WHI Protocol Modified Due to PEPI Data

April 1, 1996

BETHESDA, Md--Data on a single slide presented in November, 1994, led quickly to a key change in the hormone arm of the Women's Health Initiative (WHI), sponsored by the National Institutes of Health.

BETHESDA, Md--Data on a single slide presented in November, 1994,led quickly to a key change in the hormone arm of the Women'sHealth Initiative (WHI), sponsored by the National Institutesof Health.

As a result, any women in the program who still had her uterusfaced no grave worries when she heard about findings from thePostmenopausal Estrogen/Progestin Interventions (PEPI) study.WHI investigators had already stopped giving unchallenged estrogento women with intact uteruses.

PEPI researchers found that a daily 0.625 mg dose of conjugatedequine estrogens significantly increased a woman's chances ofdeveloping endometrial hyperplasia. However, no risk was foundamong women in the study who took the estrogen in combinationwith either medroxyprogesterone acetate or micronized progesterone(JAMA Feb. 7, 1996).

Findings Spotted at 1994 Meeting

Although many physicians did not learn of the PEPI hyperplasiafindings until their formal publication, WHI researchers spottedindications of potential problems for their study in a slide displayedduring a report at the American Heart Association's 1994 scientificmeeting that described preliminary results from PEPI.

WHI's hormone study seeks to learn the overall risks and benefitsof such treatments on women's health, particularly the effectivenessof estrogen in preventing coronary heart disease and osteopor-osisand its possible role in breast cancer.

Originally, the hormone trial, which begin enrolling postmenopausalparticipants in September, 1993, randomly assigned women to oneof three groups: estrogen alone, an estrogen-progestin combination,or placebo. WHI officials modified that protocol as a result ofthe early findings from PEPI.

At the 1994 Heart meeting, one slide shown at the PEPI presentationgave rates of adenomatous and atypical hyperplasia. "Thosewere significantly high for us to sit up and take notice,"Dr. Jacques Rossouw, WHI's Lead Project Officer, said in an interviewwith Oncology News International.

WHI officials met with PEPI investigators, who shared additionaldata from the study's as-yet-unpublished findings. "Fromthe answers we got, we were convinced that we had to change thetrial," Dr. Rossouw said.

On Dec. 16, 1994, researchers at WHI's 40 clinical center's nationwidestopped randomizing women with a uterus into the estrogen-onlygroup and began randomizing them to either the hormone-combinationor placebo groups. They continued randomizing women without auterus into the estrogen-only or placebo group.

More than 300 women with uteruses who were already in the studyand were receiving estrogen alone were asked to switch to theestrogen-progestin group in the spring of 1995.

"We lost a number of women because whenever you change aprotocol, people get disturbed and worried," Dr. Rossouwsaid. About two thirds of the women did continue in the study.Those that stayed were all converted to the combination therapyby May, 1995.

Some women with uteruses who were assigned to the estrogen-onlygroup did develop endometrial problems during their time on thehormone.

"If there was any bleeding problem at the time, we did anendometrial assessment," Dr. Rossouw said. "If theredidn't appear to be a serious endometrial problem, then we offeredthe woman the combination therapy."

Dr. Rossouw noted that, without the change, "we would havehad more and more problems as we went along." The WHI estimated,based on the PEPI data, that before the midway point of the trial,half of the women with a uterus who were receiving estrogen onlywould have had to discontinue treatment.

More than 7,000 women have volunteered for WHI's hormone studyand officials hope to enroll a total of 27,500. Participants willbe followed for an average of 9 years, and the WHI expects topublish its first results in 2005. Information on participatingin the trial is available by calling 1-800-54-WOMEN.