20 February, 2017: 

One of the main issues discussed in relation to postmenopausal hormone therapy (HT) is the risk for venous thromboembolic (VTE) events. In fact, this safety aspect of HT use is probably the only significant one in healthy women younger than 60 or during the first decade of use. A history of VTE usually deters physicians from prescribing HT as these women have anyway a higher risk for recurrent VTE in the future. Is this true also for women who were already using HT when the index VTE occurred?

Kiconco and colleagues investigated the outcomes in women whose initial VTE event was hormone-related and compared them to women whose initial event had no obvious cause [1]. Their cohort utilized the Clinical Practice Research Datalink linked to Hospital Episode Statistics data from England. The investigators selected 4170 women aged between 15 and 64 years who were diagnosed with a first VTE event between 1997 and 2011, and treated for a while with anticoagulants, which were then discontinued. The median follow-up time after stopping anticoagulation was around 2 years. Recurrent VTE events were higher in non-users than in users of hormones (15.3% vs. 9.5%; 51 cases per 1000 vs. 37 cases per 1000). Further to the significant difference in the absolute number of events in each subgroup, hormone users had 29% lower recurrence risk than non-users (adjusted HR = 0.71; 95% CI 0.58–0.88), a relationship which existed both in women aged 15–44 years (predominantly oral contraceptive users) and those aged 45–64 years (predominantly HT users). The conclusion was that having a hormone-associated VTE was associated with a lower recurrence risk than that related to unprovoked VTE after cessation of both the hormone-containing preparation and the subsequent anticoagulation. Furthermore, if this is the case, then prolonged anticoagulation may be unjustified in such women.

Comment

VTE episodes are categorized as provoked or unprovoked [2]. Patients who develop VTE associated with a transient surgical procedure (surgically provoked VTE) have a very low rate of recurrence, estimated at 0.7% per year in the 2 years after stopping anticoagulation therapy. Patients who develop a non-surgical, provoked VTE (e.g. immobilization, pregnancy, use of estrogen-containing contraception) have a slightly higher recurrence risk, estimated at 4.2% per year in the same 2-year period after discontinuing anticoagulation therapy. Patients who develop VTE without a provoking factor have a higher rate of recurrence, estimated at 7.4% per year in the 2 years after discontinuing anticoagulation treatment. An episode of unprovoked VTE may initiate prolonged, even permanent anticoagulation. The risk of recurrent VTE over 10 years after a first episode is consistently around 30% [1], and is higher in patients whose index VTE is unprovoked or caused by a risk factor which is non-reversible. Current guidelines recommend that patients who develop VTE receive either oral anticoagulants or low-molecular-weight heparin for several months, and longer treatment duration is advised if the VTE was unprovoked [3].

VTE risk is related to reproductive factors and hormonal medications [4]. In the menopause, oral estrogen or combined estrogen–progestin combinations increase the risk by about 50%, whereas transdermal preparations seem safer in this respect [5,6]. The prescribing information of HT or contraceptives includes a contraindication phrased simply as 'active DVT, PE, or a history of these conditions'. Still, it would be of interest to learn about the consequences in the case VTE occurred while the patient was on estrogen-associated therapy. The standard, routine approach is to initiate a cascade of recommended actions: immediate withdrawal of hormones, proper anticoagulation started, then discontinued after a while based on the characteristics of the VTE and the estimated future risk for recurrence. Based on their study results, Kiconco and colleagues believe that anticoagulation should not be given for long, since HT-associated VTE fits into the provoked-type list, and as such the risk returns to basal levels after discontinuation of HT. Is there a support from other studies for this conclusion? A secondary analysis of pooled data from seven separate cohorts showed that women with hormone-associated VTE (oral contraceptives or oral HT) and no other risk factors had a recurrence which was lower than that in women with unprovoked VTE and no previous hormone use (HR 0.5, 95% CI 0.3-0.8) [7]. Tosetto and colleagues developed a new tool that predicts recurrence risk which was based on clinical data from a cohort of 1818 persons with unprovoked VTE [8]. The model included the following parameters: D-dimer values after stopping anticoagulation, age, gender and hormonal therapy at the time of the initial VTE. The lowest risk score was associated with a 3% annual incidence of recurrence, while the highest risk score had a much greater impact with a 20% annual incidence of recurrence. Hormone use at baseline was found to be an independent term in a subsequent risk calculator, contributing to a significant attenuation of the risk.

Hormone therapy, whether contraceptive or postmenopausal, increases the risk of thromboembolism as a result of a change in the hemostatic balance [9]. The risk of VTE appears to be greatest soon after the initiation of HT, but is reversible after discontinuation of treatment. Patients with VTE are at risk of VTE recurrence and therefore should receive an anticoagulant agent. Since it is important to balance the bleeding risks associated with extended anticoagulation against the reduction in VTE recurrence risk, estimating the post-HT chances of a repeat event will translate into the length of needed anticoagulation. The few studies on this clinical issue point at a relative low risk of recurrence, which allows a short (3-month) therapeutic course. It should be noted, though, that thrombophilia and its outcomes are a separate entity that is not discussed in my commentary.

Amos Pines

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

References

1. Kiconco S, Abdul Sultan A, Grainge MJ. Recurrence risk of venous thromboembolism and hormone use in women from England: a cohort study using clinical practice research datalink. Br J Haematol 2017 Jan 20. Epub ahead of print
   http://www.ncbi.nlm.nih.gov/pubmed/28106922
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   http://www.ncbi.nlm.nih.gov/pubmed/25832602
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   http://www.ncbi.nlm.nih.gov/pubmed/17906973
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   http://www.ncbi.nlm.nih.gov/pubmed/23825156
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   http://www.ncbi.nlm.nih.gov/pubmed/20230416
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   http://www.ncbi.nlm.nih.gov/pubmed/26276103
7. Douketis J, Tosetto A, Marcucci M, et al. Risk of recurrence after venous thromboembolism in men and women: patient level meta-analysis. BMJ 2011;342:d813
   http://www.ncbi.nlm.nih.gov/pubmed/21349898
8. Tosetto A, Iorio A, Marcucci M, et al. Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH). J Thromb Haemost 2012;10:1019-25
   http://www.ncbi.nlm.nih.gov/pubmed/22489957
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   http://www.ncbi.nlm.nih.gov/pubmed/24007716