Raloxifene benefits in breast cancer, increases risk of fatal stroke

The selective estrogen-receptor modulator (SERM) raloxifene reduces the risks of invasive breast cancer and vertebral fracture in postmenopausal women but also increases the risks of venous thromboembolism and fatal stroke, a study in the New England Journal of Medicine (NEJM) concluded.

And while the difference in the absolute rates of events that were decreased was similar to the difference in the absolute rates of events that were increased, raloxifene's effect on primary coronary events was not significant.

The RUTH (Raloxifene Use for The Heart) trial included 10,101 postmenopausal women (mean age 67.5 years) with coronary heart disease (CHD) or multiple risk factors for CHD. Each patient was randomly assigned raloxifene 60 mg daily (n=5,044) or placebo (n=5,057) and was followed for a median of 5.6 years.

Raloxifene was associated with an increased risk of fatal stroke-59 events versus 39 events (HR=1.49; 95% CI, 1.00–2.24; P=.05), an absolute risk increase of 0.7 invasive breast cancers per 1,000 women treated for 1 year. The drug also resulted in an elevated increase of venous thromboembolism-103 events versus 71 events (HR=1.44; 95% CI, 1.06–1.95; P=.02), an absolute risk increase of 1.2 events per 1,000 women treated.

The drug had no significant effect on the risk for primary coronary events: 533 events versus 553 events (HR=0.95; 95% CI, 0.84–1.07; P=.40) and is unlikely to reduce coronary risk >16% or increase the risk >7%, the researchers stated, based on the 95% confidence interval.

The coronary event results confirmed the results of the MORE trial, in which raloxifene had a null effect on coronary disease, but they did not provide support for the cardioprotective effect observed in a post hoc analysis of women at high cardiovascular risk who were in the MORE trial.

Raloxifene reduced the risk of invasive breast cancer-40 events versus 70 events (HR=0.56; 95% CI, 0.38–0.83; P=.003), which translates to an absolute risk reduction of 1.2 events per 1,000 woman-years. This benefit is probably related to estrogen antagonism resulting in regression of subclinical estrogen-receptor-positive cancers, the authors stated, although the exact reason is not clear.

As expected, raloxifene, which is approved for the treatment of osteoporosis in postmenopausal women, also lessened the risk of clinical vertebral fractures-64 events versus 97 events (HR=0.65; 95% CI, 0.47–0.89; P=.007), an absolute risk reduction of 1.3 events per 1,000 woman-years.

The patients administered raloxifene had significantly more hot flushes, leg cramps, and peripheral edema (P<.001 for the adverse events, compared with placebo), all of which have been previously documented to be associated with the drug's use.

"When considering the use of raloxifene in a postmenopausal woman, the clinician should take into account the individual woman's risk of disease and her personal preferences and weigh potential benefits against risks and against the availability of alternative interventions," the authors stated.

In an accompanying editorial, Marcia L. Stefanick, PhD, stated that the RUTH study "highlights the need to consider the risk of breast cancer as well as other risks and coexisting conditions in determining whether and when raloxifene or another SERM is warranted for an individual woman."

"For now, there is no magic bullet that can reduce the risks of major health problems related to estrogens and aging without introducing other potentially serious health concerns," Dr Stefanick stated.

SOURCES Barrett-Connor E, Mosca L, Collins P, et al, for the Raloxifene Use for The Heart (RUTH) Trial Investigators. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006;355:125–137.

Stefanick ML. Risk-benefit profiles of raloxifene for women. N Eng J Med. 2006;355:190–192.