Raloxifene May Increase Fatal Stroke Risk in Postmenopausal Women

Susan Jeffrey

December 15, 2006

December 15, 2006 (Chicago) — Further secondary analysis from the Raloxifene Use for the Heart (RUTH) trial shows that although the overall risk for stroke was not increased with treatment with raloxifene (Evista, Eli Lilly) over placebo, there was a small increased risk of fatal stroke in women receiving raloxifene.

Lori J. Mosca, MD, from Columbia University, in New York, presented these data at the American Heart Association Scientific Sessions 2006.

"In our study of more than 10,000 postmenopausal women who had or were at increased risk for coronary heart disease, treatment with raloxifene for more than 5 years had no overall effect on stroke incidence and no overall effect on total mortality," Dr. Mosca concluded. "However, the incidence of death due to stroke was higher in the raloxifene group compared with placebo."

"The risk/benefit ratio of raloxifene in postmenopausal women with a history of stroke or other significant stroke risk factors should be considered when making treatment decisions about raloxifene," she concluded.

Raloxifene and Breast Cancer Benefit

The RUTH trial enrolled 10,101 postmenopausal women with coronary heart disease or multiple CHD risk factors and randomized them to receive either 60 mg per day of raloxifene, a selective estrogen-receptor modulator (SERM), or placebo (Barrett-Connor E et al. N Engl J Med. 2006;355:125-137). Primary end points of the trial were death from coronary causes, MI, hospitalization for an acute coronary syndrome, and invasive breast cancer. The average age of participants was 67.5 years, and they had been postmenopausal for approximately 20 years.

After a median follow-up of 5.6 years, raloxifene was shown to have no significant effect on the risk for primary coronary events but was associated with a significantly lower risk for invasive breast cancer, with a 44% reduction compared with placebo. There was also a substantial reduction in vertebral fractures with raloxifene.

However, although the rates of death from any cause or total stroke were not significantly different between groups, raloxifene was associated with an increased risk for fatal stroke and venous thromboembolism (VTE).

In this present analysis, Dr. Mosca and colleagues looked more closely at the stroke events, overall and according to subgroups. Stroke and all-cause mortality were prespecified secondary end points. Strokes were adjudicated by a neurologist blinded to treatment assignment, she noted.
"There was no significant impact of treatment on stroke overall or by any of these subtypes: hemorrhagic, ischemic, or undetermined," Dr. Mosca said.

RUTH: Stroke Events in Postmenopausal Women Treated With Raloxifene vs Placebo (Number of Events [Annualized Rate, %])

End point
HR (95% CI)
224 (0.86)
249 (0.95)
1.10 (0.92 – 1.32)
30 (0.11)
18 (0.07)
0.59 (0.33 – 1.06)
171 (0.65)
198 (0.75)
1.15 (0.93 – 1.41)
30 (0.11)
39 (0.15)
1.28 (0.80 – 2.07)

There was no difference between groups in total mortality, but there was a significant increase in fatal stroke in women treated with raloxifene vs those on placebo that became evident after 3 years, she noted.

RUTH: Retrospective Analysis of Deaths Due to Stroke by Stroke Subtype
End point
HR (95% CI)
Fatal stroke, n (annualized rate %)
39 (0.15)
59 (0.22)
1.49 (1.00 – 2.24)

When they looked retrospectively at stroke subtypes, the primary contribution to deaths due to stroke were due to ischemic strokes, although there were a number of deaths due to underdetermined causes or that were unadjudicatable, she noted, 11 in the placebo group and 19 in the raloxifene group. There was a slight trend toward a decrease in deaths due to hemorrhagic stroke with treatment, she said.

RUTH: Retrospective Analysis of Fatal Strokes by Subtype
End points
HR (95% CI)
All stroke deaths
1.49 (1.00 – 2.21)
Hemorrhagic stroke deaths
0.82 (0.36 – 1.90)
Ischemic stroke death
1.79 (0.97 – 3.30)
Undetermined stroke death or unadjudicatable
1.71 (0.81 – 3.59)

They performed 20 subgroup analyses for stroke and also for stroke deaths. "Overall, for total strokes and for deaths due to stroke, there were no significant interactions except for smoking," she said. There was a wide confidence interval, but those who were current smokers had an elevated hazard ratio over nonsmokers, she said. There was a trend to higher risk with treatment in women with a prior history of atrial fibrillation, stroke, and left ventricular hypertrophy, but none of these interactions reached statistical significance.

There were some limitations to their analysis, Dr. Mosca pointed out. The definition of a cerebrovascular death was not prespecified in the protocol; it was determined that all cerebrovascular deaths were due to strokes through a post hoc review of the 98 cases. The analysis of death due to stroke by stroke subtype was also post hoc and based on the last adjudicated stroke, she noted, and they did not collect data on stroke severity.

A Chance Finding?

This finding of no effect on overall stroke rates but an increase in fatal stroke was seen previously in the Women's Estrogen for Stroke Trial (WEST), where women with prior stroke were treated with estradiol therapy (Viscoli CM et al. N Engl J Med. 2006; 345:1243-1249), Dr. Mosca said. Other studies of hormonal agents such as the Women's Health Initiative have shown increases in the overall incidence of stroke, but not fatal stroke, she noted.

The mechanisms by which hormonal therapy or SERMs such as raloxifene might increase fatal stroke may relate to prothrombotic effects, she added, "but the challenge is that there seems to be quite mixed effects in terms of the thrombotic effects — it's very difficult mechanistically to explain our finding."

"Of course it could always be due to chance," she added, "but my concern is that we've observed VTE risk, prothrombotic risk, with similar types of agents. We've now observed this stroke finding for hormone therapy, estrogen alone, estrogen plus progestin, tamoxifen, and now raloxifene, although this finding was limited to fatal strokes."

After her presentation, an audience member asked whether she thought this borderline effect was really likely to be a true finding.

"You're correct in that it's a very borderline finding, and there is the possibility that this could be due to chance," she reiterated. "My personal opinion is that it is not. In the context of all that we know about hormonal agents and nonhormonal agents for menopausal conditions, there are trends that lead me to believe that this could possibly be a real finding, one that we should actively pursue and begin to understand what those thrombotic mechanisms might be, so that we can, again, identify women who can enjoy the benefit of therapy but not necessarily be put at risk by being on therapy."

Dr. Mosca reported that she is a consultant for Eli Lilly, maker of raloxifene and sponsor of the RUTH trial.

AHA 2006 Scientific Sessions: Abstract 2181.


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