The drug raloxifene, currently marketed in the United States as Evista for the prevention and treatment of osteoporosis in postmenopausal women, had no significant effect on coronary events in a placebo-controlled clinical trial of more than 10,000 women from 26 countries who had known coronary heart disease or were at high risk for heart attack. Raloxifene did, however, reduce the risk of invasive breast cancer and clinical vertebral fractures in the trial group, which was followed for an average of 5.6 years.
Results of the RUTH study (Raloxifene Use for the Heart) are published in the July 13 issue of the New England Journal of Medicine. Nanette Wenger, MD, professor of medicine at Emory University School of Medicine and chief of cardiology at Grady Memorial Hospital, served as principal investigator for the RUTH trial at Emory and was the co-principal investigator for this international study.
"Overall there was no effect on coronary events--no increase and no decrease," Dr. Wenger said. "The lack of increase is important, given the adverse coronary events that were seen with estrogen/progestin therapy. Importantly, there was a reduced risk of invasive breast cancer in these women. There was also a reduced risk of clinical vertebral fractures, as has been shown in other studies. The harms included an increase in fatal stroke risk, although the number of total strokes did not differ between the raloxifene and the placebo group. As anticipated, there was an increased risk of venous thromboembolism, which has been known with raloxifene and is included on the package insert concerning its use for osteoporosis."
The RUTH trial was a placebo-controlled study designed to assess the effect of raloxifene on the risk of coronary events, such as heart attack, and the risk of invasive breast cancer in postmenopausal women who had cardiovascular heart disease (CHD) or multiple risk factors for CHD. Raloxifene is a nonsteroidal selective estrogen-receptor modulator (SERM) that binds to estrogen receptors, causing estrogen-like effect in some tissues and acting as an estrogen antagonist in others, such as in breast tissue.
According to the study results, raloxifene reduced the risk of clinical vertebral fractures, but not of nonvertebral fractures. However, raloxifene increased the relative risks of venous thromboembolism (44 percent) and fatal stroke (49 percent). Other adverse outcomes reported to be more common with raloxifene included hot flashes, leg cramps, peripheral edema, and gallbladder disease.
Between June 1998 and August 2000, 10,101 post-menopausal women were randomly assigned to treatment with raloxifene or placebo at 177 sites in 26 countries. Eligible women were 55 years of age or older, were one year or more postmenopausal, and had established CHD or were at increased risk for CHD. Of the 5,057 women who took the placebo, 595 died and 483 discontinued the study. Of the 5,044 given raloxifene, 554 died and 430 discontinued the study.
Of those given the placebo, 553 experienced cardiovascular events such as acute myocardial infarction, sudden death, heart failure, or death related to a coronary-artery procedure, compared to 533 who were given raloxifene. There were 40 cases of breast cancer reported for those taking raloxifene compared to 70 for those taking the placebo. The incidence of fatal stroke was 49 percent higher in the raloxifene group than in the placebo group, although total stroke did not differ between groups. Investigators reported 103 events related to venous thromboembolism in the raloxifene group compared to 71 events for those taking the placebo.
"The conclusion from the study is that the benefits of raloxifene in reducing the risk of invasive breast cancer and vertebral fracture should be weighed against the increased risk of venous thromboembolism and fatal stroke," Dr. Wenger says.