Q&A: At 20 years, WHI emphasizes personalized postmenopausal care, shared decision-making
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Key takeaways:
- Women’s Health Initiative trials highlight the importance of shared decision-making in menopause care.
- Trial participants will continue to be followed, but the clinical implications are unlikely to change.
Results of Women’s Health Initiative trials highlight the importance of personalized health care in combination with shared decision-making for postmenopausal women, according to a review published in JAMA.
The Women’s Health Initiative (WHI) enrolled 161,808 postmenopausal U.S. women aged 50 to 79 years from 1993 to 1998. All women were followed for up to 20 years.
In the menopause hormone therapy trials, researchers assessed the benefits and risks of hormone therapy for reducing risks of chronic diseases, including coronary heart disease, stroke, dementia and cancer. This trial did not support the use of hormone therapy to prevent chronic diseases, but the findings do support its use for treatment of moderate to severe menopausal symptoms in early menopause.
The calcium and vitamin D trial evaluated whether supplementation lowered risks for hip fractures and other fractures among postmenopausal women at typical risk for fracture, not selected for low bone mineral density. Although calcium plus vitamin D supplementation did not significantly reduce hip fractures and should not be recommended routinely for all postmenopausal women, the authors state that it has a role in filling gaps in these nutrients not met by diet.
In the dietary modification trial, researchers assessed whether a diet reducing total fat consumption to 20% of total energy intake, increasing fruit and vegetable intake to at least five servings daily and increasing grain intake to at least six servings daily reduced risks for invasive breast cancer, colorectal cancer or coronary heart disease. Although the trial did not show significant decreases in breast or colorectal cancer incidence, it did result in lower rates of breast cancer mortality and some weight loss, offering one of many dietary options for women.
“There’s no one-size-fits-all answer to any of these interventions. We don’t have a blanket recommendation that all postmenopausal women should use any of these treatments, whether hormone therapy, calcium, vitamin D or low-fat dietary pattern,” JoAnn E. Manson, MD, MPH, DrPH, professor of medicine at Harvard Medical School and chief of preventive medicine at Brigham and Women’s Hospital, told Healio. “However, some of the women did benefit from each of these interventions.”
Healio spoke with Manson to understand WHI trial results and the program’s implications for future women’s health research.
Healio: Will you briefly summarize your review and tell us why you and your colleagues wrote it now?
Manson: It’s a 20-year update on all the WHI randomized trials. This is the first time we’ve had a paper focusing on the clinical translation of all the WHI randomized trials. It’s focused on all trials, the intervention phase, plus up to 20 years of follow-up. We highlighted the clinical messages and the translation of the findings to clinical practice and to the general public. What do health care providers need to know, and what do women need to know to have shared decision-making with their clinicians?
The WHI trials have some clear messages. For hormone therapy, the absolute risk of adverse events is low in women younger than 60 years, and hormone therapy continues to have an important role in treating moderate to severe or bothersome hot flashes, night sweats and other menopausal symptoms. That's an FDA-approved indication. When hormone therapy is started for symptom management in women younger than age 60 years, it's likely to have a favorable benefit-risk ratio.
On the other hand, we affirm that hormone therapy should not be used for the express purpose of trying to prevent heart disease, stroke, dementia or other chronic diseases. The bar is set very high for the use of a medication for prevention purposes, and the risks must be negligible for medications to be used for long-term prevention.
In the case of hormone therapy, the WHI randomized trials were designed to answer the question of whether hormone therapy should be used for prevention of chronic disease across different age groups in women aged 50 to 79 years at the start of the study. The findings support hormone therapy as an appropriate for treatment for menopausal symptoms starting in early menopause, but it’s not recommended for prevention of chronic disease.
Participants will continue to be followed longer term. We’re hoping for at least another decade of follow-up, but these findings are unlikely to change because the active intervention ended many years ago. The clinical messages can thus be interpreted as the final ones.
Healio: Since the initiation of WHI, more hormone therapy doses and delivery options have become available. Might these different doses and delivery options lower risks of coronary heart disease, stroke, dementia or other chronic diseases in postmenopausal women?
Manson: It's important for women to understand that they have more options for treatment now. When the WHI trials started in the early 1990s, we tested the most common formulations at the time, and these were also the formulations that had shown benefits in the observational studies, which looked at what women chose to take or were being prescribed by their doctors and how that related to health outcomes. There was a strong rationale for the choice of these formulations to be tested in WHI because these were the most common regimens being used, and the results looked favorable in the observational studies.
However, since that time, the use of transdermal estradiol as a patch, gel or spray delivered through the skin has become more common, and lower doses are available. Bioidentical forms of both estrogen and progesterone are available. Many clinicians, based on their experience, and observational studies are finding that these hormones seem to have lower risk than the oral estrogen. The type of estrogen taken by pill form is more likely to increase the risk of blood clots than the transdermal or patch estrogen.
But it's also important for clinicians and the public to know that we don't have large scale, randomized trials of these other formulations to say what exactly the benefit-risk profile is. We have observational studies, which suggest these are safer, and I do think there’s enough evidence in terms of effects on clotting factors to lean toward the use of transdermal and lower doses than what was tested in the WHI, which was an oral form of conjugated estrogen, which may be more likely to cause blood clots. I think the lower doses and the transdermal route of delivery have some advantages over pill form, especially for women who have risk factors for cardiovascular disease.
Healio: Might women at a higher risk for fracture benefit from the calcium plus vitamin D supplementation studied in the WHI?
Manson: There are some randomized trials of older women who have known osteoporosis or a history of fracture, especially those in nursing facilities, where they may have a lower quality diet and get minimal time outdoors being physically active where calcium and vitamin D supplementation is of benefit. We know that calcium and vitamin D are reasonable for the treatment of osteoporosis and preventing recurrent fracture. However, for most in the population at typical risk of fracture, routine supplementation with calcium and vitamin D is not recommended. It shouldn't be a routine or universal treatment for all postmenopausal women. But certainly when there's a diagnosis of osteoporosis or treatment with medication for osteoporosis, then it becomes a matter of clinical judgment regarding use of supplementation. The WHI did not address specifically the question of whether calcium or vitamin D should be used in the setting of osteoporosis or low bone mineral density or prior fracture.
We did see several signals for bone health benefits in the WHI trial, suggesting that the National Academy of Medicine’s guidelines for calcium and vitamin D are important to reach. This includes 1,200 mg a day of calcium and at least 600 to 800 IUs a day of vitamin D for postmenopausal women. For those who are not obtaining those nutrients from diet alone, a supplement would be reasonable to fill nutrient gaps. For example, if a woman is able to get only 700 mg a day of calcium, then it could be reasonable to take a 500 mg supplement of calcium. But taking 1,000 mg a day routinely is not recommended based on the WHI findings. Dietary calcium is generally preferred and the benefit-risk ratio of supplementation needs to be considered.
Healio: After 20 years, adhering to a low-fat diet with more vegetables, fruits and grains was associated with reduced mortality from breast cancer and a small amount of weight loss. However, it did not prevent breast or colorectal cancer in postmenopausal women, which were the primary outcomes. Are studies evaluating this diet for other outcomes among postmenopausal women?
Manson: These recent findings of lower risk of mortality due to breast cancer may stimulate additional research on this dietary pattern for women who are at increased risk for breast cancer. We need more research, both for women who already have a diagnosis of breast cancer and those with risk factors. Based on this randomized trial, which was not specifically focusing on women at high risk of breast cancers across the board, a signal did emerge for a reduced risk of death from breast cancer with long-term follow-up. This dietary pattern may of particular benefit for women with metabolic syndrome and adiposity-related risk factors for developing postmenopausal breast cancer.
Overall, it’s a diet that is reasonably well tolerated. It replaces fat with fruits, vegetables and grains. We certainly know that higher intake of fruits and vegetables is important, but we can't disentangle the effects of reducing fat from the effects of increasing fruits, vegetables and grains, because it was the dietary pattern that was tested. Unless you're trying to reduce calories, overall, you have to replace the calories somewhere. So, in this particular trial, the calories were replaced primarily by increased fruits, vegetables and grains.
Healio: Is there anything else you’d like to add?
Manson: The study results emphasize the importance of individualized and personalized health care with shared decision-making between the clinician and the patient because, for many women, it comes down to their personal preferences. Some women may be an appropriate candidate for hormone therapy, but if they don't want to take hormones, that's not the right decision for them. However, if they're having significant vasomotor symptoms and they're very open to hormone therapy, that could be a good choice. It’s the same with a low-fat diet and calcium and vitamin D supplementation. It's going to depend on the patient’s overall risk factor status, baseline diet and other factors. The findings underscore the importance of personalized health care. It’s important for women to be informed about the trial results, so they can share in decision-making about their personal health care.
For more information:
JoAnn E. Manson, MD, MPH, DrPH, can be reached at jmanson@bwh.harvard.edu.