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Risk for Venous Thrombosis from Hormone Therapy

Who is at greatest risk, and from which type of therapy?

The Women's Health Initiative (WHI) researchers documented significantly greater risk for venous thrombosis (VT) from combination hormone replacement therapy (HRT; conjugated equine estrogen plus progestin) than from placebo. Now, we get further insights into the VT-HRT link from a focused analysis of the WHI cohort (16,000 postmenopausal women without coronary heart disease; age range, 50-79) and from a separate observational study of VT risk from esterified versus conjugated estrogen.

During 5.6 years of follow-up in the WHI trial, VT rates were 2.5 per 1000 person-years with combination HRT and 1.7 per 1000 person-years with placebo (hazard ratio, 2.06; 95% CI, 1.57-2.70). The older the combination-HRT recipient and the greater her body-mass index, the greater was her risk for VT. In a subset of participants who underwent genetic testing, VT risk was significantly associated with the factor V Leiden mutation, but not with other genetic factors.

In the other study, researchers used a large HMO database to examine VT risk in peri- and postmenopausal women (age range, 30-89) before and after October 1999, when standard estrogen treatment in the HMO formulary was switched from esterified therapy to conjugated equine therapy. From 1995 to 2001, 586 women experienced a first VT. Women who were not using HRT were the reference group in an analysis adjusted for potential confounders (e.g., age, treated hypertension status, history of cancer). In this analysis, VT was not associated with esterified estrogen use, but it was associated with conjugated estrogen use (odds ratio, 1.65; 95% CI, 1.24-2.19). Use of higher doses of conjugated estrogen and use of concomitant progestin further increased the odds of developing VT.

Comment: Together, these two studies elucidate the risk for venous thrombosis from estrogen therapy, particularly in combination with progestin. The WHI data document particularly high risk associated with older age, obesity, and factor V Leiden. The other study's results suggest that esterified estrogen might be a safer alternative to conjugated equine estrogen, at least with respect to VT. Further studies are needed to confirm these findings.

— JoAnne M. Foody, MD

Published in Journal Watch Cardiology December 3, 2004

Citation(s):

Cushman M et al. for the Women's Health Initiative Investigators. Estrogen plus progestin and risk of venous thrombosis. JAMA 2004 Oct 6; 292:1573-80.

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• Medline abstract (Free)

Smith NL et al. Esterified estrogens and conjugated equine estrogens and the risk of venous thrombosis. JAMA 2004 Oct 6; 292:1581-7.

• Original article (Subscription may be required)
• Medline abstract (Free)