Garnet Anderson, Ph.D.
Co-Principal Investigator and Biostatistician
WHI Clinical Coordinating Center
Member, Public Health Sciences Division
Fred Hutchinson Cancer Research Center

July 9, 2002

Press Conference Remarks

Release of the Results of the Estrogen Plus Progestin Trial of the Women's Health Initiative:
Data and Safety Monitoring

Thank you, Marcia.

At the Women's Health Initiative Clinical Coordinating Center, we are responsible for managing, analyzing and reporting the data from the more than 40 clinical research sites of the WHI. I am here to explain how the data were monitored, leading us to the conclusions we are discussing today.

Throughout the estrogen plus progestin trial, we placed a high priority on monitoring and maintaining participant safety, as well as on ensuring that all WHI participants were well informed about any potential risks associated with the study. One of the primary mechanisms for ensuring the safety of research subjects in any clinical trial is oversight by an independent Data and Safety Monitoring Board, or DSMB.

In accordance with NIH policy, members of the Data and Safety Monitoring Board for WHI were appointed by the National Heart, Lung, and Blood Institute. The group was composed of 12 individuals with expertise in clinical trials, statistics, ethics and all of the relevant areas of medicine.

The DSMB met every six months to review the emerging results. A plan established in advance was used to guide the board in interpreting the data. The plan was set up to ensure that clear answers to the primary questions about heart disease and breast cancer would be obtained, while keeping open the possibility that important effects of estrogen plus progestin on other diseases could emerge. Thus, hip fractures, pulmonary embolism, stroke, endometrial cancer and colorectal cancer were all designated as outcomes requiring monitoring, based on findings from previous studies of hormones. To assure that serious effects not previously identified would not be overlooked, deaths from all other causes were also monitored.

To weigh the observed risks and benefits to the participants' health, the DSMB used a "global index," which summed all of these designated health outcomes.

The monitoring plan allowed for a variety of possible scenarios and indicated how the DSMB would evaluate the data in each of these circumstances. For example, if the data showed that estrogen plus progestin helped prevent heart disease, and the global index indicated overall benefit, then the DSMB would consider recommending that the study be stopped because the benefits of hormones would have been adequately determined. Conversely, if breast cancer or other risks became clear and the global index pointed to overall harm, the board would consider recommending that the study be stopped for adverse effects. For all other scenarios, the study would continue as planned because the balance of risks and benefits would not have been adequately determined.

So, here is how the estrogen plus progestin study unfolded. First, in late 1999, with an average of two and a half years' worth of data on the trial participants, the DSMB noted that the rates of coronary heart disease, strokes and pulmonary embolism, or blood clots, were higher among the women taking the combined hormones than among those taking placebo. The DSMB recommended that participants be told these interim findings. The WHI investigators did so in the early spring of 2000 and again in spring 2001when it became clear that the risk persisted beyond the first few years.

These results did not meet the established criteria for stopping the trial, however, and they were not strong enough to rule out the possibility of longer-term benefits for either these cardiovascular conditions or for other health concerns. In addition, no other significant risks had been identified at that time. Therefore, the DSMB recommended that the trial continue with no changes to the protocol.

More recently, during its May 31st meeting, the DSMB reviewed WHI data through February 2002. Then, with an average of 5 years of participant follow-up, the increased risk for heart disease, strokes, and blood clots was still apparent. The DSMB also discovered for the first time, that breast cancer rates were markedly increased among women assigned to the estrogen plus progestin group. Because this effect emerged suddenly, we wanted to be sure that it was not a random or temporary fluke in the data. We looked at additional data accumulated through April 30th and found that the picture had not changed. Compared to women on placebo, more women on estrogen plus progestin had been diagnosed with coronary heart disease, stroke, blood clots AND breast cancer.

There were some benefits to the use of estrogen plus progestin--women on these hormones had fewer hip fractures and colon cancers--but the magnitude of these benefits was not sufficient to overcome the accumulated risks observed for other diseases.

The increased risk of invasive breast cancer among women taking estrogen plus progestin surpassed the disease-specific criterion defined in the monitoring plan for stopping the study because of harm. The global index also supported a finding of overall harm, satisfying the second criterion of the monitoring plan. Based on these results, the DSMB concluded that estrogen plus progestin produced harmful effects on women's health that exceeded any benefits generated by these hormones and unanimously recommended to the NHLBI that the estrogen plus progestin study be stopped.

NHLBI followed the board's recommendation and began informing the relevant parties. The Institute has briefed the WHI Investigators, and they are working collaboratively to explain the findings to study participants. All WHI participants, even those who are not in the estrogen plus progestin study, are being sent letters about the results. In addition, women in the estrogen plus progestin study are being instructed to stop taking their hormone pills immediately, and staff at each WHI clinical center are scheduling counseling sessions with each participant. These participants are being asked to continue their clinic visits so that their safety and health outcomes can be monitored.

Dr. Rossouw.