revascularization would have improved our predictive ability and allowed follow-up to the time of the cardiovascular procedure. The use of the California death registry was a minor limitation. Only eight patients died from California when we compared the deaths to those reported using the social security death index, and we considered these eight deaths to be cardiovascular causes.
Recently, there has been important data showing the utility of exercise treadmill data in the recovery period after the completion of exercise. The use of heart rate recovery, ST depression during recovery, and ventricular ectopy have all been shown to have prognostic importance (37,38). The absence of this data is a limitation, as there may be more predictive variables in a treadmill score. Another issue is in regards to the angiographic data using 50% stenosis to define significant angiographic CAD. It is appreciated now that a reduction in coronary flow reserve is associated with 70% stenosis. However, in a meta-analysis of 150 angiographic correlative studies, the study concluded that there were no appreciable differences in test characteristics between 50% and 70% diameter obstruction as a criterion for defining disease (39).
Another limitation is the reduction of the utility of the ST segment response by inclusion of exercise tests with low heart rates, baseline ECGs with up to 1.0 mm ST depression, and the higher prevalence of heart-rate-limiting drugs in the elderly. Furthermore, we are limited by selection bias, which is especially pertinent in the elderly.
Our findings demonstrate the importance of exercise testing as an important prognostic and diagnostic modality in the elderly. The exercise test offers additional value over clinical variables alone both for diagnosis and prognosis. This study demonstrates that exercise test scores can be helpful for the diagnosis and prognosis of coronary disease in the elderly.
☆ Views expressed are those of the authors and do not necessarily reflect those of the Department of Veterans Affairs.
- area under the curve
- coronary artery bypass graft
- coronary artery disease
- Duke Treadmill Score
- left anterior descending coronary artery
- metabolic equivalent
- myocardial infarction
- pressure rate product
- receiver operator characteristic
- Veterans Affairs/University of West Virginia angiographic diagnostic score
- Received March 13, 2003.
- Revision received July 2, 2003.
- Accepted July 15, 2003.
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