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

NCT ID: NCT01828697

Last Updated: 2022-05-26

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 1110 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-04-24
• Study Completion Date: 2021-10-31

Brief 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.

Conditions

Deep Venous Thrombosis; Pulmonary Embolism

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: PREVENTION
• Blinding Strategy: NONE

Study Groups

Low dose LMWH

Fixed low dose low-molecular-weight heparin:

• Fixed low dose nadroparin, or;
• Fixed low dose enoxaparin, or;
• Fixed low dose dalteparin, or;
• Fixed low dose tinzaparin.

Group Type: ACTIVE_COMPARATOR

Low dose nadroparin

Intervention Type: DRUG

Fixed low dose nadroparin:

• < 100 kg: 2850 IU subcutaneously once-daily
• 100 kg and above: 3800 IU subcutaneously once-daily

Low dose enoxaparin

Intervention Type: DRUG

Fixed low dose enoxaparin:

• < 100 kg: 40 mg subcutaneously once-daily
• 100 kg and above: 60 mg subcutaneously once-daily

Low dose dalteparin

Intervention Type: DRUG

Fixed low dose dalteparin:

• < 100 kg: 5000 IU subcutaneously once-daily
• 100 kg and above: 7500 IU subcutaneously once-daily

Fixed low dose tinzaparin

Intervention Type: DRUG

Fixed low dose tinzaparin:

• < 100 kg: 3500 IU subcutaneously once-daily
• 100 kg and above: 4500 IU subcutaneously once-daily

Intermediate dose LMWH

Intermediate dose low-molecular-weight heparin. Dosing is weight-adjusted according to the protocol.

• Intermediate dose nadroparin, or;
• Intermediate dose enoxaparin, or;
• Intermediate dose dalteparin, or;
• Intermediate dose tinzaparin.

Group Type: ACTIVE_COMPARATOR

Intermediate dose nadroparin

Intervention Type: DRUG

Intermediate weight-adjusted dose nadroparin:

• < 50 kg: 3800 IU subcutaneously once-daily;
• 50 to < 70 kg: 5700 IU subcutaneously once-daily;
• 70 to < 100 kg: 7600 IU subcutaneously once-daily;
• 100 kg or above: 9500 IU subcutaneously once-daily.

Intermediate dose enoxaparin

Intervention Type: DRUG

Intermediate weight-adjusted dose enoxaparin:

• < 50 kg: 60 mg subcutaneously once-daily, or;
• 50 kg to < 70 kg: 80 mg subcutaneously once-daily, or;
• 70 kg to < 100 kg: 100 mg subcutaneously once-daily, or;
• 100 kg or above: 120 mg subcutaneously once-daily.

Intermediate dose dalteparin

Intervention Type: DRUG

Intermediate weight-adjusted dose dalteparin:

• < 50 kg: 7500 IU subcutaneously once-daily, or;
• 50 kg to < 70 kg: 10000 IU subcutaneously once-daily, or;
• 70 kg to < 100 kg: 12500 IU subcutaneously once-daily, or;
• 100 kg or above: 15000 IU subcutaneously once-daily.

Intermediate dose tinzaparin

Intervention Type: DRUG

Intermediate weight-adjusted dose tinzaparin:

• < 50 kg: 4500 IU subcutaneously once-daily, or;
• 50 kg to < 70 kg: 7000 IU subcutaneously once-daily, or;
• 70 kg to < 100 kg: 10000 IU subcutaneously once-daily, or;
• 100 kg or above: 12000 IU subcutaneously once-daily.

Interventions

Low dose nadroparin

Fixed low dose nadroparin:

• < 100 kg: 2850 IU subcutaneously once-daily
• 100 kg and above: 3800 IU subcutaneously once-daily

Intervention Type: DRUG

Intermediate dose nadroparin

Intermediate weight-adjusted dose nadroparin:

• < 50 kg: 3800 IU subcutaneously once-daily;
• 50 to < 70 kg: 5700 IU subcutaneously once-daily;
• 70 to < 100 kg: 7600 IU subcutaneously once-daily;
• 100 kg or above: 9500 IU subcutaneously once-daily.

Intervention Type: DRUG

Low dose enoxaparin

Fixed low dose enoxaparin:

• < 100 kg: 40 mg subcutaneously once-daily
• 100 kg and above: 60 mg subcutaneously once-daily

Intervention Type: DRUG

Intermediate dose enoxaparin

Intermediate weight-adjusted dose enoxaparin:

• < 50 kg: 60 mg subcutaneously once-daily, or;
• 50 kg to < 70 kg: 80 mg subcutaneously once-daily, or;
• 70 kg to < 100 kg: 100 mg subcutaneously once-daily, or;
• 100 kg or above: 120 mg subcutaneously once-daily.

Intervention Type: DRUG

Low dose dalteparin

Fixed low dose dalteparin:

• < 100 kg: 5000 IU subcutaneously once-daily
• 100 kg and above: 7500 IU subcutaneously once-daily

Intervention Type: DRUG

Intermediate dose dalteparin

Intermediate weight-adjusted dose dalteparin:

• < 50 kg: 7500 IU subcutaneously once-daily, or;
• 50 kg to < 70 kg: 10000 IU subcutaneously once-daily, or;
• 70 kg to < 100 kg: 12500 IU subcutaneously once-daily, or;
• 100 kg or above: 15000 IU subcutaneously once-daily.

Intervention Type: DRUG

Fixed low dose tinzaparin

Fixed low dose tinzaparin:

• < 100 kg: 3500 IU subcutaneously once-daily
• 100 kg and above: 4500 IU subcutaneously once-daily

Intervention Type: DRUG

Intermediate dose tinzaparin

Intermediate weight-adjusted dose tinzaparin:

• < 50 kg: 4500 IU subcutaneously once-daily, or;
• 50 kg to < 70 kg: 7000 IU subcutaneously once-daily, or;
• 70 kg to < 100 kg: 10000 IU subcutaneously once-daily, or;
• 100 kg or above: 12000 IU subcutaneously once-daily.

Intervention Type: DRUG

Other Intervention Names

nadroparin; Fraxiparin; nadroparin; Fraxiparin; enoxaparin; Clexane; enoxaparin; Clexane; dalteparin; Fragmin; dalteparin; Fragmin; tinzaparin; Innohep; tinzaparin; Innohep

Eligibility 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.

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 50 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Netherlands Organisation for Scientific Research

OTHER_GOV

Sponsor Role: collaborator

Aspen Pharma

UNKNOWN

Sponsor Role: collaborator

CHU of Saint Etienne: French Ministry of Health Grant (sponsor of the French part of the study)

UNKNOWN

Sponsor Role: collaborator

Rotunda Hospital: Definitive Interventions and Feasibility Awards (DIFA) 2017 (sponsor of the Irish part of the study))

UNKNOWN

Sponsor Role: collaborator

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

OTHER

Sponsor Role: lead

Responsible Party

S. Middeldorp

prof.dr. S. Middeldorp

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Saskia Middeldorp, MD PhD

Role: PRINCIPAL_INVESTIGATOR

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Locations

Weill Cornell Medicine | NewYork-Presbyterian

New York, New York, United States

KU Leuven

Leuven, , Belgium

The Ottawa Hospital

Ottawa, , Canada

Aalborg University Hospital

Aalborg, , Denmark

Aarhus University Hospital

Aarhus, , Denmark

CHU de Besancon

Besançon, , France

CHU de Bordeaux

Bordeaux, , France

CHU de Brest

Brest, , France

CHU de Caen

Caen, , France

CHU de Clermont - Ferrand

Clermont-Ferrand, , France

APHP Louis Mourier

Colombes, , France

CHU de Grenoble

Grenoble, , France

CHU de Limoges

Limoges, , France

Hopiteaux de Marseille

Marseille, , France

Marseille St Joseph

Marseille, , France

CHU de Nancy

Nancy, , France

CHU de Nice

Nice, , France

CHU de Nîmes

Nîmes, , France

APHP Antoine Béclère

Paris, , France

APHP Port Royal

Paris, , France

CHU de Poitiers

Paris, , France

Centra Hospitalier de Roanne

Roanne, , France

La Réunion - Saint-Denis

Saint-Denis, , France

Hopital Nord, CHU de Saint Etienne

Saint-Etienne, , France

La Réunion deSt Pierre

Saint-Pierre, , France

Polyclinique de Sète

Sète, , France

CHIC de Toulon

Toulon, , France

CHU de Tours

Tours, , France

Corke University Hospital

Cork, , Ireland

Coombe Women's Hospital

Dublin, , Ireland

Rotunda Hospital

Dublin, , Ireland

The National Maternity Hospital

Dublin, , Ireland

Letterkenny University Hospital

Letterkenny, , Ireland

University Hospital Limerick

Limerick, , Ireland

Academic Medical Center

Amsterdam, North Holland, Netherlands

Jeroen Bosch Ziekenhuis

's-Hertogenbosch, , Netherlands

Flevoziekenhuis

Almere Stad, , Netherlands

OLVG oost

Amsterdam, , Netherlands

SLAZ

Amsterdam, , Netherlands

VU medical center

Amsterdam, , Netherlands

Gelre Ziekenhuizen

Apeldoorn, , Netherlands

Rijnstate hospital

Arnhem, , Netherlands

Wilhelmina Ziekenhuis

Assen, , Netherlands

Rode Kruis Ziekenhuis

Beverwijk, , Netherlands

Amphia ziekenhuis

Breda, , Netherlands

Reinier de Graaf Groep

Delft, , Netherlands

Deventer Ziekenhuis

Deventer, , Netherlands

Slingeland

Doetinchem, , Netherlands

Albert Schweitzer

Dordrecht, , Netherlands

Gelderse Vallei

Ede, , Netherlands

Admiraal de Ruijter Ziekenhuis

Goes, , Netherlands

Groene Hart Ziekenhuis

Gouda, , Netherlands

Martini Ziekenhuis

Groningen, , Netherlands

UMCG

Groningen, , Netherlands

Spaarne Gasthuis

Haarlem, , Netherlands

St Jansdal

Harderwijk, , Netherlands

Atrium MC

Heerlen, , Netherlands

MC Leeuwarden

Leeuwarden, , Netherlands

LUMC

Leiden, , Netherlands

MUMC

Maastricht, , Netherlands

Canisius-Wilhelmina Ziekenhuis

Nijmegen, , Netherlands

St. Radboud UMC

Nijmegen, , Netherlands

Erasmus MC

Rotterdam, , Netherlands

Bronovo ziekenhuis

The Hague, , Netherlands

HAGA ziekenhuis

The Hague, , Netherlands

TweeSteden

Tilburg, , Netherlands

Diakonessen Utrecht

Utrecht, , Netherlands

UMCU

Utrecht, , Netherlands

Máxima MC

Veldhoven, , Netherlands

Oslo University Hospital

Oslo, , Norway

Federal State Institution "Research Center for Obstetrics, Gynecology and Perinatology"

Moscow, , Russia

Vall d'Hebron Hospital

Barcelona, , Spain

Countries

United States; Belgium; Canada; Denmark; France; Ireland; Netherlands; Norway; Russia; Spain

References

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.

Reference Type: BACKGROUND

PMID: 10217099 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 12130523 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 18690344 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22315276 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15811953 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20464719 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 10365733 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 11762651 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 15869590 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 21232006 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 21314819 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 22102641 (View on PubMed)

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.

Reference Type: BACKGROUND

PMID: 20335572 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 36695396 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 36354038 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 33779986 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 25903529 (View on PubMed)

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.

Reference Type: DERIVED

PMID: 24768093 (View on PubMed)

Other Identifiers

2012-001505-24

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

NL40326.018.12

Identifier Type: OTHER

Identifier Source: secondary_id

NTR3894

Identifier Type: REGISTRY

Identifier Source: secondary_id

Highlow study

Identifier Type: -

Identifier Source: org_study_id