Semin Thromb Hemost 2016; 42(07): 789-797
DOI: 10.1055/s-0036-1592304
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Direct Oral Anticoagulants and Women

Hannah Cohen
1   Haemostasis Research Unit, Department of Haematology, University College London, London, United Kingdom
2   Department of Haematology, University College London Hospitals NHS Foundation Trust, London, United Kingdom
Deepa R. J. Arachchillage
3   Department of Haematology, Imperial College Healthcare NHS Trust, London, United Kingdom
4   Department of Haematology, Imperial College London, London, United Kingdom
Jan Beyer-Westendorf
5   Center for Vascular Medicine and Department of Medicine III, University Hospital “Carl Gustav Carus,” Technische Universität Dresden, Germany
Saskia Middeldorp
6   Department of Vascular Medicine, Academic Medical Center, University of Amsterdam, Holland
Rezan A. Kadir
7   Katharine Dormandy Haemophilia Center and Thrombosis Unit, The Royal Free Hospital NHS Foundation Trust, London, United Kingdom
8   Department of Obstetrics and Gynaecology, The Royal Free Hospital NHS Foundation Trust, London, United Kingdom
› Author Affiliations
Further Information

Publication History

Publication Date:
05 October 2016 (online)


Direct oral anticoagulants (DOACs) provide an effective, safe, and convenient therapeutic alternative to warfarin and other vitamin K antagonists (VKAs), and are now established for a wide range of indications. The use of DOACs in women merits special consideration due to two main situations: first, in relation to fertility, pregnancy, and lactation in women of reproductive age; second, because of their bleeding risk, leading to abnormal uterine and/or other genital tract bleeding. This review focuses on these two clinical situations, including approaches to management in the context of available information.

  • References

  • 1 Eliquis 2.5 mg film-coated tablets film-coated tablets. Summary of Product Characteristics (SPC)s last updated on the eMC: Available at: . Accessed August 29, 2016
  • 2 Pradaxa 150mg hard capsules. Summary of product characteristics (SPC), EU. Boehringer Ingelheim International GmBH. Available at: . Accessed August 29, 2016
  • 3 Xarelto 20 mg film-coated tablets. Summary of Product Characteristics last updated on the eMC. Available at: . Accessed August 29, 2016
  • 4 Lixiana 60 mg Film-Coated Tablets. Summary of Product Characteristics last updated on the eMC. Available at: Accessed August 29, 2016
  • 5 Agnelli G, Buller HR, Cohen A , et al; PLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013; 368 (8) 699-708
  • 6 Bauersachs R, Berkowitz SD, Brenner B , et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363 (26) 2499-2510
  • 7 Büller HR, Prins MH, Lensin AW , et al; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366 (14) 1287-1297
  • 8 Schulman S, Kearon C, Kakkar AK , et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361 (24) 2342-2352
  • 9 Büller HR, Décousus H, Grosso MA , et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369 (15) 1406-1415
  • 10 Ganapathy V, Prasad PD, Ganapathy ME, Leibach FH. Placental transporters relevant to drug distribution across the maternal-fetal interface. J Pharmacol Exp Ther 2000; 294 (2) 413-420
  • 11 Werth S, Halbritter K, Beyer-Westendorf J. Efficacy and safety of venous thromboembolism prophylaxis with apixaban in major orthopedic surgery. Ther Clin Risk Manag 2012; 8: 139-147
  • 12 Wong PC, Pinto DJ, Zhang D. Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor. J Thromb Thrombolysis 2011; 31 (4) 478-492
  • 13 Wang L, He K, Maxwell B , et al. Tissue distribution and elimination of [14C]apixaban in rats. Drug Metab Dispos 2011; 39 (2) 256-264
  • 14 Bapat P, Kedar R, Lubetsky A , et al. Transfer of dabigatran and dabigatran etexilate mesylate across the dually perfused human placenta. Obstet Gynecol 2014; 123 (6) 1256-1261
  • 15 Bapat P, Pinto LS, Lubetsky A, Berger H, Koren G. Rivaroxaban transfer across the dually perfused isolated human placental cotyledon. Am J Obstet Gynecol 2015; 213 (5) 710.e1-710.e6
  • 16 Moore KL, Persaud TVN, Torchia MG. Human birth defects in the developing human. Clinically Oriented Embryology, 9th ed. Philadelphia, PA: Saunders/Elsevier; 2013: 471-501
  • 17 Königsbrügge O, Langer M, Hayde M, Ay C, Pabinger I. Oral anticoagulation with rivaroxaban during pregnancy: a case report. Thromb Haemost 2014; 112 (6) 1323-1324
  • 18 Hoeltzenbein M, Beck E, Meixner K, Schaefer C, Kreutz R. Pregnancy outcome after exposure to the novel oral anticoagulant rivaroxaban in women at suspected risk for thromboembolic events: a case series from the German Embryotox Pharmacovigilance Centre. Clin Res Cardiol 2016; 105 (2) 117-126
  • 19 Savaysa Edoxaban PI. . Accessed April 24, 2016
  • 20 Rudd KM, Winans AR, Panneerselvam N. Possible Rivaroxaban Failure during the Postpartum Period. Pharmacotherapy 2015; 35 (11) e164-e168
  • 21 Beyer-Westendorf J, Michalski F, Tittl L , et al. Pregnancy outcome in patients exposed to direct oral anticoagulants - and the challenge of event reporting (e-pub ahead of print). Thromb Haemost 2016; 11 (3)
  • 22 Cohen H, Arachchillage DRJ, Beyer-Westendorf JM, Abdul-Kadir R. Management of direct oral anticoagulants in women of childbearing potential: guidance from the International Society on Thrombosis and Haemostasis. J Thromb Haemost 2016; 14 (8) 1673-1676
  • 23 Kamel H, Navi BB, Sriram N, Hovsepian DA, Devereux RB, Elkind MS. Risk of a thrombotic event after the 6-week postpartum period. N Engl J Med 2014; 370 (14) 1307-1315
  • 24 International registry of pregnancy during NOAC use - Inclusion. SSC Subcommittee on Women's Issues in Thrombosis and Hemostasis, 26 October 2015. Available at: . Access June 29, 2016
  • 25 Gursel T, Biri A, Kaya Z, Sivaslıoglu S, Albayrak M. The frequency of menorrhagia and bleeding disorders in university students. Pediatr Hematol Oncol 2014; 31 (5) 467-474
  • 26 Lethaby A, Farquhar C. Treatments for heavy menstrual bleeding. BMJ 2003; 327 (7426) 1243-1244
  • 27 Liu Z, Doan QV, Blumenthal P, Dubois RW. A systematic review evaluating health-related quality of life, work impairment, and health-care costs and utilization in abnormal uterine bleeding. Value Health 2007; 10 (3) 183-194
  • 28 National Institute for Clinical E. Heavy Menstrual Bleeding. London, UK: National Institute for Health and Clinical Excellence. NICE Guidelines; 2007
  • 29 Critchley HO, Munro MG, Broder M, Fraser IS. A five-year international review process concerning terminologies, definitions, and related issues around abnormal uterine bleeding. Semin Reprod Med 2011; 29 (5) 377-382
  • 30 Hallberg L, Högdahl AM, Nilsson L, Rybo G. Menstrual blood loss—a population study. Variation at different ages and attempts to define normality. Acta Obstet Gynecol Scand 1966; 45 (3) 320-351
  • 31 Higham JM, O'Brien PM, Shaw RW. Assessment of menstrual blood loss using a pictorial chart. Br J Obstet Gynaecol 1990; 97 (8) 734-739
  • 32 Barlow DH, Lumsden MA, Fauser BC, Terrill P, Bestel E. Individualized vaginal bleeding experience of women with uterine fibroids in the PEARL I randomized controlled trial comparing the effects of ulipristal acetate or placebo. Hum Reprod 2014; 29 (3) 480-489
  • 33 Kadir RA, Sabin CA, Pollard D, Lee CA, Economides DL. Quality of life during menstruation in patients with inherited bleeding disorders. Haemophilia 1998; 4 (6) 836-841
  • 34 Själander A, Friberg B, Svensson P, Stigendal L, Lethagen S. Menorrhagia and minor bleeding symptoms in women on oral anticoagulation. J Thromb Thrombolysis 2007; 24 (1) 39-41
  • 35 Huq FY, Tvarkova K, Arafa A, Kadir RA. Menstrual problems and contraception in women of reproductive age receiving oral anticoagulation. Contraception 2011; 84 (2) 128-132
  • 36 Martinelli I, Lensing AW, Middeldorp S , et al. Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use. Blood 2016; 127 (11) 1417-1425
  • 37 Alotaibi GS, Almodaimegh H, McMurtry MS, Wu C. Do women bleed more than men when prescribed novel oral anticoagulants for venous thromboembolism? A sex-based meta-analysis. Thromb Res 2013; 132 (2) 185-189
  • 38 Ferreira M, Barsam S, Patel JP , et al. Heavy menstrual bleeding on rivaroxaban. Br J Haematol 2016; 173 (2) 314-315
  • 39 Myers B, Webster A. Heavy menstrual bleeding on Rivaroxaban - Comparison with Apixaban (e-pub ahead of print). Br J Haematol 2016; ; doi: 10.1111/bjh.14003.
  • 40 De Crem N, Peerlinck K, Vanassche T , et al. Abnormal uterine bleeding in VTE patients treated with rivaroxaban compared to vitamin K antagonists. Thromb Res 2015; 136 (4) 749-753
  • 41 Beyer-Westendorf J, Michalski F, Tittl L, Hauswald-Dörschel S, Marten S. Vaginal bleeding and heavy menstrual bleeding during direct oral anti-Xa inhibitor therapy. Thromb Haemost 2016; 115 (6) 1234-1236
  • 42 Schulman S, Angerås U, Bergqvist D, Eriksson B, Lassen MR, Fisher W ; Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in surgical patients. J Thromb Haemost 2010; 8 (1) 202-204
  • 43 Lethaby AE, Cooke I, Rees M. Progesterone/progestogen releasing intrauterine systems versus either placebo or any other medication for heavy menstrual bleeding. Cochrane Database Syst Rev 2000; (2) CD002126
  • 44 Stewart A, Cummins C, Gold L, Jordan R, Phillips W. The effectiveness of the levonorgestrel-releasing intrauterine system in menorrhagia: a systematic review. BJOG 2001; 108 (1) 74-86
  • 45 Mansour D. Modern management of abnormal uterine bleeding: the levonorgestrel intra-uterine system. Best Pract Res Clin Obstet Gynaecol 2007; 21 (6) 1007-1021
  • 46 Ibraheim M, Ikomi A. An evaluation of troublesome inter-menstrual bleeding in menorrhagic users of the LNG-IUS. J Obstet Gynaecol 2005; 25 (4) 384-385
  • 47 Coulter A, Kelland J, Peto V, Rees MC. Treating menorrhagia in primary care. An overview of drug trials and a survey of prescribing practice. Int J Technol Assess Health Care 1995; 11 (3) 456-471
  • 48 Iyer V, Farquhar C, Jepson R. Oral contraceptive pills for heavy menstrual bleeding. Cochrane Database Syst Rev 2000; (2) CD000154
  • 49 Fraser IS, McCarron G. Randomized trial of 2 hormonal and 2 prostaglandin-inhibiting agents in women with a complaint of menorrhagia. Aust N Z J Obstet Gynaecol 1991; 31 (1) 66-70
  • 50 Baglin T, Bauer K, Douketis J, Buller H, Srivastava A, Johnson G ; SSC of the ISTH. Duration of anticoagulant therapy after a first episode of an unprovoked pulmonary embolus or deep vein thrombosis: guidance from the SSC of the ISTH. J Thromb Haemost 2012; 10 (4) 698-702
  • 51 Poulter NR, Chang CL, Farley TM, Meirik O. Risk of cardiovascular diseases associated with oral progestagen preparations with therapeutic indications. Lancet 1999; 354 (9190) 1610
  • 52 Vasilakis C, Jick H, del Mar Melero-Montes M. Risk of idiopathic venous thromboembolism in users of progestagens alone. Lancet 1999; 354 (9190) 1610-1611
  • 53 Sundström A, Seaman H, Kieler H, Alfredsson L. The risk of venous thromboembolism associated with the use of tranexamic acid and other drugs used to treat menorrhagia: a case-control study using the General Practice Research Database. BJOG 2009; 116 (1) 91-97
  • 54 Goshtasebi A, Moukhah S, Gandevani SB. Treatment of heavy menstrual bleeding of endometrial origin: randomized controlled trial of medroxyprogesterone acetate and tranexamic acid. Arch Gynecol Obstet 2013; 288 (5) 1055-1060
  • 55 Henry DA, Moxey AJ, Carless PA , et al. Anti-fibrinolytic use for minimising perioperative allogeneic blood transfusion. Cochrane Database Syst Rev 2001; (1) CD001886
  • 56 Zufferey P, Merquiol F, Laporte S , et al. Do antifibrinolytics reduce allogeneic blood transfusion in orthopedic surgery?. Anesthesiology 2006; 105 (5) 1034-1046