What Can We Learn from Design Faults in the Women's Health Initiative Randomized Clinical Trial‪?‬

The WHI is a study that was designed to allow randomized controlled evaluation of three distinct interventions: 1. a low fat eating pattern, hypothesized to prevent breast cancer and colorectal cancer and, secondarily, coronary heart disease; 2) hormone replacement therapy (HRT), hypothesized to reduce the risk of coronary heart disease and, secondarily, to reduce the risk of hip and other fractures, with increased breast cancer risk as possible adverse outcome; and 3. calcium and vitamin D supplementation, hypothesized to prevent hip fractures and, secondarily, other fractures and colorectal cancer. (1) Both estrogen in combination with progesterone (E+P) and estrogen-only (E) arms were terminated prematurely after 5 and 8 years, respectively, although an observational study continues. Briefly, the absolute increase in events for the E+P arm of WHI was as follows: seven more cases of coronary artery disease and eight more cases of invasive breast cancer per 10,000 women per year. However, final results of WHI E+P arm showed that both nominal and adjusted confidence intervals for heart disease or breast cancer either touched or crossed 1 and therefore were not statistically significant. As for the results of the E-only arm, there were five fewer coronary events and seven fewer invasive breast cancer events per 10,000 women per year. The smaller number of coronary and breast cancer events in the E-only arm did not reach a statistical significance. (2) Both arms showed an increased rate of thromboembolic events and stroke. Both arms showed protection against fractures, but with protection against colon cancer only in the E+P arm. (3) These results have been widely generalized as a negative risk-benefit ratio for HRT in menopausal women. The WHI results are at odds with the results of numerous large observational studies that, on average, showed significant (approximately 40% reduction) protection against cardiovascular disease. The main design flaw was to study a population that did not approximate the populations of the observational studies that inspired the WHI