In July 2002, safety concerns that terminated an arm of the Women's Health Initiative (WHI) jettisoned what little remained of the conventional wisdom--that hormone replacement therapy (HRT) is beneficial to all healthy women in menopause--and sent multitudes of women scurrying for quick answers.
In July 2002, safety concerns that terminated an arm of the Women's Health Initiative (WHI) jettisoned what little remained of the conventional wisdomthat hormone replacement therapy (HRT) is beneficial to all healthy women in menopauseand sent multitudes of women scurrying for quick answers. It also caused the Food & Drug Administration to mandate revised product labeling. Now, many months later, the details are still being sorted out.
Andrea Coffee, Pharm.D., BCPS, Pharmacy Clinical Specialist who works in a collaborative practice in Temple, Texas, stated, "The physician I work with believes, and I agree wholeheartedly, you have to assess why each individual woman is on HRT." She noted that current evidence discredits the use of HRT to prevent cardiovascular disease but clinical use substantiates its benefit in treating vasomotor symptoms. "And in some women it's just simply a quality-of-life issue. They try to stop it, and they just don't feel good."
Candace Brown, Pharm.D., BCCP, MSN, professor of Pharmacy Practice, University of Tennessee, commented, "When the WHI first came out, everybody just treated this like a crisis situation. Physicians took the women immediately off [HRT], then you get rebound withdrawal effects. Women were getting their hot flashes back, and many who wanted to get off HRT then wanted to get back on it."
These remarks underscore the conundrum over the use of HRT in menopause. Brown commented, "We know that estrogen really is the best for vasomotor symptoms." But as multiple studies have shown, HRT does not offer all the benefits it was formerly believed to possess. And, it is not without risk, particularly when used long term.
The conventional wisdom of using HRT to prevent chronic disease has been eroding for some time. Consider the following:
The PEPI (Postmenopausal Estrogen/Progestin Interventions) trial suggested postmenopausal hormone therapy rapidly increases the concentration of C-reactive protein (an inflammation factor linked to heart disease).
The HERS and HERS II (Heart and Estrogen/progestin Study) cast doubt on the cardiovascular benefit of HRT, and the American Heart Association changed its guidelines about prevention of heart disease in 2001, excluding HRT.
An article in the Journal of the American Medical Association (JAMA) (2000) showed an increased risk of breast cancer with combination HRT.
But perhaps the knockout blow to the conventional wisdom was the premature termination of the combination-therapy arm of WHI because of safety concerns.
The WHI, a landmark multicenter randomized controlled primary prevention trial that began recruitment in 1993, had two arms. In one, women with uteruses were treated with combined estrogen and progestin (0.625 mg conjugated equine estrogen and 2.5 mg medroxyprogesterone acetate, Prempro, Wyeth) or placebo. In the other arm, women who had previous hysterectomies were treated with estrogen alone. The goal of WHI was to determine whether HRT would actually reduce the risk of osteoporosis fractures, increase or decrease the risk of selected cancers, and lower the risk of cardiovascular disease.
Although the trial was planned for an 8.5-year follow-up, the combination-therapy arm was stopped after the five-year interim analysis. Data showed that after four years of treatment, breast cancer, though rare, was occurring at a rate greater than acceptable by the predetermined risk statistic. There was also excessive heart disease, stroke, and pulmonary embolism in the HRT-treated group, and these risks outweighed the evidence of benefits. Meanwhile, the other arm of the WHI, comparing the use of estrogen in postmenopausal women who have had hysterectomies to controls, is continuing because the risk/benefit ratio is not yet clear. Results are not expected until after 2005.
Results of the main portion of the WHI combination-therapy arm were published in JAMA on July 17, 2002, but as many as 30 other papers are still in progress. The May 8 issue of the New England Journal of Medicine will publish the WHI results about quality of life, showing that the estrogen and progestin combination therapy fails to make menopausal women feel better by improving their memory, sleep, or sex lives.
In light of the WHI findings of increased risk, the FDA has revised the labeling of Prempro, Premphase, and Premarin for patients and physicians. Labeling now also recommends that when these products are being prescribed solely for the symptoms of vulvar and vaginal atrophy, that topical products be considered, and when used for osteoporosis prevention that the risks for osteoporosis must outweigh the risk of estrogen or estrogen/progestin therapy.
Some clinicians wonder whether the risks of HRT are common to all forms of estrogen and progestin therapy or limited to conjugated equine estrogen and medroxyprogesterone that were implicated in the WHI trial. Nevertheless, the FDA has approached the issue conservatively, announcing in January that all companies manufacturing drugs that contain estrogen or estrogen and progestin for menopausal women must include a boxed warning on labels stating that the drugs may slightly increase the risk of heart attacks, strokes, blood clots, and breast cancer.
Florence Houn, M.D., director of the Office of Drug Evaluation III, Center for Drug Evaluation and Research, FDA, suggested that manufacturers' response has been positive. "Companies are very interested in ensuring the important safety information found in the Women's Health Initiative be in their labeling and responding to the FDA's request to change labeling," she said.
The published results of the combination-therapy arm of WHI were an important underpinning of the most recent recommendations from the U.S. Preventive Services Task Force (USPSTF). The 2002 USPSTF recommends against routine use of estrogen and progestin for the prevention of chronic conditions in postmenopausal women. Significantly, though, USPSTF did not address short-term therapy for the treatment of symptoms of menopause. And until the second arm of the study is completed, USPSTF found the data insufficient to recommend for or against the use of unopposed estrogen for the prevention of chronic conditions in postmenopausal women who have had a hysterectomy.
Alfred O. Berg, M.D., MPH, chair of USPSTF, sees the recommendations of the task force as a starting point for the HRT decision, subject to individual considerations. He stated, "All the calculations we did were based on treating 10,000 women for five years. At five to eight years, these adverse events are very uncommon for most women. The reason that's important is if she is already experiencing overwhelming wonderful benefits for her perimenopausal symptoms [with HRT], the relatively modest risk of hormone treatment might be worth taking. This is the decision that she and the clinicians should make."
Critical to good decision-making is good information. Berg noted that there's a lot of information on the Web about HRT, but not all of it is good. "I think patients are asking questions of a lot of people. Fundamentally, it's the patient's decision and we should all be giving them the best information we can but try not to take ownership of [the HRT decision] for them."
The results of WHI led to the American College of Obstetricians and Gynecologists to advise, "With respect to women on short-term use of combination hormone therapy for relief of menopausal symptoms, the WHI authors note that although such use was not the focus of this study, it may be reasonable for women to continue to use it for this purpose since the benefits are likely to outweigh the risks."
So what's the trend in clinical practice with women who have been taking HRT? Coffee said, "We use a lot of conjugated estrogen 0.3 mg or estradiol 0.5 mg, that kind of thing. We may keep women on it, especially if they feel like they want to be on it, but we just see if we can get them down to a lower dose. The old conjugated estrogen 0.625as the gold standardis pretty much out the window now." Indeed, in March, Wyeth Pharmaceuticals obtained FDA approval for low-dose Prempro (0.45 mg conjugated estrogen and 1.5 mg medroxyprogesterone acetate) for use in women (with a uterus) for the treatment of moderate to severe vasomotor symptoms and the treatment of moderate to severe symptoms of vulvar and vaginal atrophy.
Brown pays attention to HRT dose and the length of therapy. She noted that the risks of side effects are believed to increase as a cumulative effect of dose. "Typically, if somebody has been on it more than four years, that's a reason you might want to consider taking her off." But, she admits not all women have hot flashes for only four or five years, "some women have them longer than that."
Coffee advised that the best way to reduce existing HRT is by using a "lower dose or taper. Too many women try to 'cold turkey' it. I think that primary care physicians especially recommend to some of their patients that they do that. That's the hard way to go off hormones, especially if you've been taking them quite a while."
To avoid risks of HRT, some women are opting for other drug therapies to deal with symptoms of menopause. Brown said, "I've seen paroxetine most often but also fluoxetine. They also use venlafaxine and then, finally, gabapentin." Women are also turning to herbs and natural products. She noted that the strongest evidence for treating menopausal symptoms exists for soy products or black cohosh. She did voice some concern, however: "The thing you have to worry about with black cohosh and the soy products is they're not sure exactly how they work. They think that they have weak estrogenic effects. If they do, does that mean that they might be harmful, particularly for women who have had breast cancer?"
Coffee qualified her recommendations about natural products too. "We do tell women, especially if they are having a lot of vasomotor symptoms, this may not do it for you. And also, as we talk to a lot of women, we have found soy is not real big in the American diet. As a general rule, most of us don't like the taste of a lot of soy products." Brown gave this recommendation: "If you're going to take soy products, eat the food rather than the supplements because there's more evidence on the food."
Coffee sees a valuable role for retail pharmacists in helping women with HRT. She said, "When those refills come through, especially for older women on higher doses, this is the opportunity to say, 'Have you discussed continuing the medication with your physician?' Because sometimes patients really are not getting any benefit [from the HRT]sometimes they're also on alendronate or on a statin, and this has been going on and on. And the physicians are so busy that they don't always reassess, but you can try to get the patient to ask. They're on multiple drugs, and that's a cost issue. Obviously this class [HRT] isn't that expensive, but to some patients every penny counts. This might be a prime opportunity for pharmacists to intervenenot real strongly, but just to get the patient thinking."
HRT decisions, circa 2003, are very different from even decisions five years ago. The additional information that has become available more clearly delineates the risks and benefits, but it is information that has to be assimilated into the decision-making process by women themselves. Now, more than ever, HRT is a carefully considered decision, made by women in conjunction with input from various healthcare providers.
By being informed, pharmacists can help women better understand the existing information. By monitoring drug therapy, they can act as a safety net, helping patients to minimize their therapeutic risks.
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Kathy Hitchens. Unraveling the puzzle of hormone replacement therapy. Drug Topics Women's Health Supplement;147:26s.