04.04.2016

by Molly Walker
Contributing Writer

For women who used hormone replacement therapy to treat menopausal symptoms, risk of blood clots tended to vary depending on the type of therapy used, a small Swedish case-control study found.

While the risk of venous thromboembolism (VTE) was moderately higher with estrogen-only therapy compared with untreated, age-matched controls, it was nearly three times greater with combined estrogen-progestogen therapy (OR 2.85 versus OR 1.31, respectively), reported Annica Bergendal, MD, of the Karolinska Institute in Stockholm, and colleagues.

In fact, there was a statistically significant difference in the use of combined estrogen-progestogen compared with estrogen-only therapy (OR 2.18, P=0.009), the authors wrote in Menopause.

Overall, use of any hormone replacement therapy was associated with a 72% increased risk of VTE, which is consistent with recent observational studies of post-menopausal women. Other observational studies have found estrogens plus progestogens to be associated with a higher risk of VTE than estrogens only, though the authors add that “the impact on VTE risk by route of systemic estrogen administration, and the role of progestogens is, however, still unclear.”

JoAnn Pinkerton, MD, executive director of the North American Menopause Society(NAMS), characterized the absolute risk for blood clots as “infrequent” for healthy women under the age of 60 or within 10 years of menopause.

“Women using both estrogen and synthetic progestin appear to be at highest risk of blood clots and this is most likely dose related, with less risk with lower dose or less potent hormones such as micronized progesterone although adequate clinical trial data is lacking as there are no head-to-head studies,” she wrote in an email to MedPage Today.

Bergendal’s team further examined the risk of VTE associated with different types of estrogen therapy. They found a statistically significant increased risk for blood clots associated with oral estrogen compared to vaginal estrogen (OR 2.64, P=0.003), but a nonsignificant difference in risk associated with oral estrogen compared with transdermal estrogen.

However, the risk of VTE did not increase either with transdermal estrogen (OR 0.90) or vaginal estrogen (OR 0.69). Local vaginal estrogen is primarily used to treat genitourinary syndrome of menopause or prevent recurrent yeast infections.

“Low dose vaginal estrogen was not associated with blood clot risk and thus the boxed warning developed for systemic estrogen does not apply to vaginal estrogen for risk of blood clots,” said Pinkerton.

When examining varying types of progestogen, there was no significant difference in the increased risk of VTE between the two most commonly used progestogens, medroxyprogesterone acetate and norethisterone acetate (P=0.41).

But medroxyprogesterone acetate was associated with a possibly greater increased risk of VTE compared to norethisterone acetate (OR 2.94 versus OR 2.29, respectively), consistent with a recent study that found medroxyprogesterone acetate linked to a relatively higher VTE risk.

“A possible explanation for potential differences in VTE risk regarding the type of progestogen in [hormone replacement therapy] might be that oral estrogens or transdermal estrogens combined with norpregnanes may have impact on activated protein C (APC) resistance, prothrombotic state or a decreased blood flow,” the authors wrote.

Pinkerton suggested that other baseline factors may contribute to a woman’s increased risk of VTE.

“Blood clot risks are higher in the first year of hormone use and higher in women with other risk factors including obesity or factor V Leiden [a clotting factor mutation], surgery or immobilization,” she said.

Bergendal’s team examined a cohort from the ThromboEmbolismHormoneStudy (TEHS), comprised of 838 cases of VTE to 891 age-matched controls. Women were a mean age of 55 years in both groups, and data was collected via telephone interview. There were 28.3% of the cases and 21.4% of controls currently using hormone replacement therapy. The most common therapy was systemic treatment with combinations of estrogen and progestogen (18% of cases and 9.1% of controls). Adjustments were made for smoking status, BMI and immobilization (such as bed rest, trauma, or plaster cast).

Limitations to the study include the possibility of selection bias, recall bias, limited sample size, and lack of laboratory data to define menopause status.

• Reviewed by Robert Jasmer, MD Associate Clinical Professor of Medicine, University of California, San Francisco