Objective: Determine whether hormone-associated venous thromboembolism (VTE) risk varies by exposure route and formulation in 50-64 year-old US women. Design: Nested case-control study. Setting: Large US commercially-insured population with patient-level claims data. Participants: Women aged 50-64 years with at least one year of enrollment. Controls were matched to incident cases (10:1) on VTE date and case's age (+/- 2yrs). Exclusions included prior VTE, intravascular vena cava (IVC) filter within twelve months, and anticoagulant exposure within 14 days. Exposures: All estrogen and progestogen prescriptions (with route and formulation) filled within 12 months prior to index date were coded as current (0-60 days), past (61-365 days), or none. Contraceptives were categorized separately. Outcome: Acute VTE cases were identified with ICD codes plus anticoagulant, IVC filter, or death within 30 days. Results: Conditional logic regression analyses controlled for differences between cases (n=20,359) and controls (n=203,590) in Elixhauser comorbidities and VTE risk factors. Odds ratios (OR) were as follows: for current oral, unopposed estradiol 1.24 (95% CI: 1.09 to 1.40) or conjugated equine estrogen (CEE) 1.46 (95% CI: 1.28 to 1.68); for progestogens with estradiol 1.14 (95% CI: 0.95 to 1.37), with CEE 1.52 (95% CI: 1.25 to 1.84), or with ethinyl estradiol 2.35 (95% CI: 1.71 to 3.25). Current transdermal estradiol had the lowest ORs, whether unopposed, 0.70 (95% CI: 0.59 to 0.83) or combined with progestogens, 0.73 (95% CI: 0.56 to 0.96), but varied by progestogen. The OR for estrogen-progestogen contraceptives was 5.22 (95% CI: 4.67 to 5.84) compared to no exposure and 4.24 (95% CI: 3.64 to 4.98) compared to combined MHT. Conclusions: In 50-64-year-old women, transdermal menopausal hormone therapy (estradiol with or without progestogens) did not elevate VTE risk. In contrast, contraceptives markedly increased VTE risk.

The authors have declared no competing interest.

Funding The data were obtained with a grant to SCW from the Texas Academy of Family Physicians Foundation.

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Project has University of Texas Medical Branch Institutional Review Board Approval (#20-0313)

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Data availability statement Data were obtained from a third party and are not publicly available. All data relevant to the study are summarised in the article. No further data are available. Data are proprietary of Optum Health Systems. However, requests for re-analyses will be considered.