A recent study indicates that older women who use vaginal estrogen tablets do not face a higher risk of recurrent ischemic stroke. This finding bolsters the growing movement too have the Food and Drug Administration (FDA) revise its boxed warning for these products.

According to Dr.Kimia ghias Haddadan, a study investigator in the Department of Cardiology at Copenhagen University Hospital, Copenhagen, Denmark, prior research has not shown an elevated stroke risk with vaginal estrogen use in healthy women. However, the risk hadn’t been specifically addressed in women with a history of ischemic stroke. Dr. Haddadan told Medscape Medical News, “Our study fills that gap by extending the evidence to a high-risk group.”

Dr. Haddadan added, “Our findings are reassuring for both clinicians and patients, as it suggests that women with prior stroke may safely use vaginal estradiol tablets.”

The study was published online on August 21 in Stroke.

‘Compelling’ Data

“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.”

For the study, Dr. Haddadan and colleagues analyzed prescription data from Danish national registries to determine any link between vaginal estradiol tablet use and recurrent ischemic stroke through a nested case-control study.

The researchers examined a cohort of over 34,000 women, aged 45 and older, who had experienced a first ischemic stroke.They matched 3353 women who had a recurrent stroke with 3353 control individuals who did not, with both groups having a median age of 75 years.

Vaginal estradiol tablet use was categorized as current (0-3 months before index), recent (3-24 months before index), and past use (more than 24 months before index).

After adjusting for factors such as comorbidity, medications, income, and education, the study found that vaginal estradiol tablet use did not correlate with an increased rate of recurrent ischemic stroke. The adjusted hazard ratio was 0.79 for current use (P =.27), 1.09 for recent use (P = .67), and 1.48 for past use (P = .08).

Time to Ditch the Boxed Warning?

Dr.JoAnn Manson,professor of medicine at Harvard Medical School and Brigham and Women’s hospital,Boston,commented that 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.”

Dr. Manson, a lead investigator on the Women’s Health initiative and past president of The Menopause Society, stated, “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.”

Last month, an FDA expert panel on hormone therapy supported this action.

dr. Manson clarified that the black box warning on all hormone therapy products, regardless of formulation, is due to “class labeling” and lacks an evidence base.

Dr. Manson told Medscape Medical News that “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.”

Dr.Manson added, “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.”

The boxed warning also suggests that these hormone therapy products increase the risk for other cardiovascular disorders, breast cancer, endometrial cancer, and probable dementia. However, dr. Manson pointed out that “there is no rigorous research documenting an elevated risk of any of these conditions with low-dose vaginal estrogen and, actually, a large body of research has shown that these hormones do not increase these risks.”

Vaginal Estrogen ‘Under-prescribed’

Dr. Stephanie Faubion, medical director of The Menopause Society and director of the Mayo Clinic center for Women’s Health, jacksonville, Florida, also commented, stating there is “very good observational data that vaginal estrogen is not associated with long-term cardiovascular or cancer risk.”

Dr. Faubion noted that the main issue is that vaginal estrogen “is dramatically under-prescribed, and there are a number of barriers that are getting in the way.”

Dr. Faubion explained, “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.”