VTE Treatment with NOACs in Women

This section covers sex-specific issues relevant to use of the NOACs for the treatment of VTE in women

In this section:

Facts and controversies

Compared with men, women appear to have a lower risk of first and recurrent VTE (blood clots). However, in women of reproductive age, the incidence of VTE is about twice as high as in men of the same age. because of the use of hormonal contraceptives and pregnancy during this phase of a woman’s life.

The NOACs (including the direct Factor Xa inhibitors apixaban, edoxaban and rivaroxaban and the direct thrombin inhibitor dabigatran) are guideline-recommended options for the treatment of VTE in most patients (excluding pregnant and breast-feeding women and patients with acute cancer-associated thrombosis), irrespective of sex. In pregnant women with VTE, guidelines recommend the use of injectable heparin-based anticoagulants (LMWH or UFH), and in women with VTE who are breastfeeding, either LMWH, UFH or an oral VKA (e.g. warfarin).

Data on the use of NOACs for VTE treatment in women

The major phase III clinical trials of the NOACs for VTE treatment included acute treatment trials, comparing NOACs with standard anticoagulant therapy, and extended treatment trials, comparing NOACs with placebo or active comparator. Overall, women composed 39–47% of the enrolled patient populations in these trials. In prospective real-world datasets, 46–50% of patients were female.

Proportion of women in the major phase III clinical trials of the NOACs for VTE treatment

Trial Acute or extended treatment trial NOAC Comparator Enrolled patients, N Women, n (%)
AMPLIFY Acute Apixaban Enoxaparin/warfarin 5395 2228 (41.3)
Hokusai-VTE Acute Edoxaban* Warfarin* 8240 3524 (42.8)
EINSTEIN DVT Acute Rivaroxaban Enoxaparin/VKA 3449 1489 (43.2)
EINSTEIN PE Acute Rivaroxaban Enoxaparin/VKA 4832 2276 (47.1)
RE-COVER Acute Dabigatran* Warfarin* 2539 1055 (41.6)
RE-COVER II Acute Dabigatran* Warfarin* 2568# 1011 (39.4)
AMPLIFY EXT Extended Apixaban Placebo 2482 1058 (42.6)
EINSTEIN EXT Extended Rivaroxaban Placebo 1196 503 (42.1)
EINSTEIN CHOICE Extended Rivaroxaban ASA 3365 1500 (44.6)
RE-MEDY Extended Dabigatran Warfarin 2856 1114 (39.0)
RE-SONATE Extended Dabigatran Placebo 1343 598 (44.5)

After (NOAC) or overlapping with (warfarin) an initial period of parenteral therapy for ≥5 days; #2589 patients were randomized, but 21 patients did not receive study medication, so they were excluded from the analysis. Baseline characteristics, including patient sex, were only available for the 2568 patients who received study medication.

Across all the phase III VTE treatment trials, the efficacy and safety profiles of the tested NOAC versus comparator were broadly similar between sexes – each NOAC was an effective and safe treatment option in both men and women.

A meta-analysis comparing outcomes between men and women treated with NOACs in nine of these trials (AMPLIFY, AMPLIFY EXT, EINSTEIN PE, EINSTEIN DVT, EINSTEIN EXT, RE-COVER, RE-MEDY, RE-SONATE and Hokusai-VTE) showed no differences in the incidence of recurrent VTE between sexes. However, compared with men, women with VTE treated with Factor Xa inhibitors had a higher incidence of clinically significant bleeding (i.e. a major bleeding or a bleeding event that prompts a patient to seek medical attention).

NOACs for VTE treatment in men versus women

Meta-analysis of the efficacy and safety of NOACs for VTE treatment in men versus women

Post hoc analyses from the EINSTEIN PE, EINSTEIN DVT and AMPLIFY trials suggested that this was caused by an increased incidence of abnormal uterine bleeding. This is supported by real-world data, which shows that heavy or prolonged menstrual bleeding is commonly reported by female patients receiving Factor Xa inhibitors for the treatment of VTE. It is important to note that heavy or prolonged menstrual bleeding events are a common complication of all direct Factor Xa inhibitors (rivaroxaban, apixaban and edoxaban), affecting 25–35% of all women of reproductive age.

Pregnancy and hormonal contraceptives

The use of NOACs for the treatment of VTE in women (especially those of childbearing age) is associated with specific challenges because of the need to avoid pregnancy and controversies relating to the use of hormonal contraceptives in women with VTE.

Preclinical studies indicated that the NOACs can cross the placenta and reproductive toxicity has been observed in animal models. Consequently, NOACs are not recommended (apixaban, dabigatran) or contraindicated (edoxaban, rivaroxaban) during pregnancy.

Avoidance of use of hormonal contraceptives in women with VTE treated with NOACs

The International Society on Thrombosis and Haemostasis (ISTH) recommends that all women of childbearing potential receive counselling on the adequate and appropriate use of contraception prior to initiating treatment with a NOAC. Worldwide, commonly used forms of contraception include oral contraceptives, intrauterine devices, barrier methods and sterilization. The use of hormonal contraceptives (including oral, transdermal, injectable and vaginal ring preparations) is associated with a 2–8-fold increased risk of VTE; this increased risk is associated with both combined hormonal contraceptives (i.e. those containing both an oestrogen and a progestogen) and high-dose progestogen-only preparations (but not low-dose progestogen-only oral preparations [the ‘mini pill’] or progestogen-releasing intrauterine devices).

As a result, the 2015 World Health Organization (WHO) guidelines state that combined hormonal contraceptives should not be used in women with acute VTE (or any history of VTE) even if on anticoagulants. By contrast, ISTH guidance suggests the use of hormonal contraceptives may be considered in women with VTE treated with anticoagulants because any prothrombotic effect of hormonal therapy is likely to be suppressed by therapeutic-intensity anticoagulation.

There are only very limited data on the risk of VTE recurrence in women receiving anticoagulant treatment and using hormonal therapies. A post hoc analysis from EINSTEIN PE and EINSTEIN DVT compared the incidence of recurrent VTE, with and without concomitant hormonal therapy, in women (N=1888) aged <60 years. Similar rates of VTE recurrence were observed irrespective of hormone treatment, including in women receiving oestrogen-containing versus progestin-only therapy, supporting the ISTH guidance.

Recurrent VTE in women from the EINSTEIN trials

Post hoc pooled analysis from EINSTEIN PE and EINSTEIN DVT trials showing recurrent VTE in women <60 years old treated with rivaroxaban or enoxaparin/warfarin with and without concomitant hormone therapy

If anticoagulant treatment is stopped in a woman with a history of VTE, further use of hormonal contraceptives associated with an increased VTE risk is discouraged (e.g. combined oral contraceptives) and alternative contraceptive measures that do not increase the risk of VTE should be used (e.g. barrier methods or progestogen-releasing intrauterine devices).

Next section: Abnormal Uterine Bleeding in Women Receiving NOACs

Approval No.: G.COM.GM.XA.10.2017.1894

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