Director of Preventive Cardiology, St. Luke’s-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, NY.
The Women’s Health Initiative (WHI)—the largest federally funded study of women’s health, the study that arose in response to long-standing complaints that our medical knowledge was based on the 70-kg white male—was supposed to give us answers.
But in February 2006, 2 of the world’s most prestigious medical journals published a series of reports from the WHI that seemingly raised more questions than answers. To make matters worse, headlines and sound bites carried the breaking news to the public, with proclamations that were absent the specifics needed to appreciate the uncertainties of medical research.
Back up a bit to the early 1990s and the start of the WHI. The National Institutes of Health funded this multicenter, randomized trial of postmenopausal women, aged 50 to 79 years, to assess the risks and benefits of hormone replacement therapy and dietary modification. At that time, observational studies had suggested that estrogen replacement and low-fat diets were beneficial for the prevention of osteoporosis and breast cancer, respectively. However, in July 2002, the estrogen-plus-progestin arm of the trial was stopped early following preliminary results showing that this regimen was associated with an increased risk of breast cancer, coronary events, stroke, and venous thromboembolism.
In February 2004, the estrogen-only arm (in women with hysterectomies) was also halted because of the findings of lack of effect of this therapy on heart disease but an increase in the number of strokes. There was a decrease in the number of hip fractures, but the benefits of this regimen were not thought to outweigh the risks.
Although the participants were asked to stop taking hormones, other aspects of the trial went on, including dietary modification. Monitoring continued for approximately 8 years. In February 2006, the Journal of the American Medical Association published 3 reports (JAMA. 2006;295:629-642; 634-654; 655-666), each concluding that low-fat diets did not seem to reduce the risk of coronary heart disease, stroke, invasive breast cancer, or colorectal cancer. At the same time, 2 reports were published in the New England Journal of Medicine (2006;354:669-683; 684-696) suggesting that calcium and vitamin D did not reduce the risk of osteoporotic fractures or colorectal cancer.
The media, used to reporting medical findings as straightforward and with certainty, now had to report an about-face to a public that had been told for years to eat right—right being a low-fat diet with plenty of calcium and vitamin D. Now, who was right and who was wrong?
Lost in the public media frenzy was the knowledge, common in the medical world, that “discoveries” do not just happen. They are developed with years of research and based on many, many studies, some contradictory. Studies use different methods with different populations. And most studies have acknowledged limitations.
A closer look at these recent reports shows that the findings were not so un?expected, given the limitations. In an accompanying editorial to the New England Journal of Medicine article on calcium plus vitamin D and fractures, Joel S. Finkelstein, MD (N Engl J Med. 2006;354:750-752) discussed several aspects of the study design that may have reduced the chances of showing a benefit. Participants were not selected on the basis of high risk for osteoporotic fractures. Any study with relatively healthy people makes it much harder to show a reduction in adverse events. In addition, the dose of vitamin D used was less than what is recommended now and may have been too low to provide a benefit. Also, many of the women in the placebo group were taking supplemental calcium and vitamin D on their own—thereby blurring the distinction between the control and treatment groups. Last, the study may not have been powered to detect a reduction in the rate of hip fractures, as the number of fractures in the placebo group was half what was predicted.
The studies in JAMA reporting on a low-fat diet also had limitations. First of all, the women assigned to the low-fat diet were asked to reduce their intake to 20% of total calories. They averaged 24% in the first year and were up to 29% by the sixth year. The comparison group was at 37%. So the hypothesis about a low-fat diet was never truly tested, and the power to detect differences between the groups was not achieved. The trial was not designed to specifically lower saturated fat and trans fatty acids; both were believed to increase the risk of cardiovascular disease. The diet also did not specifically address modifications that would lower blood pressure, and, hence, the impact on blood pressure was small and limited to diastolic blood pressure.
So, did any useful information come out of these studies? The low-fat diet group did not achieve a statistically significant reduction in risk of breast cancer, but several trends were observed that support dietary modifications to reduce cancer risk. There were also trends toward a greater reduction in coronary heart disease events in those with lower intakes of saturated or trans fat or greater intakes of fruits and vegetables. In their accompanying editorial (JAMA. 2006;295:693), Cheryl A. M. Anderson, PhD, MPH, and Lawrence J. Appel, MD, MPH, state that the “WHI investigators designed an intervention that was feasible and state-of-the-art at the time the study was initiated.” Despite the null findings, “the results from WHI have implications for the design of future lifestyle intervention trials in which cardiovascular disease is an outcome.”
To put the WHI results into perspective, it is important to look back on other medical practices once considered standard but later debunked. At one time, patients with heart attacks were put on complete and prolonged bed rest; now they are up and about as soon as possible.
The WHI did not produce results that were expected or that fit neatly in with existing information. Many editorials and public comments later, the investigators are still trying to reconcile the findings. So, what is a woman to do? There is still powerful evidence that diet is important in maintaining health and preventing disease. Will recent research discount that? Perhaps. In the meantime, physicians and the media must strive to present research as black and white - as well as gray.