Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use

Ida Martinelli, Anthonie W.A. Lensing, Saskia Middeldorp, Marcel Levi, Jan Beyer-Westendorf, Bonno van Bellen, Henri Bounameaux, Timothy A. Brighton, Alexander T. Cohen, Mila Trajanovic, Martin Gebel, Phuong Lam, Philip S. Wells and Martin H. Prins

Key points

  • Estrogen-containing or progestin-only hormonal therapy is not associated with increased recurrent VTE risk in women on anticoagulant therapy.

  • Abnormal uterine bleeding occurred more frequently with rivaroxaban than with enoxaparin/vitamin K antagonists.


Women receiving vitamin K antagonists (VKAs) require adequate contraception because of the potential for fetal complications. It is unknown if the use of hormonal therapy, especially those containing estrogens, is associated with recurrent venous thromboembolism (VTE) during anticoagulation. Despite the absence of data, World Health Organization guidelines state that use of estrogen-containing contraceptives confers an "unacceptable health risk" during established anticoagulation for VTE. We compared the incidences of recurrent VTE and abnormal uterine bleeding with and without concomitant hormonal therapy in women aged <60 years who were receiving anticoagulation with rivaroxaban or enoxaparin/VKA for confirmed VTE. Incidence-densities in %/year were computed for the 'on' and 'off' estrogen-containing or progestin-only therapy periods. Cox regression models were fitted, with hormonal therapy ('on' versus 'off') as a time-dependent variable to derive the hazard ratio (HR) for the effects on recurrent VTE and abnormal uterine bleeding. In total, 1888 women were included. VTE incidence-densities 'on' and 'off' hormonal therapy were 3.7%/year and 4.7%/year (adjusted HR 0.56; 95% confidence interval [CI] 0.23-1.39), respectively, and were 3.7%/year and 3.8%/year, respectively, for estrogen-containing and progestin-only therapy. The adjusted HR for all abnormal uterine bleeding ('on' versus 'off' hormonal therapy) was 1.02 (95% CI, 0.66-1.57). Abnormal uterine bleeding occurred more frequently with rivaroxaban than with enoxaparin/VKA (HR 2.13; 95% CI, 1.57-2.89). Hormonal therapy was not associated with an increased risk of recurrent VTE in women receiving therapeutic anticoagulation. The observed increased risk of abnormal uterine bleeding with rivaroxaban needs further exploration.

  • Submitted August 28, 2015.
  • Accepted November 3, 2015.