VTE risk appears lower with transdermal vs. oral hormone replacement therapy

Nested case-control studies using two U.K. primary care databases found that oral hormone replacement therapy was associated with a significantly increased risk for venous thromboembolism (VTE), while transdermal formulations were not.


Transdermal hormone replacement therapy (HRT) was associated with lower risk for venous thromboembolism (VTE) than oral formulations, a recent observational study found.

Researchers in the United Kingdom performed nested case-control studies using two national primary care research databases. Women with a primary diagnosis of VTE between 1998 and 2017 were matched with controls by age, general practice, and index date. Exposure to HRT was determined for the year before the index date, with a focus on recent exposure (within 90 days). The study's main outcome measure was VTE as recorded in general practice, death, or hospital records. Results were published by BMJ on Jan. 9.

Overall, 80,896 women ages 40 to 79 years with a primary diagnosis of VTE were matched to 391,494 controls. A total of 5,795 women with VTE and 21,760 controls had had HRT exposure in the 90 days before the index date (7.2% vs. 5.5%). VTE was more likely to occur in women who were ages 65 years and older. Women with VTE were also more likely than controls to have comorbid conditions, to have had recent medical events, and to take antidepressants.

Oral HRT was used by 85% of women with VTE and 78% of women without and was associated with a significantly increased VTE risk versus no HRT exposure (adjusted odds ratio [OR], 1.58; 95% CI, 1.52 to 1.64). This risk was seen for both estrogen-only preparations and for combined preparations (adjusted ORs, 1.40 [95% CI, 1.32 to 1.48] and 1.73 [95% CI, 1.65 to 1.81], respectively). Risk appeared lower with estradiol than with conjugated equine estrogen in both estrogen-only preparations and combined preparations (adjusted ORs, 0.85 [95% CI, 0.76 to 0.95] and 0.83 [95% CI, 0.76 to 0.91], respectively). Conjugated equine estrogen with medroxyprogesterone acetate had the highest risk and estradiol with dydrogesterone had the lowest risk versus no exposure (adjusted ORs, 2.10 [95% CI, 1.92 to 2.31] and 1.18 [95% CI, 0.98 to 1.42]). No increased VTE risk was associated with any type of transdermal preparation (overall adjusted OR, 0.93; 95% CI, 0.87 to 1.01).

The authors noted that they did not have access to tests confirming VTE diagnosis, that exposure information was based on HRT prescriptions rather than actual use, and that they did not have enough information available on some HRT preparations to assess their risks individually, among other limitations. However, they concluded that oral HRT preparations involving conjugated equine estrogen appear to confer a higher VTE risk than those involving estradiol and that an association was also seen between higher estrogen dose and VTE risk. Although transdermal HRT seems to confer the lowest risk of VTE, it continues to be underused versus oral formulations, the authors said.