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

Condition(s) targeted: Deep Venous Thrombosis; Pulmonary Embolism

Intervention: Low dose nadroparin (Drug); Intermediate dose nadroparin (Drug); Low dose enoxaparin (Drug); Intermediate dose enoxaparin (Drug); Low dose dalteparin (Drug); Intermediate dose dalteparin (Drug); Fixed low dose tinzaparin (Drug); Intermediate dose tinzaparin (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Official(s) and/or principal investigator(s):
S. Middeldorp, MD PhD, Principal Investigator, Affiliation: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Overall contact:
S. M. Bleker, MD, Email: s.m.bleker@amc.nl

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.

Official title: Low-molecular-weight Heparin to Prevent Recurrent VTE in Pregnancy: a Randomized Controlled Trial of Two Doses

Study design: Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention

Primary outcome:

Symptomatic confirmed deep venous thrombosis

Symptomatic confirmed pulmonary embolism

Secondary outcome:

Symptomatic confirmed deep venous thrombosis

Symptomatic confirmed pulmonary embolism

Minimum age: 18 Years. Maximum age: 50 Years. Gender(s): Female.

Criteria:

Inclusion Criteria:

- Age: 18 years or older, and;

- Pregnancy confirmed by urinary pregnancy test, and;

- Gestational age < 14 weeks, and;

- Previous objectively confirmed VTE, either unprovoked, in the presence of use of oral

contraceptives or estrogen/progestagen use, or related to pregnancy or the postpartum period, or minor risk factors (e. g. long distance travel, minor trauma). Exclusion Criteria:

- Previous VTE related to a major provoking risk factor (e. g. surgery, major trauma or

plaster cast immobilisation in the 3 months prior to VTE) as the sole risk factor, or;

- Indication for treatment with therapeutic dose anticoagulant therapy (e. g. treatment

of acute VTE; permanent use of therapeutic anticoagulants outside of pregnancy), or;

- Inability to provide informed consent, or;

- Any contraindication listed in the local labelling of LMWH.

S. M. Bleker, MD, Email: s.m.bleker@amc.nl

Medizinische Universitaet Wien - Universitaetsklinik fuer Innere Medizin I, Vienna, Austria; Not yet recruiting
Ingrid Pabinger, Email: ingrid.pabinger@meduniwien.ac.at

KU Leuven, Leuven, Belgium; Not yet recruiting
Peter Verhamme, Email: peter.verhamme@uzleuven.be

Hopital Nord, CHU de Saint Etienne, Saint Etienne, France; Not yet recruiting
Andréa Buchmuller, Email: andrea.buchmuller@chu-st-etienne.fr
Hervé Decousus, Email: herve.decousus@chu-st-etienne.fr

Mater Misericordiae Hospital, Dublin, Ireland; Not yet recruiting
Fionnuala Ni Ainle, MD PhD, Email: fniainle@mater.ie

Jeroen Bosch Ziekenhuis, 's-Hertogenbosch, Netherlands; Recruiting
Robert Rijnders, Email: r.rijnders@jbz.nl

Flevoziekenhuis, Almere, Netherlands; Not yet recruiting
Gunilla Kleiverda, Email: gkleiverda@flevoziekenhuis.nl

OLVG, Amsterdam, Netherlands; Recruiting
E.S.A. van den Akker, Email: e.s.a.vandenakker@olvg.nl

SLAZ, Amsterdam, Netherlands; Not yet recruiting
Brenda Hermsen, Email: b.hermsen@slaz.nl
Reinhard Maas, Email: r.maas@slaz.nl

VU medical center, Amsterdam, Netherlands; Recruiting
Marion van Hoorn, Email: m.vanhoorn@vumc.nl

Gelre Ziekenhuizen, Apeldoorn, Netherlands; Recruiting
Thomas van Bemmel, Email: t.van.bemmel@gelre.nl

Rijnstate hospital, Arnhem, Netherlands; Not yet recruiting
Marcel Hovens, Email: mhovens@rijnstate.nl

Wilhelmina Ziekenhuis, Assen, Netherlands; Recruiting
A. Koops, Email: j.h.m.keurentjes@umcg.nl

Amphia ziekenhuis, Breda, Netherlands; Recruiting
D Papatsonis, Email: dpapatsonis@amphia.nl

Reinier de Graaf Groep, Delft, Netherlands; Recruiting
H Bremer, Email: bremer@rdgg.nl

Bronovo ziekenhuis, Den Haag, Netherlands; Recruiting
Wim van Wijngaarden, Email: wvwijngaarden@bronovo.nl

HAGA ziekenhuis, Den Haag, Netherlands; Recruiting
Paula Ypma, Email: p.ypma@hagaziekenhuis.nl

Deventer Ziekenhuis, Deventer, Netherlands; Recruiting
Joost Zwart, Email: j.zwart@dz.nl

Slingeland, Doetinchem, Netherlands; Active, not recruiting

Albert Schweitzer, Dordrecht, Netherlands; Not yet recruiting
Sabina Rombout-de Weerd, Email: s.rombout-de.weerd@asz.nl
Peter Westerweel, Email: p.e.westerweel@asz.nl

Groene Hart Ziekenhuis, Gouda, Netherlands; Not yet recruiting
Claudia van Meir, Email: claudia.van.meir@ghz.nl
Bea Tanis, Email: bea.tanis@ghz.nl

Martini Ziekenhuis, Groningen, Netherlands; Active, not recruiting

UMCG, Groningen, Netherlands; Recruiting
Maureen Franssen, Email: m.t.m.franssen@umcg.nl

Kennemer Gasthuis, Haarlem, Netherlands; Not yet recruiting
Paula Pernet, Email: pernet@kg.nl

Atrium MC, Heerlen, Netherlands; Recruiting
J Langenveld, Email: j.langenveld@atriummc.nl

MC Leeuwarden, Leeuwarden, Netherlands; Not yet recruiting

LUMC, Leiden, Netherlands; Active, not recruiting

MUMC, Maastricht, Netherlands; Active, not recruiting

Canisius-Wilhelmina Ziekenhuis, Nijmegen, Netherlands; Not yet recruiting
D.H. Schippers, Email: gerard.zijderveld@radboudumc.nl

St. Radboud UMC, Nijmegen, Netherlands; Recruiting
M Woiski, Email: m.woiski@obgyn.umcn.nl

Erasmus MC, Rotterdam, Netherlands; Not yet recruiting
Marieke Kruip, Email: m.kruip@erasmusmc.nl

TweeSteden, Tilburg, Netherlands; Active, not recruiting

Diakonessen Utrecht, Utrecht, Netherlands; Not yet recruiting
Nico Schuitemaker, Email: nschuite@diakhuis.nl

UMCU, Utrecht, Netherlands; Recruiting
Martijn Oudijk, Email: m.a.oudijk@umcutrecht.nl

Máxima MC, Veldhoven, Netherlands; Active, not recruiting

Academic Medical Center, Amsterdam, Noord-Holland 1105 AZ, Netherlands; Recruiting
S. M. Bleker, MD, Email: s.m.bleker@amc.nl
N. van Es, MD, Email: n.vanes@amc.nl

Study website

Related publications:

Greer IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet. 1999 Apr 10;353(9160):1258-65. Review.

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.

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.

Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO; American College of Chest Physicians. 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-736S. doi: 10.1378/chest.11-2300.

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. Epub 2005 Apr 5. Review.

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. Review. Update in: Cochrane Database Syst Rev. 2014;2:CD001689.

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, Hamulyák K, Theunissen IM, Hunt BJ, Büller HR. Safety of low-molecular-weight heparin in pregnancy: a systematic review. Thromb Haemost. 1999 May;81(5):668-72. Review.

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.

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.

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.

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.

Roshani S, Cohn DM, Stehouwer AC, Wolf H, van der Post JA, Büller 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.

Kaandorp SP, Goddijn M, van der Post JA, Hutten BA, Verhoeve HR, Hamulyák K, Mol BW, Folkeringa N, Nahuis M, Papatsonis DN, Büller 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.

Starting date: April 2013
Last updated: July 1, 2015