HRT: A 'Complex' Risk-Benefit Profile

By Kristina Fiore, Staff Writer, MedPage Today
Reviewed by F. Perry Wilson, MD, MSCE; Instructor of Medicine, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse

The breast cancer risk seen with combination hormone therapy in the Women's Health Initiative (WHI) trial persists in the long run, but estrogen alone may protect against it, according to long-term follow-up.

Over 13 years, the combination of estrogen and progestin (Prempro) was associated with a 28% increased risk of invasive breast cancer, comparable with the 24% greater risk seen in the original reporting of the trial, according to JoAnn Manson, MD, DrPH, of Brigham and Women's Hospital in Boston, and colleagues.

Conversely, null results for breast cancer with estrogen alone (Premarin) in women seen during the intervention who'd had a hysterectomy turned into a 21% decreased risk of the disease in long-term follow up, the researchers reported in the Oct. 2 issue of the Journal of the American Medical Association.

Although there were no significant cardiovascular effects in the long run, outcomes seemed to be worse with a longer time since menopause for women on the combination hormone therapy, and younger women did better than older ones on estrogen alone, they reported.

"Menopausal hormone therapy has a complex pattern of risks and benefits," the authors wrote.

"Although hormone therapy remains a reasonable option for the management of moderate-to-severe menopausal symptoms in early menopause, the findings from the WHI don't really support the use of hormone therapy for long-term chronic disease prevention," Manson told MedPage Today.

In 2002, the estrogen-plus-progestin arm of the WHI hormone therapy trial was stopped early, after an average follow-up of almost 6 years, because its risks were found to outweigh its benefits.

Halting of the estrogen-alone arm followed shortly after in 2004 over safety concerns as well.

Together, the two trials enrolled 27,347 postmenopausal women, ages 50 to 79, at 40 centers in the U.S. Those who still had a uterus were randomized to placebo or to estrogen-plus-progestin, while those with a prior hysterectomy were given either placebo or estrogen alone.

To assess whether those risks persist over time, Manson and colleagues followed the women through Sept. 30, 2010, for a mean total of 13 years.

About 80% of patients were followed through that time, but less than 4% of these women still used the therapy after the trials had officially ended.

Combination Therapy Arm

For combination therapy among women who still had their uterus, Manson and colleagues found that the increased risk of invasive breast cancer persisted during the 13 years of follow-up (hazard ratio 1.28, 95% CI 1.11-1.48).

A nonsignificant increase in heart disease also persisted, and while there didn't appear to be any effects by age, there was a trend for a difference by time since the onset of menopause.

Specifically, there was a significantly higher risk of coronary heart disease among women who were more than 20 years past menopause onset, as well as a significant difference by time since menopause onset for myocardial infarction (MI), the researchers reported (P=0.02).

Most of the other risks and benefits seen with combination hormone therapy during the intervention phase appeared to attenuate during the long-term follow-up, they found.

The initially observed 98% increased risk of pulmonary embolism fell to a borderline significant 26% (95% CI 1.00-1.59) increased risk, and a significant stroke risk persisted, but fell from a 37% increased risk to a 16% increased risk, they reported.

A reduced risk of hip fracture continued over 13 years (HR 0.81, 95% CI 0.68-0.97), and Manson and colleagues also saw a lower risk of endometrial cancer that didn't appear in the earlier part of the trial (HR 0.67, 95% CI 0.49-0.91).

Estrogen-Alone Arm

Women with a hysterectomy who were treated only with estrogen didn't have any significant effects on coronary heart disease or invasive breast cancer in the intervention phase, but during the 13-year follow-up, the drug seemed to significantly protect against breast cancer (HR 0.79, 95% CI 0.65-0.97).

Given that this vastly differs from the increased risk of breast cancer with combination therapy, the researchers said this "points to a determinant influence of progestin on the breast epithelium."

For coronary heart disease in this group, there was a nonsignificant trend for lower risk among younger women, and benefits for younger women in terms of MI became more pronounced over time, they reported (P=0.007).

Also, the 35% increased risk of stroke fell to 15% during the 13 years of follow-up, Manson and colleagues wrote.

There were no effects at all, for either group, in terms of all-cause mortality, they added.

Manson and colleagues concluded that although hormone therapy "is a reasonable option for the management of moderate-to-severe menopausal symptoms among generally healthy women during early menopause, the risks associated with hormone therapy ... preclude a recommendation in support of its use for disease prevention even among younger women."

Manson also told MedPage Today that the findings may assist clinicians in "improving individualization of the decision-making process" for women who are candidates for hormone therapy, adding that more information is needed on different formulations on hormone therapy and lower doses, as well as different routes of delivery such as the transdermal route.

"There is some evidence from observational studies that lower doses and transdermal estrogen may have a lower risk than the oral route at higher doses," Manson said, "but we don't have large randomized controlled trials with head-to-head comparisons, so much of this evidence remains inconclusive."

In an accompanying editorial, Elizabeth Nabel, MD, also of Brigham and Women's Hospital, agreed that hormone therapy has a "complex profile of risks and benefits."

"Even though short-term use of hormone therapy may be useful for menopausal symptom relief," Nabel wrote, "long-term use of hormone therapy for chronic disease prevention is not warranted."

A former director of the National Heart, Lung, and Blood Institute, Nabel noted the importance of the role of publicly-funded research in helping to better understand complex issues that change practice.

For original article click here.

The WHI was funded by the NHLBI. Wyeth-Ayerst donated the study drugs.

The researchers reported relationships with Novartis, Amgen, AstraZeneca, Pfizer, Educational Concepts Group, Merck, and the Ologen Collagen Matrix Study.

The editorialist reported no conflicts of interest.

Primary source: Journal of the American Medical Association
Source reference: Manson JE, et al "Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials" JAMA 2013; 310(13): 1353-1368.

Additional source: Journal of the American Medical Association
Source reference:Nabel EG "The women's health initiative – A victory for women and their health" JAMA 2013; 310(13): 1349-1350.