Oral HRT More than Doubles Thrombotic Risk

By Judith Groch
VILLEJUIF CEDEX, France, 24 may 2008-- Among postmenopausal women taking oral hormone replacement therapy (HRT), the risk of venous thromboembolism was 2.5 times greater than that for non-users, but transdermal delivery appeared to be safer, according to a meta-analysis.
The increased risk was higher within the first year of treatment, with no noticeable difference in risk between women taking unopposed and opposed oral estrogen, Marianne Canonico, Ph.D., of Université Paris-Sud here, and colleagues reported in BMJ Online First.
By contrast, the risk of clots among women using transdermal estrogen was no different from that of non-users of estrogen, the researchers said.
HRT is regularly prescribed to relieve postmenopausal symptoms, despite evidence that oral estrogen activates blood coagulation.
Until now, however, no systematic meta-analysis has assessed the size of the increased risk, or whether the risk varies according to the type of delivery, such as a skin patch versus oral HRT, the investigators said.
Their findings, from a Medline analysis, came from eight observational studies and nine randomized controlled trials.
Analysis of the observational studies showed that oral estrogen -- but not transdermal estrogen -- increased the risk of venous thromboembolism. Conjugated estrogens and estradiol were used in both the observational and the randomized trials that showed increased risk.
Compared with non-users of estrogen, the odds ratio of a first-time venous thromboembolism in current users of oral estrogen was 2.5 (95% CI 1.9 to 3.4); it was 1.2 (0.9 to 1.7) in current users of transdermal estrogen.
Past users of oral estrogen had a similar risk of thromboembolism to never-users.
Information on duration of treatment for oral estrogen was available for only five case-control studies. These results showed that the clot risk in women using oral estrogen was significantly higher in the first year of treatment (OR 4.0, 95% CI 2.9 to 5.7) compared with treatment for more than one year (pooled OR 2.1, 95% CI 1.3 to 3.8, P<0.05).
No noticeable difference in the clot risk was observed between unopposed oral estrogen (OR 2.2, 95% CI 1.6 to 3.0) and opposed oral estrogen (OR 2.6, 95% CI 2.0 to 3.2).
Results from the nine randomized controlled trials confirmed the increased clot risk among women using oral estrogen (OR 2.1, 95% CI 1.4 to 3.1).
The combination of oral estrogen and thrombogenic mutations or obesity further enhanced the risk, whereas transdermal estrogen did not seem to confer additional risk even among women at high risk of venous clots.
Women with prothrombotic mutations or a high body mass index should avoid oral estrogens, the investigators advised.
Reviewing biological mechanisms for these findings, the researchers wrote that oral estrogen is absorbed into the blood stream, thus affecting the liver. This may impair the balance between procoagulant factors and antithrombotic mechanisms.
Oral estrogen increases plasma concentrations of prothrombin fragments 1 + 2, lowers antithrombin concentrations, and causes an acquired resistance to activated protein C. However, transdermal estrogen seems to have little or no effect on hemostasis, the investigators said.
Among the study's limitations, the researchers noted the limited data for transdermal-patch users. Thus these results need to be interpreted with caution, they said.
Another limitation is the lack of data on the impact of progestogens. Although this study found a similar risk for estrogen alone and opposed estrogen, recent data have found progestogen to be a risk.
Heterogeneity among studies of oral estrogen users in this analysis may have affected the results, especially differences in duration of treatment, the investigators noted.
More data are required to investigate differences in risks across the wide variety of hormone regimens, especially the different types of progestogens, the researchers said.
In addition, they said, recent guidelines recommend that women receive the lowest effective dose of hormone replacement therapy for the shortest time possible, inasmuch as pulmonary embolism becomes a main adverse effect from oral therapy within the first year of treatment.
Reducing clot risks by using transdermal estrogen could improve the benefit and risk profile of hormone replacement therapy.
Future randomized trials of transdermal estrogen compared with placebo will clarify the skin patch's apparent safety, they concluded.
In an accompanying editorial, Helen Roberts, M.D., of the University of Auckland, New Zealand, discussed the need for more research.
In the meantime, she said, healthy menopausal women ages 50 to 59 can be advised that the risk 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 studies have shown that a dose response seems to exist, these absolute risks may be lower with lower doses of hormones, she said.
However, women with previous venous thromboembolism or a mutation affecting prothrombin should be offered alternatives to estrogen, Dr. Roberts said.
Dr. Canonico and co-author Pierre-Yves Scarabin are funded by Inserm (Institut National de la Santé et de la Recherche Biomédicale). Other authors received funding from Assistance Publique des Hôpitaux de Paris, and the University of Glasgow.
Dr. Canonico and Dr. Roberts, the editiorialist, declared no competing interests.
Primary source: BMJSource reference:Canonico M, et al "Hormone replacement therapy and risk of venous thromboembolism in postmenopausal women: Systemic review and meta-analysis" BMJ 2008; DOI: 10.1136/bmj.39555.441944.BE Additional source: BMJSource reference: Roberts H "Type of hormone replacement therapy and risk of venous thromboembolism" BMJ 2008; DOI: 10.1136/bmj.39556.666944.80