MHT Thrombotic Risks Differ by Route, Dose, and Duration

New research published in The BMJ highlights important differences in thrombotic risks associated with different forms of menopausal hormone therapy (MHT).In a nationwide Danish study, oral MHT was associated with increased rates of venous blood clots, while ischemic stroke and myocardial infarction (heart attack) risks varied by dose and duration. Transdermal therapy had a much better safety profile, minus a higher risk for heart attack when using combined cyclic therapy (hazard ratio [HR], 2.1; 95% CI, 1.1-4.1). “The risk profile of different preparations is genuinely complex, as our study shows,” said Amani Meaidi, MD, PhD, a physician and research group leader in the Department of Gynecology and Obstetrics at Copenhagen University Hospital in Denmark and an author of the study. “What matters is staying evidence-based and continuing to refine our understanding of the risk profile of hormone therapy, so that women can make their own informed benefit-risk assessment — rather than swinging like a pendulum from one paradigm to the next.”Compared with no current hormone therapy, oral MHT (alone or with progestin) was associated with a 60% higher rate of blood clots (HR, 1.6; 95% CI, 1.5-1.8), 30% higher rate of stroke (HR, 1.3; 95% CI, 1.2-1.4), and 20% higher rate of heart attack (HR, 1.2; 95% CI, 1.1-1.3).Compared with no hormone therapy, blood clot risk was increased across doses and treatment durations. Oral estradiol combined with levonorgestrel was an exception.Low-dose oral estradiol was not associated with increased stroke or heart attack risk regardless of duration. Higher dose usage for more than 1 year did increase these risks. Researchers used Danish national health registry data from 2003 through 2021 on women aged 50-69 years. Women with a history of venous or arterial thrombosis, cancer, liver disease, thrombophilia, oophorectomy, infertility treatment, endometriosis, or polyendocrine metabolic ovarian syndrome were excluded.Researchers identified 9807 women with a first venous blood clot, 18,460 with a first stroke, and 11,974 with a first heart attack. Each case was matched by birth year with five women who had not experienced that outcome at the time. Prescription records were used to determine current MHT use, including route, dose, and duration.Despite the increases in relative risk, the absolute increases were small: Oral MHT was associated with approximately nine additional blood clots, six strokes, and three myocardial infarctions per 10,000 women per year.“These absolute numbers show that thrombotic events remain a rare side effect of oral hormone therapy,” Meaidi said. But because MHT is widely used and these events can be fatal, “even a small absolute risk translates into a meaningful number of events at a population level,” she said.The risks should be considered in the context of each patient's cardiovascular and thrombotic risk and balanced against the potential benefits of MHT, said Michael Solotke, MD, a clinical assistant professor in the Department of Obstetrics and Gynecology at Feinberg School of Medicine in Chicago, who was not associated with the study. Meaidi said the research offers clinicians guidance for balancing risks with the need to effectively treat symptoms. “Our findings support an individualized approach: When oral therapy is appropriate, clinicians should consider using the lowest effective dose, ideally a maximum of 1 mg estradiol per day, and regularly reassess the ongoing need for treatment,” Meaidi said.But “although 1 mg is a common oral estradiol dose, it is not unusual for patients to have inadequate symptom control at that dose, so they may increase to a dose > 1 mg,” Solotke said. The study data should not be interpreted as showing causation, but they provide helpful information to incorporate when discussing higher oral estradiol doses with patients, he said.In an accompanying opinion piece, Meaidi cautioned against allowing growing enthusiasm for MHT to swing too far from the fears that have surrounded the treatment for decades.“It's the clinician's responsibility, when treatment is needed, to recommend not just the most effective option, but the safest one — rather than reducing the conversation to a simple ‘safe or unsafe’ label,” she said.Brittany Vargas is an independent journalist covering medicine, mental health, and wellness Meaidi reported receiving presentation fees from Astellas. Solotke reported no disclosures.