Results:

Of 4,532 women contacted, 727 were randomly assigned: 230 (31.6%) to o-CEE, 222 (30.5%) to t-E₂, and 275 (37.8%) to placebo. Of 727 randomly assigned women, 89.3% had at least one follow-up CIMT and 79.8% had CIMT at 48 months. Mean duration of treatment was 37.4 months for o-CEE, 34.6 months for t-E₂, and 37.6 months for placebo. Participants had a mean age of 52.7 years. The majority of participants had a college degree, never smoked, and earned an annual income of $60,000 or greater. None of the baseline characteristics differed significantly among treatment groups except for the high-density lipoprotein (HDL) cholesterol level, which was lower in the placebo group. Mean CIMT increases of 0.007 mm/year were similar across groups. The percentages of participants in whom CAC score increased did not differ significantly across groups. No changes in blood pressure were observed with o-CEE or t-E₂. Low-density lipoprotein and HDL cholesterol levels improved and levels of C-reactive protein and sex hormone–binding globulin, but not interleukin-6 increased with o-CEE. Insulin resistance decreased with t-E₂. Serious adverse events did not differ by treatment. Serious adverse events leading to study withdrawal included six cases of breast cancer (three in the o-CEE group, two in the t-E₂ group, and one in the placebo group) among eight diagnosed cases, one transient ischemic attack in the o-CEE group, one suspected stroke (later determined not to be) in the t-E₂ group, and two cases of venous thrombotic disease (one in the t-E₂ group and one in the placebo group).