Villejuif Cedex, France - Transdermal delivery of estrogen does not appear to be associated with the same risk of venous thromboembolism as that seen with oral estrogen, a new meta-analysis suggests [1].

Noting that pulmonary embolism accounts for about one-third of the excess incidence of potentially fatal events associated with long-term hormone replacement therapy (HRT), the authors say that the findings of the present meta-analysis may have important clinical implications. "Since recent guidelines recommend that women are prescribed the lowest effective dose of HRT for the shortest time possible, pulmonary embolism becomes a main adverse effect owing to oral estrogen therapy within the first year of treatment. In contrast, there is little increase in the risk of stroke and breast cancer within the first year of treatment. Therefore, reducing the risk of venous thromboembolism by using transdermal estrogen could improve the benefit and risk profile of HRT, especially among women at high risk of venous thromboembolism—for example, women with known prothrombotic mutations or a high body-mass index," they conclude.

The meta-analysis, published online May 23, 2008 in BMJ, was conducted by a group led by Dr Marianne Canonico (Inserm, Villejuif Cedex, France).

They explain that HRT is known to increase the risk of venous thromboembolism, but most studies of this association were done among women taking oral conjugated equine estrogens either alone or with medroxyprogesterone acetate, and so the results should not be generalized to other HRT regimens. Noting that recent data have suggested the importance of the route of estrogen administration in determining risk of venous thromboembolism, they conducted a new meta-analysis of eight observational studies and nine randomized controlled trials of HRT that reported venous thromboembolism, taking into account the characteristics of the HRT preparations used.

Meta-analysis of the eight observational studies showed that oral estrogen, but not transdermal estrogen, increased the risk of venous thromboembolism by two- to threefold. The risk of venous thromboembolism in women using oral estrogen was higher in the first year of treatment compared with subsequent years of treatment. No noticeable difference in the risk of venous thromboembolism was observed between unopposed oral estrogen and opposed oral estrogen. Past users of oral estrogen had a similar risk of venous thromboembolism to never users.

Results from the nine randomized controlled trials confirmed the increased risk of venous thromboembolism among women using oral estrogen, but no additional information could be found on transdermal estrogen, as no randomized trials have investigated the effect of this delivery form of HRT on the risk of venous thromboembolism.

Canonico et al note that, overall, with a baseline risk for venous thromboembolism of about one per 1000 woman-years, use of oral estrogen would cause an additional 1.5 events per 1000 women each year, but no such increased risk is associated with transdermal use. They also point out that their results show a substantial increase in the risk of venous thromboembolism among women using oral estrogen who were overweight or obese (OR 5.4, 95% CI 2.9-10.0), but that in one study current use of transdermal estrogen did not confer an additional risk on such women.

However, they warn that in the current meta-analysis, assessment of the risk of venous thromboembolism among users of transdermal estrogen was based on relatively few data, and the results should therefore be interpreted with caution. They also note that although this meta-analysis showed a similar risk of venous thromboembolism among users of oral estrogen alone and opposed oral estrogen, recent studies have suggested that use of progestogens may increase the risk.

In an accompanying editorial [2], Dr Helen Roberts (University of Auckland, New Zealand) reviews other data on transdermal estrogen and notes that the Papworth study, which randomized women with angiographically confirmed ischemic heart disease to transdermal therapy or placebo, found no significant difference in rates of cardiac events in the transdermal group; and the observational Million-Women Study showed similar increased risks for transdermal and oral estrogens with respect to breast cancer.

She says that further investigation into the association between venous thromboembolism and transdermal estrogen is needed. "In the meantime, we can advise healthy menopausal women aged 50 to 59 that the risk of venous thromboembolism with oral preparations is about 11 additional cases per 10 000 women per year for combined therapy and two additional cases per 10 000 women per year for estrogen only. Because a dose response seems to exist, these absolute risks may be lower with lower doses of hormones. Women with previous venous thromboembolism or a mutation affecting prothrombin should be offered alternatives to estrogen," she concludes.