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Management of direct oral anticoagulants in women of childbearing potential: guidance from the SSC of the ISTH: reply

2016; Elsevier BV; Volume: 15; Issue: 1 Linguagem: Inglês

10.1111/jth.13535

1538-7933

Hannah Cohen, Deepa J. Arachchillage, Saskia Middeldorp, Jan Beyer‐Westendorf, Rezan A. Kadir,

Venous Thromboembolism Diagnosis and Management

We thank Desborough et al. for their response to the recently published guidance from the SSC of the ISTH on the management of direct oral anticoagulants (DOACs) in women of childbearing potential 1.Desborough M.J. Pavord S. Hunt B.J. Management of direct oral anticoagulants in women of childbearing potential: guidance from the SSC of the ISTH: comment.J Thromb Haemost. 2016; 14: 194-206Google Scholar, 2.Cohen H. Arachchillage D.R. Middeldorp S. Beyer‐Westendorf J. Abdul‐Kadir R. Management of direct oral anticoagulants in women of childbearing potential: guidance from the SSC of the ISTH.J Thromb Haemost. 2016; 14: 1673-6Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar. We have carefully examined their view and seriously considered their proposal regarding the recommendation of this guidance as detailed below. We hereby provide a detailed response to their letter."Should pregnancy be desired, we recommend that the DOAC is switched to an alternative anticoagulant preconceptually, with the main alternative anticoagulant options vitamin K antagonists (VKAs) (to be switched to low molecular weight heparin [LMWH] as soon as possible when pregnant and before 6 weeks of gestation), or LMWH, with cognizance that the latter may result in prolonged subcutaneous injections until pregnancy is achieved." There is uncertainty about the teratogenic risk of DOACs in humans. To assess the risk of DOAC embryopathy, we reviewed cases of DOAC exposure in pregnancy collected from clinicians, the literature, and pharmacovigilance systems of drug authorities and manufacturers. The methods for acquisition of data are detailed elsewhere 3.Beyer‐Westendorf J. Michalski F. Tittl L. Middeldorp S. Cohen H. Abdul‐Kadir R. Jayakody Arachchillage D. Arya R. Ay C. Marten S. Pregnancy outcome in patients exposed to direct oral anticoagulants – and the challenge of event reporting.Thromb Haemost. 2016; 116: 651-8Crossref PubMed Scopus (84) Google Scholar. Of 137 pregnancies with reported outcomes, seven showed abnormalities (5.1%), of which three (2.2%) could potentially be interpreted as embryopathy 3.Beyer‐Westendorf J. Michalski F. Tittl L. Middeldorp S. Cohen H. Abdul‐Kadir R. Jayakody Arachchillage D. Arya R. Ay C. Marten S. Pregnancy outcome in patients exposed to direct oral anticoagulants – and the challenge of event reporting.Thromb Haemost. 2016; 116: 651-8Crossref PubMed Scopus (84) Google Scholar. Despite the limitations (small numbers; incomplete outcome data), the results do not indicate that DOAC exposure in pregnancy carries a high risk of embryopathy. This is reflected in our guidance, which includes the following recommendations: first, inadvertent exposure to a DOAC would not in itself be regarded as medical grounds for termination of pregnancy; second, women considering elective pregnancy termination should receive non‐directive counseling; and third, in women who become pregnant while receiving DOAC treatment and who decide to continue with pregnancy, we recommend early obstetric review and fetal monitoring 2.Cohen H. Arachchillage D.R. Middeldorp S. Beyer‐Westendorf J. Abdul‐Kadir R. Management of direct oral anticoagulants in women of childbearing potential: guidance from the SSC of the ISTH.J Thromb Haemost. 2016; 14: 1673-6Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar. Desborough et al. allude to the teratogenicity of VKAs 1.Desborough M.J. Pavord S. Hunt B.J. Management of direct oral anticoagulants in women of childbearing potential: guidance from the SSC of the ISTH: comment.J Thromb Haemost. 2016; 14: 194-206Google Scholar, 4.van Driel D. Wesseling J. Rosendaal F.R. Odink R.J. van der Veer E. Gerver W.J. Geven‐Boere L.M. Sauer P.J. Growth until puberty after in utero exposure to coumarins.Am J Med Genet. 2000; 95: 438-43Crossref PubMed Scopus (18) Google Scholar, 5.Hung L. Rahimtoola S.H. Prosthetic heart valves and pregnancy.Circulation. 2003; 107: 1240-6Crossref PubMed Scopus (97) Google Scholar, 6.Chan W.S. Anand S. Ginsberg J.S. Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature.Arch Intern Med. 2000; 160: 191-6Crossref PubMed Scopus (617) Google Scholar, 7.Xu Z. Fan J. Luo X. Zhang W.B. Ma J. Lin Y.B. Ma S.H. Chen X. Wang Z.P. Ou J.S. Zhang X. Anticoagulation regimens during pregnancy in patients with mechanical heart valves: a systematic review and meta‐analysis.Can J Cardiol. 2016; : 1248.e1-1248.e9Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar. The most substantive data on this are from a multicenter (n = 12), observational, prospective study by the European Network of Teratology Information Service, an organization of services that offer counseling on drug risks during pregnancy. They compared 666 pregnant women exposed to various VKAs with a non‐exposed control group (n = 1094) who had been counseled during pregnancy about exposures known to be non‐teratogenic. Data were collected by collaborating institutes during individual risk counseling between 1988 and 2004. There were two coumarin embryopathies (0.6%; both phenprocoumon), both of which were in women in whom heparin substitution started after the 6th gestational week 8.Schaefer C. Hannemann D. Meister R. Eléfant E. Paulus W. Vial T. Reuvers M. Robert‐Gnansia E. Arnon J. De Santis M. Clementi M. Rodriguez‐Pinilla E. Dolivo A. Merlob P. Vitamin K antagonists and pregnancy outcome. A multi‐centre prospective study.Thromb Haemost. 2006; 95: 949-57Crossref PubMed Scopus (165) Google Scholar. This, together with the other literature, supports the idea that the risk of teratogenicity with VKAs is extremely low provided that the women are switched to LMWH before 6 weeks of gestation 6.Chan W.S. Anand S. Ginsberg J.S. Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature.Arch Intern Med. 2000; 160: 191-6Crossref PubMed Scopus (617) Google Scholar, 7.Xu Z. Fan J. Luo X. Zhang W.B. Ma J. Lin Y.B. Ma S.H. Chen X. Wang Z.P. Ou J.S. Zhang X. Anticoagulation regimens during pregnancy in patients with mechanical heart valves: a systematic review and meta‐analysis.Can J Cardiol. 2016; : 1248.e1-1248.e9Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar. In addition, warfarin and other VKAs have a head start of > 60 years over DOACs 4.van Driel D. Wesseling J. Rosendaal F.R. Odink R.J. van der Veer E. Gerver W.J. Geven‐Boere L.M. Sauer P.J. Growth until puberty after in utero exposure to coumarins.Am J Med Genet. 2000; 95: 438-43Crossref PubMed Scopus (18) Google Scholar, 5.Hung L. Rahimtoola S.H. Prosthetic heart valves and pregnancy.Circulation. 2003; 107: 1240-6Crossref PubMed Scopus (97) Google Scholar, 6.Chan W.S. Anand S. Ginsberg J.S. Anticoagulation of pregnant women with mechanical heart valves: a systematic review of the literature.Arch Intern Med. 2000; 160: 191-6Crossref PubMed Scopus (617) Google Scholar, 7.Xu Z. Fan J. Luo X. Zhang W.B. Ma J. Lin Y.B. Ma S.H. Chen X. Wang Z.P. Ou J.S. Zhang X. Anticoagulation regimens during pregnancy in patients with mechanical heart valves: a systematic review and meta‐analysis.Can J Cardiol. 2016; : 1248.e1-1248.e9Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar, 8.Schaefer C. Hannemann D. Meister R. Eléfant E. Paulus W. Vial T. Reuvers M. Robert‐Gnansia E. Arnon J. De Santis M. Clementi M. Rodriguez‐Pinilla E. Dolivo A. Merlob P. Vitamin K antagonists and pregnancy outcome. A multi‐centre prospective study.Thromb Haemost. 2006; 95: 949-57Crossref PubMed Scopus (165) Google Scholar, 9.Wardrop D. Keeling D. The story of the discovery of heparin and warfarin.Br J Haematol. 2008; 141: 757-63Crossref PubMed Scopus (247) Google Scholar with regard to the acquisition of such information; we simply do not have sufficient information about the latter. In conclusion, on the basis of current information, we do not agree that we can advise women that it is safer to continue with the DOAC and switch to LMWH when pregnancy is confirmed, before 6 weeks of gestation. We also do not agree that we can extrapolate the absence of reproductive toxicity with apixaban in rats or rabbits and use it as an appropriate valid basis to advise women that apixaban has the lowest risk of teratogenicity. After having carefully reviewed the available data on pregnancy outcome following DOAC exposure, we found that 75% of all exposures were observed in patients treated with rivaroxaban, whereas dabigatran (11%), apixaban (9%) and edoxaban (4%) contributed very limited information on the potential harm of DOAC exposure in our case collection 3.Beyer‐Westendorf J. Michalski F. Tittl L. Middeldorp S. Cohen H. Abdul‐Kadir R. Jayakody Arachchillage D. Arya R. Ay C. Marten S. Pregnancy outcome in patients exposed to direct oral anticoagulants – and the challenge of event reporting.Thromb Haemost. 2016; 116: 651-8Crossref PubMed Scopus (84) Google Scholar. We feel that there is currently no sufficient solid evidence for accurate determination of embryopathy risks in patients exposed to DOACs in general, particularly for DOACs other than rivaroxaban. We therefore have left the recommendation unchanged at this stage. However, as is the case for any guidance, an individualized approach may be required that does not conform to the guidance for clinically justifiable reasons. This would be the case, for example, when a VKA may not be appropriate and LMWH may be unacceptable. Such management requires documented discussion of the risks (largely unknown for DOACs) and benefits, with a management plan that ensures conversion to LMWH prior to 6 weeks of gestation. We highly recommend that clinicians collect data on the course and outcomes of pregnancy after DOAC exposure, and report their findings to DOAC manufacturers and to the responsible health and regulatory authorities, in order to improve knowledge of potential risks and harms. We also encourage clinicians to report all cases of DOAC exposure during pregnancy to the international ISTH registry (http://www.surveygizmo.com/s3/2394649/International-registry-of-pregnancy-during-NOAC-use-Inclusion). We feel that this constitutes a reasonable and objective approach to acquire the relevant information on DOACs that would, in turn, underpin a revised recommendation in due course, based on emerging evidence. H. Cohen wrote the initial draft of this response, which was critically reviewed by D. R. Arachchillage, S. Middeldorp, J. Beyer‐Westendorf, and R. Abdul‐Kadir. The response was endorsed by the ISTH SSC Subcommittee on Women's Health Issues in Thrombosis and Haemostasis. H. Cohen has received institutional research support and honoraria for lectures and Advisory Board from Bayer. D. R. Arachchillage has received honoraria from Bayer and Boehringer‐Ingelheim for participation in national and international meetings. J. Beyer‐Westendorf reports receiving honoraria for lectures and Advisory Boards from Bayer, Boehringer‐Ingelheim, Daiichi‐Sankyo, and Pfizer, and institutional research support from Bayer, Boehringer‐Ingelheim, Pfizer, and Daiichi Sankyo. S. Middeldorp reports receiving grant support from Sanquin, grant support and fees paid to her institution from Aspen, GlaxoSmithKline, and Bristol‐Myers Squibb/Pfizer, and fees paid to her institution from Bayer, Boehringer Ingelheim, and Daiichi Sankyo.