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Exercise Capacity and Mortality among Men Referred for Exercise Testing

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Exercise capacity is known to be an important prognostic factor in patients with cardiovascular disease, but it is uncertain whether it predicts mortality equally well among healthy persons. There is also uncertainty regarding the predictive power of exercise capacity relative to other clinical and exercise-test variables. We studied a total of 6213 consecutive men referred for treadmill exercise testing for clinical reasons during a mean (+/-SD) of 6.2+/-3.7 years of follow-up. Subjects were classified into two groups: 3679 had an abnormal exercise-test result or a history of cardiovascular disease, or both, and 2534 had a normal exercise-test result and no history of cardiovascular disease. Overall mortality was the end point. There were a total of 1256 deaths during the follow-up period, resulting in an average annual mortality of 2.6 percent. Men who died were older than those who survived and had a lower maximal heart rate, lower maximal systolic and diastolic blood pressure, and lower exercise capacity. After adjustment for age, the peak exercise capacity measured in metabolic equivalents (MET) was the strongest predictor of the risk of death among both normal subjects and those with cardiovascular disease. Absolute peak exercise capacity was a stronger predictor of the risk of death than the percentage of the age-predicted value achieved, and there was no interaction between the use or nonuse of beta-blockade and the predictive power of exercise capacity. Each 1-MET increase in exercise capacity conferred a 12 percent improvement in survival. Exercise capacity is a more powerful predictor of mortality among men than other established risk factors for cardiovascular disease.
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The New England
Journal
of
Medicine
Copyright © 2002 by the Massachusetts Medical Society
VOLUME 346
M
ARCH
14, 2002
NUMBER 11
N Engl J Med, Vol. 346, No. 11
·
March 14, 2002
·
www.nejm.org
·
793
EXERCISE CAPACITY AND MORTALITY AMONG MEN REFERRED
FOR EXERCISE TESTING
J
ONATHAN
M
YERS
, P
H
.D., M
ANISH
P
RAKASH
, M.D., V
ICTOR
F
ROELICHER
, M.D., D
AT
D
O
, M.D., S
ARA
P
ARTINGTON
, B.S
C
.,
AND
J. E
DWIN
A
TWOOD
, M.D.
A
BSTRACT
Background
Exercise capacity is known to be an
important prognostic factor in patients with cardiovas-
cular disease, but it is uncertain whether it predicts
mortality equally well among healthy persons. There
is also uncertainty regarding the predictive power of
exercise capacity relative to other clinical and exercise-
test variables.
Methods
We studied a total of 6213 consecutive
men referred for treadmill exercise testing for clinical
reasons during a mean (±SD) of 6.2±3.7 years of fol-
low-up. Subjects were classified into two groups: 3679
had an abnormal exercise-test result or a history of
cardiovascular disease, or both, and 2534 had a nor-
mal exercise-test result and no history of cardiovascu-
lar disease. Overall mortality was the end point.
Results
There were a total of 1256 deaths during the
follow-up period, resulting in an average annual mor-
tality of 2.6 percent. Men who died were older than
those who survived and had a lower maximal heart
rate, lower maximal systolic and diastolic blood pres-
sure, and lower exercise capacity. After adjustment for
age, the peak exercise capacity measured in metabolic
equivalents (MET) was the strongest predictor of the
risk of death among both normal subjects and those
with cardiovascular disease. Absolute peak exercise ca-
pacity was a stronger predictor of the risk of death than
the percentage of the age-predicted value achieved,
and there was no interaction between the use or non-
use of beta-blockade and the predictive power of exer-
cise capacity. Each 1-MET increase in exercise capacity
conferred a 12 percent improvement in survival.
Conclusions
Exercise capacity is a more powerful
predictor of mortality among men than other estab-
lished risk factors for cardiovascular disease. (N Engl
J Med 2002;346:793-801.)
Copyright © 2002 Massachusetts Medical Society.
From the Division of Cardiovascular Medicine, Stanford University Med-
ical 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@aol.com.
URING the past two decades, exercise ca-
pacity and activity status have become well-
established predictors of cardiovascular and
overall mortality.
1,2
The fact that exercise
capacity is a strong and independent predictor of out-
comes supports the value of the exercise test as a clin-
ical tool; it is noninvasive, is relatively inexpensive, and
provides a wealth of clinically relevant diagnostic and
prognostic information.
3,4
However, recent guidelines
4
and commentaries on the topic
5,6
have identified sev-
eral areas related to the prognostic usefulness of exer-
cise testing that are in need of further study. For ex-
ample, the majority of previous studies have not clearly
assessed the independent prognostic power of exercise
capacity relative to other clinical variables and infor-
mation from exercise testing. In addition, whereas the
literature is filled with long-term follow-up studies
conducted in relatively healthy populations,
7-11
few
studies have focused on more clinically relevant pop-
ulations — that is, patients referred for exercise test-
ing for clinical reasons. Moreover, although exercise
capacity expressed in terms of metabolic equivalents
(MET) is the common clinical measure of exercise tol-
erance, exercise capacity is strongly influenced by age
and activity status. It is not known which has greater
prognostic value: the absolute peak exercise capacity
(measured in MET) or exercise capacity expressed as
a percentage of the value predicted on the basis of age.
Finally, the use of beta-blocker therapy is common
among the patients who are typically referred for exer-
cise testing; although beta-blockade improves surviv-
al, it can also reduce exercise capacity. Data related to
the influence of beta-blockade on the prognostic val-
ue of exercise tolerance are sparse.
D
794
·
N Engl J Med, Vol. 346, No. 11
·
March 14, 2002
·
www.nejm.org
The New England Journal of Medicine
In the present study, we assessed the prognostic
value of exercise capacity among patients referred for
exercise testing for clinical reasons. We addressed the
questions of whether exercise capacity is an independ-
ent predictor of the risk of death; whether it is as
strong a marker of risk as other established cardiovas-
cular risk factors; whether the percentage of age-pre-
dicted exercise capacity achieved is a better marker
of risk than the absolute peak exercise capacity; and
whether beta-blockade influences the prognostic val-
ue of exercise capacity.
METHODS
Exercise Testing
The study population consisted of 6213 consecutive men referred
for exercise testing for clinical reasons. Beginning in 1987, a thor-
ough clinical history, current medications, and risk factors in these
subjects were recorded prospectively on computerized forms at the
time of the exercise tests.
12,13
After providing written informed con-
sent, the subjects underwent symptom-limited treadmill testing ac-
cording to standardized graded
14
or individualized
15
ramp-treadmill
protocols. Before testing, the subjects were given a questionnaire,
which we used to estimate their exercise capacity; the use of this
estimate allowed most subjects to reach maximal exercise capacity
within the recommended range of 8 to 12 minutes.
16
We have pre-
viously observed that this protocol results in the closest relation
between the measured and estimated exercise capacity.
15
(One MET
is defined as the energy expended in sitting quietly, which is equiv-
alent to a body oxygen consumption of approximately 3.5 ml per
kilogram of body weight per minute for an average adult.) Subjects
were discouraged from using the handrails for support. Target heart
rates were not used as predetermined end points. Subjects were
placed in a supine position as soon as possible after exercise.
17
Med-
ications were not changed or stopped before testing.
ST-segment depression was measured visually. Ventricular tachy-
cardia was defined as a run of three or more consecutive premature
ventricular contractions, and if 10 percent or more of all ventricular
contractions were premature, the subject was considered to have
frequent premature ventricular contractions.
18
Exercise capacity (in
MET) was estimated on the basis of the speed and grade of the
treadmill.
19
Subjects with either a decrease of 10 mm Hg in sys-
tolic blood pressure after an initial increase with exercise or a de-
crease to 10 mm Hg below the value measured while standing be-
fore testing were considered to have exertional hypotension.
20
No test results were classified as indeterminate.
21
The exercise tests
were performed, analyzed, and reported according to a standardized
protocol and with the use of a computerized data base.
22
Normal
standards for age-predicted exercise capacity were derived from re-
gression equations developed on the basis of results in veterans who
were referred for exercise testing
23
and the predicted peak exercise
capacity was calculated as 18.0¡(0.15¬age). The percentage of nor-
mal exercise capacity achieved was defined as follows: (achieved ex-
ercise capacity÷the predicted energy expenditure)¬100.
We defined subjects with cardiovascular disease as those with a
history of angiographically documented coronary artery disease, my-
ocardial infarction, coronary bypass surgery, coronary angioplasty,
congestive heart failure, peripheral vascular disease, or an abnormal
result on an exercise test that was suggestive of coronary artery dis-
ease (ST-segment depression of »1.0 mm, exercise-induced angina,
or both). Seven percent of the population (435 subjects) had a his-
tory 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 clas-
sified as normal.
Follow-up
The Social Security death index was used to match all subjects to
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 statistical analy-
ses. Overall mortality was used as the end point for survival analysis.
Censoring was not performed, since data on interventions were not
available for all subjects. Survival analysis was performed with the use
of Kaplan–Meier curves for the comparison of variables and cutoff
points, and a Cox proportional-hazards model was used to deter-
mine which variables were independently and significantly associat-
ed with the time to death. Analyses were 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 quintile of exercise
capacity; subjects with an exercise capacity of less than 5 MET were
considered to have a high risk of death, and those with an energy
expenditure of more than 8 MET were considered to have a low
risk. Receiver-operating-characteristic curves were constructed in
order to compare the absolute exercise capacity achieved and ex-
ercise capacity expressed as a percentage of the age-predicted val-
ue in terms of their discriminatory accuracy in predicting survival.
The receiver-operating-characteristic curves 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 per-
cent. No major complications occurred, although
nonsustained ventricular tachycardia (three or more
consecutive beats) occurred during 1.1 percent of the
exercise tests. A total of 83 percent of the subjects who
were classified as normal achieved a maximal heart rate
that was at least 85 percent of the age-predicted value.
Demographic Characteristics
As compared with the normal subjects, subjects
with cardiovascular disease were older, had a slightly
lower body-mass index (defined as the weight in kilo-
grams divided by the square of the height in meters),
and had more extensive use of medicines in addition
to more cardiovascular interventions (Table 1).
Exercise-Test Results
Age-adjusted demographic characteristics and the
results of exercise testing in the subjects who sur-
vived and those who died in both groups are pre-
sented in Table 2. The regression equation that
predicted the peak exercise capacity on the basis of
age was 18.4¡(0.16¬age); with this equation,
r(±SE)=¡0.50±0.31, P<0.001. The regression
equation used to predict the maximal heart rate on
the basis of age was 187¡(0.85¬age); with this equa-
tion, r(±SE)=¡0.39±0.23, P< 0.001.
Predictors of Death from Any Cause
Clinical and exercise-test predictors of mortality
from the Cox proportional hazards model are present-
EXERCISE CAPACITY AND MORTALITY
N Engl J Med, Vol. 346, No. 11
·
March 14, 2002
·
www.nejm.org
·
795
*Plus–minus values are means ±SD. To convert values for height to centimeters, multiply by 2.54;
to convert values for weight to kilograms, multiply by 0.45. For comparisons where no P value is
given, the differences are due to the classification criteria specified in the study design.
T
ABLE
1.
D
EMOGRAPHIC
AND
C
LINICAL
C
HARACTERISTICS
OF
N
ORMAL
S
UBJECTS
AND
S
UBJECTS
WITH
C
ARDIOVASCULAR
D
ISEASE
.*
V
ARIABLE
A
LL
S
UBJECTS
(N=6213)
N
ORMAL
S
UBJECTS
(N=2534)
S
UBJECTS
WITH
C
ARDIOVASCULAR
D
ISEASE
(N=3679)
P
V
ALUE
Demographic characteristics
Age (yr) 59±11.2 55.5±11.8 61.5±10.1 <0.001
Height (in.) 69.2±4.1 69.4±3.4 69.2±3.6 0.02
Weight (lb) 191.2±39 193.7±37 188.8±36 <0.001
Body-mass index 28.0±5.2 28.4±5.1 27.3±5.0 <0.001
Medications (%)
Digoxin 5.4 0 9.1
Calcium antagonist 27.3 17.2 34.3 <0.001
Beta-blocker 18.9 12.0 23.7 <0.001
Nitrate 23.3 9.5 32.9 <0.001
Antihypertensive agent 24.0 19.3 27.3 <0.001
Medical history (%)
Atrial fibrillation 3.1 0.8 2.7 <0.001
Pulmonary disease 6.9 0 11.7
Stroke 3.6 0 6.1
Claudication 5.3 0 8.9
Typical angina 31.3 7 31.2 <0.001
Myocardial infarction 29.3 0 49.4
Congestive heart failure 8.4 0 14.2
Interventions (%)
Coronary bypass surgery 9.3 0 14.1
Percutaneous transluminal cor-
onary angioplasty, stenting,
or both
5.2 0 8.7
*Plus–minus values are means ±SD. P values are for comparisons between the subjects who survived and those who died in each group.
To convert values for height to centimeters, multiply by 2.54; to convert values for weight to kilograms, multiply by 0.45. MET denotes
metabolic equivalents.
T
ABLE
2.
A
GE
-A
DJUSTED
C
HARACTERISTICS
AND
E
XERCISE
-T
EST
R
ESPONSES
AMONG
S
UBJECTS
W
HO
D
IED
AND
S
UBJECTS
W
HO
S
URVIVED
.*
V
ARIABLE
N
ORMAL
S
UBJECTS
S
UBJECTS
WITH
C
ARDIOVASCULAR
D
ISEASE
TOTAL
(
N
=2534)
SURVIVED
(
N
=2246)
DIED
(
N
=288) P
VALUE
TOTAL
(
N
=3679)
SURVIVED
(
N
=2711)
DIED
(
N
=968) P
VALUE
Age (yr) 55±12 55±12 62±10 <0.001 61±10 60±10 65±9 <0.001
Height (in.) 69.4±3.4 69.4±3.1 69.7±4.9 0.08 69.2±3.7 69.2±3.5 69.3±4.2 0.34
Weight (lb) 193.7±37.5 194.1±37.1 191.0±40.1 0.19 188.8±36.1 190.7±36.3 183.7±34.4 <0.001
Body-mass index 28.3±5.1 28.4±5.1 27.5±5.0 0.005 27.8±5.0 28.1±5.0 26.9±4.7 <0.001
Resting values
Heart rate (beats/min) 78±16 78±16 83±16 <0.001 78±26 77±29 79±16 0.24
Blood pressure (mm Hg)
Diastolic 84±12 84±12 83±13 0.16 82±18 82±19 80±12 <0.001
Systolic 132±20 133±20 131±21 0.13 134±23 135±23 132±24 <0.001
Maximal values
Heart rate (beats/min) 145±24 145±23 140±25 <0.001 132±29 133±28 127±32 <0.001
Blood pressure (mm Hg)
Diastolic 86±16 86±15 85±16 0.37 86±23 86±20 85±30 0.53
Systolic 184±28 184±27 178±32 <0.001 174±31 176±31 168±32 <0.001
Exercise capacity (MET) 9.5±3.8 9.7±3.7 8.4±3.5 <0.001 7.2±3.3 7.4±3.3 6.5±2.8 <0.001
796
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The New England Journal of Medicine
ed in Table 3. After adjustment for age, the best pre-
dictor of an increased risk of death among normal sub-
jects was peak exercise capacity, followed by pack-years
of smoking. Among subjects with cardiovascular dis-
ease, the best predictor of an increased risk of death
from any cause was peak exercise capacity, followed by
a history of congestive heart failure, history of myo-
cardial infarction, pack-years of smoking, left ventric-
ular hypertrophy on electrocardiography while at rest,
pulmonary disease, and exercise-induced ST-segment
depression. According to the model for the total
group, every 1-MET increase in exercise capacity
conferred a 12 percent improvement in survival.
The age-adjusted relative risks of death for subjects
with each of the major risk factors among those achiev-
ing a peak exercise capacity of less than 5 MET and
5 to 8 MET, as compared with the fittest subjects
(those achieving a peak of more than 8 MET), are
shown in Figure 1. For subjects with any of these risk
factors, the relative risk of death from any cause in-
creased significantly as exercise capacity decreased. The
age-adjusted relative risks of death from any cause for
subjects in each quintile of fitness in each group are
shown in Figure 2. In both groups, subjects with low-
er exercise capacity had a higher risk of death. The rel-
ative risk for the subjects in the lowest quintile of ex-
ercise capacity, as compared with those in the highest
quintile, was 4.5 among the normal subjects and 4.1
among those with a history of cardiovascular or pul-
monary disease, abnormal results on exercise testing,
or both.
Absolute Exercise Capacity versus Percentage
of Age-Predicted Value
Absolute peak exercise capacity (with or without
adjustment for age) predicted survival more accurately
than the percentage of age-predicted values achieved
when entered into the proportional-hazards model. In
addition, the area under the receiver-operating-char-
acteristic curve was greater for absolute exercise ca-
pacity than for the percentage of age-predicted values
(0.67 vs. 0.62, P<0.01), indicating that the absolute
value had greater discriminatory power. For subjects
over 65 years of age, however, the areas under the
receiver-operating-characteristic curves were similar
(0.60). The survival curves for normal subjects who
achieved an exercise capacity of less than 5 MET, 5 to
8 MET, and more than 8 MET are shown in Figure
3A; the survival curves for normal subjects who
achieved an exercise capacity of less than 50 percent,
50 to 74 percent, 75 to 100 percent, and more than
100 percent of the age-predicted value are shown in
Figure 3B. The corresponding curves for the subjects
with cardiovascular disease are shown in Figures 3C
and 3D. For both the absolute exercise capacity and
the percentage of the age-predicted value, there were
significant differences in mortality rate among groups
defined according to exercise level (P<0.001), al-
though the curves were shifted downward in the group
with cardiovascular or pulmonary disease.
Effect of Beta-Blockade
There was no interaction between the use or non-
use of beta-blockade and the predictive power of the
peak exercise capacity; this was the case throughout
the typical range of values for exercise capacity (2 to
10 MET). The results were similar when subjects were
included in the beta-blockade subgroup only if they
were taking a beta-blocker and had a blunted heart-
rate response to exercise (a peak heart rate of less than
85 percent of the age-predicted value). The results
were also similar (i.e., beta-blockade had no effect)
when the survival curves were based on various cut-
*Data are from the Cox proportional-hazards model. Metabolic equiva-
lents (MET) were calculated from the peak speed and grade of the tread-
mill and were evaluated as a continuous variable. Left ventricular hypertro-
phy was defined according to electrocardiographic criteria in a resting
patient. Exercise-induced arrhythmia was defined as three or more prema-
ture ventricular contractions in succession, premature ventricular contrac-
tions that accounted for 10 percent or more of total beats during exercise,
or both. Maximal heart rate was measured at peak exercise. ST-segment de-
pression was defined as an exercise-induced change of 1.0 mm or more. CI
denotes confidence interval.
TABLE 3. AGE-ADJUSTED RISK OF DEATH, ACCORDING TO
CLINICAL AND EXERCISE-TEST VARIABLES.*
VARIABLE
HAZARD RATIO
FOR DEATH
(95% CI)
P
VALUE
Normal subjects
Peak exercise capacity (for each 1-MET in-
crement)
0.84 (0.79–0.89) <0.001
Pack-yr of smoking (for each 10-yr incre-
ment)
1.09 (1.03–1.14) <0.001
History of hypertension 0.75 (0.56–1.02) 0.07
Diabetes 1.30 (0.84–2.00) 0.24
Total cholesterol level >220 mg/dl (5.7
mmol/liter)
1.21 (0.88–1.64) 0.25
Left ventricular hypertrophy 1.22 (0.57–2.63) 0.61
Exercise-induced ventricular arrhythmia 1.14 (0.64–2.01) 0.66
Maximal heart rate (for each increment of
10 beats/min)
1.00 (0.92–1.08) 0.93
Subjects with cardiovascular disease
Peak exercise capacity (for each 1-MET in-
crement)
0.91 (0.88–0.94) <0.001
History of congestive heart failure 1.67 (1.37–2.04) <0.001
History of myocardial infarction 1.60 (1.35–1.90) <0.001
Pack-yr of smoking (for each 10-yr incre-
ment)
1.05 (1.02–1.08) 0.001
Left ventricular hypertrophy 1.50 (1.13–1.99) 0.005
Pulmonary disease 1.34 (1.06–1.68) 0.01
ST-segment depression 1.22 (1.03–1.44) 0.02
Total cholesterol level >220 mg/dl (5.7
mmol/liter)
0.88 (0.74–1.04) 0.14
Maximal heart rate (for each increment of
10 beats/min)
0.97 (0.93–1.01) 0.17
Exercise-induced ventricular arrhythmia 1.19 (0.92–1.53) 0.18
Diabetes 0.90 (0.69–1.16) 0.41
History of hypertension 1.07 (0.90–1.25) 0.47
EXERCISE CAPACITY AND MORTALITY
N Engl J Med, Vol. 346, No. 11 · March 14, 2002 · www.nejm.org · 797
off points for the percentage of age-predicted exer-
cise capacity achieved (e.g., 50 percent or 75 percent
of age-predicted values).
DISCUSSION
Our results demonstrate that exercise capacity is a
strong predictor of the risk of death in patients re-
ferred for exercise testing for clinical reasons. The
importance of exercise capacity, physical-activity sta-
tus, or both in predicting survival has been reported
in asymptomatic populations such as those of the
Framingham Study,
11
the Aerobics Center Longitu-
dinal Study,
8,9
the Lipid Research Clinics Trial,
7
and
the Harvard Alumni study.
24
Our population was
unique in that it afforded us the opportunity to assess
subjects both with and without documented cardio-
vascular disease. Whereas the above-mentioned studies
involved generally healthy populations, our data dem-
onstrate that exercise capacity is a similarly important
marker of risk in a clinically referred population and
among men both with and without existing cardiovas-
cular disease. Unlike the estimates of activity status or
the submaximal exercise tests used in many studies, the
maximal exercise testing used in the present study pro-
vided an objective measure of physical fitness.
25
In both healthy subjects and those with cardiovas-
cular disease, the peak exercise capacity achieved was
a stronger predictor of an increased risk of death than
clinical variables or established risk factors such as hy-
pertension, smoking, and diabetes, as well as other ex-
ercise-test variables, including ST-segment depression,
the peak heart rate, or the development of arrhythmias
during exercise. Our data also confirm the protective
role of a higher exercise capacity even in the presence
of other risk factors.
7-9,24, 25
In all subgroups defined
according to risk factors, the risk of death from any
cause in subjects whose exercise capacity was less than
5 MET was roughly double that of subjects whose ex-
ercise capacity was more than 8 MET (Fig. 1).
Poor physical fitness is a modifiable risk factor, and
improvements in fitness over time have been demon-
strated to improve prognosis.
2,9
Our observation that
every 1-MET increase in treadmill performance was
associated with a 12 percent improvement in survival
underscores the relatively strong prognostic value of
exercise capacity. In addition, it confirms the presence
of a graded, inverse relation between exercise capacity
and mortality from any cause.
7-11
Recent long-term
findings from the National Exercise and Heart Disease
Project
26
among patients who had had a myocardial
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.
0.0
2.5
History of
Hypertension
COPD Diabetes
(1.2–1.6)
(1.7–2.3)
Smoking BMI »30 Total Cholesterol
>220 mg/dl
0.5
1.0
1.5
2.0
Risk Factors
Relative Risk of Death
>8 MET (n=2743)
5–8 MET (n=1885)
<5 MET (n=1585)
(0.8–2.1)
(1.0–2.7)
(0.9–1.9)
(1.5–3.5)
(1.1–1.6)
(1.6–2.3)
(1.2–2.0)
(1.8–3.0)
(1.2–1.8)
(1.6–2.3)
798 · N Engl J Med, Vol. 346, No. 11 · March 14, 2002 · www.nejm.org
The New England Journal of Medicine
infarction demonstrated that every 1-MET increase in
exercise capacity after a training period was associat-
ed with a reduction in mortality from any cause that
ranged from 8 percent to 14 percent over the course
of 19 years of follow-up. In a study involving serial
evaluations in nearly 10,000 men, Blair et al.
9
observed
a 7.9 percent reduction in mortality for every one-min-
ute increase in treadmill time (roughly equivalent to
the 1-MET change in our study).
In combination, these findings demonstrate that
both a relatively high degree of fitness at base line and
an improvement in fitness over time yield marked re-
ductions in risk. The relative weight of exercise capac-
ity in the model for assessing risk in both normal
subjects and those with cardiovascular or pulmonary
disease in our study, along with the fact that an im-
provement in exercise capacity lowers the risk of
death,
9,26
suggests that health professionals should
incorporate into their practices strategies for promot-
ing physical activity, in addition to the routine treat-
ment of hypertension and diabetes, the encourage-
ment of smoking cessation, and the like.
Our findings in normal subjects are similar to those
of other studies
8,27,28
in that we observed the most
striking difference in mortality rates between the least-
fit quintile and the next-least-fit quintile. This obser-
vation concurs with the consensus (reflected in the
recommendations of the Centers for Disease Control
and Prevention and the American College of Sports
Medicine
2
and the report of the Surgeon General on
physical activity and health
29
) that the greatest health
benefits are achieved by increasing physical activity
among the least fit. Among subjects with cardiovascu-
lar disease, however, we observed a nearly linear reduc-
tion in risk with increasing quintiles of fitness. Since
most studies assessing the relation between fitness and
mortality have excluded subjects with cardiovascular
disease,
30
these findings require confirmation.
Few studies have similarly assessed the prognostic
value of exercise tolerance among patients specifically
referred for exercise testing for clinical reasons. Roger
et al.
31
retrospectively assessed 2913 men and women
from Olmsted County, Minnesota, and reported that
among exercise-test variables, exercise capacity had the
strongest association with overall mortality and cardi-
ac events among subjects of both sexes. More recently,
this group addressed the association between clinical
and exercise-test variables among young and elderly
subjects in Olmsted County and observed that the
peak workload achieved was the only treadmill-test
Figure 2. Age-Adjusted Relative Risks of Death from Any Cause According to Quintile of Exercise Capacity among Nor-
mal 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.
0.0
5.0
1234
5
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
Quintiles of Exercise Capacity
Relative Risk of Death
(3.0–6.8)1.0–5.9 MET
(3.3–5.2)1.0–4.9 MET
(1.5–3.8)6.0–7.9 MET
(2.4–3.7)5.0–6.4 MET
(1.1–2.8)8.0–9.9 MET
(1.7–2.8)6.5–8.2 MET
(0.7–2.2)10.0–12.9 MET
(1.4–2.2)8.3–10.6 MET
»13.0 MET
»10.7 MET
Normal subjects
Subjects with cardiovascular disease
EXERCISE CAPACITY AND MORTALITY
N Engl J Med, Vol. 346, No. 11 · March 14, 2002 · www.nejm.org · 799
Figure 3. Survival Curves for Normal Subjects Stratified According to Peak Exercise Capacity (Panel A) and According to the Per-
centage of Age-Predicted Exercise Capacity Achieved (Panel B) and Survival Curves for Subjects with Cardiovascular Disease Strat-
ified 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 dif-
ferent mortality rates that is, the survival rate was lower as exercise capacity decreased (P<0.001).
0
100
B
Normal Subjects
0 3.5 7.0 10.5 14.0
75
50
25
Years of Follow-up
>100%
75–100%
50–74%
<50%
Percentage Surviving
0
100
A
Normal Subjects
0 3.5 7.0 10.5 14.0
75
50
25
>8 MET
5–8 MET
<5 MET
Percentage Surviving
0
100
D
Subjects with Cardiovascular Disease
0 3.5 7.0 10.5 14.0
75
50
25
Years of Follow-up
>100%
75–100%
50–74%
<50%
Percentage Surviving
0
100
C
Subjects with Cardiovascular Disease
0 3.5 7.0 10.5 14.0
75
50
25
>8 MET
5–8 MET
<5 MET
Percentage Surviving
variable that was significantly associated with mortal-
ity from any cause.
32
These investigators also observed
that each 1-MET increment in the peak treadmill
workload was associated with a 14 percent reduction
in cardiac events among younger subjects (those less
than 65 years old) and an 18 percent reduction among
elderly subjects.
In recent years, questions have been raised about
which variable has superior prognostic power: exercise
capacity relative to age- and sex-predicted standards
or absolute exercise capacity.
33-35
We found that exer-
cise capacity expressed as a percentage of the age-pre-
dicted value was not superior to the absolute peak ex-
ercise capacity in terms of predicting survival. Other
studies in this area have focused only on patients with
congestive heart failure and have had conflicting find-
ings.
33-35
We were also interested in whether our results
800 · N Engl J Med, Vol. 346, No. 11 · March 14, 2002 · www.nejm.org
The New England Journal of Medicine
would be affected by beta-blockade, given that such
treatment favorably influences survival and is known
to either improve or inhibit exercise tolerance, depend-
ing on the presence or absence of symptoms during
exercise, among other factors. Previous data in this
area, although sparse, have demonstrated that beta-
blockade does not interfere with the prognostic power
of a finding of a low exercise capacity.
36,37
Approxi-
mately 19 percent of the subjects in our study under-
went exercise testing while receiving beta-blocker ther-
apy, and the overall survival rate was slightly lower
among those taking beta-blockers (18.4 percent vs.
21.0 percent among those not taking such drugs,
P=0.03). Subjects achieving an exercise capacity of
5 MET or more had a higher survival rate than those
achieving an exercise capacity of less than 5 MET, and
this remained true when subjects were stratified ac-
cording to the use or nonuse of a beta-blocker. Sim-
ilarly, beta-blockade had no effect on survival within
groups of subjects stratified according to exercise ca-
pacity within the clinically relevant range (2 to 10
MET). This issue has rarely been addressed in previ-
ous studies, although presumably a substantial propor-
tion of subjects were taking beta-blockers in the Cor-
onary Artery Surgery Study,
38
the Olmsted County
Study,
31,32
the Kuopio Ischemic Heart Disease Risk
Factor Study,
10
and other follow-up studies that quan-
tified exercise tolerance and survival.
Our findings are applicable only to men, which is
noteworthy, given that exercise-test results have been
shown to differ significantly between men and wom-
en.
39
In addition, we had information only on death
from any cause; we did not know the specific causes
of death, nor were we able to censor data at the time
of cardiovascular interventions. Finally, our exercise-
capacity data were estimated on the basis of the speed
and grade of the treadmill. Although this type of es-
timate is the most common clinical measure of exercise
tolerance, directly measured exercise capacity (peak ox-
ygen consumption) is known to be a more accurate
and reproducible measure of exercise tolerance,
40
as
well as a more robust predictor of outcomes.
34,35
The present results confirm the prognostic useful-
ness of exercise capacity in men. The prognostic power
of exercise capacity is similar among apparently healthy
persons and patients with cardiovascular conditions
who are referred for exercise testing and similar among
subjects who are taking beta-blockers and those who
are not taking beta-blockers. Expressing exercise ca-
pacity as a percentage of the age-predicted value does
not improve its prognostic power. Our findings dem-
onstrate an association between exercise capacity and
overall mortality, not necessarily a causal relation. Nev-
ertheless, given the high prognostic value of exercise
capacity relative to other markers of risk in this and
other recent studies, clinicians who are reviewing ex-
ercise-test results should encourage patients to improve
their exercise capacity. In terms of reducing mortality
from any cause, improving exercise tolerance warrants
at least as much attention as other major risk factors
from physicians who treat patients with or at high
risk for cardiovascular disease.
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... Studies have highlighted a relationship between ADHD and obesity, which increases cardiovascular risk, both in children/adolescents and adults (Cortese et al., 2016). However, associations of ADHD with well-established cardiovascular risk indicators such as both high systolic blood pressure (SBP) and diastolic blood pressure (DBP), low SBP, elevated resting heart rate (RHR), low physical fitness, and high pulse pressure (PP) (Myers et al., 2002;Tverdal et al., 2008;Yi et al., 2016), remain unclear with contradictory results across studies (Meyer et al., 2017). ...
... However, evidence shows that individuals with ADHD are more likely to live a sedentary lifestyle and engage in other unhealthy behavior such as smoking or disordered eating (Quesada et al., 2018). These findings are clinically important as previous studies found that fitness capacity and obesity are predictors of mortality and impaired cardiac function (Myers et al., 2002). Importantly, we showed that the positive relationship between obesity and low physical fitness with ADHD was present before ADHD medication was introduced, indicating that ADHD medication does not explain the observed associations of ADHD with BMI and physical fitness. ...
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Objective (1) investigate the associations of attention-deficit/hyperactivity disorder (ADHD) with systolic and diastolic blood pressure, resting heart rate, pulse pressure (PP), physical fitness, and BMI; (2) explore whether cardiovascular risk factors and ADHD share genetic and environmental influences; (3) assess if pharmacological treatment for ADHD influences these associations. Methods We identified 395,978 individuals born between 1973 and 1991 who had military conscription examinations at a mean age of 18.3 years (SD = 0.57) and their full-siblings within the same cohort (N = 208,060) by linking population-based registers in Sweden. Results Significantly increased risk of ADHD was observed in individuals with low systolic blood pressure (SBP) and PP, low physical fitness, and in those who had overweight or obesity after adjustments (adjusted Odds Ratio [OR] ranging from 1.10 to 1.45). Full siblings of individuals with low SBP, low physical fitness, and obesity were more likely to receive an ADHD diagnosis compared to full siblings without those risk factors (OR ranging from 1.17 to 1.31). Additionally, analyses showed robust associations between ADHD and low SBP, low physical fitness, and obesity, even in ADHD medication-naïve individuals. Conclusions Individuals with several cardiovascular risk factors are more often diagnosed with ADHD, regardless of psychiatric comorbidity. These association are not explained by ADHD pharmacotherapy, rather, they are in part due to shared familial risk factors.
... A clinically significant improvement in exercise capacity has been suggested at one MET (with each MET reducing mortality by 12%) [51]. The results from Fig. 3 show that in 11 of the 20 included study populations in the meta-analysis, improvements in exercise capacity reached or exceeded one MET at the end of the study in ACS patients with diabetes. ...
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Aim The benefits of cardiac rehabilitation (CR) after acute coronary syndrome (ACS) are well established. However, the relative benefit of CR in those with comorbidities, including diabetes, is not well understood. This systematic review and meta-analysis examined the benefit of CR on exercise capacity and secondary outcomes in ACS patients with a co-diagnosis of diabetes compared to those without. Methods Five databases were searched in May 2021 for randomised controlled trials (RCTs) and observational studies reporting CR outcomes in ACS patients with and without diabetes. The primary outcome of this study was exercise capacity expressed as metabolic equivalents (METs) at the end of CR and ≥ 12-month follow-up. Secondary outcomes included health-related quality of life, cardiovascular- and diabetes-related outcomes, lifestyle-related outcomes, psychological wellbeing, and return to work. If relevant/possible, studies were pooled using random-effects meta-analysis. Results A total of 28 studies were included, of which 20 reported exercise capacity and 18 reported secondary outcomes. Overall, the studies were judged to have a high risk of bias. Meta-analysis of exercise capacity was undertaken based on 18 studies (no RCTs) including 15,288 patients, of whom 3369 had diabetes. This analysis showed a statistically significant smaller difference in the change in METs in ACS patients with diabetes (standardised mean difference (SMD) from baseline to end of CR: − 0.15 (95% CI: − 0.24 to − 0.06); SMD at the ≥ 12-month follow-up: − 0.16 (95% CI: − 0.23 to − 0.10, four studies)). Conclusion The benefit of CR on exercise capacity in ACS patients was lower in those with diabetes than in those without diabetes. Given the small magnitude of this difference and the substantial heterogeneity in the results of the study caused by diverse study designs and methodologies, further research is needed to confirm our findings. Future work should seek to eliminate bias in observational studies and evaluate CR based on comprehensive outcomes.
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... Cardiopulmonary testing performed 6 months after the start of the CR program showed a significant increase in VO 2 peak in patients of both groups (15.96 ± 6.07 mL/kg/min vs. 12.88 ± 4.52 mL/kg/min, p = 0.005). VO 2 peak is a marker for aerobic exercise capacity and an independent predictor factor for all-cause mortality and cardiac mortality in PAD [38,39]. The physical performance of patients in the high-intermediate and high risk group was inferior, a fact explained by the higher degree of disability associated with multiple comorbidities, older age, and previous physical deconditioning. ...
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The management of patients with peripheral artery disease (PAD) is integrative and multidisciplinary, in which cardiac rehabilitation (CR) plays a prognostic role in terms of functional status, quality of life, and long-term impact on morbidity and mortality. We conducted a prospective cohort study on 97 patients with PAD admitted to a single tertiary referral center. Based on a prognostic index developed to stratify long-term mortality risk in PAD patients, we divided the cohort into two groups: low and low-intermediate risk group (45 cases) and high-intermediate and high risk group (52 cases). We analyzed demographics, clinical parameters, and paraclinical parameters in the two groups, as well as factors associated with cardiological reassessment prior to the established deadline of 6 months. Obesity (p = 0.048), renal dysfunction (p < 0.001), dyslipidemia (p < 0.001), tobacco use (p = 0.048), and diabetes mellitus (p < 0.001) are comorbidities with long-term prognostic value. Low-density lipoprotein cholesterol (p = 0.002), triglycerides (p = 0.032), fasting glucose (p = 0.011), peak oxygen uptake (p = 0.005), pain-free walking distance (p = 0.011), maximum walking time (p < 0.001), and maximum walking distance (p = 0.002) influence the outcome of PAD patients by being factors associated with clinical improvement at the 6-month follow-up. PAD patients benefit from enrollment in CR programs, improvement of clinical signs, lipid and carbohydrate profile, and weight loss and maintenance of blood pressure profile within normal limits, as well as increased exercise capacity being therapeutic targets.
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(1) Background: Several studies have shown that active breaks have led to different improvements in their participants. However, no studies have assessed how they affect physical literacy (PL). (2) Aims: Therefore, this study will examine the effect of the PLBreaks programme on school children’s PL and body composition. (3) Methods: A parallel-group randomised controlled trial will be conducted with assessments of PL (Canadian Assessment of Physical Literacy Development) and body composition (height, bodyweight, fat mass and fat-free mass) before and after an active breaks programme. PLBreak programme will run for 3 months and will be carried out 3 days a week for 20 min each day. The PLBreaks programme will consist of two blocks of 10 min of different physical activities (PA). The first block will be focused on the acquisition of knowledge and healthy life habits that will contribute to the development of the domains of knowledge and understanding and daily activity. The second block will be focused on physical competence and motivation throughout games. (4) Conclusions: The present study will investigate the efficacy of PLBreaks in schoolchildren in improving their PL and body composition. If the efficacy of the program is demonstrated, including the programme in public education programmes can be possible. This could be a scientific breakthrough in terms of health-related PA improvement and adherence, as well as the prevention of diseases associated with inactivity.
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Background and hypothesis: The rehabilitation effect of circuit resistance training in coronary heart disease (CHD) patients remains unclear. We perform this review to examine the rehabilitation effect of circuit resistance training in CHD patients and to provide a basis for the formulation of reasonable individual exercise prescriptions for CHD patients. Methods: Randomized controlled trials (RCTs) were searched on PubMed, Web of Science, The Cochrane Library, Embase, Clinical Trials, and CNKI. About 1232 studies were identified. Nine RCTs were finally used for the present meta-analysis to determine the rehabilitation effect of circuit resistance training in CHD patients, compared to aerobic training. Individuals enrolled for the studies were at a mean age of 60.5 years old and were all CHD patients. Following the PRISMA guidelines, we extracted basic information about the study and patient characteristics, as well as measurements (e.g., the peak oxygen uptake, the body mass index [BMI], the body fat percentage, the systolic blood pressure, the total cholesterol, and triglycerides). Subsequently, this meta-analysis determined the overall effect by using standardized mean difference (SMD) and 95% confidence interval (CI). Results: Compared with aerobic training, circuit resistance training significantly decrease the BMI and the body fat percentage. Conclusions: As suggested from the present meta-analysis of RCTs, circuit resistance training is effective in improving the BMI and the body fat percentage in CHD patients and may help delay the progression of CHD. CRT has the advantage of lower load in most cases with a similar effect.
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Objectives Balance quickly diminishes after the mid-50s increasing the risk for falls and other adverse health outcomes. Our aim was to assess whether the ability to complete a 10- s one-legged stance (10-second OLS) is associated with all-cause mortality and whether it adds relevant prognostic information beyond ordinary demographic, anthropometric and clinical data. Methods Anthropometric, clinical and vital status and 10-s OLS data were assessed in 1702 individuals (68% men) aged 51–75 years between 2008 and 2020. Log-rank and Cox modelling were used to compare survival curves and risk of death according to ability (YES) or inability (NO) to complete the 10-s OLS test. Results Overall, 20.4% of the individuals were classified as NO. During a median follow-up of 7 years, 7.2% died, with 4.6% (YES) and 17.5% (NO) on the 10-s OLS. Survival curves were worse for NO 10-s OLS (log-rank test=85.6; p<0.001). In an adjusted model incorporating age, sex, body mass index and comorbidities, the HR of all-cause mortality was higher (1.84 (95% CI: 1.23 to 2.78) (p < 0.001)) for NO individuals. Adding 10-s OLS to a model containing established risk factors was associated with significantly improved mortality risk prediction as measured by differences in −2 log likelihood and integrated discrimination improvement. Conclusions Within the limitations of uncontrolled variables such as recent history of falls and physical activity, the ability to successfully complete the 10-s OLS is independently associated with all-cause mortality and adds relevant prognostic information beyond age, sex and several other anthropometric and clinical variables. There is potential benefit to including the 10-s OLS as part of routine physical examination in middle-aged and older adults.
Background: Sedentary behaviour (SB) and physical inactivity (PI) are associated with an increased risk of chronic diseases and a significant economic burden. This pilot study aims to estimate the possible cost savings for the Veneto Regional Health Service (Italy) due to a population-based physical activity (PA) intervention. Methods: The PA-related cost-savings were assessed for four chronic diseases in the whole and sedentary populations of the Veneto region. The SB and PA epidemiological data, regarding an additional percutaneous coronary intervention in coronary artery disease, hospitalizations in chronic obstructive pulmonary disease, surgery for colorectal cancer, and femur fracture, were obtained from national and regional administrative sources. A relative risk reduction, due to PA, was obtained from the recent literature. The annual healthcare costs were estimated using the regional diagnosis-related group tariffs. Results: The annual estimated cost-savings for the regional healthcare service related to these four outcomes: an amount between EUR 5,310,179 (if a conservative analysis was performed) and EUR 17,411,317. Conclusion: By a downward estimate, regarding the direct healthcare costs, PA interventions could lead to important cost-savings in the Veneto region. The savings would be greater when considering the cross-sectional impact on other healthcare costs, comorbidities, and indirect costs.
Article
Purpose: This systematic review aimed to identify the characteristics and determine the effects of exercise interventions on improving health-related physical fitness in adults with asthma. Review methods: A systematic search was completed in MEDLINE, CINAHL, Embase, and SPORTDiscus for peer-reviewed publications of experimental studies that investigated the effects of an exercise training intervention on performance-based health-related physical fitness outcomes in adults with asthma. Two reviewers independently screened studies for inclusion according to predetermined criteria and performed data extraction and quality assessment of included studies. Summary: Forty-five articles were included, in which results for 39 unique studies were reported. Subjects (n = 2135) were aged 22 ± 4 to 71 ± 11 yr with mild-severe asthma. Most exercise programs used aerobic exercise, either alone or in combination with resistance or breathing/stretching exercises. The most common exercise program characteristics were supervised moderate-to-vigorous intensity aerobic exercise performed for 30-45 min 3 d/wk. Meta-analyses revealed significant improvements in cardiorespiratory fitness (V˙o2peak: unstandardized mean difference [MD] 3.1 mL/kg/min, 95% CI, 1.9-4.3), functional fitness (walking distance: MD 41 m, 95% CI, 27-54), and overall health-related physical fitness (standardized mean difference [SMD] 0.67, 95% CI, 0.46-0.89) in favor of groups who underwent experimental exercise training interventions. Aerobic exercise elicited superior improvements in health-related physical fitness compared with breathing/stretching exercise (SMD 0.47, 95% CI, 0.14-0.81).Supervised exercise training programs, particularly those aerobic in nature, are effective in eliciting clinically meaningful improvements in cardiorespiratory and functional fitness in adults with asthma.PROSPERO registration ID number = CRD42018092828.
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Health care now emphasizes cost efficiency and places the standard exercise test as a gatekeeper to more expensive modalities. Clinical Strategies directing patients with possible or established CAD to appropriate levels of evaluation and treatment need to be applied. The application of scores front clinical and exercise test variables have been demonstrated to improve the exercise test. Computers hosting expert systems enable these scores to be easily applied. In this article, we describe an evidence-based expert system called EXTRA that serves as a database and report generator for exercise testing. EXTRA utilizes rules and provides definitions for all data fields assuring that the test is applied and interpreted properly. It is an interpretive program for exercise testing comparable to the available programs for the resting ECG designed as an aide to the practicing physician. The immediate generation of typed reports avoids the need for dictation or illegible hand written notes.
Article
Objective: To encourage increased participation in physical activity among Americans of all ages by issuing a public health recommendation on the types and amounts of physical activity needed for health promotion and disease prevention. Participants: A planning committee of five scientists was established by the Centers for Disease Control and Prevention and the American College of Sports Medicine to organize a workshop. This committee selected 15 other workshop discussants on the basis of their research expertise in issues related to the health implications of physical activity. Several relevant professional or scientific organizations and federal agencies also were represented. Evidence: The panel of experts reviewed the pertinent physiological, epidemiologic, and clinical evidence, including primary research articles and recent review articles. Consensus process: Major issues related to physical activity and health were outlined, and selected members of the expert panel drafted sections of the paper from this outline. A draft manuscript was prepared by the planning committee and circulated to the full panel in advance of the 2-day workshop. During the workshop, each section of the manuscript was reviewed by the expert panel. Primary attention was given to achieving group consensus concerning the recommended types and amounts of physical activity. A concise "public health message" was developed to express the recommendations of the panel. During the ensuing months, the consensus statement was further reviewed and revised and was formally endorsed by both the Centers for Disease Control and Prevention and the American College of Sports Medicine. Conclusion: Every US adult should accumulate 30 minutes or more of moderate-intensity physical activity on most, preferably all, days of the week.