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Intermediate-dose versus low-dose low-molecular-weight heparin in pregnant and post-partum women with a history of venous thromboembolism (Highlow study): an open-label, multicentre, randomised, controlled trial

2022; Elsevier BV; Volume: 400; Issue: 10365 Linguagem: Inglês

10.1016/s0140-6736(22)02128-6

1474-547X

Ingrid M. Bistervels, Andréa Buchmuller, Hanke M.G. Wiegers, Fionnuala Ní Áinle, Bernard Tardy, Jennifer Donnelly, Peter Verhamme, Anne Flem Jacobsen, Anette Tarp Hansen, Marc Rodger, Maria T. DeSancho, R.G. Shmakov, Nick van Es, Martin H. Prins, Céline Chauleur, Saskia Middeldorp, Eline S. van den Akker, Mireille N. Bekker, Thomas van Bemmel, Laurent Bertoletti, Julie Blanc, Suzanne M. Bleker, Aude Bourtembourg-Matras, Florence Bretelle, B. Byrne, Françis Couturaud, Pierre Delorme, Elise S. Eerenberg, Maureen TM Franssen, Jens Fuglsang, Wessel Ganzevoort, François Goffinet, Jiska M de Haan-Jebbink, Wieteke M. Heidema, Monique A Hertzberg, Marcel M.C. Hovens, Menno V. Huisman, Leonie de Jong-Speksnijder, Pieter W. Kamphuisen, Denis J O'Keeffe, Karine Lacut, Josje Langenveld, M Simone Lunshof, Caroline P. Martens, A. Merah, Emmanuelle Le Moigne, Dimitri N.M. Papatsonis, Gilles Pernod, F. Perrotin, Edith Peynaud-Debayle, Fabrice Pierre, Geneviève Bureau, Tiphaïne Raia-Barjat, Robbert JP Rijnders, Roger Rosario, M. Ruivard, Jeannot Schmidt, Marieke Sueters, Thomas Vanassche, Marie-Noëlle Varlet, Alexandre J. Vivanti, Matthieu Y. van der Vlist, Lucet F. van der Voet, Karlijn C. Vollebregt, Johanna I. de Vries, Sabina de Weerd, Peter E. Westerweel, Lia DE Wijnberger, Marije ten Wolde, Paula F. Ypma, Catherine Zuily-Lamy, Joost J. Zwart, Alexandra Benachi, G. Beucher, H. Bézanahary, Karin Boer, Marjon A. de Boer, Frantz Bousquet, Henk A. Bremer, Luc Bressollette, Aurélie Brossard, C. Chau, Brian Cleary, Fabienne Comte, Thomas Corsini, Anne Coustel, Barbara Debaveye, Raoul Desbrière, Cécile Duvillard, A. Eckman, Jeroen Eikenboom, Antoine Élias, Laura M. Faber, Émile Ferrari, Denis Gallot, Emilie Gauchotte, Ingrid Gaugler, Abby E. Geerlings, Audrey O'Gorman, Vincent Grobost, Pieter-Kees de Groot, David P. van der Ham, Brenda Hermsen, Kim Kamphorst, Alan Karovitch, Gunilla Kleiverda, Aiste Kloster, Annemarieke Koops, Inneke Krabbendam, Marieke J.H.A. Kruip, Saskia Kuipers, Judith van Laar, Damien Lanéelle, Suzanne Lima, Peter MacMahon, Laurent Mandelbrot, Claudia A van Meir, C. Menez, Leonard P. Morssink, Nathalie Moulin, E. Mousty, Matthieu Muller, Lucy Eldersveld Murphy, Kathelijne Peerlinck, Alma O'Reilly, Maartje de Reus, Magali Hilmi Le Roux, Kevin M. Ryan, Bettina Samren, Daniela H. Schippers, Nico Schuitemaker, Chloé Schweizer, Hanneke van der Straaten, Cécile Tromeur, Kristine Vanheule, Tamara Verhagen, Jantien Visser, Michael R. Watts, Wim J. van Wijngaarden, Mallory Woiski, Maartje Zelis,

Maternal and fetal healthcare

Background: Pregnancy-related venous thromboembolism (VTE) is a leading cause of maternal morbidity and mortality, and thromboprophylaxis is indicated in pregnant and postpartum women with a history of VTE.The optimal dose of low-molecular-weight heparin to prevent recurrent venous thromboembolism in pregnancy and the postpartum period is uncertain.Methods: In this international, open-label, randomised trial, pregnant women with a history of venous thromboembolism were randomised before 14 weeks of gestational age to weight-adjusted intermediatedose or fixed low-dose low-molecular-weight heparin until 6 weeks postpartum.The primary efficacy outcome was objectively confirmed venous thromboembolism.The primary safety outcome was major bleeding.Findings: A total of 1,110 pregnant women were randomised and included in the intention-to-treat population.Venous thromboembolism occurred in 11 of 555 (2•0%) women assigned to weight-adjusted intermediate-dose low-molecular-weight heparin and in 16 of 555 (2•9%) assigned to fixed low-dose lowmolecular-weight heparin (relative risk, 0•69; 95% confidence interval [CI], 0•32-1•47; P=0•33).Venous thromboembolism occurred antepartum in five (0•9%) and five (0•9%) women, and postpartum in six (1•1%) and 11 women (2•0%) in the intermediate-dose and low-dose groups, respectively.On-treatment venous thromboembolism in the per-protocol population (N=972) occurred in 1•0% and 2•4% (relative risk, 0•43; 95% CI, 0•15-1•20).On-treatment major bleeding in the safety population (N=1,045) occurred in 4•4% and in 3•8% receiving intermediate-dose or low-dose low-molecular-weight heparin, respectively (relative risk, 1•16; 95% CI, 0•65-2•09).Interpretation: In women with a history of venous thromboembolism, weight-adjusted intermediate-dose low-molecular-weight heparin during the combined antepartum and postpartum periods was not associated with a lower risk of recurrence than fixed low-dose low-molecular-weight heparin.These results indicate that low-dose low-molecular-weight heparin for thromboprophylaxis during pregnancy is the appropriate dose.Postpartum, intermediate-dose low-molecular-weight heparin may be more effective than low dose low-molecular-weight heparin.(ClinicalTrials.govnumber, NCT01828697)