Effects of Raloxifene on Cardiovascular Events and Breast Cancer in Postmenopausal Women

Abstract

Raloxifene is a nonsteroidal selective estrogen receptor modulator that has favorable effects on markers of cardiovascular risk and has been associated with a reduced risk of coronary heart disease (CHD) in postmenopausal women. Raloxifene also has antiestrogenic effects on the breast and in animals has suppressed the growth of estrogen-stimulated mammary cancers. The Raloxifene Use for The Heart (RUTH) trial was a randomized, double-blind, placebo-controlled study carried out at 177 sites in 26 countries. The 10,101 participants were women aged 55 and older who were at least 12 months postmenopausal and who either had established CHD or were at increased risk. They were assigned to receive either 60 mg raloxifene orally each day or a placebo. The 2 groups were similar in baseline characteristics except for slightly higher cardiovascular risk scores for women assigned to raloxifene. During a median follow up of 5.6 years, no significant differences were found with respect to deaths from coronary causes, nonfatal myocardial infarction, or hospital admission because of an acute coronary syndrome. Women with established CHD and those at increased risk for CHD had similar outcomes. For the primary coronary outcome, the results of as-treated analyses were comparable to those of intention-to-treat analyses. Raloxifene was associated with a decreased incidence of invasive breast cancer; the hazard ratio was 0.56 with a 95% confidence interval of 0.38 to 0.83. The absolute risk reduction for every 1000 women given raloxifene for 1 year was 1.2 cases for both invasive breast cancer and estrogen receptor-positive invasive breast cancer. Among secondary outcomes, the incidence of stroke did not differ significantly between the raloxifene and placebo groups, but fatal strokes were 49% more frequent in raloxifene-treated women. Venous thromboembolic events were 44% more frequent in the raloxifene group. Incidence rates of all breast cancers and of clinical vertebral fractures were lower in the raloxifene group. More than 90% of women in both groups reported adverse events. Rates of discontinuance because of side effects were 22% in the raloxifene group and 20% in the placebo group. Serum levels of low-density lipoprotein cholesterol declined in women given raloxifene but increased in placebo recipients. Levels of high-density lipoprotein cholesterol increased in both groups but more so in women treated with raloxifene. Raloxifene treatment, given for a median of over 5 years to postmenopausal women at increased risk of CHD, did not significantly alter CHD risk in the RUTH study. Its beneficial effects in lowering the risk of invasive breast cancer and vertebral fracture must be weighed against increased risks of fatal stroke and venous thromboembolism.