USPSTF Recommendation Against HRT for Chronic Conditions Stands

Nancy A Melville

May 16, 2017

UPDATED — The US Preventive Services Task Force has issued a draft recommendation upholding its previous position of recommending against the use of hormone-replacement therapy (HRT), including either estrogen alone or combined with progestin, for the prevention of chronic conditions.

"The benefits of using menopausal hormone therapy to prevent chronic conditions like heart disease and diabetes do not outweigh the harms in women who have gone through menopause," said task force member Maureen G Phipps, MD, MPH, in a press statement.

Critics of the recommendation, however, include a primary investigator on the task force's main source of evidence for the recommendation — the pivotal Women's Health Initiative (WHI) clinical trial.

"Women with indications for menopausal hormone therapy will likely continue to be frightened away from its use — even for vasomotor symptoms — because the lack of change in the USPSTF recommendations will perpetuate the scare that began with the misrepresentation of the WHI findings implying breast-cancer risk and lack of coronary benefit in 2002," Robert D Langer, MD, an associate dean for clinical and translational research and professor of family medicine at the University of Nevada Reno School of Medicine, told Medscape Medical News.

Used by nearly half of postmenopausal women in the country during the late 1980s and 1990s, HRT utilization plummeted to as low as 4.7% by 2010, primarily as the result of 2002 WHI findings.

As argued by Dr Langer and many others, the risk was shown to be largely limited to women in the study who initiated HRT more than 10 years after menopause, while findings indicating prevention of coronary heart disease and reduced breast cancer in women who started hormone therapy before the age of 60 were largely ignored.

Proponents note that, in addition to the possible heart disease benefits, HRT has shown benefit in preventing osteoporosis and has approval from the US Food and Drug Association (FDA) for use in women at an increased risk of osteoporosis and fractures.

In its previous assessment of the complicated mix of evidence showing harms and benefits of the treatment in preventing chronic conditions, the task force concluded in 2012 that the harms outweighed the benefits, and in these newest draft recommendations, designed as a routine update of evidence, the findings are, by and large, unchanged.

Latest Update Still Relies on Only WHI Trial for Assessment of Primary Prevention

For the 5-year update, the task force identified 18 clinical trials considered to be of fair or good quality. Only the WHI, however, a large randomized controlled trial of HRT vs placebo, was considered sufficiently powered for the review of primary prevention of the multiple conditions that have been associated with HRT.

With the inclusion of posttrial phases, the WHI trial provided up to 13 years of follow-up to assess benefits and harms of HRT in prevention of chronic conditions.

Overall, the task force has given the evidence a rating of "D," recommending against the combined use of estrogen and progestin for the prevention of chronic conditions and also against the use of estrogen alone for chronic conditions in postmenopausal women who have had a hysterectomy.

The task force details the degree of evidence for different conditions, with estrogen alone and combined estrogen and progestin for the reduction of fracture risk in postmenopausal women described as "convincing," showing a "moderate benefit," while evidence for HRT to reduce the risk of diabetes is described as "adequate" and showing only a small benefit.

The evidence for estrogen alone to reduce the risk for developing or dying of breast cancer is convincing of a moderate benefit; however, evidence is also convincing that estrogen does not convey a benefit on coronary heart disease.

In terms of harms, the evidence is furthermore "convincing" that combined estrogen and progestin is associated with moderate harms such as an increased risk for invasive breast cancer and venous thromboembolism, and evidence is also convincing of a small to moderate harm of an increased risk for coronary heart disease, the task force states.

There is also "adequate" evidence of moderate harms associated with combination therapy, such as increased risk for stroke, dementia, gallbladder disease, and urinary incontinence.

The evidence on estrogen use alone is "adequate" in showing moderate harms, including an increased risk for stroke, dementia, gallbladder disease, urinary incontinence, and venous thromboembolism.

"Combined estrogen and progestin therapy is associated with a decreased risk of fractures, diabetes, and colorectal cancer; however, it is also associated with an increased risk of invasive breast cancer, coronary heart disease, thromboembolic events, stroke, dementia, gallbladder disease, and self-reported urinary incontinence," the task force concludes.

The overall assessment fails to show benefit in an average-risk population, it adds.

"The USPSTF concludes with moderate certainty that the use of combined estrogen and progestin has no net benefit for the prevention of chronic conditions in most postmenopausal women," the task force says, adding, "with moderate certainty that the use of estrogen alone has no net benefit for the prevention of chronic conditions in most postmenopausal women who have had a hysterectomy."

Timing of Initiation of HRT Is Considered

The review did include a close look at the important issue of timing of therapy, but subgroup analyses of WHI data of women treated with early vs late initiation show conflicting evidence, the task force concludes.

For example, one analysis shows no difference in coronary risk according to timing of hormone therapy, while another shows a significantly lower risk in those treated within 10 years of menopause compared with those treated more than 20 years postmenopause.

In considering that evidence, the scales still tip more heavily toward risks than benefits, task force member Ann E Kurth, PhD, MPH, told Medscape Medical News.

"There is obviously conflicting evidence on whether beginning hormone therapy closer to the time of menopause may be more or less effective in preventing chronic conditions, but again, the big picture is that we found the benefits do not outweigh the harms," said Dr Kurth, dean of the Yale School of Nursing, New Haven, Connecticut, and the Linda Koch Lorimer professor of nursing.

Dr Kurth underscores the fact that these recommendations relate specifically to use of HRT for prevention of chronic conditions, and not for other purposes.

"We want to make clear the point that this is not about managing the symptoms of menopause, such as hot flashes or night sweats," she said.

The task force notes that the recommendations are consistent with those of many other major medical groups, including the American Heart Association (AHA) and American College of Obstetricians and Gynecologists (ACOG), which recommend against the use of HRT for the primary or secondary prevention of heart disease. In general, most clinical guidelines recommend against HRT for prevention of any chronic conditions, according to the USPSTF.

Dr Kurth notes that patients have various other options for the prevention of chronic conditions.

"There are other mechanisms and interventions that women who are concerned about development of chronic conditions can look at," she said.

HRT Is Appropriate for Chronic Disease Prevention in Some Patients

Dr Langer counters, however, that HRT in appropriate patients is often preferable.

For example, "estrogen is the most physiologic medication available for prevention and treatment of osteoporosis," he said.

"As a primary-care physician myself, I believe that selecting and managing menopausal hormone therapy is no more complicated than selecting and managing antihypertensive or lipid-lowering therapy."

Dr Langer strongly criticized what he calls the "misinterpretation" of WHI findings in a paper published in April (Climacteric. 2017;20; 91-96).

These latest task force draft recommendations continue that misinterpretation, he told Medscape Medical News.

"Unfortunately, the USPSTF has consistently chosen to take the publications of the WHI at face value without a critical reading of the actual data that have frequently been misrepresented in those reports."

He notes that subsequent data have suggested that WHI findings turned out not to be statistically significant when properly adjusted, in addition to not being uniform across all age groups.

"Critically, the data on [estrogen] alone demonstrated outcomes in the opposite direction, with a suggestion of reduction for breast cancer overall, and with protection against coronary events in women within 10 years of menopause," he said.

Furthermore, Dr Langer pointed to evidence of the fallout from the dramatic shift in the use of HRT, including studies showing increases in the risk of hip fractures (Menopause. 2011;18:1172–1177) and cardiovascular events (J Clin Endocrinol Metab. 2015;100: 4588-4594) among women who discontinued postmenopausal HRT.

"The chronic diseases that menopausal hormone therapy can prevent are some of the most prevalent and expensive faced by our society, so the public-health implications are huge," he noted.

Balance the Pros and Cons

Meanwhile, Rhoda Cobin, MD, clinical professor of medicine at the Icahn School of Medicine at Mount Sinai in New York City and past president of the American Association of Clinical Endocrinologists, said the task force's recommendations are consistent with the group's guidelines.

She underscored that guidelines specifically do not support universal recommendation of HRT for prevention of chronic conditions, but that the treatment may be appropriate in a wide range of exceptions.

"You have to balance the pros and cons and use clinical judgment in considering everything from age and blood pressure to comorbidities and family history," she told Medscape Medical News.

"But, for instance, if the patient is a woman who has had a hysterectomy and has osteoporosis and is having symptoms, then it's clear that treatment with estrogen would be an appropriate choice."

Dr Cobin agrees that the fear generated by the early WHI interpretations had negative effects on the use of HRT, not just in appropriate preventive uses but even for the control of menopausal symptoms.

"I would completely agree that there are far too many women who do have symptoms of osteoporosis and no contraindications and for whom hormone therapy would be beneficial who are not getting the treatment due to the concerns," she said.

"And hormone therapy is definitely being underused even for menopausal symptoms. So, in the right settings and with the right patients, it's very beneficial, but I don't think many people agree that a universal recommendation for prevention of cardiovascular disease is appropriate."

The USPSTF draft recommendations can be accessed on the task force's website. The public comment period for the draft recommendations is open through June 12, 2017.

None of the task force investigators had disclosures or financial relationships relating to the recommendation. Dr Langer has received travel support and honoraria from Pfizer for presentations on HRT, but the sponsor had no control over the content presented. Dr Cobin had no disclosures to report.

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