Older women using vaginal estrogen tablets do not face an increased risk for recurrent ischemic stroke, a finding that adds to growing calls for removal of the FDA boxed warning on these products.
“Existing research shows no increased risk of stroke associated with use of vaginal estrogen in healthy women, but none had addressed the risk in women with prior ischemic stroke. Our study fills that gap by extending the evidence to a high-risk group,” study investigator Kimia Ghias Haddadan, MD, Department of Cardiology, Copenhagen University Hospital, Copenhagen, Denmark, told Medscape Medical News.
“Our findings are reassuring for both clinicians and patients, as it suggests that women with prior stroke may safely use vaginal estradiol tablets,” Haddadan added.
The study was published online on August 21 in Stroke.
‘Compelling’ Data
For the study Haddadan and colleagues used prescription data from national Danish registries to examine the association between vaginal estradiol tablet use and recurrent ischemic stroke in a nested case-control study.
From a cohort of more than 34,000 women who had a first ischemic stroke at age 45 or older, they matched 3353 who had a recurrent stroke to 3353 control individuals who did not. Cases and control individuals had a median age of 75 years.
They categorized vaginal estradiol tablet use as current (0-3 months before index), recent (3-24 months before index), and past use (> 24 months before index).
After adjusting for comorbidity, medications, income, and education, vaginal estradiol tablet use was not associated with an increased rate of recurrent ischemic stroke. The adjusted hazard ratio was 0.79 for current (P = .27); 1.09 for recent (P = .67), and 1.48 for past use (P = .08).
Time to Ditch the Boxed Warning?
Reached for comment, JoAnn Manson, MD, professor of medicine, Harvard Medical School and Brigham and Women’s Hospital, Boston, said the study “adds to the compelling evidence base that low-dose (nonsystemic) vaginal estrogen does not increase the risk of cardiovascular disease in postmenopausal women, even at older ages.”
“It’s time to remove the black box warning on low-dose vaginal estrogen, which is misleading women and harming their health and quality of life,” said Manson, one of the lead investigators on the Women’s Health Initiative, and a past president of The Menopause Society.
Last month, an FDA expert panel on hormone therapy endorsed doing just that.
Manson explained that the black box warning on all hormone therapy products, regardless of formulation or whether local or systemic, is due to “class labeling” of all of these products and is not evidence-based.
“Low-dose vaginal estrogen, used primarily to treat genitourinary syndrome of menopause — including painful sex, vaginal dryness, and recurrent urinary tract infections — does not raise the blood levels of estradiol and other estrogens above the normal menopausal range, in contrast to systemic hormone therapy given orally or transdermally,” Manson told Medscape Medical News.
“A growing chorus of experts has called for removal of the inappropriate boxed warning on low-dose vaginal estrogen, which scares women and leads to underutilization of a safe and effective treatment for these symptoms,” Manson added.
The boxed warning also states that these hormone therapy products increase the risk for other cardiovascular disorders, breast cancer, endometrial cancer, and probable dementia. However, Manson noted “there is no rigorous research documenting an elevated risk of any of these conditions with low-dose vaginal estrogen and, in fact, a large body of research has shown that these hormones do not increase these risks.”
Vaginal Estrogen ‘Under-Prescribed’
Also commenting for Medscape Medical News, Stephanie Faubion, MD, MBA, director of the Mayo Clinic Center for Women’s Health, Jacksonville, Florida, said there is “very good observational data that vaginal estrogen is not associated with long-term cardiovascular or cancer risk.”
Faubion, who serves as medical director of The Menopause Society, said the bigger issue is that vaginal estrogen “is dramatically under-prescribed, and there are a number of barriers that are getting in the way.”
“One is clinicians comfort level with prescribing anything with estrogen. Another is women’s lack of understanding that their genitourinary symptoms are related to menopause and that estrogen would fix them. And really, it’s the clinicians that should be asking women about it proactively, but don’t,” said Faubion.
The study had no specific funding. Haddadan, Manson, and Faubion had no relevant disclosures.