CEE Raises Venous Thrombosis Risk vs Estradiol for Oral HRT in Case-Control Study

October 01, 2013

SEATTLE, WA — In a case-control study based on a cohort of women on oral hormone-replacement therapy (HRT), those using conjugated equine estrogens (CEEs) showed twice the risk of incident venous thrombosis when followed for up to seven years compared with women taking estradiol[1]. A trend of increasing MI risk with CEEs was well short of significance, and there was no significant difference for risk of ischemic stroke in the analysis, based on the experience of women in a Washington state health maintenance organization (HMO).

"If confirmed, the results would provide valuable information to women and their healthcare professionals when making safety decisions regarding available hormone-therapy options for menopausal symptom management," write the authors, led by Dr Nicholas L Smith (University of Washington, Seattle). Their analysis, based on a Heart and Vascular Health (HVH) study cohort, was published online September 30, 2013 in JAMA Internal Medicine.

The findings suggest that the risk of "avoidable venous and possibly cardiac thrombotic events may be lowered by selecting lower-risk medications." Whether estradiol is in fact lower risk compared with CEEs in such patients must be left to more definitive studies, according to the group.

Participants in the case-control study, all women on oral HRT, were followed for venous thrombosis, MI, and ischemic stroke from January 1, 2003 to the end of 2009. Comparison of the two types of oral estrogen was made possible by a February 1, 2005 change in the HMO's preferred formulary estrogen from CEE to estradiol, which it did "to save on drug costs."

Women in the cohort study who experienced a venous thrombosis (that is, deep vein thrombosis or pulmonary embolism [n=68]), MI (n=67), or ischemic stroke (n=48) were matched to 201 controls based on sex, decade of age, treated hypertension status, and calendar year of identification. The controls had no history of such ischemic events. All were on oral HRT, and none were on anticoagulants.

Adjusted* Risk of Venous Thrombosis, MI, and Ischemic Stroke Associated With Current Use of Oral CEE vs Oral Estradiol

End points OR (95% CI) p
Venous thrombosis 2.08 (1.02–4.27) 0.045
MI 1.87 (0.91–3.84) 0.09
Ischemic stroke 1.13 (0.55–2.31) 0.74

*All three analyses adjusted for age, race/ethnicity, body-mass index, current statin use, estrogen daily dose, current progestogen use, current smoking status, treated hypertension, treated diabetes, prevalent cardiovascular disease, and the number of clinic visits in the year before the index date; venous thrombosis further adjusted for cancer history; MI and ischemic stroke further adjusted for systolic blood pressure and total-cholesterol level.

In a substudy of 140 controls, users of CEEs compared with those on estradiol showed a significantly increased (p<0.001) endogenous thrombin potential-based normalized activated protein C sensitivity ratio, "indicating stronger clotting propensity." That analysis was adjusted for age, race or ethnicity, current smoking, body-mass index, factor V Leiden variant, self-reported general health, cancer, treated diabetes status, current statin use, progestogen use, and estrogen daily dose.

"Although no statistical differences were observed in subgroups," the group writes, "the relative risks of venous thrombosis and MI were only slightly elevated for low-dose CEEs users compared with low-dose estradiol users."

The HVH study is supported by grants from the National Heart, Lung, and Blood Institute. Smith had no conflicts of interest; disclosures for the coauthors are listed in the paper.

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