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.

Autor:	Bistervels IM; Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands., Buchmüller A; CIC 1408 Centre Hospitalier Universitaire de Saint-Etienne, Saint-Etienne, France; FCRIN INNOVTE, CHU de Saint Etienne, Saint-Etienne, France., Wiegers HMG; Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands., Ní Áinle F; Rotunda Hospital, Dublin, Ireland; School of Medicine, University College Dublin, Dublin, Ireland., Tardy B; CIC 1408 Centre Hospitalier Universitaire de Saint-Etienne, Saint-Etienne, France; FCRIN INNOVTE, CHU de Saint Etienne, Saint-Etienne, France., Donnelly J; School of Medicine, University College Dublin, Dublin, Ireland; Royal College of Surgeons in Ireland, Dublin, Ireland., Verhamme P; University of Leuven, Leuven, Belgium., Jacobsen AF; Oslo University Hospital, Oslo, Norway; University of Oslo, Oslo, Norway., Hansen AT; Aalborg University Hospital, Aalborg, Denmark; Aarhus University Hospital, Aarhus, Denmark., Rodger MA; The Ottawa Hospital, Ottawa, ON, Canada., DeSancho MT; Weill Cornell Medicine, New York Presbyterian Hospital, New York, NY, USA., Shmakov RG; Institute of Obstetrics, National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Healthcare of the Russian Federation, Moscow, Russia., van Es N; Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands., Prins MH; Department of Epidemiology and Technology Assessment, University of Maastricht, Maastricht, Netherlands., Chauleur C; CIC 1408 Centre Hospitalier Universitaire de Saint-Etienne, Saint-Etienne, France; University Jean Monnet, University Hospital of Saint-Etienne, Mines Saint-Etienne, INSERM U 1059, Saint-Etienne, France., Middeldorp S; Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands; Radboud university medical center, Nijmegen, Netherlands. Electronic address: saskia.middeldorp@radboudumc.nl.
Jazyk:	angličtina
Zdroj:	Lancet (London, England) [Lancet] 2022 Nov 19; Vol. 400 (10365), pp. 1777-1787. Date of Electronic Publication: 2022 Oct 28.
DOI:	10.1016/S0140-6736(22)02128-6
Abstrakt:	Background: Pregnancy-related venous thromboembolism is a leading cause of maternal morbidity and mortality, and thromboprophylaxis is indicated in pregnant and post-partum women with a history of venous thromboembolism. The optimal dose of low-molecular-weight heparin to prevent recurrent venous thromboembolism in pregnancy and the post-partum period is uncertain. Methods: In this open-label, randomised, controlled trial (Highlow), pregnant women with a history of venous thromboembolism were recruited from 70 hospitals in nine countries (the Netherlands, France, Ireland, Belgium, Norway, Denmark, Canada, the USA, and Russia). Women were eligible if they were aged 18 years or older with a history of objectively confirmed venous thromboembolism, and with a gestational age of 14 weeks or less. Eligible women were randomly assigned (1:1), before 14 weeks of gestational age, using a web-based system and permuted block randomisation (block size of six), stratified by centre, to either weight-adjusted intermediate-dose or fixed low-dose low-molecular-weight heparin subcutaneously once daily until 6 weeks post partum. The primary efficacy outcome was objectively confirmed venous thromboembolism (ie, deep-vein thrombosis, pulmonary embolism, or unusual site venous thrombosis), as determined by an independent central adjudication committee, in the intention-to-treat (ITT) population (ie, all women randomly assigned to treatment). The primary safety outcome was major bleeding which included antepartum, early post-partum (within 24 h after delivery), and late post-partum major bleeding (24 h or longer after delivery until 6 weeks post partum), assessed in all women who received at least one dose of assigned treatment and had a known end of treatment date. This study is registered with ClinicalTrials.gov, NCT01828697, and is now complete. Findings: Between April 24, 2013, and Oct 31, 2020, 1339 pregnant women were screened for eligibility, of whom 1110 were randomly assigned to weight-adjusted intermediate-dose (n=555) or fixed low-dose (n=555) low-molecular-weight heparin (ITT population). Venous thromboembolism occurred in 11 (2%) of 555 women in the weight-adjusted intermediate-dose group and in 16 (3%) of 555 in the fixed low-dose group (relative risk [RR] 0·69 [95% CI 0·32-1·47]; p=0·33). Venous thromboembolism occurred antepartum in five (1%) women in the intermediate-dose group and in five (1%) women in the low-dose group, and post partum in six (1%) women and 11 (2%) women. On-treatment major bleeding in the safety population (N=1045) occurred in 23 (4%) of 520 women in the intermediate-dose group and in 20 (4%) of 525 in the low-dose group (RR 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 post-partum 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 for the prevention of pregnancy-related recurrent venous thromboembolism. Funding: French Ministry of Health, Health Research Board Ireland, GSK/Aspen, and Pfizer. Competing Interests: Declaration of interests FNÁ reports grants as principal investigator from the Irish Health Research Board during the conduct of the study, and grants as principal investigator from Daiichi-Sankyo, Bayer, and Sanofi (investigator-initiated studies, fees paid to university) outside of the submitted work. AB reports grants from the French Ministry of Health, during the conduct of the study. JD reports grants as principal investigator from the Irish Health Research Board during the conduct of the study. NvE reports fees for scientific presentation from Bristol-Meyers Squibb (fee transferred to institution) and advisory board fees from LEO Pharma and Bayer (fees transferred to institution), outside of the submitted work. AFJ reports personal fees from Sanofi-Aventis outside of the submitted work. SM reports grants from GSK, Aspen, and Pfizer during the conduct of the study; grants and personal fees from Daiichi-Sankyo, Bayer, Pfizer, and Boehringer Ingelheim; and personal fees from Portola/Alexion, AbbVie, Pfizer/Bristol-Meyers Squibb, Norgine, Viatris, and Sanofi, outside of the submitted work. MTD reports personal fees from Sanofi Genzyme and Bioproducts Laboratory outside of the submitted work. PV reports grants and personal fees from LEO Pharma, Boehringer Ingelheim, Daiichi-Sankyo, Bayer, and Pfizer/Bristol-Meyers Squibb and personal fees from Anthos and Portola/Alexion, outside of the submitted work. All other authors declare no competing interests (Copyright © 2022 Elsevier Ltd. All rights reserved.)
Databáze:	MEDLINE
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