Comparison of Low and Intermediate Dose Low-molecular-weight Heparin to Prevent Recurrent Venous Thromboembolism in Pregnancy

Summary

This is a randomized-controlled open-label trial comparing two different doses of low-molecular-weight heparin (LMWH) in pregnant patients with a history of previous venous thromboembolism (VTE). Both doses are recommended doses in the 2012 guidelines of the American College of Chest Physicians (ACCP), but it is not known which dose is more efficacious in preventing recurrent venous thromboembolism in pregnancy. Patients enter the study and will be randomized as soon as a home test confirms pregnancy. LMWH will be administered until 6 weeks postpartum. Follow-up will continue until 3 months postpartum. Patients will be recruited by their treating physician, either an obstetrician or internist.

Timeline

Start

2013-04-24

Primary completion

2021-10-31

Completion

2021-10-31

Publications

• Background Greer IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet. 1999 Apr 10;353(9160):1258-65. doi: 10.1016/S0140-6736(98)10265-9.
• Background Pabinger I, Grafenhofer H, Kyrle PA, Quehenberger P, Mannhalter C, Lechner K, Kaider A. Temporary increase in the risk for recurrence during pregnancy in women with a history of venous thromboembolism. Blood. 2002 Aug 1;100(3):1060-2. doi: 10.1182/blood-2002-01-0149.
• Background White RH, Chan WS, Zhou H, Ginsberg JS. Recurrent venous thromboembolism after pregnancy-associated versus unprovoked thromboembolism. Thromb Haemost. 2008 Aug;100(2):246-52.
• Background Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e691S-e736S. doi: 10.1378/chest.11-2300.
• Background Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood. 2005 Jul 15;106(2):401-7. doi: 10.1182/blood-2005-02-0626. Epub 2005 Apr 5.
• Background Tooher R, Gates S, Dowswell T, Davis LJ. Prophylaxis for venous thromboembolic disease in pregnancy and the early postnatal period. Cochrane Database Syst Rev. 2010 May 12;(5):CD001689. doi: 10.1002/14651858.CD001689.pub2.
• Background Sanson BJ, Lensing AW, Prins MH, Ginsberg JS, Barkagan ZS, Lavenne-Pardonge E, Brenner B, Dulitzky M, Nielsen JD, Boda Z, Turi S, Mac Gillavry MR, Hamulyak K, Theunissen IM, Hunt BJ, Buller HR. Safety of low-molecular-weight heparin in pregnancy: a systematic review. Thromb Haemost. 1999 May;81(5):668-72.
• Background Lepercq J, Conard J, Borel-Derlon A, Darmon JY, Boudignat O, Francoual C, Priollet P, Cohen C, Yvelin N, Schved JF, Tournaire M, Borg JY. Venous thromboembolism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies. BJOG. 2001 Nov;108(11):1134-40. doi: 10.1111/j.1471-0528.2003.00272.x.
• Background Pabinger I, Grafenhofer H, Kaider A, Kyrle PA, Quehenberger P, Mannhalter C, Lechner K. Risk of pregnancy-associated recurrent venous thromboembolism in women with a history of venous thrombosis. J Thromb Haemost. 2005 May;3(5):949-54. doi: 10.1111/j.1538-7836.2005.01307.x.
• Background Roeters van Lennep JE, Meijer E, Klumper FJ, Middeldorp JM, Bloemenkamp KW, Middeldorp S. Prophylaxis with low-dose low-molecular-weight heparin during pregnancy and postpartum: is it effective? J Thromb Haemost. 2011 Mar;9(3):473-80. doi: 10.1111/j.1538-7836.2011.04186.x.
• Background Lindqvist PG, Bremme K, Hellgren M; Working Group on Hemostatic Disorders (Hem-ARG), Swedish Society of Obstetrics and Gynecology. Efficacy of obstetric thromboprophylaxis and long-term risk of recurrence of venous thromboembolism. Acta Obstet Gynecol Scand. 2011 Jun;90(6):648-53. doi: 10.1111/j.1600-0412.2011.01098.x. Epub 2011 Apr 15.
• Background Roshani S, Cohn DM, Stehouwer AC, Wolf H, van der Post JA, Buller HR, Kamphuisen PW, Middeldorp S. Incidence of postpartum haemorrhage in women receiving therapeutic doses of low-molecular-weight heparin: results of a retrospective cohort study. BMJ Open. 2011 Nov 14;1(2):e000257. doi: 10.1136/bmjopen-2011-000257. Print 2011.
• Background Kaandorp SP, Goddijn M, van der Post JA, Hutten BA, Verhoeve HR, Hamulyak K, Mol BW, Folkeringa N, Nahuis M, Papatsonis DN, Buller HR, van der Veen F, Middeldorp S. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. N Engl J Med. 2010 Apr 29;362(17):1586-96. doi: 10.1056/NEJMoa1000641. Epub 2010 Mar 24.
• Bistervels IM, Wiegers HMG, Ainle FN, Bleker SM, Chauleur C, Donnelly J, Jacobsen AF, Rodger MA, DeSancho MT, Verhamme P, Hansen AT, Shmakov RG, Ganzevoort W, Buchmuller A, Middeldorp S; Highlow Investigators. Onset of labor and use of analgesia in women using thromboprophylaxis with 2 doses of low-molecular-weight heparin: insights from the Highlow study. J Thromb Haemost. 2023 Jan;21(1):57-67. doi: 10.1016/j.jtha.2022.11.004. Epub 2022 Dec 22.
• Bistervels IM, Buchmuller A, Wiegers HMG, Ni Ainle F, Tardy B, Donnelly J, Verhamme P, Jacobsen AF, Hansen AT, Rodger MA, DeSancho MT, Shmakov RG, van Es N, Prins MH, Chauleur C, Middeldorp S; Highlow Block writing committee; Highlow Investigators. 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. Lancet. 2022 Nov 19;400(10365):1777-1787. doi: 10.1016/S0140-6736(22)02128-6. Epub 2022 Oct 28.
• Middleton P, Shepherd E, Gomersall JC. Venous thromboembolism prophylaxis for women at risk during pregnancy and the early postnatal period. Cochrane Database Syst Rev. 2021 Mar 29;3(3):CD001689. doi: 10.1002/14651858.CD001689.pub4.
• Middeldorp S. New studies of low-molecular-weight heparin in pregnancy. Thromb Res. 2015 Feb;135 Suppl 1:S26-9. doi: 10.1016/S0049-3848(15)50436-2. Epub 2015 Feb 9.
• Bleker SM, Coppens M, Middeldorp S. Sex, thrombosis and inherited thrombophilia. Blood Rev. 2014 May;28(3):123-33. doi: 10.1016/j.blre.2014.03.005. Epub 2014 Apr 1.

Drugs

Indications