Elizabeth Barrett-Connor a and Cynthia A Stuenkel b disease, or in any other cardiovascular endpoint. In the first year of the trial there was actually a 50% increased risk in women on active treatment, with a suggestion that this was reversed later in the 4-year study. The late benefit may have been overstated in the publication; there was no significant trend toward less heart disease in the last 2 years when account is made for the increased risk in the first year. To better evaluate delayed benefit, a 3-year extended follow-up study is underway. The HERS results were unexpected and unpopular, and the trial has been criticized for many reasons. One common critique is that it is only one trial—with no other trial evidence of early harm. In fact, a review of 22 small published trials in 4124 women found a 1.4-fold increased risk of cardiovascular disease after short-term (usually less than 2 years) therapy. 17 A second paper that added data from six unpublished short trials in 645 women yielded a cumulative 1.8-fold increased risk of cardiovascular disease in women treated with (mainly unopposed) estrogen. 18

In 2000, the Women’s Health Initiative (WHI) investigators and participants were advised that a small increased risk of cardiovascular disease (both myocardial infarction and stroke) was observed in the first year of this very large (27 348 women) trial as well. 19 According to the press release, the excess risk was seen in WHI women with and without heart disease and in women using CEE alone or with MPA. These results appear to disprove two other common comments about HERS: that harm, if real, would be seen only in women on combined therapy or only in women with heart disease. Recently the results of the Estrogen Replacement and Atherosclerosis (ERA) study were published. 20 This study of 300 women randomly assigned to placebo, opposed, or unopposed estrogen found no change in coronary artery atherosclerosis after three years.(Coronary atherosclerosis was ascertained by angiography, which may be insensitive to changes that could be seen using coronary artery intravascular ultrasound.) It is therefore premature to conclude there is any immediate or delayed cardiovascular benefit from HRT, at least in its present most commonly prescribed regimens. Unfortunately, HERS, WHI, and ERA all used the same oral estrogen and dose, so nothing can be concluded about the possible benefit of other estrogens, other doses, other progestogens, or non-oral drug delivery. It should be noted, however, that a large majority of the observational studies initially suggesting benefit were conducted in the US where more than 80% of estrogen and progestogen used were the same products used in these trials.