A comprehensive Danish registry study has found that vaginal estrogen tablets do not increase the risk of recurrent ischemic stroke in postmenopausal women who have previously experienced a stroke, offering potential reassurance for a vulnerable patient population often excluded from hormone therapy research.
The study, published in Stroke, analyzed data from 34,274 postmenopausal women aged 45 and older who had experienced their first ischemic stroke between January 1, 2008, and December 31, 2017. During the 10-year follow-up period, 3,353 women developed recurrent ischemic stroke and were matched with an equal number of women who did not experience a second stroke.
Key Findings Challenge Current Treatment Limitations
The research revealed that women who experienced recurrent stroke actually had a lower prevalence of current vaginal estradiol tablet use at 1.9% compared with those who did not have another stroke at 3.2%. When compared with no use, investigators reported no significant association between current, recent, or past use of vaginal estradiol tablets and recurrent ischemic stroke.
"It is well known that taking systemic hormone replacement therapy, such as oral estrogen tablets, may increase the risk of stroke after menopause," said lead author Dr. Kimia Ghias Haddadan from Copenhagen University Hospital. "While other studies have not detected an increased risk of stroke associated with the use of vaginal estrogen in healthy postmenopausal women, there is no data on whether vaginal estrogen tablets pose an increased risk for women who have already had a stroke."
Addressing a Critical Knowledge Gap
Currently, systemic estrogen replacement therapy is contraindicated for women with a history of ischemic stroke due to stroke recurrence risk. However, vaginal estrogen tablets work differently than oral formulations, dissolving locally and being absorbed through the vaginal mucosa to manage menopausal symptoms such as vaginal dryness and discomfort during intercourse.
The study found no association between high- and low-dose estradiol tablets and recurrent stroke, nor between total cumulative dose and recurrent ischemic stroke. Even women with higher cumulative use of vaginal estrogen tablets did not demonstrate increased risk compared to non-users.
Clinical Implications and Expert Perspective
"We were cautiously hopeful about the findings, and it was reassuring to discover that the use of vaginal estrogen did not raise the risk of recurrent stroke in this high-risk population," Haddadan noted. "It is important to note that these findings suggest that vaginal estrogen is likely safe for this high-risk group of women who have already had a stroke; however, they do not imply that vaginal estrogen prevents strokes."
Dr. Samar R. El Khoudary, a professor in the department of epidemiology at the University of Pittsburgh School of Public Health who was not involved in the study, emphasized both the value and limitations of the research. "As an epidemiologist, I see this study as a valuable contribution because it focuses on a population often excluded from hormone therapy research, midlife women with a prior stroke, and examines an increasingly used route of administration: vaginal tablets," she said.
Study Strengths and Limitations
The research leveraged Denmark's comprehensive national registries to provide accurate tracking of stroke diagnoses, prescriptions, and relevant health and demographic information across the entire population. Researchers adjusted for various health and demographic factors, including medications, medical conditions, income, and education levels.
However, the study has several limitations. Estrogen use was determined from prescription records, which indicate medication was dispensed but not necessarily taken as prescribed. Women using vaginal estrogen might have been healthier overall, potentially affecting results. The study focused solely on vaginal estrogen tablets, the most common treatment mode in Denmark, and findings may not apply to other estrogen formulations such as creams, patches, or rings.
Future Implications for Patient Care
The findings may have broad applicability to postmenopausal women in the United States and other countries where similar vaginal estrogen products are used. The study's large, nationwide design provided a comprehensive view of real-world clinical outcomes in a high-risk population that is typically excluded from clinical trials.
"We hope our findings reassure health professionals caring for postmenopausal women with a history of stroke," Haddadan concluded. "For these women, especially those with troubling menopause symptoms, the study shows that this type of therapy may be a safe choice. It could improve their quality of life without raising the risk of another stroke."
