The French ESTHER Study of VTE

Abstract & Commentary

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

Synopsis: A French case-control study reported an increased risk of venous thromboembolism (VTE) with oral postmenopausal estrogen therapy, but no increase with transdermal treatment. In addition, results suggested an increase with estrogen combined with norpregnane progestins.

Source: Canonico M, et al. Hormone therapy and venous thromboembolism among postmenopausal women. Impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation. 2007;115:840-845.

The EStrogen and THromboEmbolism Risk (ESTHER) study is a case-control study performed with cases from 8 French hospitals and controls from the general population.1 The results were as follows:

    Cases Controls Adjusted
Odds Ratio
Oral estrogen   4 39 4.2 (1.5-11.6)
Transdermal       
  estrogen 67 180 0.9 (0.4-2.1)
With micronized      
  progesterone 9 63 0.7 (0.3-1.9)
With pregnane       
  progestins 39 79 0.9 (0.4-2.3)
With norpregnane       
  progestins 40 37 3.9 (1.5-10.0)
         
(table adapted by L. Speroff)

The authors concluded that transdermal estrogen is not associated with an increased risk of VTE, and that norpregnane progestins may be thrombogenic.

Commentary

This current report is an update of a previous report from the ESTHER study in which no increase in VTE risk was found with transdermal estrogen therapy.2 In addition, this study has reported that oral estrogen treatment adds to the risk of VTE associated with obesity, but transdermal estrogen does not.3 They have also reported (although limited by small numbers) that transdermal treatment, in contrast to oral estrogen, does not further increase the risk of VTE associated with Leiden or prothrombin mutations.4

France is unique in that transdermal estrogen therapy is very popular, providing sufficient numbers to perform a case-control study of a relatively infrequent event. In addition, a wide variety of progestational agents is in use in Europe, allowing subgroup analyses of different progestins.

But there are some problems with this French case-control study. First, look at the wide confidence interval for the significant odds ratio associated with oral estrogen treatment. Usually this reflects small numbers, but the number of cases and controls in this study should allow greater precision. It is possible that this imprecise conclusion is influenced by the fact that the cases and controls differed significantly in several characteristics that influence the risk of VTE, specifically greater body weight and a positive family history of VTE. Nevertheless, we know that an increased risk of VTE is uniformly reported, including the data from the Women's Health Initiative (WHI).5, 6 It is very likely that the French estimate is higher compared with the usual 2-fold increased risk because of the confounding differences between their cases and controls. It is worth noting that in the WHI, the cases of venous thrombosis were concentrated in the first year of exposure, in the oldest women in the study, and in the heaviest women in the study. It makes you wonder how large the risk is, if any, in younger, normal weight postmenopausal women.

The French case-control study found no increase in VTE risk associated with estrogen combined with progesterone or pregnane derivatives, and an increase with norpregnane derivatives. The pregnane group includes synthetic progestins familiar to us such as medroxyprogesterone acetate, chlormadinone, and cyproterone. The norpregnanes (progesterone without the 19-carbon) included two progestins, nomegestrol acetate and promegestone, which are not used in the US (Nomegestrol acetate is the progestin in Uniplant, a single rod implant contraceptive). But can we make the conclusion that the norpregnanes are thrombogenic? The confidence interval in the norpregnane group is very wide, again apparently not due to small numbers, but this makes this conclusion shaky and suspect.

In this study, oral hormone users used almost exclusively estradiol in doses that averaged 1.5 mg per day. Transdermal users most commonly used an estradiol dose of 50 µg or less daily. There is another problem here. To legitimately compare oral and transdermal methods, one would have to be sure the two groups had similar blood levels, to account for the wide variation in metabolism and clearance among individuals. It is possible that the difference between the oral and transdermal groups represent differences in estrogen doses.

A greater safety with transdermal administration of estrogen in regards to VTE makes some sense because of the known lesser impact on clotting proteins when the first-pass liver effect is avoided. This is supported by transdermal's almost negligible effect on activated protein C resistance when compared with oral therapy.7, 8 Therefore, the ESTHER study supports the clinical choice of a transdermal method for women who are at higher risk for VTE. The data are too weak to make any statements with confidence regarding the effect of various progestins.

References

  1. Canonico M, et al. Hormone therapy and venous thromboembolism among postmenopausal women. Impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation. 2007;115:840-845.
  2. Scarabin PY, et al. Differential association of oral and transdermal oestrogen-replacement therapy with venous thromboembolism risk. Lancet. 2003;362:428-432.
  3. Canonico M, et al. Obesity and risk of venous thromboembolism among postmenopausal women: differential impact of hormone therapy by route of estrogen administration. The ESTHER Study. J Thromb Haemost. 2006;4:1259-1265.
  4. Straczek C, et al. Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration. Circulation. 2005;112:3495-500.
  5. Curb JD, et al. Venous thrombosis and conjugated equine estrogen in women without a uterus. Arch Intern Med. 2006;166:772-780.
  6. Cushman M, et al. Estrogen plus progestin and risk of venous thrombosis. JAMA. 2004;292:1573-1580.
  7. Lowe GD, et al. Different effects of oral and transdermal hormone replacement therapies on factor IX, APC resistance, t-PA, PAI, and C-reactive protein—a cross-sectional population survey. Thromb Haemost. 2001;86:550-556.
  8. Post MS, et al. Effect of oral and transdermal estrogen replacement therapy on hemostatic variables associated with venous thrombosis: a randomized, placebo-controlled study in postmenopausal women. Arterioscler Thromb Vasc Biol. 2003;23:1116-1121.