Background Exercise capacity is known to be an important prognosticfactor in patients with cardiovascular disease, but it is uncertainwhether it predicts mortality equally well among healthy persons.There is also uncertainty regarding the predictive power ofexercise capacity relative to other clinical and exercise-testvariables.
Methods We studied a total of 6213 consecutive men referredfor treadmill exercise testing for clinical reasons during amean (±SD) of 6.2±3.7 years of follow-up. Subjectswere classified into two groups: 3679 had an abnormal exercise-testresult or a history of cardiovascular disease, or both, and2534 had a normal exercise-test result and no history of cardiovasculardisease. Overall mortality was the end point.
Results There were a total of 1256 deaths during the follow-upperiod, resulting in an average annual mortality of 2.6 percent.Men who died were older than those who survived and had a lowermaximal heart rate, lower maximal systolic and diastolic bloodpressure, and lower exercise capacity. After adjustment forage, the peak exercise capacity measured in metabolic equivalents(MET) was the strongest predictor of the risk of death amongboth normal subjects and those with cardiovascular disease.Absolute peak exercise capacity was a stronger predictor ofthe risk of death than the percentage of the age-predicted valueachieved, and there was no interaction between the use or nonuseof beta-blockade and the predictive power of exercise capacity.Each 1-MET increase in exercise capacity conferred a 12 percent improvement in survival.
During the past two decades, exercise capacity and activitystatus have become well-established predictors of cardiovascularand overall mortality.1,2 The fact that exercise capacity isa strong and independent predictor of outcomes supports thevalue of the exercise test as a clinical tool; it is noninvasive,is relatively inexpensive, and provides a wealth of clinicallyrelevant diagnostic and prognostic information.3,4 However,recent guidelines4 and commentaries on the topic5,6 have identifiedseveral areas related to the prognostic usefulness of exercisetesting that are in need of further study. For example, themajority of previous studies have not clearly assessed the independentprognostic power of exercise capacity relative to other clinicalvariables and information from exercise testing. In addition,whereas the literature is filled with long-term follow-up studiesconducted in relatively healthy populations,7,8,9,10,11 fewstudies have focused on more clinically relevant populations— that is, patients referred for exercise testing forclinical reasons. Moreover, although exercise capacity expressedin terms of metabolic equivalents (MET) is the common clinicalmeasure of exercise tolerance, exercise capacity is stronglyinfluenced by age and activity status. It is not known whichhas greater prognostic value: the absolute peak exercise capacity(measured in MET) or exercise capacity expressed as a percentageof the value predicted on the basis of age. Finally, the useof beta-blocker therapy is common among the patients who aretypically referred for exercise testing; although beta-blockadeimproves survival, it can also reduce exercise capacity. Datarelated to the influence of beta-blockade on the prognosticvalue of exercise tolerance are sparse.
In the present study, we assessed the prognostic value of exercisecapacity among patients referred for exercise testing for clinicalreasons. We addressed the questions of whether exercise capacityis an independent predictor of the risk of death; whether itis as strong a marker of risk as other established cardiovascularrisk factors; whether the percentage of age-predicted exercisecapacity achieved is a better marker of risk than the absolutepeak exercise capacity; and whether beta-blockade influencesthe prognostic value of exercise capacity.
Methods
Exercise Testing
The study population consisted of 6213 consecutive men referredfor exercise testing for clinical reasons. Beginning in 1987,a thorough clinical history, current medications, and risk factorsin these subjects were recorded prospectively on computerizedforms at the time of the exercise tests.12,13 After providingwritten informed consent, the subjects underwent symptom-limitedtreadmill testing according to standardized graded14 or individualized15ramp-treadmill protocols. Before testing, the subjects weregiven a questionnaire, which we used to estimate their exercisecapacity; the use of this estimate allowed most subjects toreach maximal exercise capacity within the recommended rangeof 8 to 12 minutes.16 We have previously observed that thisprotocol results in the closest relation between the measuredand estimated exercise capacity.15 (One MET is defined as theenergy expended in sitting quietly, which is equivalent to abody oxygen consumption of approximately 3.5 ml per kilogramof body weight per minute for an average adult.) Subjects werediscouraged from using the handrails for support. Target heartrates were not used as predetermined end points. Subjects wereplaced in a supine position as soon as possible after exercise.17Medications were not changed or stopped before testing.
ST-segment depression was measured visually. Ventricular tachycardiawas defined as a run of three or more consecutive prematureventricular contractions, and if 10 percent or more of all ventricularcontractions were premature, the subject was considered to havefrequent premature ventricular contractions.18 Exercise capacity(in MET) was estimated on the basis of the speed and grade ofthe treadmill.19 Subjects with either a decrease of 10 mm Hgin systolic blood pressure after an initial increase with exerciseor a decrease to 10 mm Hg below the value measured while standingbefore testing were considered to have exertional hypotension.20
No test results were classified as indeterminate.21 The exercisetests were performed, analyzed, and reported according to astandardized protocol and with the use of a computerized database.22 Normal standards for age-predicted exercise capacitywere derived from regression equations developed on the basisof results in veterans who were referred for exercise testing23and the predicted peak exercise capacity was calculated as 18.0– (0.15 x age). The percentage of normal exercise capacityachieved was defined as follows: (achieved exercise capacity÷ the predicted energy expenditure) x 100.
We defined subjects with cardiovascular disease as those witha history of angiographically documented coronary artery disease,myocardial infarction, coronary bypass surgery, coronary angioplasty,congestive heart failure, peripheral vascular disease, or anabnormal result on an exercise test that was suggestive of coronaryartery disease (ST-segment depression of 1.0 mm, exercise-inducedangina, or both). Seven percent of the population (435 subjects)had a history of mild pulmonary disease and were included inthe group with an abnormal exercise-test result, a history ofcardiovascular disease, or both, which included a total of 3679subjects. The other 2534 subjects, who had no evidence of cardiovasculardisease, were classified as normal.
Follow-up
The Social Security death index was used to match all subjectsto their records according to name and Social Security number.Vital status was determined as of July 2000.
Statistical Analysis
NCSS software (Salt Lake City) was used for all statisticalanalyses. Overall mortality was used as the end point for survivalanalysis. Censoring was not performed, since data on interventionswere not available for all subjects. Survival analysis was performedwith the use of Kaplan–Meier curves for the comparisonof variables and cutoff points, and a Cox proportional-hazardsmodel was used to determine which variables were independentlyand significantly associated with the time to death. Analyseswere adjusted for age in single years as a continuous variable.
In order to compare our results with those of previous studies,the relative risk of death was calculated for each quintileof exercise capacity; subjects with an exercise capacity ofless than 5 MET were considered to have a high risk of death,and those with an energy expenditure of more than 8 MET wereconsidered to have a low risk. Receiver-operating-characteristiccurves were constructed in order to compare the absolute exercisecapacity achieved and exercise capacity expressed as a percentageof the age-predicted value in terms of their discriminatoryaccuracy in predicting survival. The receiver-operating-characteristiccurves were compared with the use of the z statistic.
Results
The mean (±SD) follow-up period was 6.2±3.7 years,and the average annual mortality was 2.6 percent. No major complicationsoccurred, although nonsustained ventricular tachycardia (threeor more consecutive beats) occurred during 1.1 percent of theexercise tests. A total of 83 percent of the subjects who wereclassified as normal achieved a maximal heart rate that wasat least 85 percent of the age-predicted value.
Demographic Characteristics
As compared with the normal subjects, subjects with cardiovasculardisease were older, had a slightly lower body-mass index (definedas the weight in kilograms divided by the square of the heightin meters), and had more extensive use of medicines in additionto more cardiovascular interventions (Table 1).
Table 1. Demographic and Clinical Characteristics of Normal Subjects and Subjects with Cardiovascular Disease.
Exercise-Test Results
Age-adjusted demographic characteristics and the results ofexercise testing in the subjects who survived and those whodied in both groups are presented in Table 2. The regressionequation that predicted the peak exercise capacity on the basisof age was 18.4 – (0.16 x age); with this equation, r(±SE)= –0.50±0.31, P<0.001. The regression equationused to predict the maximal heart rate on the basis of age was187 – (0.85 x age); with this equation, r(±SE)= –0.39±0.23, P<0.001.
Table 3. Age-Adjusted Risk of Death, According to Clinical and Exercise-Test Variables.
The age-adjusted relative risks of death for subjects with eachof the major risk factors among those achieving a peak exercisecapacity of less than 5 MET and 5 to 8 MET, as compared withthe fittest subjects (those achieving a peak of more than 8MET), are shown in Figure 1. For subjects with any of theserisk factors, the relative risk of death from any cause increasedsignificantly as exercise capacity decreased. The age-adjustedrelative risks of death from any cause for subjects in eachquintile of fitness in each group are shown in Figure 2. Inboth groups, subjects with lower exercise capacity had a higherrisk of death. The relative risk for the subjects in the lowestquintile of exercise capacity, as compared with those in thehighest quintile, was 4.5 among the normal subjects and 4.1among those with a history of cardiovascular or pulmonary disease,abnormal results on exercise testing, or both.
Figure 1. Relative Risks of Death from Any Cause among Subjects with Various Risk Factors Who Achieved an Exercise Capacity of Less Than 5 MET or 5 to 8 MET, as Compared with Subjects Whose Exercise Capacity Was More Than 8 MET.
Numbers in parentheses are 95 percent confidence intervals for the relative risks. BMI denotes body-mass index, and COPD chronic obstructive pulmonary disease.
Figure 2. Age-Adjusted Relative Risks of Death from Any Cause According to Quintile of Exercise Capacity among Normal Subjects and Subjects with Cardiovascular Disease.
The subgroup of subjects with the highest exercise capacity (quintile 5) was used as the reference category. For each quintile, the range of values for exercise capacity represented appears within each bar; 95 percent confidence intervals for the relative risks appear above each bar.
Absolute Exercise Capacity versus Percentage of Age-Predicted Value
Absolute peak exercise capacity (with or without adjustmentfor age) predicted survival more accurately than the percentageof age-predicted values achieved when entered into the proportional-hazardsmodel. In addition, the area under the receiver-operating-characteristiccurve was greater for absolute exercise capacity than for thepercentage of age-predicted values (0.67 vs. 0.62, P<0.01),indicating that the absolute value had greater discriminatorypower. For subjects over 65 years of age, however, the areasunder the receiver-operating-characteristic curves were similar(0.60). The survival curves for normal subjects who achievedan exercise capacity of less than 5 MET, 5 to 8 MET, and morethan 8 MET are shown in Figure 3A; the survival curves for normalsubjects who achieved an exercise capacity of less than 50 percent,50 to 74 percent, 75 to 100 percent, and more than 100 percentof the age-predicted value are shown in Figure 3B. The correspondingcurves for the subjects with cardiovascular disease are shownin Figure 3C and Figure 3D. For both the absolute exercise capacityand the percentage of the age-predicted value, there were significantdifferences in mortality rate among groups defined accordingto exercise level (P<0.001), although the curves were shifteddownward in the group with cardiovascular or pulmonary disease.
Figure 3. Survival Curves for Normal Subjects Stratified According to Peak Exercise Capacity (Panel A) and According to the Percentage of Age-Predicted Exercise Capacity Achieved (Panel B) and Survival Curves for Subjects with Cardiovascular Disease Stratified According to Peak Exercise Capacity (Panel C) and According to the Percentage of Age-Predicted Exercise Capacity Achieved (Panel D).
In all the analyses, the stratification according to exercise capacity discriminated among groups of subjects with significantly different mortality rates — that is, the survival rate was lower as exercise capacity decreased (P<0.001).
Effect of Beta-Blockade
There was no interaction between the use or non-use of beta-blockadeand the predictive power of the peak exercise capacity; thiswas the case throughout the typical range of values for exercisecapacity (2 to 10 MET). The results were similar when subjectswere included in the beta-blockade subgroup only if they weretaking a beta-blocker and had a blunted heart-rate responseto exercise (a peak heart rate of less than 85 percent of theage-predicted value). The results were also similar (i.e., beta-blockadehad no effect) when the survival curves were based on variouscutoff points for the percentage of age-predicted exercise capacityachieved (e.g., 50 percent or 75 percent of age-predicted values).
Poor physical fitness is a modifiable risk factor, and improvementsin fitness over time have been demonstrated to improve prognosis.2,9Our observation that every 1-MET increase in treadmill performancewas associated with a 12 percent improvement in survival underscoresthe relatively strong prognostic value of exercise capacity.In addition, it confirms the presence of a graded, inverse relationbetween exercise capacity and mortality from any cause.7,8,9,10,11Recent long-term findings from the National Exercise and HeartDisease Project26 among patients who had had a myocardial infarctiondemonstrated that every 1-MET increase in exercise capacityafter a training period was associated with a reduction in mortalityfrom any cause that ranged from 8 percent to 14 percent overthe course of 19 years of follow-up. In a study involving serialevaluations in nearly 10,000 men, Blair et al.9 observed a 7.9percent reduction in mortality for every one-minute increasein treadmill time (roughly equivalent to the 1-MET change inour study).
In combination, these findings demonstrate that both a relativelyhigh degree of fitness at base line and an improvement in fitnessover time yield marked reductions in risk. The relative weightof exercise capacity in the model for assessing risk in bothnormal subjects and those with cardiovascular or pulmonary diseasein our study, along with the fact that an improvement in exercisecapacity lowers the risk of death,9,26 suggests that healthprofessionals should incorporate into their practices strategiesfor promoting physical activity, in addition to the routinetreatment of hypertension and diabetes, the encouragement ofsmoking cessation, and the like.
Our findings in normal subjects are similar to those of otherstudies8,27,28 in that we observed the most striking differencein mortality rates between the least-fit quintile and the next-least-fitquintile. This observation concurs with the consensus (reflectedin the recommendations of the Centers for Disease Control andPrevention and the American College of Sports Medicine2 andthe report of the Surgeon General on physical activity and health29)that the greatest health benefits are achieved by increasingphysical activity among the least fit. Among subjects with cardiovasculardisease, however, we observed a nearly linear reduction in riskwith increasing quintiles of fitness. Since most studies assessingthe relation between fitness and mortality have excluded subjectswith cardiovascular disease,30 these findings require confirmation.
Few studies have similarly assessed the prognostic value ofexercise tolerance among patients specifically referred forexercise testing for clinical reasons. Roger et al.31 retrospectivelyassessed 2913 men and women from Olmsted County, Minnesota,and reported that among exercise-test variables, exercise capacityhad the strongest association with overall mortality and cardiacevents among subjects of both sexes. More recently, this groupaddressed the association between clinical and exercise-testvariables among young and elderly subjects in Olmsted Countyand observed that the peak workload achieved was the only treadmill-testvariable that was significantly associated with mortality fromany cause.32 These investigators also observed that each 1-METincrement in the peak treadmill workload was associated witha 14 percent reduction in cardiac events among younger subjects(those less than 65 years old) and an 18 percent reduction amongelderly subjects.
In recent years, questions have been raised about which variablehas superior prognostic power: exercise capacity relative toage- and sex-predicted standards or absolute exercise capacity.33,34,35We found that exercise capacity expressed as a percentage ofthe age-predicted value was not superior to the absolute peakexercise capacity in terms of predicting survival. Other studiesin this area have focused only on patients with congestive heartfailure and have had conflicting findings.33,34,35
Our findings are applicable only to men, which is noteworthy,given that exercise-test results have been shown to differ significantlybetween men and women.39 In addition, we had information onlyon death from any cause; we did not know the specific causesof death, nor were we able to censor data at the time of cardiovascularinterventions. Finally, our exercise-capacity data were estimatedon the basis of the speed and grade of the treadmill. Althoughthis type of estimate is the most common clinical measure ofexercise tolerance, directly measured exercise capacity (peakoxygen consumption) is known to be a more accurate and reproduciblemeasure of exercise tolerance,40 as well as a more robust predictorof outcomes.34,35
The present results confirm the prognostic usefulness of exercisecapacity in men. The prognostic power of exercise capacity issimilar among apparently healthy persons and patients with cardiovascularconditions who are referred for exercise testing and similaramong subjects who are taking beta-blockers and those who arenot taking beta-blockers. Expressing exercise capacity as apercentage of the age-predicted value does not improve its prognosticpower. Our findings demonstrate an association between exercise capacity and overall mortality, not necessarily a causal relation.Nevertheless, given the high prognostic value of exercise capacityrelative to other markers of risk in this and other recent studies,clinicians who are reviewing exercise-test results should encouragepatients to improve their exercise capacity. In terms of reducingmortality from any cause, improving exercise tolerance warrantsat least as much attention as other major risk factors fromphysicians who treat patients with or at high risk for cardiovasculardisease.
Source Information
From the Division of Cardiovascular Medicine, Stanford University Medical Center and the Veterans Affairs Palo Alto Health Care System — both in Palo Alto, Calif.
Address reprint requests to Dr. Myers at the Cardiology Division (111C), Veterans Affairs Palo Alto Health Care System, 3081 Miranda Ave., Palo Alto, CA 94304, or at drj993{at}aol.com.
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Exercise Capacity and Mortality
Palatini P., Ko D. T., Hebert P. R., Krumholz H. M., Perlo D. H., Myers J., Froelicher V., Balady G. J.
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1.0 mm, exercise-induced angina, or both). Seven percent of the population (435 subjects) had a history of mild pulmonary disease and were included in the group with an abnormal exercise-test result, a history of cardiovascular disease, or both, which included a total of 3679 subjects. The other 2534 subjects, who had no evidence of cardiovascular disease, were classified as normal. 
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