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716

N Engl J Med, Vol. 347, No. 10

September 5, 2002

www.nejm.org

T h e N e w E n g l a n d Jo u r n a l o f Me d i c i n e

WALKING COMPARED WITH VIGOROUS EXERCISE FOR THE PREVENTION OF CARDIOVASCULAR EVENTS IN WOMEN

E. M

ANSON

, M.D., D

.P.H., P

HILIP

REENLAND

, M.D., A

NDREA

Z. L

ROIX

, P

.D., M

ARCIA

L. S

TEFANICK

, P

.D., C

HARLES

P. M

OUTON

, M.D., A

LBERT

BERMAN

, M.D., M.P.H., M

ICHAEL

G. P

ERRI

, P

.D., D

AVID

S. S

HEPS

, M.D., M

ARY

B. P

ETTINGER

, M.S.,

AND

AVID

S. S

ISCOVICK

, M.D., M.P.H.

BSTRACT

Background

The role of walking, as compared with vigorous exercise, in the prevention of cardiovascular disease remains controversial. Data for women who are members of minority racial or ethnic groups are particularly sparse.

Methods

We prospectively examined the total physical-activity score, walking, vigorous exercise, and hours spent sitting as predictors of the incidence of coronary events and total cardiovascular events among 73,743 postmenopausal women 50 to 79 years of age in the Women’s Health Initiative Observational Study. At base line, participants were free of diagnosed cardiovascular disease and cancer, and all participants completed detailed questionnaires about physical ac- tivity. We documented 345 newly diagnosed cases of coronary heart disease and 1551 total cardiovascular events.

Results

An increasing physical-activity score had a strong, graded, inverse association with the risk of both coronary events and total cardiovascular events. There were similar findings among white women and black women. Women in increasing quintiles of ener- gy expenditure measured in metabolic equivalents (the MET score) had age-adjusted relative risks of cor- onary events of 1.00, 0.73, 0.69, 0.68, and 0.47, respec- tively (P for trend, <0.001). In multivariate analyses, the inverse gradient between the total MET score and the risk of cardiovascular events remained strong (ad- justed relative risks for increasing quintiles, 1.00, 0.89, 0.81, 0.78, and 0.72, respectively; P for trend <0.001). Walking and vigorous exercise were associated with similar risk reductions, and the results did not vary substantially according to race, age, or body-mass in- dex. A brisker walking pace and fewer hours spent sitting daily also predicted lower risk.

Conclusions

These prospective data indicate that both walking and vigorous exercise are associated with substantial reductions in the incidence of cardio- vascular events among postmenopausal women, irre- spective of race or ethnic group, age, and body-mass index. Prolonged sitting predicts increased cardio- vascular risk. (N Engl J Med 2002;347:716-25.)

From the Division of Preventive Medicine, Harvard Medical School and Brigham and Women’s Hospital, Boston (J.E.M.); the Department of Pre- ventive Medicine, Northwestern University Medical School, Chicago (P.G.); the Fred Hutchinson Cancer Research Center (A.Z.L., M.B.P.) and the De- partments of Medicine and Epidemiology (D.S.S.), University of Washing- ton, Seattle; Stanford Center for Research in Disease Prevention, Stanford, Calif. (M.L.S.); the University of Texas Health Science Center, San Antonio (C.P.M.); the Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham (A.O.); and the Department of Clinical and Health Psychology (M.G.P.) and Division of Cardiology (D.S.S.), Univer- sity of Florida, Gainesville. Address reprint requests to Dr. Manson at the Division of Preventive Medicine, Brigham and Women’s Hospital, 900 Com- monwealth Ave., Boston, MA 02215, or at [email protected].

HYSICAL activity has been associated with a reduced risk of cardiovascular disease in ep- idemiologic studies,

1,2

but data for women and members of minority ethnic groups have

been sparse. Moreover, the specific role of walking, the most common form of exercise among women,

has been addressed only minimally. Federal guidelines from the Centers for Disease Control and Prevention and the American College of Sports Medicine,

as well as the Surgeon General’s Report on Physical Activity and Health,

endorse at least 30 minutes of moderate- intensity physical activity on most, and preferably all, days of the week, in contrast to earlier guidelines that recommended vigorous endurance exercise for at least 20 minutes three or more times per week.

Although the federal guidelines encourage a level of activity that is safe, accessible, and feasible for most Americans

(at least 75 percent of whom have less than the recom- mended level of activity

), the potential benefits of moderate-intensity activity in preventing cardiovascu- lar events remain uncertain. Moreover, the role of time spent in sedentary behavior, such as sitting, in predict- ing risk remains relatively unexplored.

We therefore compared the roles of walking and vigorous exercise in the prevention of coronary and cardiovascular events in a large, ethnically diverse co- hort of postmenopausal women. Using detailed assess- ments of physical activity, we examined the magnitude of associations between each of the measures of phys- ical activity (the total physical-activity score, the inten- sity of exercise [walking vs. vigorous exercise], and the hours spent sitting) and the incidence of cardiovascular events.

METHODS

Study Population

The study population consisted of 73,743 women who were en- rolled in the Women’s Health Initiative Observational Study, which

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involved a national, multicenter cohort of postmenopausal women who were 50 to 79 years of age at entry. The Women’s Health Ini- tiative is a prospective, ethnically and racially diverse, multicenter clinical trial and observational study designed to address the major causes of illness and death in postmenopausal women (see the Ap- pendix for a list of study investigators). A total of 93,676 women were enrolled in the observational study at 40 clinical centers be- tween 1994 and 1998. Criteria for exclusion from the study includ- ed the presence of any medical condition associated with predicted survival of less than three years (e.g., class IV congestive heart fail- ure, obstructive lung disease requiring supplemental oxygen, or se- vere chronic liver or kidney disease), alcoholism, mental illness, or dementia. In addition, women were excluded from the present analyses if, at base line, they had a history of coronary heart disease, stroke, or cancer; were nonambulatory (unable to walk at least one block); or had missing data on the physical-activity questionnaire. After women had been excluded for these reasons, 73,743 women remained in the analysis. Of these women, 61,574 were non-His- panic white, 5661 were non-Hispanic black, 2880 were Hispanic, 2288 were Asian or Pacific Islander, and 1340 were American In- dian or of other racial or ethnic background. Race was self-assigned. Details of the scientific rationale, design, eligibility requirements, and base-line characteristics of the cohort have been published elsewhere.

Exposure Assessment

All women enrolled in the Observational Study were required to come for a clinic visit for base-line screening. At this visit, women completed self-administered questionnaires related to personal and family medical history, physical activity, smoking, diet, and other behavioral and lifestyle-related factors. Clinical measurements in- cluding height, weight, waist and hip circumferences, and blood pressure were obtained by trained staff members. All women pro- vided written informed consent, and the study protocol was ap- proved by the institutional review board of each center.

Recreational physical activity was assessed by a detailed question- naire on the frequency and duration of walking and of several other types of activity (strenuous, moderate, and mild). Walking was as- sessed by a series of questions about the frequency of walks out- side the home for more than 10 minutes without stopping, the av- erage duration of each walk, and the usual walking pace. Vigorous exercise was defined as that in which “you work up a sweat and your heart beats fast,” and examples included aerobics, aerobic dancing, jogging, tennis, and swimming laps. Moderate exercise was defined as that which was “not exhausting,” and examples included biking outdoors, using an exercise machine (such as a stationary bicycle or a treadmill), calisthenics, easy swimming, and popular or folk danc- ing. Examples of mild exercise were slow dancing, bowling, and golf. Using a standardized classification of the energy expenditure associated with physical activities,

we calculated a weekly energy- expenditure score in metabolic equivalents (MET score) for walking and for total physical activity. Finally, participants were asked to estimate the number of hours per day they spent engaged in seden- tary behavior, including time spent sitting as well as lying down or sleeping.

Reproducibility and Validation of the Physical-Activity Assessment

A sample of participants in the Observational Study (1092 wom- en) was recruited into a reliability study to assess the reproducibility of selected questionnaires, including the physical-activity assessment. The average time between base line and repeated assessments was three months. The test–retest reliability for recreational physical activity, including walking and strenuous activity, was assessed (weighted kappas among all women ranged from 0.67 to 0.71).

The intraclass correlation coefficient for the primary summary var- iable (total energy expenditure in MET from all recreational phys-

ical activity) was 0.77. A similar physical-activity questionnaire has been found to be correlated with physical-activity diaries (r=0.62) and with one-week recall of activity (r=0.79) in a cohort of female health professionals.

Ascertainment of End Points

The primary end points for this study were newly diagnosed cor- onary heart disease (nonfatal myocardial infarction or death from coronary causes) and total cardiovascular events (myocardial infarc- tion, death from coronary causes, coronary revascularization, angi- na, congestive heart failure, stroke, or carotid revascularization) that occurred after the return of the base-line questionnaire but before August 27, 2000. Newly diagnosed cardiovascular events were iden- tified on the basis of annual mailed follow-up questionnaires (re- sponse rates have been above 95 percent), and permission to review medical records was requested. Study physicians with no knowledge of the self-reported risk-factor status reviewed the records. The di- agnosis of nonfatal myocardial infarction was confirmed if data in the hospital record met standardized criteria of diagnostic electro- cardiographic changes, elevated cardiac-enzyme levels, or both.

Treatment with coronary or carotid revascularization was confirmed by documentation of the procedure in the medical record. The pres- ence of angina was confirmed by hospitalization and confirmatory evidence on angiography, diagnostic stress test, or diagnosis by a physician and medical treatment. The occurrence of stroke was con- firmed by documentation in the medical record of the rapid onset of a neurologic deficit consistent with stroke and lasting at least 24 hours or until death. The presence of congestive heart failure was confirmed by hospitalization and diagnostic confirmatory tests.

Fatal coronary disease was considered confirmed if there was doc- umentation in the hospital or autopsy records or if coronary disease was listed as the cause of death on the death certificate and evidence of previous coronary disease was available. For deaths from other cardiovascular causes, a review of confirmatory evidence by physi- cian-adjudicators was required.

Statistical Analysis

Our primary analyses used the detailed physical-activity assess- ment at base line. Person-time for each woman was calculated from the date of return of the base-line questionnaire to the date of a con- firmed cardiovascular event, death from any cause, or August 27, 2000, whichever came first. Age-adjusted relative risks were com- puted as the incidence rate in a specific category of activity divid- ed by the incidence rate in the lowest quintile, with adjustment for one-year age categories. We conducted tests of linear trend by treating the categories as a continuous variable and assigning the median score for each category.

All tests of statistical significance were two-sided.

We used Cox proportional-hazards regression

to adjust simul- taneously for potential confounding variables, including age, smok- ing status, body-mass index (the weight in kilograms divided by the square of the height in meters), the ratio of the waist circumfer- ence to the hip circumference, alcohol consumption, age at meno- pause, use of hormone-replacement therapy, parental history of pre- mature myocardial infarction (before 55 years of age in the father or before 65 years of age in the mother), race or ethnic group, ed- ucation, family income, and several dietary variables. Additional models controlled for history or absence of history of hypertension, diabetes, and high cholesterol levels, as well as for functional status and a summary score for mental and emotional health.

The total MET score, the MET score for walking, time spent in vigorous ex- ercise, walking pace, and hours spent sitting and lying down or sleeping were analyzed separately. Differences in the results for ac- tivity according to race (white women vs. black women), age, and body-mass index were assessed. Secondary analyses excluded data for the first year of follow-up in order to minimize potential bias caused by the presence of subclinical disease.

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N Engl J Med, Vol. 347, No. 10

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T h e N e w E n g l a n d Jo u r n a l o f Me d i c i n e

RESULTS

During up to 5.9 years of follow-up (mean, 3.2 years; total, 232,971 person-years), we documented 345 newly diagnosed cases of coronary disease (287 nonfatal myocardial infarctions and 58 deaths from coronary causes), 309 strokes, and 1551 first cardio- vascular events among the 73,743 women 50 to 79 years of age who completed a detailed physical-activ- ity questionnaire, were ambulatory, and were free of cardiovascular disease and cancer at base line. The base-line characteristics of the cohort and the distri-

bution of physical-activity profiles and other risk fac- tors have been described elsewhere.

The total physical-activity score (in MET-hours per week) at base line had a strong inverse relation with the risk of coronary heart disease during the follow-up period (Table 1). In age-adjusted analyses, the rela- tive risk declined with increasing quintiles of the to- tal MET score (1.00, 0.73, 0.69, 0.68, and 0.47, re- spectively; P for trend <0.001). Risk reductions for increasing categories of walking (P for trend=0.004) were similar to those for increasing categories of vig-

*Coronary heart disease includes nonfatal myocardial infarction and fatal coronary disease. Multivariate models included age (as a continuous variable), smoking status (0, 1 to 14, 15 to 24, or »25 cigarettes per day), race or ethnic group (non-Hispanic white, non-Hispanic black, Hispanic, Asian, or other), level of education (5 categories), family income (7 categories), body-mass index (<25.0, 25.0 to 29.9, or »30.0), waist-to-hip ratio (as a continuous variable), level of alcohol intake (0, 1 to 4, 5 to 14, or »15 g per day), parental history of premature myocardial infarction, age at menopause, use or nonuse of hormone- replacement therapy, percentage of calories from saturated fat, number of servings of fruit and vegetables per day, and dietary fiber intake (g per day). MET denotes metabolic equivalent, and CI confidence interval.

ABLE

ELATIVE

ISKS

ARDIOVASCULAR

ISEASE

CCORDING

UINTILE

OTAL

HYSICAL

-A

CTIVITY

CORE

AND

ATEGORIES

ALKING

AND

IGOROUS

XERCISE

ATEGORY

UINTILE

OTAL

MET-H

PER

P V

ALUE

FOR

REND

1 (

LOWEST

) 2 3 4 5

(

HIGHEST

)

Total exercise

Total MET score (MET-hr/wk) Median Range

0 0–2.4

4.2 2.5–7.2

10.0 7.3–13.4

17.5 13.5–23.3

32.8 »23.4

Coronary heart disease No. of cases 92 70 68 70 45 No. of person-years 44,989 45,329 46,003 49,338 47,312 Age-adjusted relative risk (95% CI) 1.00 0.73 (0.53–0.99) 0.69 (0.51–0.95) 0.68 (0.50–0.93) 0.47 (0.33–0.67) <0.001

Total cardiovascular disease No. of cases 396 342 304 281 228 No. of person-years 44,448 44,836 45,550 48,948 46,972 Age-adjusted relative risk (95% CI) 1.00 0.83 (0.71–0.95) 0.72 (0.62–0.84) 0.63 (0.54–0.74) 0.55 (0.47–0.65) <0.001 Multivariate relative risk (95% CI) 1.00 0.89 (0.75–1.04) 0.81 (0.68–0.97) 0.78 (0.66–0.93) 0.72 (0.59–0.87) <0.001

Walking

Energy expenditure (MET-hr/wk) Median Range

0 None

1.5 0.1–2.5

3.8 2.6–5.0

7.5 5.1–10.0

16.7 >10.0

Coronary heart disease No. of cases 133 64 52 47 49 Age-adjusted relative risk (95% CI) 1.00 0.71 (0.53–0.96) 0.60 (0.44–0.83) 0.54 (0.39–0.76) 0.61 (0.44–0.84) 0.004

Total cardiovascular disease No. of cases 550 322 249 236 194 Age-adjusted relative risk (95% CI) 1.00 0.88 (0.77–1.01) 0.70 (0.60–0.81) 0.66 (0.57–0.77) 0.58 (0.49–0.68) <0.001 Multivariate relative risk (95% CI) 1.00 0.91 (0.78–1.07) 0.82 (0.69–0.97) 0.75 (0.63–0.89) 0.68 (0.56–0.82) <0.001

Vigorous exercise

Energy expenditure (min of strenuous exercise/wk)

Median Range

0 None

30 1–60

90 61–100

140 101–150

210 >150

Coronary heart disease No. of cases 269 35 13 14 14 Age-adjusted relative risk (95% CI) 1.00 1.12 (0.79–1.60) 0.56 (0.32–0.98) 0.73 (0.43–1.25) 0.58 (0.34–0.99) 0.008

Total cardiovascular disease No. of cases 1220 125 78 61 67 Age-adjusted relative risk (95% CI) 1.00 0.87 (0.72–1.04) 0.73 (0.58–0.92) 0.69 (0.53–0.89) 0.60 (0.47–0.76) <0.001 Multivariate relative risk (95% CI) 1.00 0.91 (0.73–1.12) 0.81 (0.63–1.06) 0.85 (0.64–1.13) 0.76 (0.58–1.00) 0.01

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Figure 1.

Age-Adjusted Relative Risks of Cardiovascular Disease According to Quintile of Total MET Score in Subgroups Defined by Race, Age, and Body-Mass Index (BMI). The reference category is the lowest quintile of MET score.

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.00

0.81

0.58 0.48

0.68

Black women (n=5661)

1.00

0.82 0.73

0.63 0.55

White women (n=61,574)

A g

e -A

d ju

st e

d R

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is k

o f

C a

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D is

e a

0.0

0.2

0.4

0.6

0.8

1.0

1.2

70–79 yr (n=15,856)50–59 yr (n=24,803) 60–69 yr (n=32,127)

0.63 0.54

0.45

1.00

0.68 0.63

0.56 0.50

1.00

0.79 0.86

0.75

0.64

1.00 0.93

1.00

0.75 0.84

0.61 0.60

1.00

0.82

0.67 0.71

0.58

1.00 0.96

0.73 0.80

0.65

0.0

0.2

0.4

0.6

0.8

1.0

1.2

Race

Age

Body-Mass Index

BMI »30.0 (n=16,806)BMI 25.0–29.9 (n=24,590)BMI <25.0 (n=30,583)

Quintile of total MET score

1 2 3 4 5 Lowest Highest

P for trend <0.001 P for trend=0.02

P for trend <0.001 P for trend <0.001 P for trend <0.001

P for trend <0.001 P for trend <0.001 P for trend=0.007

Total Physical Activity

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N Engl J Med, Vol. 347, No. 10

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T h e N e w E n g l a n d Jo u r n a l o f Me d i c i n e

Figure 2.

Age-Adjusted Relative Risks of Cardiovascular Disease According to Energy Expenditure from Walking (MET-Hr/Wk) in Subgroups Defined by Race, Age, and Body-Mass Index (BMI). The reference category is the lowest category of energy expenditure from walking.

1.00

0.78

0.49 0.51 0.46

1.00 0.91

0.70 0.66

0.49

1.00

0.89 0.78

0.72 0.72

1.00 0.95

0.71 0.75

0.67

1.00 0.90

0.71 0.75 0.64

1.00

0.79 0.78

0.56 0.59

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.00

0.67 0.73

0.65

1.00

0.85

0.70 0.66

0.55

1.00

0.0

0.2

0.4

0.6

0.8

1.0

1.2

0.0

0.2

0.4

0.6

0.8

1.0

1.2

70–79 yr (n=15,856)50–59 yr (n=24,803)

BMI <25.0 (n=30,583)

Black women (n=5661)White women (n=61,574)

60–69 yr (n=32,127)

Race

Age

Body-Mass Index

BMI »30.0 (n=16,806)BMI 25.0–29.9 (n=24,590)

Energy expenditure from walking (MET-hr/wk)

0 0.1–2.5 2.6–5.0 5.1–10.0 >10.0

A g

e -A

d ju

st e

d R

e la

ti v

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o f

C a

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sc u

la r

D is

e a

Walking

P for trend <0.001 P for trend=0.11

P for trend <0.001 P for trend <0.001 P for trend=0.004

P for trend=0.003 P for trend <0.001 P for trend <0.001

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orous exercise (activities with MET scores of 6 or higher; P for trend=0.008) (Table 1).

Reductions in the risk of total cardiovascular events with increasing categories of total MET scores, walk- ing, and vigorous exercise were similar to those for the risk of coronary disease (Table 1). Women who either walked or exercised vigorously at least 2.5 hours per week had a risk reduction of approximately 30 percent. Similar reductions in the risk of cardiovascular events with an increasing MET score were observed for white women and for black women (for other racial and eth- nic groups, the samples were not large enough to be analyzed separately), as well as for women in different categories of age or body-mass index (Fig. 1). The rel- ative risk of cardiovascular disease in the highest quin- tile of MET score as compared with the lowest quin- tile was 0.55 (95 percent confidence interval, 0.47 to 0.65) among white women and 0.48 (95 percent con- fidence interval, 0.25 to 0.93) among black women. Moreover, increasing categories of walking were in- versely associated with the risk of cardiovascular events in each of these subgroups (Fig. 2). Women who en- gaged in both walking and vigorous exercise had great- er reductions in cardiovascular risk than those who did either one alone (the age-adjusted relative risk for those in the highest category of each was 0.37 [95 percent confidence interval, 0.25 to 0.57]) (Fig. 3).

In multivariate analyses, after simultaneous control for age, race or ethnic group, smoking status, body- mass index, waist-to-hip ratio, socioeconomic status, several dietary factors, and other covariates, physical activity remained a powerful predictor of the subse- quent risk of cardiovascular events (Table 1). For in- creasing quintiles of the total MET score, the relative risks were 1.00, 0.89, 0.81, 0.78, and 0.72, respec- tively (P for trend <0.001). Increasing categories of walking were associated with similar reductions in risk (relative risks, 1.00, 0.91, 0.82, 0.75, and 0.68, respec- tively; P for trend <0.001), which were also similar to the risk reductions with vigorous exercise (Table 1) and remained unchanged after simultaneous inclusion of walking and vigorous exercise in the model. These results were not substantially altered after further con- trol for biologic variables that could be considered to be in the causal pathway, such as hypertension, hyper- cholesterolemia, and diabetes, and for the summary score for mental and emotional health

(the relative risks of cardiovascular events with increasing total MET scores were 1.00, 0.92, 0.87, 0.83, and 0.77, respectively; P for trend=0.008). When we exclud- ed data from the first year of follow-up (to minimize potential bias caused by the influence of subclinical disease on the activity level), the results were not ma- terially altered (the multivariate relative risk of car-

Figure 3.

Joint Association of Walking and Vigorous Exercise with the Age-Adjusted Relative Risk of Cardiovascular Disease. RR denotes relative risk.

Energy Expenditure from Walking (MET-hr/wk)

A g

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0.0

0.2

0.4

0.6

0.8

1.0

2.6–10.0«2.5 >10.0

0 min/wk of vigorous exercise

1–100 min/wk of vigorous exercise

>100 min/wk of vigorous exercise

0.71

0.78

1.00

0.49

0.72 0.70

0.37

0.43

0.67

P<0.05 for all comparisons with reference group (RR=1.00)

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722 · N Engl J Med, Vol. 347, No. 10 · September 5, 2002 · www.nejm.org

T h e N e w E n g l a n d Jo u r n a l o f Me d i c i n e

diovascular disease for women in the highest quintile of total MET score was 0.76 [95 percent confidence interval, 0.61 to 0.96; P for trend=0.02]).

Walking pace was also an important determinant of reduction in cardiovascular risk (Fig. 4). As com- pared with women who never or rarely walked (the reference category, with a relative risk of 1.00), wom- en who walked at faster paces of 2 to 3 miles per hour (mph) (3.2 to 4.8 km per hour), 3 to 4 mph (4.8 to 6.4 km per hour), and more than 4 mph had relative risks of cardiovascular disease of 0.86, 0.76, and 0.58, respectively (P for trend=0.002), according to multi- variate models that included control for time spent walking.

Finally, we assessed the relation between hours spent sitting, as well as hours spent lying down or sleeping, and the risk of cardiovascular events. After we accounted for age and recreational energy expend- iture (total MET score), the relative risk of cardiovas- cular disease was 1.38 (95 percent confidence interval, 1.01 to 1.87) among women who spent 12 to 15 hours per day lying down or sleeping and 1.68 (95

percent confidence interval, 1.07 to 2.64) among women who spent at least 16 hours per day sitting, as compared with those who spent less than 4 hours per day. Other durations of sitting or lying down were not significantly associated with cardiovascular risk.

DISCUSSION

These prospective data from an ethnically diverse cohort of postmenopausal women indicate that both walking and vigorous exercise are associated with sub- stantial reductions in the incidence of cardiovascular events. In contrast, prolonged time spent sitting pre- dicts increased risk. We observed similar magnitudes of risk reduction with walking and vigorous exercise, and the results were similar among white women and black women as well as among women in different age groups and categories of body-mass index. These find- ings extend those of previous analyses from predom- inantly white populations14-17 to a racially and ethni- cally diverse cohort of women in the United States. The results also lend further support to current fed- eral exercise guidelines that endorse moderate-inten-

Figure 4. Multivariate Relative Risk of Cardiovascular Disease and Relative Risk Adjusted for Age and Walking Time, According to Walking Pace. Multivariate relative risks were adjusted for age, time spent walking, smoking status (0, 1 to 14, 15 to 24, or »25 cigarettes per day), race or ethnic group, level of education, annual family income, body-mass index, waist-to-hip ratio, level of alcohol intake, parental history of premature myocardial infarction, age at menopause, use or nonuse of hormone-replacement therapy, percentage of cal- ories from saturated fat, number of servings of fruit and vegetables per day, and dietary fiber intake. To convert values for distance to kilometers, multiply by 1.6.

Walking Pace (mph) among Walkers

R e

la ti

v e

R is

k o

f C

a rd

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a sc

u la

r D

is e

a se

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1.1

<2 mph (easy, casual)

(n=10,690)

2 to 3 mph (average)

(n=30,523)

3 to 4 mph (brisk)

(n=17,555)

>4 mph (very brisk)

(n=990)

Rarely or never walk

(n=10,896)

Multivariate P for trend=0.002

Adjusted for age and walking time P for trend <0.001

1.00 1.00

0.73

0.86

0.57

0.76

0.40

0.58

1.07 1.06

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sity exercise for at least 30 minutes on most, and preferably all, days of the week.3,4 Women who either walked briskly or exercised vigorously at least 2.5 hours per week had a risk reduction of approximately 30 percent. Evidence of the applicability of these guide- lines to nonwhite women is of particular importance because of the high prevalence of sedentary lifestyles, obesity, and related conditions in minority popula- tions.3

Strengths of the present study include the prospec- tive design, the large size, the racial and ethnic diver- sity of the cohort, the detailed assessment of physical activity as well as sedentary behavior, and the uniform and strict criteria for the coronary and cardiovascular end points. Women with diagnosed cardiovascular dis- ease or cancer at base line and those who were non- ambulatory (unable to walk at least one block) were excluded from the analyses. These exclusions and the prospective design minimized any influence of preex- isting disease on the level of physical activity. More- over, we performed secondary analyses excluding data from the first year of follow-up in order to minimize bias related to the presence of subclinical disease. The strong dose–response gradient observed between the physical-activity level and the reduced risk of cardio- vascular disease and the consistency of the findings across strata of age, race, and body-mass index lend further credence to a causal interpretation. Other strengths of the study include the high follow-up rate and the detailed information about potential con- founding variables.

Because our multivariate analyses controlled for several factors that could be considered to be interme- diate biologic variables,3 such as body-mass index and waist-to-hip ratio, and additional models controlled for history of hypertension, hypercholesterolemia, and diabetes, our analyses provide a conservative estimate of the relation between activity and cardiovascular disease. Physical activity may be associated with even greater reductions in cardiovascular risk — closer to the 50 percent reductions found in our age-adjusted analyses — given that the relative risks derived from the multivariate models estimate the effects of exercise without taking into account its favorable influence on adiposity and related morbidity.

Some limitations of our study also deserve atten- tion. Physical activity was assessed by questionnaire, and some misclassification of exposure was inevitable. Nondifferential misclassification of exposure, howev- er, would be expected to bias the risk estimate toward unity; thus, it cannot explain the strong inverse asso- ciations observed between the level of physical activity and the incidence of cardiovascular events. Despite the fact that we controlled for a large number of poten- tially confounding variables in our multivariate analy- ses, residual confounding by lifestyle-related factors

cannot be excluded. Finally, our study population of volunteers in the Women’s Health Initiative, although of more diverse racial and ethnic background and so- cioeconomic status than most previously studied co- horts, is not an entirely representative cross-section of women in the United States.

More than 40 epidemiologic studies have addressed the relation between exercise and cardiovascular dis- ease,1,2 but only one third of published studies have included women,14-28 and few of these have specifical- ly addressed the role of walking.14-19 In previous stud- ies, results for women have been generally similar to those for men, indicating that risk among both sexes is reduced by 30 to 50 percent with regular physical activity. Recent reports from several large-scale cohort studies involving women14,15,20 have suggested that moderate and vigorous exercise have similar cardio- vascular benefits, but these cohorts were predominant- ly white. Moreover, to our knowledge, no previous large-scale study has addressed the relation between walking and cardiovascular events in black women or the role of sitting after accounting for recreational en- ergy expenditure in women. The evidence that mod- erate-intensity activity is associated with a similar mag- nitude of reduction in cardiovascular risk among white women and black women, among younger and older postmenopausal women, and across the spectrum of adiposity is important for the targeting of these diverse groups with health-promotion activities. The cardio- vascular benefits of walking29 and even moderate lev- els of physical fitness27,30 also appear to apply to men.

An important role for both moderate and vigorous exercise in reducing cardiovascular risk is also biolog- ically plausible. Increasing intensity or duration of ex- ercise has a graded relation to improvements in lipid levels3,31 and insulin sensitivity.32 Moderate-intensity activity may produce reductions in diastolic blood pressure similar to those achieved with vigorous exer- cise and may produce even greater reductions in sys- tolic blood pressure.3 Moderate exercise coupled with modification of the diet led to a reduced risk of type 2 diabetes among subjects with impaired glucose tol- erance.33,34 Moreover, equivalent energy expenditure with moderate or vigorous exercise leads to similar reductions in adipose mass.3 Finally, physical activity of any intensity has been linked to improvement in emotional well-being.3

In conclusion, these prospective data from a large and diverse cohort of postmenopausal women indicate that both walking and vigorous exercise are associat- ed with substantial reductions in the risk of cardio- vascular events. A graded inverse relation was observed among both white women and black women, lean women and obese women, and younger women and older women. Moreover, prolonged time spent sitting predicted increased risk. These findings lend support

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T h e N e w E n g l a n d Jo u r n a l o f Me d i c i n e

to current federal guidelines that endorse moderate- intensity activity, including walking. Although vig- orous exercise should not be discouraged for those who choose a higher intensity of activity, our results indicate that moderate-intensity exercise confers sub- stantial health benefits for postmenopausal women.

Supported by the National Heart, Lung, and Blood Institute and a re- search contract (N01-WH-3-2109) from the National Institutes of Health.

We are indebted to the participants, investigators, and staff of the Women’s Health Initiative for their outstanding dedication and com- mitment and to Philomena Quinn for her expert assistance.

APPENDIX

The following persons are members of the Women’s Health Initiative Study Group. Program office: J.E. Rossouw, L. Pottern, S. Ludlam, J. McGow- an, N. Morris (National Heart, Lung, and Blood Institute, Bethesda, Md.). Clinical coordinating center: R. Prentice, G. Anderson, A. LaCroix, R. Patter- son, A. McTiernan (Fred Hutchinson Cancer Research Center, Seattle); S. Shumaker, P. Rautaharju (Bowman Gray School of Medicine, Winston- Salem, N.C.); E. Stein (Medical Research Labs, Highland Heights, Ky.); S. Cummings (University of California at San Francisco, San Francisco); J. Himes (University of Minnesota, Minneapolis); S. Heckbert (University of Wash- ington, Seattle). Clinical centers: S. Wassertheil-Smoller (Albert Einstein Col- lege of Medicine, Bronx, N.Y.); J. Hays (Baylor College of Medicine, Hous- ton); J. Manson (Brigham and Women’s Hospital and Harvard Medical School, Boston); A.R. Assaf (Brown University, Providence, R.I.); L. Phillips (Emory University, Atlanta); S. Beresford (Fred Hutchinson Cancer Research Center, Seattle); J. Hsia (George Washington University Medical Center, Washington, D.C.); C. Ritenbaugh (Kaiser Permanente Center for Health Research, Portland, Oreg.); B. Caan (Kaiser Permanente Division of Re- search, Oakland, Calif.); J. Morley Kotchen (Medical College of Wisconsin, Milwaukee); B.V. Howard (Medstar Research Institute, Washington, D.C.); L. Van Horn (Northwestern University, Chicago and Evanston, Ill.); H. Black (Rush–Presbyterian–St. Luke’s Medical Center, Chicago); M.L. Stefanick (Stanford Center for Research in Disease Prevention, Stanford University, Stanford, Calif.); D. Lane (State University of New York at Stony Brook, Stony Brook); R. Jackson (Ohio State University, Columbus); C.B. Lewis (University of Alabama at Birmingham, Birmingham); T. Bassford (University of Arizona, Tucson and Phoenix); M. Trevisan (State University of New York at Buffalo, Buffalo); J. Robbins (University of California at Davis, Sac- ramento); A. Hubbell (University of California at Irvine, Orange); H. Judd (University of California at Los Angeles, Los Angeles); R.D. Langer (Uni- versity of California at San Diego, LaJolla and Chula Vista); M. Gass (Uni- versity of Cincinnati, Cincinnati); M. Limacher (University of Florida, Gainesville and Jacksonville); D. Curb (University of Hawaii, Honolulu); R. Wallace (University of Iowa, Iowa City and Davenport); J. Ockene (Uni- versity of Massachusetts, Worcester); N. Lasser (University of Medicine and Dentistry of New Jersey, Newark); M.J. O’Sullivan (University of Miami, Miami); K. Margolis (University of Minnesota, Minneapolis); R. Brunner (University of Nevada, Reno); G. Heiss (University of North Carolina, Chap- el Hill); L. Kuller (University of Pittsburgh, Pittsburgh); K.C. Johnson (Uni- versity of Tennessee, Memphis); R. Schenken (University of Texas Health Science Center, San Antonio); C. Allen (University of Wisconsin, Madison); G. Burke (Wake Forest University School of Medicine, Winston-Salem, N.C.); S. Hendrix (Wayne State University School of Medicine and Hutzel Hospital, Detroit).

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