Subgroup analysis of data from a large controlled trial suggests that the risk of stroke and venous thromboembolism (VTE) with raloxifene is generally consistent across a number of different subgroups, except that smokers are at a higher risk of stroke.

The trial (known as RUTH) aimed to determine whether raloxifene improved cardiovascular outcomes based on evidence from earlier studies that it improved some markers of cardiovascular risk. It involved 10,101 postmenopausal women who had coronary heart disease (CHD) or multiple risk factors for CHD. They were randomised to receive either raloxifene or placebo daily; primary outcomes were coronary events and invasive breast cancer, and a range of secondary outcomes was specified. The primary outcomes after about five years follow-up were reported in 2006 (NEJM 2006; 355: 125-37); this paper reports the analysis of strokes, stroke deaths, and VTE.

Participants in RUTH had a mean age of 67.5 years, and all were high risk – about half had pre-existing CHD and 46% had diabetes. There were 473 who had a stroke during the trial, and 98 stroke deaths.

As previously reported, there were more stroke deaths in the raloxifene group than in the placebo group, the difference just reaching statistical significance (59 versus 39; hazard ratio, 1.49; 95% CI, 1.00 to 2.24; p=0.0499): the absolute risk increase (ARI) was 0.07 per 100 women per year. Raloxifene was also associated with an increased risk of VTE (HR 1.44; 95% CI, 1.06 to 1.95; ARI, 0.12 per 100 woman-years).

Analysis across a wide range of subgroups showed no significant difference in overall stroke risk between raloxifene and placebo groups, except for current smoking (12.4% of the study population). In current smokers, raloxifene was associated with an increased risk compared to placebo (HR, 1.84; 95% CI, 0.98 to 3.48), whereas non-smokers had no increased risk (HR, 1.04; 95% CI, 0.86 to 1.26; interaction probability value 0.09).

The authors conclude that in this study of women at high risk of cardiovascular events, current smoking was associated with a significantly increased risk of stroke compared to non-smokers. This was the only sub-group analysed in which a significant effect was found.