Hormone Therapy Given Closer to Menopause Onset Is Safest

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April 7, 2007 — There is new evidence that timing of initiation of hormone therapy (HT) may determine the extent of its cardiovascular effects, this time from a new analysis of the Women's Health Initiative (WHI) randomized controlled trials. The study suggests that coronary heart disease (CHD) risk associated with hormone therapy is not significantly increased in women who take hormone therapy within 10 years of the onset of menopause, and even showed a trend toward reduced CHD risk, but that this risk increases if women start taking hormone therapy after a longer gap. Risk for stroke, however was increased at any time point postmenopause.

Lead author Jacques E. Rossouw, MD, from the National Heart, Lung, and Blood Institute in Bethesda, Maryland, emphasized to heartwire that the findings should be viewed as "reassuring" for younger women with moderate to severe menopause symptoms who have worried about the risks of starting hormone therapy. The study should not, however, be viewed as supporting any role for hormone therapy to reduce cardiovascular events.

"This analysis should be appreciated mainly for the somewhat positive message for the short-term use of hormone therapy for menopausal symptoms," he said. "For those women who were afraid to use it before, there's some encouragement here that it might be a reasonable thing to do in the short term. But it doesn't change anything about our overall recommendations, that is, you don't use hormone therapy for the prevention of heart disease at any age."

Studies Combined
Rossouw and colleagues report the results of the WHI analysis in the April 4 issue of JAMA. While subgroup analyses of both the estrogen-only WHI trial, as well as the estrogen plus progesterone WHI trial have suggested a trend toward reduced CHD deaths in women age 50 to 59 years, this new analysis, combining the 2 studies, carries greater statistical power for assessing the association, authors say.

For their study, Rossouw and colleagues evaluated CHD outcomes and "other" outcomes among the 10,739 postmenopausal women who had undergone a hysterectomy, randomized to either placebo or estrogen in the estrogen-only WHI study and among the 16,608 postmenopausal women, without hysterectomy, randomized to placebo or estrogen plus progesterone in the combination therapy study. All women were between the ages of 50 and 79 years and recruited from 1 of 40 US centers in the 1990s.

When analyzed by time since menopause began, risk for CHD and risk for total mortality was nonsignificantly reduced in patients taking hormone therapy within 10 years of menopause, but rose as time since menopause increased. Risk for stroke, however, was elevated across all time points. In an age-based analysis, the number of events increased with age, but there was no statistically significant added effect of hormone therapy for any outcome, by age, although risk for CHD events tended to be higher in women without prior cardiovascular disease.

"What the findings suggest is that CAD [coronary artery disease] risk from hormones is not increased close to menopause; however there is increasing risk in women from hormone therapy as they move further from the menopause," Dr. Rossouw commented. "We also find that the stroke risk from hormones is increased irrespective of years since menopause. Finally, we found that the increased risk in the older women is really confined to those who have persistent hot flashes and night sweats and in part that seems to be because those women have more of the conventional risk factors like high blood pressure, high cholesterol, diabetes, overweight, and so forth, and that's a new finding, too."

Hormone Therapy: No Role for CVD Prevention
Dr. Rossouw cautioned that the finding of a trend toward reduced CHD events in women who were closer to menopause should not be overblown. "We know for sure that older women who start [hormone therapy] are at higher risk, so even if you have lower risk when you started, we have no way of being sure that if you start early and continue for ten or twenty years that any benefit or lack of harm will persist. As women get older, their arteries get older, and so at what point does any potential benefit switch to risk? That's really unknown, and unknowable, because you could never do such long term trials."

As such, he says, "The recommendation that hormone therapy not be used for preventing heart disease stands. This supports that. But it's also an approved indication that it can be used for women with moderate to severe menopausal symptoms and those are symptoms that interfere with daily activities."

The stroke findings, however, suggest that any woman considering hormone therapy soon after the start of menopause should be screened for stroke risk factors, primarily high blood pressure, Dr. Rossouw said. The risk for breast cancer also needs to be taken into account, the authors note, pointing out that in this study, 72 cases of breast cancer occurred in women with less than 10 years since menopause while they were taking estrogen plus progesterone compared with 57 cases among women taking placebo.

To heartwire, Dr. Rossouw reiterated that the study findings are in keeping with current recommendations that specify hormone therapy should only be used short term, to treat moderate to severe vasomotor symptoms, and primarily in younger women close to menopause.

While other studies have indicated that hormone therapy may have CHD benefits — or at least less risk — in women younger than 50 years, or in women who are even closer to last menstrual period, the current analysis was not powered to look at this interaction. Researchers are exploring this possibility in other studies and are also investigating whether it is younger age or time since menopause that is more important. Preliminary statistical tests for strength of the trend suggest it is the delay postmenopause, not age, that may be more important, but this is only hypothesis-generating at this stage, Dr. Rossouw commented.

"It seems that it's the lowering of estrogen levels, rather than age, which is somewhat more important, but it's hard to be sure, because they are so highly correlated," he said. "For what it's worth, we think that years since menopause, that is, years since reproductive hormone levels were decreased either naturally or surgically, seem to be the more important factor. It does support a hormone hypothesis."

Commenting on the study to heartwire, Marian C. Limacher, MD, FACC, from the University of Florida, Gainesville, who was an original investigator for the WHI but not an author on the current study, said the analysis "lends hard data to some of the speculation" on the hormone therapy timing hypothesis.

"It's not a perfect confirmation of the theory that beginning hormone therapy before vascular injury is protective, but it is somewhat reassuring that women who are closer to menopausal years did not have an increase in CV [cardiovascular] endpoints."

She also warned of the hazards of over-interpreting the stroke endpoint, since the absolute number of events in both the hormone therapy and placebo groups was very small, particularly in the youngest age group (44 [0.98%] of 4476 patients in the hormone therapy group and 37 [0.85%] of 4356 in placebo-treated patients aged 50 - 59 years).

Risk vs Benefit Clear in Older Women
During a Wyeth-sponsored teleconference discussing the WHI article, Lila Nachtigall, MD, from the New York University School of Medicine, suggested that the WHI analysis should be reassuring not only for younger women "who have really been suffering from hot flashes" but worried about starting hormone therapy, but also their cardiologists.

"Their cardiologists often take them off [hormone therapy] if we put them on because they're so afraid that we're increasing the risk of heart disease, which clearly we're not doing," Dr. Nachtigall stated.

But Dr. Limacher pointed out to heartwire that most of the women seeing a cardiologist would be older than 60 years. "Most of the patients being seen by the typical cardiologist will be older, and there is no evidence that hormone therapy should be continued; in fact, the longer one is away from the age of menopause, the higher the risk. I think it is reasonable for cardiologists treating patients largely with or at high risk for coronary disease to recommend discontinuation of these forms of hormone therapy."

JAMA. 2007;297:1465-1477.


Source: http://www.medscape.com/viewarticle/554659?src=mp