Hormone Therapy Doesn’t Impact Long-term All-Cause, CV, or Cancer Mortality: WHI Analysis

Women who choose to take hormone therapy—whether estrogen alone or in combination with progestin—to curb menopausal symptoms have no higher or lower long-term risks of all-cause, cardiovascular, or cancer mortality than women who don’t take the drugs, according to long-term follow-up from the two Women’s Health Initiative (WHI) trials. Among individuals who start therapy in their 50s, there are also hints of a survival benefit.

The findings, from over 18 years of cumulative follow-up among more than 27,000 participants in the WHI studies, were published September 12, 2017, in the Journal of the American Medical Association.

“All-cause mortality is a critically important summary measure,” lead author JoAnn E. Manson, MD, DrPH (Brigham and Women’s Hospital, Boston, MA), told TCTMD. “It’s the ultimate bottom line when looking at the net effect of a medication on serious and life-threatening health outcomes. And this is particularly relevant to menopausal hormone therapy, which has a complex pattern of benefits and risks.

“We know that it’s effective for treating hot flashes and menopausal symptoms. It reduces hip fracture, other fractures, and it seems to decrease the risk of diabetes. But it also has been linked to increased risks of venous blood clots, stroke, and some cancers,” she continued. On that background, she said, the current results are “reassuring.”

All-cause mortality is . . . the ultimate bottom line when looking at the net effect of a medication on serious and life-threatening health outcomes. JoAnn E. Manson

Melissa McNeil, MD, MPH (University of Pittsburgh, PA), who wrote an editorial accompanying the paper, agreed that the news is positive and observed to TCTMD that the findings support current practice.

“What we say now is if you’re within 10 years of menopause and don’t have underlying cardiovascular disease, it is safe to start hormone therapy. And we knew that in the short term there would not be any adverse consequences,” McNeil said. “What we didn’t know before this study is, fast forward 20 years, if you got hormones in your mid-50s, what would be the impact on your heart when you were in your mid-70s?”

As McNeil put it, “If you take all-comers you can be reassured that there is no negative impact on mortality. Lifespan isn’t shortened for women who take hormone therapy.” But whether there is a real survival advantage for women in early menopause “is still unclear,” she said, “because of the statistical limitations of the study and because even though [they] followed these women for 18 years, [there was a] small number of outcomes.”

Nearly Two Decades of Follow-up

The WHI trials enrolled 27,347 postmenopausal women aged 50 to 79 years between 1993 and 1998. In one of the studies, women who had not had a hysterectomy were randomly assigned to receive placebo or daily oral estrogen plus progestin (median duration 5.6 years). The trial was stopped early due to an increased risk of breast cancer and overall risks exceeding benefits. In the second trial, women who had had a hysterectomy were randomized to placebo or daily oral estrogen alone (median 7.2 years); this trial was stopped early due to a heightened risk of stroke. Follow-up continued through the end of 2014, with mortality data available for more than 98% or participants.

In the new analysis, Manson and colleagues found that over cumulative 18-year follow-up, risks of all-cause mortality were similar in the hormone therapy and placebo groups, as were cardiovascular and cancer mortality. The same patterns were seen for patients on estrogen alone or with progestin.

Mortality Risk: Cumulative 18-Year Follow-up

Among women aged 50-59 years, hormone therapy was associated with a lower risk of all-cause mortality versus placebo (HR 0.69; 95% CI 0.51-0.94). This benefit was not seen among women aged 60-69 or 70-79 years.

Dementia and Breast Cancer

One “surprising” finding worthy of additional study, Manson said, is that the risk of death from Alzheimer’s disease and other forms of dementia was reduced among women who received estrogen alone (HR 0.74; 95% CI 0.59-0.94). The same was not true among those who also received progestin.

“There has been theory that estrogen is protective for cognitive decline, but this certainly was not supported by our earlier research in WHI on the diagnosis of dementia. If anything, higher rates were seen of developing dementia,” she noted. Here, though, researchers were looking at conditions that were severe enough to result in death. “We need to understand this better,” Manson said. “At this point we consider it exploratory and certainly not ready for prime time in terms of use of hormone therapy for cognition purposes.”

Also noteworthy is that breast cancer mortality was not increased with hormone therapy. In fact, with estrogen alone, the 18-year risk of dying of breast cancer was lower than with placebo (HR 0.55; 95% CI 0.33-0.92). Due to “heterogeneity” in risk between the two hormone-therapy cohorts, researchers chose not to pool them when calculating risk for this outcome.

According to McNeil, the takeaway, for now, is that although women on hormone therapy are more likely to be diagnosed with breast cancer, overall there appears to be “no impact on breast cancer mortality. That’s a little bit of a hard sell, right? Bad news you’ll get breast cancer, good news you won’t die from it.” That said, she feels it’s an important message for women who are afraid to take hormone therapy due to what they’ve heard about breast cancer. The mortality risk, McNeil said, is “on the order of having a couple of drinks a day.”

On a Backdrop of ‘Conflicting Data’

Observational studies dating back to the 1980s and 1990s initially had raised hopes that postmenopausal women on hormone therapy might live longer. But when the Women’s Health Initiative findings were first published in 2002, they not only showed no such benefit but also suggested therapy carried higher risks of MI, breast cancer and stroke, McNeil pointed out.

“We were sad that there wasn’t a prolongation of life and we were concerned that the increase in the heart attack, breast cancer, and stroke might mean, if followed longer, women who had received and/or were on hormones might in fact a worsening mortality,” she said. “So that’s where we stood at the end of the Women’s Health Initiative—we had conflicting data.”

For the right patient at the right time of her life, hormones [taken for 5 to 7 years] can be considered safe and effective, both in the short term and in the long term. Melissa McNeil

Despite the reassurance provided by the JAMA paper, there are some questions.

Both Manson and McNeil pointed out that rather than oral estrogen, today the preference is transdermal delivery, thought to be less apt to cause blood clots. Doses are also now lower. “If anything,” McNeil added, “what we would use today is probably safer. But again, long-term data sometimes surprises us.”

However, the prospect that future research will be able to fill in these gaps is slim, she said. “What we know about hormone therapy is that the risks and benefits really take a long time to see and require large, large numbers of women to be in the study. Those numbers are just financially untenable in this current climate.”

As a result, “clinicians are going to need to make decisions with the information we have,” McNeil advised, adding, “It’s all about individualizing. It requires a well-informed patient and a well-informed provider.”

Back “in the 70s hormones were good for everybody. After the Women’s Health Initiative [in 2002], we said they were poison and no one should take them,” she concluded. “And now the take-home message is that for the right patient at the right time of her life, hormones [taken for 5 to 7 years] can be considered safe and effective, both in the short term and in the long term.”