Venous Thrombosis and Type of Treatment

Abstract & Commentary

Synopsis: A case-control study suggests that the risk of venous thrombosis differs according to the type of estrogen used.

Source: Smith NL, et al. JAMA. 2004;292:1581-1587.

Smith and colleagues performed a case-control study of venous thrombosis and hormone users in postmenopausal women registered in a large health maintenance organization (the Group Health Cooperative) in the state of Washington. In October 1999 this organization switched hormone users from esterified estrogens to conjugated equine estrogens. This allowed the investigators to compare the risk of venous thrombosis associated with these 2 types of estrogen treatment. An increased risk of venous thrombosis was associated with the use of conjugated equine estrogens (OR = 1.65, 1.24-2.19), but not found with the use of esterified estrogens (OR = 0.92, 0.69-1.22). Surprisingly, the use of conjugated equine estrogens without a progestin was not associated with an increased risk.

Comment by Leon Speroff, MD

Esterified estrogens contain approximately 80% estrone sulfate and 11% equilin sulfate. These are the 2 predominant estrogens in conjugated equine estrogens, but of course there is a large collection of steroids in this product, including not only estrogens, but very small amounts of progestins and androgens. There is potential, therefore, for different biologic behavior when comparing these two agents.

Smith et al performed a dose-response analysis, finding a statistically significant increase only with the standard dose of conjugated equine estrogens and an even higher risk with higher doses of conjugated equine estrogens. However, the number of cases with low doses of conjugated equine estrogens totalled only 8, and the number of cases with high doses of esterified estrogens included only 3. I think it is difficult to make dose-response conclusions with these small numbers, even though I believe that higher doses of estrogen carry a higher risk of venous thrombosis.

Contrary to almost all of the previous literature, this study did not find a higher risk of venous thrombosis associated with use in the first year of exposure. The numbers of cases in this subgroup analysis were not provided, and it is possible that the statistical power of the study was insufficient for detection of an effect in recent exposure.

It is very unlikely that the use of conjugated equine estrogens without a progestin would not have an increased risk of venous thrombosis. This finding more likely again reflects the power to detect increases in this relatively infrequent event.

In my view, the fundamental question is whether equivalent doses of these 2 estrogens produce bioequivalent biologic responses. Is it possible that the blood levels of estrogens differ significantly comparing the 2 products because of differences in metabolism and clearance? This case-control study raises a question, but does not provide sufficient evidence to influence prescribing choices. The proper study would require comparing women with similar blood concentrations of the estrogens.

Leon Speroff, MD, Professor of Obstetrics and Gynecology, Oregon Health Sciences University, Portland, is Editor for OB/GYN Clinical Alert.