The cardiovascular issue

Peter Collins
Department of Cardiac Medicine, National Heart and Lung Institute and Royal
Brompton Hospital, Faculty of Medicine, Imperial College, London, UK

There is a large body of biologic evidence which supports the notion that estrogens and progestins may have protective properties in the cardiovascular system. Despite this, four randomized clinical trials have now been published; all four studies found no benefit on cardiovascular outcomes. They have included just under 20 000 women followed for 3.5 years, on average. The two largest studies investigated the effect of hormone therapy on coronary endpoints in women with (secondary) and without (primary) cardiovascular disease. Oral continuous equine estrogen (0.625 mg) plus medroxyprogesterone acetate (2.5 mg) was used in the two larger trials, whilst unopposed oral estradiol valerate (2 mg) and transdermal 17ß-estradiol (80 mg per patch per day) and norethisterone acetate (120 mg per patch per day) were used as the intervention in the two smaller secondary prevention trials. The largest trial was the Women’s Health Initiative (WHI; n = 16 608) which was terminated early in 2002, the reason being an increased risk of breast cancer in the hormone therapy group. There was also, surprisingly, an increased risk of myocardial infarction associated with hormone therapy. The absolute risk of harm associated with estrogen–progestin therapy was small and translates to four additional coronary events for every 1000 women followed for 5.2 years. The reason(s) for these results and the relative disparity between the longterm observational studies of hormone therapy is unknown. There are a number of plausible reasons for the differences found in randomized versus observational trials of hormone therapy. The designs of the studies differ and the observational studies may be confounded by bias, compliance bias and the inability to detect short-term effects. Biologic effects such as differences in preparations, dose and the age of the subjects may all be possible reasons for the null effects of these studies. Oral estrogen differs from nonoral estrogen in that it increases levels of plasma triglyceride and inflammatory proteins, which may be detrimental.

At present, given the current evidence, hormone therapy should not be initiated or continued for the sole purpose of preventing cardiovascular disease. The argument against using hormone therapy for the prevention of cardiovascular disease is not that the likelihood of harm is high but that the potential harm outweighs the potential benefit. Intensive research is being conducted to determine estrogen doses and regimens that may result in cardiovascular protection and avoid the potential detrimental effects of estrogen. Ongoing and future clinical trials may help to answer these important questions, as there is much more to be learned about women’s health and the use of hormone therapy. A number of these issues will be discussed and comparisons made to other cardiovascular studies that have enrolled women, such as the statin trials, where interesting anomalies are also apparent with regard to cardioprotection.