Copenhagen, Denmark - Important new information on hormone replacement therapy (HRT) and the risk of MI has emerged from a Danish observational study [1]. Gynecologist Dr Ellen Lokkegaard (Rigshospitalet, Copenhagen, Denmark) and colleagues found that the type of HRT appears to be key when it comes to the likelihood of heart attack; they report their findings online September 30, 2008 in the European Heart Journal.

The study found no overall increased risk of MI in current users of HRT compared with women who had never taken it. But they did identify some preparations of HRT that appear safer with regard to MI than others: women taking hormones on a cyclical basis (estrogen every day with seven to 10 days of progestogen each month) and those using estrogen transdermal patches or vaginal gels had lower risks of MI than those taking continuous combined estrogen and progestogen therapy, the type of HRT used in the WHI trial.

Lokkegaard et al also found an increased risk of MI in younger women (aged 51-54) who had used continuous combined HRT compared with never users—something that is contrary to the results of previous studies—and an increasing risk with longer duration of use among these younger women, something that was not seen in the older age groups.

The study "does not change indications and recommendations about the duration of HRT. The main message is that when HRT is indicated for a woman, then a cyclical combined regimen should be preferred and that application of estrogen via the skin or vagina is associated with the lowest risk of MI," Lokkegaard told heartwire. And given the findings in younger women, she said that she would particularly encourage use of these lower-risk products in that age group.

In their national observational study—the largest to look at the effects of HRT since the WHI trial was stopped early—Lokkegaard et al followed all healthy Danish women aged 51 to 69 from 1995 to 2001 and obtained information on HRT use from a central prescription registry. During this time, 4947 MI incidents occurred.

Overall, they found no increased risk of MI with current use of HRT compared with women who never used HRT (relative risk 1.03). Age-stratified rate ratios (RRs) among women aged 51-54, 55-59, 60-64, and 65-69 years were: 1.24, 0.96, 1.11, and 0.92, respectively.

An increasing risk with longer duration of use was found for younger women that was not seen in older age groups. In all age groups, the highest risk of MI was found with a continuous combined HRT regimen—equating to a 35% increased risk of heart attacks overall compared with women who had never taken HRT.

No increased risk of MI was found with unopposed estrogen, cyclical combined HRT, or tibolone, and a significantly lower risk of MI was found with dermal routes of application. If the method of taking estrogen was via a patch or gel on the skin, the risk of MI was reduced by 38%, and for vaginal application, by 44%, compared with oral unopposed estrogen therapy.

It's quite a dramatic finding, and I would not recommend that younger women use a continuous combined HRT regimen.

Lokkegaard told heartwire she could not be sure that the findings in younger women "were real" because information was not available on all possible confounding factors. Nevertheless, she said, "It's quite a dramatic finding, and I would not recommend that younger women use a continuous combined HRT regimen. This is potentially of great clinical importance."

She explained that many women originally chose the continuous combined HRT regimen because it does not produce a monthly bleed, but that women—and in particular younger age groups—need to be informed that the inconvenience of a monthly bleed should be balanced against the increased risks of MI seen with this kind of product.

The decreased risk of MI with vaginal or dermal treatment is also interesting, she notes, adding that this is the first time vaginal preparations of estrogen have been tested in a large observational study.

"This study is the first, big observational study that addresses the influence of various regimens, doses, and routes of administration," she added. "In this 'postrandomized' era, where randomized studies on HRT are not easily performed, it provides important new information."