19 May 2014

This trial was performed within the frame of the Austrian Study on Recurrent Venous Thromboembolism (AUREC), an ongoing prospective cohort study [1]. Between July 1992 and September 2008, consecutive patients with a first distal and/or proximal deep-vein thrombosis of the leg and/or pulmonary embolism who had been treated with anticoagulants for 3 to 18 months were included. Three weeks after withdrawal of anticoagulation, women were screened for biochemical and genetic risk factors of venous thromboembolism (VTE). The present prospective analysis included data collected until March 2012. The cohort was composed of 630 women (333 estrogen users, 297 non-users, average age 46 ± 17 years) with a first VTE who were followed for an average of 69 months after anticoagulation withdrawal. Excluded were women with a previous or secondary VTE; coagulation inhibitor deficiency; lupus anticoagulant; cancer; pregnancy; requirement of long-term antithrombotic therapy; or homozygosity or double heterozygosity for factor V Leiden and/or the G20210A prothrombin mutation. The endpoint was objectively documented symptomatic recurrent VTE. VTE recurred in 22 (7%) estrogen users and in 49 (17%) non-users. After 1, 2 and 5 years, the cumulative probability of recurrence was 1% (95% confidence interval (CI) 0–2), 1% (95% CI 0–2) and 6% (95% CI 3–9) among estrogen users and 5% (95% CI 2–7), 9% (95% CI 6–13) and 17% (95% CI 12–22) among non-users. Compared to non-users, estrogen users had an adjusted relative risk (RR) of recurrent VTE of 0.4 (95% CI 0.2–0.8). Compared to non-users in the respective age groups, the RR of recurrence was 0.4 (95% CI 0.2–0.8) among estrogen-containing contraceptive users and 0.7 (95% CI 0.3–1.5) among women using estrogen-containing menopausal hormone therapy. The study conclusions were therefore that women who had their first VTE while using estrogens have a low risk of recurrent VTE. These women might not benefit from extended anticoagulant therapy.

Comment

Thromboembolism, particularly DVT, remains the most significant serious adverse event of postmenopausal estrogen use in midlife, whereas cardiac issues, stroke and breast cancer become more conspicuous in older age or after a prolonged use. I believe many menopause specialists are looking for solid risk stratification that will allow the identification of those women who might be at a higher risk for VTE and therefore may not be candidates for hormone therapy. One of the major parameters to be considered in this paradigm is personal health history. I remember that I was always curious to know whether a women who used contraceptives or had many pregnancies, namely women who were exposed to high estrogen levels over a long term and did not suffer VTE, are actually women at a low risk for VTE associated with postmenopausal hormone use. This hypothesis seems very logical, but as far as I know was not tested in good-quality studies. Perhaps recent data showing the good safety profile of transdermal estradiol in this respect ease the concerns while discussing hormone therapy in the early postmenopausal period [2].

Past history of VTE is a major risk factor for recurrent events. Eischer and colleagues conclude their study by stating in the Abstract that 'Women who had their first VTE while using estrogens have a low risk of recurrent VTE' [1]. If one would read only the Abstract, which is what most of us usually do, then such a statement should translate into a great relief in regard to the potential contraindication to prescribe hormones to women who have suffered 'unprovoked' or 'idiopathic' VTE in the past. However, contrary to the phrasing of the Abstract, careful reading of the full manuscript points to different conclusions. I was misled myself since the detailed text brings three major additional pieces of information: (1) Most of the participants were on contraceptives while having their first episode of VTE; the number of women who used postmenopausal therapy was very small: 58 women, of whom 21 women used estrogens alone and 37 who used estrogens in combination with progesterone; (2) At study baseline, post the initial episode of VTE, women were strongly advised not to use estrogen any further in the future, and indeed none of the women used estrogens after withdrawal of anticoagulation; (3) In contrast to the decreased risk for future VTE in the baseline contraceptive users, the same risk for a recurrent VTE episode was obtained among women using estrogen-containing menopausal hormone therapy and the non-user counterparts from the same age group.

Thus the bottom line is that this study did not bring any breaking news. After excluding all women who had accompanying diseases or clinical situations that may be associated with elevated risk for VTE, and after removing from the cohort all women with an abnormal coagulation panel, estrogen use remained a common etiology for a first episode of VTE. Stopping postmenopausal estrogen therapy once a VTE event occurred just reduced future risk for VTE to the basal level found in non-users. The fact that there were many cases of what is usually defined as 'unprovoked' or 'idiopathic' VTE (the events recorded in the non-user subgroup) points at additional potential pathophysiological mechanisms for lower VTE threshold which are still unknown. The readers may wish to receive further education on the topic: a recent general review on DVT [3] or a discussion on estrogen and related DVT [4]. Last, but not least, article abstracts may be mis-perceived or mis-interpreted due to their concise format. Furthermore, the abstract text may not tell us the full story and sometimes may even bring conclusions which are not exactly in line with the actual data that were presented in the body of the manuscript.

Amos Pines
Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel

References

1. Eischer L, Eichinger S, Kyrle PA. The risk of recurrence in women with venous thromboembolism while using estrogens: a prospective cohort study. J Thromb Haemost 2014 Feb 18. Epub ahead of print
http://www.ncbi.nlm.nih.gov/pubmed/24548536 

2. Simon JA. What if the Women's Health Initiative had used transdermal estradiol and oral progesterone instead? Menopause 2014 Jan 6. Epub ahead of print
http://www.ncbi.nlm.nih.gov/pubmed/24398406 

3. Naess IA, Christiansen SC, Romundstad P, et al. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost 2007;5:692-9
http://www.ncbi.nlm.nih.gov/pubmed/17367492 

4. Middeldorp S. Thrombosis in women: what are the knowledge gaps in 2013? J Thromb Haemost 2013;11(Suppl 1):180-91
http://www.ncbi.nlm.nih.gov/pubmed/23809122