Long-term follow-up of women in the oestrogen-only arm of the Women’s Health Initiative study found that compared with those receiving placebo, women treated with oestrogen had no increase or decrease in risk of cardiovascular disease outcomes and a decreased risk of breast cancer.

The Women’s Health Initiative included a number of intervention trials, one of which investigated the effects of hormone replacement therapy (HRT) with conjugated oestrogens alone in those who had hysterectomy. The trial stopped early due to an increase stroke risk and lack of other benefits in the active group: this report describes outcomes on long-term follow-up. Participants were post-menopausal women aged 50 to 79 who had previous hysterectomy; they were randomised to treatment with conjugated oestrogens or matching placebo. Primary outcome for the study was coronary heart disease. It was stopped after a mean of 7.1 years follow-up, a year before the planned end. At this point, 54% of participants had stopped taking study medication. Survivors were asked to participate in a long-term follow-up observational study: primary outcomes for this phase were coronary heart disease (CHD) and invasive breast cancer.

Of the original 10,739 women enrolled into the trial, 7,645 (78%) consented to long-term follow-up. This analysis covers the period from study end (March 2004) to mid-August 2009, with a mean follow-up duration of 47.2 months. A small proportion reported oestrogen use during the follow-up period (3.6% to 4.7% from the active group and 2.7% to 3.0% from the placebo group). Over this period, there was no significant difference between the two groups in the primary outcome with an annualised post-intervention CHD risk of 0.64% vs. 0.67% in the active and placebo groups (hazard ratio [HR], 0.97; 95% CI, 0.75 to 1.25).

Over 80% of women in each group had at least one mammogram during the study period, and the risks of breast cancer in the active and placebo groups during follow-up (0.26% vs. 0.34%; HR, 0.75; 95% CI, 0.51 to 1.09) were similar to those during the intervention phase (HR, 0.79; 95% CI, 0.61 to 1.02). Over the whole period, women in the active group had a small, but statistically significant reduction in breast cancer risk (0.27% vs. 0.35%; HR, 0.77; 95% CI, 0.62 to 0.95; P=0.02).

Risks for other outcomes did not differ between the active and placebo groups. In particular, the increased stroke risk seen during the intervention phase was not present during follow-up (0.36% vs. 0.41%; HR, 0.89; 95% CI, 0.64 to 1.24; P = 0.05 for difference), and nor was the increased risk of deep vein thrombosis and pulmonary embolism maintained during follow-up (0.28% vs. 0.39%; HR, 0.72; 95% CI, 0.51 to 1.03). For all cardiovascular events, the cumulative HR associated with oestrogen use was 1.06 (95% CI, 0.98 to 1.15).

The authors conclude that four years after termination of the study, the increased risk of stroke and venous thromboembolism seen during the trial had returned to normal, and there was no difference between the groups in other cardiovascular outcomes. The decrease in breast cancer risk seen during the intervention phase continued and over the whole study period became statistically significant. Analysis by age suggested greater safety and possible benefit on the main outcomes for younger women (age 50-59) and greater harm in those over 60.

An accompanying editorial comments on the study.