Debate Reignites on HRT for Chronic Disease Prevention

October 22, 2012

October 22, 2012 (Rockville, Maryland) — Hormone-replacement therapy (HRT) should not be used for the prevention of chronic medical conditions in postmenopausal women, according to a new review by the US Preventive Services Task Force (USPSTF) [1].

The recommendations apply to average-risk women who have undergone menopause, and "this is not about the use of HRT to treat symptoms of the menopause," the task force stresses; rather it is advice on prevention for primary-care providers, family practitioners, and patients, following a review of 51 articles published since 2002, they note in a report published online October 22, 2012 in the Annals of Internal Medicine.

However, outside experts polled by heartwire say this so-called "new" review is mainly based on the findings of the Women's Health Initiative (WHI) and that it hasn't analyzed events by age. "Where I think this document is weak is that it doesn't look in context about the way preventive care should be considered or used for postmenopausal women. They should have broken the data down by decade, age 50 to 59, etc," reproductive endocrinologist Dr Wulf Utian (Case Western Reserve University, Cleveland, OH) told heartwire .

Dr Tobie de Villiers, president of the International Menopause Society (IMS), agrees: "The recommendations are not unexpected, as they are mainly based on reviews of the WHI, [which] was not designed or intended to evaluate the effects of HRT on chronic disease if started near menopause, as the vast majority of women do." The advice concerning the use of HRT for the prevention of osteoporosis and cardiovascular disease in this new review is "based on older patients [and] cannot be generalized to the younger postmenopausal patient," he noted in a statement provided to heartwire .

Women on HRT for the treatment of menopausal symptoms should therefore "not be alarmed by this report," de Villiers stressed.

Utian adds that since the document doesn't include two important and very recent studies on HRT, KEEPS and the Danish Osteoporosis Prevention Study (DOPS), "it needs revising before it's even been released. With a committee as cumbersome as the USPSTF, often the world moves on while you are busy producing documents. These two major studies have come out subsequent to this review and they completely outdate it," he says.

This document needs revising before it's even been released.

Task-force representative Dr Kristen Bibbins-Domingo told heartwire that the Danish study, just published in BMJ, "was not considered formally in this evaluation. But as we read it, we don't have concerns that it would change our overall recommendations." As for KEEPS, which was presented at a medical meeting but has not yet appeared in a journal, "we look forward to reading the full report of KEEPS when it is published," she observed.

No Change, New Data Mirror WHI Results, But There Is "Research Gap"

Bibbins-Domingo says the review was undertaken to consider new evidence in the form of additional large randomized controlled trials. But the findings from these "are generally consistent with WHI in the observed direction of effect," the task force observes, and so the calculations of the benefits and harms of HRT--found in the paper's tables 1 and 2 for estrogen plus progestin and estrogen alone, respectively--"are derived from the WHI results," it states.

These include "convincing evidence" that estrogen and progestin therapy (specifically, oral conjugated equine estrogen 0.625 mg/day, plus medroxyprogesterone acetate 2.5 mg/day) "is of moderate benefit in reducing the risk for fractures in postmenopausal women." However, its use is also associated with moderate harms, including an increase in the risk for stroke, dementia, gallbladder disease, and urinary incontinence. There is also "convincing evidence" of a "small increase" in the incidence of invasive breast cancer, deep venous thrombosis (DVT), and pulmonary embolism, as well as "convincing evidence" that HRT "does not have a beneficial effect on coronary heart disease and likely increases the risk for its occurrence."

New research to define whether there is a differential balance of benefits and harms based on age at initiation, duration of use, and dose or delivery mechanism would be useful.

And for women who have had a hysterectomy, "estrogen-alone therapy is associated with a reduction in the risk for fractures, as well as a small reduction in the risk for developing invasive breast cancer and of dying from the disease," the task force says. "However, it is also associated with important harms, such as an increased likelihood of stroke, DVT, and gallbladder disease," and "it does not reduce the risk for developing CHD."

Bibbins-Domingo says: "Our take-home from the evaluation of the existing evidence is that we would recommend against women taking HRT for the purposes of preventing chronic diseases like heart disease and dementia because it is not effective--the potential benefits are not dramatic for most of the conditions that we reviewed--and may even by harmful." And while there is a benefit for fractures, there are other means to prevent osteoporosis, she says.

However, she acknowledges that that the initiation of HRT early in menopause "is an area that we have identified as a research gap." Given that "the vast majority of women who currently use hormone therapy are women transitioning through menopause, new research to help better define whether there is a differential balance of benefits and harms based on age at initiation, duration of use, and dose or delivery mechanism would be useful," the task force states.

Harms Overexaggerated; HRT Best Prevention for Recently Menopausal

Utian says if the task force had broken down their data by age, "then I believe that for the woman who is recently menopausal, for at least a decade, there is no question that HRT is the best preventive approach. Number one, it will reduce cardiovascular disease. Two, there's very little evidence that it increases breast cancer in that period of time, for that decade of use. Three, there will be a significant reduction in osteoporotic fractures." He acknowledges, however, that "there will be an increase in DVT and stroke."

He also questions the quantification of some of the "harms" claimed by the task force. The supposed increase in dementia "was based only on women aged >65, on the WHI Memory Study," he says. Meanwhile, urinary incontinence was based on "a single response in a questionnaire that has really not been substantiated. It's hugely overweighting the risk." And the reference to gallbladder disease is misplaced, he says, because it is based "on early-year data, with high-dose oral HRT, which was associated with an increase in gallstones and the need for surgical treatment of gallstones. But in current low-dose therapies and definitely with nonoral therapies, it's not a factor."

And the recent data from DOPS and KEEPS are key too, he says. "Although KEEPS suffers from the fact that it was a cardiovascular-marker study and not an end-point study, nonetheless, it was a four-year randomized, placebo-controlled study, and the bottom line is it showed no increased risk in anything. So that really speaks to at least four years of safety with estrogen plus progestin.

"And DOPS has almost 10+ years on therapy vs open-label, untreated controls, and they have an additional seven years of follow-up. They found a reduction in heart disease and no increase in breast cancer. If you throw in the data that should be there from KEEPS and DOPS, I think that their tables 1 and 2 are out of date before they are even published."

HRT Good for Bones for a Decade, But Not for CVD Prevention Only

However, Utian is keen to stress that in women who do not need to take HRT for menopausal symptoms but who are worried about their risk of chronic disease, decisions about therapy need to be made on a highly individual basis: "It depends on what women are trying to prevent and their risk factors.

"There is absolutely no question that if osteoporosis is the prime chronic disease you are trying to prevent, for the first decade, HRT is absolutely the right thing," Utian says. At the end of that decade, "you can continue to use HRT or start looking at bisphosphonates and whatever else is available."

de Villiers concurs. The effect of HRT on fracture reduction "is understated in WHI," he notes, adding that there are limitations to other forms of osteoporosis prevention, such as bisphosphonates, in the young menopausal patient at risk of fracture, something Utian agrees with.

If they are completely asymptomatic and it's to prevent cardiovascular disease, I don't think anybody is recommending hormones as a prime therapy for this.

"But if women are completely asymptomatic and it's to prevent cardiovascular disease, I don't think anybody is recommending hormones as a prime therapy for this," Utian cautions. "They should be doing all the good stuff: no smoking, weight control, nutrition, lipid control, etc."

In its document, the USPSTF notes that the American Heart Association (AHA) and the American Congress of Obstetricians and Gynecologists (ACOG) "recommend against the use of menopausal hormonal therapy for the primary or secondary prevention of cardiovascular disease."

The North American Menopause Society advocates that individualization is of key importance in the decision to use hormone therapy and that it "should not be used for coronary protection in women of any age, and [the society] does not recommend hormone therapy to prevent cognitive aging or dementia."

Slightly vaguer are the Canadian Task Force on Preventive Health Care and the American Academy of Family Physicians, both of which "recommend against the use of hormonal therapy in postmenopausal women for the prevention of chronic conditions." The American Academy of Family Physicians, however, "is currently in the process of updating its guideline on the subject."

The authors report that they have no disclosures. Utian reports no conflicts of interest. de Villiers has disclosed past support from Adcock Ingram, Servier, Pfizer, Bayer, and Amgen and is on the speaker's bureau for Merck Sharp & Dohme.