Trial Information

BACKGROUND:

Prior to 1991, little research had focused on health issues unique to, or more common for,
women. This was especially the case for studies of chronic diseases and their prevention in
mature women. These conditions (coronary heart disease, cancer, and osteoporosis) are the
leading causes of impairment of quality of life, morbidity, and mortality in post-menopausal
United States women. The WHI, mandated by Congress, was established in 1991 by the National
Institutes of Health and located in the Office of the Director (OD). The Clinical
Coordinating Center for the clinical trial/observational study was funded in September 1992
and the 16 Vanguard Clinical Centers were funded in March 1993. The initial protocol was
developed jointly by the Clinical Coordinating Center and the Program Office and was
reviewed and approved by the Investigators Committee on April 20, 1993. Additional clinical
centers were funded in 1994.

On October 1, 1997, administration of the WHI was transferred to the NHLBI where it is
conducted as a consortium effort led by the NHLBI in cooperation with the National Institute
of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), the National Cancer Institute
(NCI), and the National Institute on Aging (NIA).

DESIGN NARRATIVE:

As has been described in the objective, the WHI has three major components: a randomized
controlled clinical trial, an observational study, and a study of community approaches to
developing healthful behaviors. Recruitment for the WHI began in September 1993 and ended
in December 1998. Six clinical centers completed recruitment in January 1997. The remaining
34 centers completed recruitment in December 1998.

CLINICAL TRIAL COMPONENT

The clinical trial component consists of three subtrials: the hormone replacement trial, the
dietary modification trial, and the calcium /vitamin D supplementation trial. Approximately
27,500 women aged 50 to 79 are participating in the HRT, which tests whether long-term HRT
reduces coronary heart disease and fractures without increasing breast cancer risk. Women
with a uterus were randomized to receive either estrogen plus progestin or a placebo.
Progestin was added to protect women with a uterus from endometrial cancer. Women who have
had a hysterectomy were randomized to receive either estrogen alone or a placebo. The
estrogen plus progestin trial was stopped early on July 8, 2002 after an average follow-up
of 5.2 years on the recommendation of the Data and Safety Monitoring Board. The estrogen
alone study continued unchanged until March 2, 2004 when the NIH instructed participants to
stop taking their study pills and to begin the follow-up phase of the study. . Participants
in the estrogen alone study will be followed for eight to 12 years and have clinic visits
every six months to assure safety and assess their health.

The dietary modification trial component studies the effect of a low-fat, high fruit,
vegetable and grain diet on breast cancer, colorectal cancer and heart disease in 48,000
postmenopausal women. Participants are randomized to a comparison group which maintains
usual dietary habits or to a dietary change group. Women in the dietary change group
decrease their fat intake to 20 percent of total daily calories, increase fruit and
vegetable consumption to five or more servings per day, and increase grains to six or more
servings per day. Additionally, they monitor their food intake and attend nutrition group
meetings to learn more about changing their diets in the first year. Thereafter they attend
four meetings per year.

The calcium/vitamin D supplementation subtrial tests whether calcium and vitamin D
supplements reduce the risk of hip and other fractures and colorectal cancer in
postmenopausal women. Women in the hormone replacement therapy and the dietary modification
trials are encouraged to join the calcium/vitamin D supplementation study. Approximately
45,000 postmenopausal women are randomized into one of two study groups. One group was
randomly assigned to receive 1,000 mg of elemental calcium (as calcium carbonate) and 400
International Units of vitamin D₃daily. The second group received a matching placebo.

Women already taking calcium supplements can continue to take them. Participants will be
followed for eight to 11 years and contacted by their clinical center every six months to
assure their safety and assess their health.

Total number of trial participants in all three subtrials is 68,135.

OBSERVATIONAL STUDY

The several goals of the study include: to give reliable estimates of extent to which known
risk factors predict heart disease, cancers, and fractures; to identify new risk factors for
these and other diseases in women; to compare risk factors, presence of disease at the start
of the study and new occurrences of disease during the WHI in all study components; and to
create a future resource to identify biological indicators of disease, especially substances
and factors found in blood. The study enrolled 93,726 postmenopausal women and will track
them for an average of nine years. Participants fill out periodic health forms and visit
the clinic three years after enrollment. They take no medication and do not change their
health habits.

COMMUNITY PREVENTION STUDY

The community prevention study consists of 12 separate studies conducted at eight of the
Centers for Disease Control and Prevention's (CDC) University-based Prevention Research
Centers through a cooperative agreement between NIH and CDC. The 12 studies began in
October 1995 and continue for an additional five years. The collaboration supports health
promotion and disease prevention research and demonstration projects that are
community-based and focus on healthy behaviors that prevent the major causes of death and
disability and that promote health practices that lead to more effective public health
interventions. Each project provides research dissemination and translation of findings
into community interventions. Topics under study include: attitudes towards hysterectomy,
oophorectomy, and surgical menopause among African Americans; reducing cardiovascular
disease risk among Black women; environmental and policy interventions to increase physical
activity among minority women ages 40 to 75; peer support intervention for cardiovascular
disease risk among African American women, aged 40 and older; assessing the effectiveness of
a brief medical-provider educational intervention for osteoporosis in minority women aged 40
and older; improving the delivery of diabetes care to women in minority groups; and
assessment of moderate physical activity among women.