Study participants and design
Recruitment. A total of 96,839 direct mailings were sent to women age 52–62 beginning in 2002. There was a 4% response rate (n = 8,320) and 4,206 were contacted, 978 women attended initial screening and 34.7% (n = 508) postmenopausal women were recruited for the trial (2003–2010). The trial was originally planned for 5 years. However, it took about 1.5 years to complete recruitment for the trial and follow-up was therefore lowered to 4 years (48 months).
Eligible women were between the ages of 52 and 62 years, had a BMI of 25–39.9 kg/m2, waist circumference >80 cm diameter, BP <140/90 mm Hg, with or without antihypertensive therapy, not on lipid-lowering drug therapy, LDL cholesterol (LDL-C) between 100 and 160 mg% and no history of CVD. Participants had an eligibility interview and two additional screening clinic visits before randomization. During the second screening visit, carotid ultrasound, arterial pulse wave velocity, coronary calcium by electron beam tomography and bone mineral density by dual energy X-ray absorptiometry were measured. Participants then completed a 3-day food record, which was used by the nutritionist for counseling, the Connor Diet Habit Survey to evaluate eating habits, and a Food Frequency Questionnaire (FFQ). Physical activity was measured using the past year version of the Modifiable Activity Questionnaire (MAQ), an interviewer-administered questionnaire (5,14).
Changes in lifestyle and risk factors were measured at baseline, 6, 18, 30, and 48 months. Pulse wave velocity and bone mineral density were repeated at 18 and 48 months and the coronary calcium and carotid ultrasound at 48 months (5).
The CEE+MPA arm of the Women's Health Initiative was stopped prematurely, within the first 5 months of participant recruitment for the WOMAN study. Accordingly, women who had already been randomized in the WOMAN study were advised to discontinue HT use, whereas women randomized after the publication of the results of Women's Health Initiative were allowed to enter the trial after discontinuation of HT use.
The WOMAN study, therefore, had three groups of women: those who entered the trial on HT and stayed on it through the trial, mostly on CEE-Alone; those who went off HT after randomization; and women who were on HT before randomization but had stopped by the time of randomization.
Health Education group. The Health Education group had a series of six seminars during the first year of participation and then several times per year through 36 months. Most of these sessions focused on women's health and not specifically on CV risk factors.
Lifestyle Change group. The intervention has been previously described. It was built on studies such as the WHLP (15) and the Diabetes Prevention Program (DPP) (16). The intervention was primarily group-based and was facilitated by a multidisciplinary team of nutritionists, exercise physiologists, and psychologists. Contact was frequent throughout the program with 40 visits during the first year and a minimum of 12 monthly visits in year 2 and beyond. The intervention program, however, was stopped because of lack of continued funding for the intervention at ∼3 years (36 months). Therefore, the results from baseline to 48 months include a period of time where there was little or no intervention (i.e., 36–48 months).
Dietary goals for the intervention (Lifestyle Change) group were to reduce the saturated fat to <7% of total energy or <10 g/day, reduction in total energy intake to 1,300 cal or 1,500 cal when baseline body weight was >175 lbs to support a 10% loss of weight and a decrease in waist circumference. They were also encouraged to increase the use of foods high in soluble fiber and nutrient-dense, high-volume, low-caloric foods such as fruits, vegetables, and whole grains. Also, during the first year of the intervention consumption of functional foods such as stanol esther-containing margarines, soy products and n-3 fatty acids from fish were encouraged (5).
At baseline, caloric intake estimated using the FFQ was ∼2,000 calories, 33% of calories were from fat, 10.5% from saturated fat, and 10 g/1,000 calories from fiber. This was similar to eating habits of women in the United States and did not differ between the Health Education and Lifestyle Change group (5,12). By 18 months, the amount of fat in the diet had been reduced by 31% in the Lifestyle Change group and 12% in the Health Education and saturated fat by 36% in Lifestyle Change and 13% in Health Education, all statistically significant. Women reported 14% decrease in total calories in both groups. The FFQ was not repeated after 18 months.
Physical activity was measured by the MAQ which assesses leisure and occupational activities. We focused on the leisure activity estimate as there was little reported occupational activity in our study population. Study participants were asked to identify if they participated in a variety of specific activities, such as walking for exercise, at least 10 times over the past year (12 months). For each activity identified, they were asked which months they had participated in that specific activity over the past year and then estimated the number of times each month and length of time that they spent doing the specific activity. Physical activity levels were calculated as the product of the duration and frequency of each activity (in h/week), weighted by an estimate of the metabolic equivalent (MET) of that activity and summed for all activities performed. Leisure physical activity data were expressed as metabolic equivalent h/week (MET h-week) (14). Baseline median leisure time physical activity based on the MAQ was 11.4 MET·h/week and was similar for the Health Education and Lifestyle Change groups (12).
The physical activity component of the lifestyle intervention began after the first 6 months of group initiation. The physical activity intervention was delayed for the first 6 months because of the very intensive dietary intervention at the beginning of the trial, including frequent sessions, meal preparations, very low saturated and trans fat and calorie intake. A recent comparison of delayed vs. nondelayed physical activity intervention documented no significant differences in weight loss among obese individuals in an intensive intervention similar to the WOMAN study (15). The content was based on the experience with the DPP and previous clinical trials that targeted healthy, middle-aged women (16,17,18). It was a stepped care approach to reach 150 min/week of moderate intensity physical activity as the standard minimum goal for all women. Women who reached the minimum goal were then encouraged to increase to 180 min and then to 240 min/week. Resistance training of large skeletal muscle groups was also encouraged to facilitate beneficial body composition changes and bone health.
CV risk factors. At baseline and 6, 18, 30, and 48 months, total LDL, high-density lipoprotein cholesterol (HDL-C), triglycerides, glucose, and insulin were determined by conventional enzymatic methods. Lipoprotein subclasses were determined by nuclear magnetic spectroscopy.
Coronary artery calcification. An Imatron C-150 Scanner (Imatron, South San Francisco, CA) was used to obtain 30–40 contiguous 3-mm thick transverse images of the heart. Coronary calcium scores were calculated according to the Agatston method. The electron beam tomography scans from this laboratory had high reproducibility, with an intraclass correlation of 0.99 (19).
Carotid ultrasound. Carotid ultrasound images were taken from the near and far walls of the distal common carotid artery (1 cm proximal to the carotid bulb), and the far walls of the carotid bulb. IMT measures were performed electronically. The mean of all average readings across the eight locations (four on each side) comprises the average IMT. The mean of the maximum reading from each segment was also calculated (20).
Walking performance. The 400-m walk test is a component of the long-distance corridor walk that utilizes a 400-m course consisting of 10 laps along a hallway (40 m/lap) with cones set 20 m apart. Participants were instructed to walk “at a pace that you can maintain for the full 10 laps” and standard encouragement was given at each lap. The 400-m walk test was previously shown to be highly reproducible for women, correlation coefficient 0.95 (confidence limits 0.92, 0.97, P < 0.0001) and significantly associated with measured (P = −0.56; P < 0.001) VO2max in a study including healthy, middle-aged women, and with risk of clinical coronary heart disease and death in older women (13,21).
Statistical methods of analysis. A detailed description of the statistical methods has been published (4). Changes in variables over time were expressed as a difference in values between follow-up and baseline. Depending on normality of distribution, either t-tests or Mann–Whitney tests for comparing continuous variables at baseline, 48-month follow-up, and change in risk factors over time by randomized group assignment. There was little difference in results by whether analysis based on means or medians (nonparametric tests). Mean differences are shown throughout the paper. There were few women lost to follow-up during the trial and such women were excluded from the analysis. Eight women with coronary calcium score ≥400 Agatston units were excluded from the analysis because they were at very high risk and referred to their physicians for pharmacological therapy for lipid-lowering, antihypertensive therapy, etc. as required by the institutional review board approval for the study. A repeated measure mixed model was used to evaluate average differences across 6-, 18-, 30-, and 48-month visits.
The power calculations have been previously published (5).