Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: systematic review and meta-analysis.
Level 1 - systematic review of randomized trials
Systematic review and meta-analysis including randomized controlled trials
PubMed 18495631 · doi:10.1136/bmj.39555.441944.BE
What was done
Authors conducted a systematic review and meta-analysis of Medline-indexed studies assessing venous thromboembolism (VTE) risk in women using hormone replacement therapy (HRT) across study designs, routes of administration, treatment duration, and clinical risk factors. The meta-analysis synthesized data from 8 observational studies and 9 randomized controlled trials using fixed-effects or random-effects models, assessing heterogeneity with chi-squared and I² statistics.
What was found
In observational studies, current oral oestrogen use increased first-time VTE risk compared to non-use (OR 2.5, 95% CI 1.9 to 3.4), whereas transdermal oestrogen did not show a statistically significant increase (OR 1.2, 95% CI 0.9 to 1.7). Past oral oestrogen users had similar risk to never-users. VTE risk was significantly higher during the first year of oral treatment (OR 4.0, 95% CI 2.9 to 5.7) than after one year (OR 2.1, 95% CI 1.3 to 3.8; P < 0.05). Risk was comparable between unopposed oral oestrogen (OR 2.2, 95% CI 1.6 to 3.0) and opposed oral oestrogen (OR 2.6, 95% CI 2.0 to 3.2). The 9 randomized controlled trials confirmed increased VTE risk with oral oestrogen (OR 2.1, 95% CI 1.4 to 3.1). Oral oestrogen combined with obesity or thrombogenic mutations further amplified VTE risk, whereas transdermal oestrogen did not confer additional risk in high-risk women.
Why it matters
This review establishes that route of administration is critical in postmenopausal HRT safety: oral oestrogen roughly doubles to quadruples VTE risk (peaking in year one), while transdermal formulations avoid this elevated risk.
Limits
The search was restricted to a single database (Medline), total participant numbers are not reported in the abstract, and transdermal findings rely on observational data rather than RCTs. Data were insufficient to assess differences across specific progestogen types.
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- supports Transdermal estrogen does not increase the risk of blood clots.