Effects of the selective estrogen receptor modulator raloxifene on coronary outcomes in the Raloxifene Use for The Heart trial: results of subgroup analyses by age and other factors

Abstract

Background: The Raloxifene Use for The Heart (RUTH) trial showed that raloxifene, a selective estrogen receptor modulator, had no overall effect on the incidence of coronary events in women with established coronary heart disease or coronary heart disease risk factors. We provide detailed results of the effect of raloxifene on coronary outcomes over time and for 24 subgroups (17 predefined, 7 post hoc).

Methods and results: Postmenopausal women (n=10 101; mean age, 67 years) were randomized to raloxifene 60 mg/d or placebo for a median of 5.6 years. Coronary outcomes were assessed by treatment group in women with coronary heart disease risk factors and those with established coronary heart disease. Raloxifene had no effect on the incidence of coronary events in any subgroup except in the case of a post hoc age subgroup analysis using age categories defined in the Women's Health Initiative randomized trials. The effect of raloxifene on the incidence of coronary events differed significantly by age (interaction P=0.0118). The incidence of coronary events in women <60 years of age was significantly lower in those assigned raloxifene (50 events) compared with placebo (84 events; hazard ratio, 0.59; 95% confidence interval, 0.41 to 0.83; P=0.003; absolute risk reduction, 36 per 1000 women treated for 1 year). No difference was found between treatment groups in the incidence of coronary events in women > or =60 and <70 or > or =70 years of age.

Conclusions: In postmenopausal women at increased risk of coronary events, the overall lack of benefit of raloxifene was similar across the prespecified subgroups.

Trial registration: ClinicalTrials.gov NCT00190593.

Figure 1

Cumulative incidence for (A) primary coronary outcome, (B) nonfatal MI (including silent MI), (C) hospitalized ACS (HACS) other than MI for the entire cohort (n = 10 101), and (D) coronary death. Cumulative incidence for the primary coronary outcome for (E) women with CHD risk factors (n = 5067) and (F) women with established CHD (n = 5034).

Figure 2

Effect of raloxifene on the primary coronary events by subgroup. HRs and 95% CIs are shown. BMI indicates body mass index; CABG, coronary artery bypass graft; CV, cardiovascular; ACE, angiotensin-converting enzyme; and ARB, angiotensin receptor blocker.

Figure 3

Effect of raloxifene on the incidence of the primary coronary end point (coronary death, nonfatal MI, or hospitalized ACS other than MI, whichever occurred first) by age. The vertical line at 60 years of age was based on the post hoc analysis to match the Women’s Health Initiative age categories.

Figure 4

Differences in mean percentage change in cardiometabolic risk factors and blood pressure from baseline in the raloxifene vs placebo group. Horizontal lines represent the 95% CIs. The differences between groups were significant (P < 0.05) for total cholesterol, LDL, HDL, non-HDL cholesterol, ratio of cholesterol to HDL, fibrinogen, body mass index, and weight. The data on the right indicate the mean percent changes in the parameters for the placebo and raloxifene groups.