title: Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use.
abstract: Women receiving vitamin K antagonists (VKAs) require adequate contraception because of the potential for fetal complications. It is unknown whether 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 percentage per year were computed for the on and off estrogen-containing or progestin-only therapy periods. Cox regression models were fitted, with hormonal therapy (on vs 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 vs 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.
authors.affiliation: A Bianchi Bonomi Hemophilia and Thrombosis Center, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy;
authors.forename: Ida
authors.initials: I
authors.lastname: Martinelli
authors.affiliation: Bayer HealthCare, Wuppertal, Germany;
authors.forename: Anthonie W A
authors.initials: AW
authors.lastname: Lensing
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands;
authors.forename: Saskia
authors.initials: S
authors.lastname: Middeldorp
authors.affiliation: Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands;
authors.forename: Marcel
authors.initials: M
authors.lastname: Levi
authors.affiliation: University Hospital "Carl Gustav Carus," Technische Universität Dresden, Dresden, Germany;
authors.forename: Jan
authors.initials: J
authors.lastname: Beyer-Westendorf
authors.affiliation: Department of Vascular Surgery, Beneficencia Portuguesa Hospital, São Paulo, Brazil;
authors.forename: Bonno
authors.initials: B
authors.lastname: van Bellen
authors.affiliation: University Hospitals and Faculty of Medicine, Geneva, Switzerland;
authors.forename: Henri
authors.initials: H
authors.lastname: Bounameaux
authors.affiliation: Department of Haematology, Prince of Wales Hospital, Sydney, Australia;
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Brighton
authors.affiliation: Department of Haematology, Guy's and St Thomas' Hospitals National Health Service Trust, London, United Kingdom;
authors.forename: Alexander T
authors.initials: AT
authors.lastname: Cohen
authors.affiliation: Bayer HealthCare Pharmaceuticals, Whippany, NJ;
authors.forename: Mila
authors.initials: M
authors.lastname: Trajanovic
authors.affiliation: Bayer HealthCare, Wuppertal, Germany;
authors.forename: Martin
authors.initials: M
authors.lastname: Gebel
authors.affiliation: Bayer HealthCare, Ho Chi Minh, Vietnam;
authors.forename: Phuong
authors.initials: P
authors.lastname: Lam
authors.affiliation: Department of Medicine, University of Ottawa, Ottawa Hospital Research Institute, Ottawa, ON, Canada; and.
authors.forename: Philip S
authors.initials: PS
authors.lastname: Wells
authors.affiliation: Maastricht University Medical Center, Maastricht, The Netherlands.
authors.forename: Martin H
authors.initials: MH
authors.lastname: Prins
mesh_terms: D000328:Adult; D000925:Anticoagulants / Q000009:adverse effects*; D003278:Contraceptives, Oral, Hormonal / Q000009:adverse effects; D004357:Drug Synergism; D017984:Enoxaparin / Q000009:adverse effects* / Q000627:therapeutic use; D015914:Estrogen Replacement Therapy / Q000009:adverse effects; D004967:Estrogens / Q000009:adverse effects* / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008875:Middle Aged; D011372:Progestins / Q000009:adverse effects* / Q000627:therapeutic use; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D012008:Recurrence; D012189:Retrospective Studies; D000069552:Rivaroxaban / Q000009:adverse effects* / Q000627:therapeutic use; D014592:Uterine Hemorrhage / Q000139:chemically induced* / Q000453:epidemiology; D054556:Venous Thromboembolism / Q000139:chemically induced* / Q000453:epidemiology / Q000517:prevention & control; D055815:Young Adult
chemical_list: D000925:Anticoagulants; D003278:Contraceptives, Oral, Hormonal; D017984:Enoxaparin; D004967:Estrogens; D011372:Progestins; D000069552:Rivaroxaban