For a 58-year-old postmenopausal woman concerned about venous thromboembolism, which hormone therapy was shown in the 2024 Swedish nationwide registry study to have no increased risk of VTE?

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Last updated: April 26, 2026 • View editorial policy

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Transdermal Unopposed Estrogen

For this 58-year-old postmenopausal woman concerned about VTE risk, transdermal unopposed estrogen should be recommended, as the 2024 Swedish nationwide registry study by Johansson and colleagues found no increased risk of venous thromboembolism with this formulation 1.

Evidence from the 2024 Swedish Study

The Johansson study was a large-scale emulated target trial involving 919,614 Swedish women aged 50-58, following them for cardiovascular outcomes over 2 years. Among the various hormone therapy options examined:

  • Transdermal unopposed estrogen showed NO increased VTE risk (hazard ratio not significantly elevated)
  • Oral combined continuous therapy: HR 1.61 (1.35-1.92) for VTE
  • Oral combined sequential therapy: HR 2.00 (1.61-2.49) for VTE
  • Oral unopposed estrogen: HR 1.57 (1.02-2.44) for VTE
  • Transdermal combined therapy: No significant VTE increase noted 1

Why Route of Administration Matters

The transdermal route avoids hepatic first-pass metabolism, which is the key mechanism behind VTE risk with oral estrogens. Oral estrogen preparations increase hepatic production of clotting factors and alter hemostatic parameters, while transdermal estradiol has a neutral effect on Sex Hormone Binding Protein (SHBP), a marker of VTE risk 2.

The ESTHER study demonstrated this dramatically: transdermal estrogens had an odds ratio of 0.9 (95% CI 0.4-2.1) for VTE compared to 4.2 (95% CI 1.5-11.6) for oral preparations 2.

Supporting Evidence Across Multiple Studies

This recommendation is reinforced by consistent findings across multiple high-quality studies:

  • A 2010 UK population-based study of 955,582 postmenopausal women found transdermal estrogen alone (RR 1.01; 95% CI 0.89-1.16) showed no increased VTE risk 3
  • A 2018 meta-analysis confirmed non-oral HT showed no increased VTE risk (OR 0.97,95% CI 0.9-1.06) while oral HT increased risk significantly (OR 1.72,95% CI 1.47-2.01) 4
  • A 2019 nested case-control study of 80,396 women found transdermal preparations were not associated with VTE risk (adjusted OR 0.93,95% CI 0.87-1.01) 5
  • A 2025 systematic review specifically examining women at higher VTE risk concluded that transdermal estrogen conferred no increased risk of VTE 6

Clinical Algorithm for This Patient

Step 1: Confirm she has an intact uterus or has had a hysterectomy

  • If intact uterus: Add progestin for endometrial protection (transdermal combined therapy also showed no VTE increase in the Swedish study)
  • If post-hysterectomy: Use transdermal unopposed estrogen

Step 2: Initiate transdermal estradiol at standard replacement doses (typically 0.05-0.1 mg/day patch)

Step 3: Avoid all oral formulations given her VTE concerns, as they consistently show 1.5-2x increased VTE risk

Important Caveats

While transdermal unopposed estrogen is the safest option for VTE risk, this patient still needs appropriate counseling:

  • Age consideration: At 58, she is at the upper end of the recommended age range for initiating hormone therapy, though still within the 10-year window from menopause onset that guidelines generally support
  • Other cardiovascular outcomes: The Swedish study found tibolone increased ischemic heart disease risk (HR 1.46) and oral estrogen-progestin therapy also increased this risk (HR 1.21), though transdermal formulations did not show these associations 1
  • Duration of use: VTE risk with oral formulations is highest in the first year of use but disappears 4 months after discontinuation 3

The evidence overwhelmingly supports transdermal unopposed estrogen as the hormone therapy with the most favorable VTE safety profile, making it the clear choice for this patient's specific concern.

References

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