Participants gave informed consent before the study.
Before 2002 the effects of hormone replacement therapy were believed to be beneficial, owing to a reduction in risk of cardiovascular disease, osteoporosis, and colon cancer.1 The negative side effects—an increased risk of breast cancer and thromboembolic disease—were thought to be outweighed by the advantages, principally on the basis of results from observational studies.2 3 In 2002 the primary results from the Women’s Health Initiative showed no cardiovascular benefit from hormone replacement therapy.
These conflicting results have led to the “timing hypothesis”; the idea that the differences in cardiovascular outcome can be accounted for by time since menopause until the start of hormone therapy.4 5 The observational studies mainly have shown positive cardiovascular effects, probably as a result of hormone therapy starting shortly after menopause, and the randomised studies have shown no or negative cardiovascular effects, often in women who start hormone therapy many years (5 to 20) after menopause.
Using the Danish national hospital discharge register, which covers all contacts to Danish hospitals, we identified women who had been admitted to hospital for a cardiovascular event.
The register was founded in 1977 and includes information on discharge diagnoses and date of discharge assigned exclusively by the doctor at discharge according to the , eighth revision until the end of 1993 and the 10th revision from 1994.
We advised the women that if they had health concerns they should contact their own general practitioner or gynaecologist. However, as data published from other trials at the time of the 10 year visit indicated that use of hormone replacement therapy might result in more harm than benefit in postmenopausal women we advised our study participants to stop treatment.11 After their 10 year visit we followed the participants in national registers, which provide data on all hospital contacts or deaths.
The primary endpoint for this study was a composite of death, admission to hospital for myocardial infarction, or heart failure.
Of these, 1006 were randomly allocated (open label) to receive hormone replacement therapy (n=502) or no treatment (n=504); the remaining 1010 women had a personal choice (of these, 221 opted for hormone replacement therapy).
The results presented here are based solely on the randomised groups.
We prespecified and adjudicated cardiovascular disease as well as cancer as safety outcome measures.
Secondary endpoints were the individual components of the primary endpoint and admission to hospital for stroke.
The criteria for inclusion in the study were healthy, recently postmenopausal white women aged 45-58, with last menstrual bleeding 3-24 months before study entry or perimenopausal symptoms (including irregular menstruations) in combination with recorded postmenopausal serum follicle stimulating hormone values (2 standard deviations over the premenopausal mean).