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

NCT01828697 | Completed Phase 4 DMC

• 4 other identifiers: Highlow study2012-001505-24NL40326.018.12NTR3894
• Study Type: interventional
• Target: 1,110
• Locations: 10 countries
• Sites: 72

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

Keywords

Low-molecular-weight heparin; Pregnancy; Venous thrombosis

Outcome Measures

Primary Outcomes (2)

• Symptomatic confirmed deep venous thrombosis

  All events of symptomatic deep venous thrombosis in subjects will be recorded from the the date of randomization up to 6 weeks postpartum. Definition of symptomatic deep venous thrombosis (DVT): Suspected (recurrent) DVT with one of the following findings: If there were no previous DVT investigations: * Abnormal compression ultrasound (CUS), * An intraluminal filling defect on venography. If there was a previous DVT investigation: * Abnormal CUS where compression had been normal or, if non-compressible during screening, a substantial increase (4 mm or more) in diameter of the thrombus during full compression, * An extension of an intraluminal filling defect, or a new intraluminal filling defect or an extension of non-visualization of veins in the presence of a sudden cut-off on venography.

  From date of randomization up to 6 weeks postpartum

• Symptomatic confirmed pulmonary embolism

  All events of symptomatic pulmonary embolism in subjects will be recorded from the the date of randomization up to 6 weeks postpartum. Definition of symptomatic pulmonary embolism (PE): Suspected PE with one of the following findings: * A (new) intraluminal filling defect in subsegmental or more proximal branches on spiral CT scan * A (new) intraluminal filling defect or an extension of an existing defect or a new sudden cut-off of vessels more than 2.5 mm in diameter on the pulmonary angiogram * A (new) perfusion defect of at least 75% of a segment with a local normal ventilation result (high-probability) on ventilation/perfusion lung scan (VPLS)

  From date of randomization up to 6 weeks postpartum

Secondary Outcomes (2)

• Symptomatic confirmed deep venous thrombosis

  From date of randomization up to 3 months postpartum

• Symptomatic confirmed pulmonary embolism

  From date of randomization up to 3 months postpartum

Other Outcomes (13)

• Major bleeding

  During pregnancy until 3 months postpartum

• Composite of major bleeding and clinically relevant non-major bleeding

  During pregnancy until 3 months postpartum

• Early postpartum hemorrhage

  Within 24 hours of delivery

Study Arms (2)

Low dose LMWH

ACTIVE COMPARATOR

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.

Drug: Low dose nadroparin; Drug: Low dose enoxaparin; Drug: Low dose dalteparin; Drug: Fixed low dose tinzaparin

Intermediate dose LMWH

ACTIVE COMPARATOR

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.

Drug: Intermediate dose nadroparin; Drug: Intermediate dose enoxaparin; Drug: Intermediate dose dalteparin; Drug: Intermediate dose tinzaparin

Interventions

Low dose nadroparin DRUG

Fixed low dose nadroparin: * \< 100 kg: 2850 IU subcutaneously once-daily * 100 kg and above: 3800 IU subcutaneously once-daily

Also known as: nadroparin, Fraxiparin

Low dose LMWH

Intermediate dose nadroparin 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.

Also known as: nadroparin, Fraxiparin

Intermediate dose LMWH

Low dose enoxaparin DRUG

Fixed low dose enoxaparin: * \< 100 kg: 40 mg subcutaneously once-daily * 100 kg and above: 60 mg subcutaneously once-daily

Also known as: enoxaparin, Clexane

Low dose LMWH

Intermediate dose enoxaparin 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.

Also known as: enoxaparin, Clexane

Intermediate dose LMWH

Low dose dalteparin DRUG

Fixed low dose dalteparin: * \< 100 kg: 5000 IU subcutaneously once-daily * 100 kg and above: 7500 IU subcutaneously once-daily

Also known as: dalteparin, Fragmin

Low dose LMWH

Intermediate dose dalteparin 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.

Also known as: dalteparin, Fragmin

Intermediate dose LMWH

Fixed low dose tinzaparin DRUG

Fixed low dose tinzaparin: * \< 100 kg: 3500 IU subcutaneously once-daily * 100 kg and above: 4500 IU subcutaneously once-daily

Also known as: tinzaparin, Innohep

Low dose LMWH

Intermediate dose tinzaparin 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.

Also known as: tinzaparin, Innohep

Intermediate dose LMWH

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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).

You may not qualify if:

• 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.

Sponsors & Collaborators

• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA): lead
• Netherlands Organisation for Scientific Research: collaborator
• Aspen Pharma: collaborator
• CHU of Saint Etienne: French Ministry of Health Grant (sponsor of the French part of the study): collaborator
• Rotunda Hospital: Definitive Interventions and Feasibility Awards (DIFA) 2017 (sponsor of the Irish part of the study)): collaborator

Study Sites (72)

Weill Cornell Medicine | NewYork-Presbyterian

New York, New York, United States

Location

KU Leuven

Leuven, Belgium

Location

The Ottawa Hospital

Ottawa, Canada

Location

Aalborg University Hospital

Aalborg, Denmark

Location

Aarhus University Hospital

Aarhus, Denmark

Location

CHU de Besancon

Besançon, France

Location

CHU de Bordeaux

Bordeaux, France

Location

CHU de Brest

Brest, France

Location

CHU de Caen

Caen, France

Location

CHU de Clermont - Ferrand

Clermont-Ferrand, France

Location

APHP Louis Mourier

Colombes, France

Location

CHU de Grenoble

Grenoble, France

Location

CHU de Limoges

Limoges, France

Location

Hopiteaux de Marseille

Marseille, France

Location

Marseille St Joseph

Marseille, France

Location

CHU de Nancy

Nancy, France

Location

CHU de Nice

Nice, France

Location

CHU de Nîmes

Nîmes, France

Location

APHP Antoine Béclère

Paris, France

Location

APHP Port Royal

Paris, France

Location

CHU de Poitiers

Paris, France

Location

Centra Hospitalier de Roanne

Roanne, France

Location

La Réunion - Saint-Denis

Saint-Denis, France

Location

Hopital Nord, CHU de Saint Etienne

Saint-Etienne, France

Location

La Réunion deSt Pierre

Saint-Pierre, France

Location

Polyclinique de Sète

Sète, France

Location

CHIC de Toulon

Toulon, France

Location

CHU de Tours

Tours, France

Location

Corke University Hospital

Cork, Ireland

Location

Coombe Women's Hospital

Dublin, Ireland

Location

Rotunda Hospital

Dublin, Ireland

Location

The National Maternity Hospital

Dublin, Ireland

Location

Letterkenny University Hospital

Letterkenny, Ireland

Location

University Hospital Limerick

Limerick, Ireland

Location

Academic Medical Center

Amsterdam, North Holland, 1105 AZ, Netherlands

Location

Jeroen Bosch Ziekenhuis

's-Hertogenbosch, Netherlands

Location

Flevoziekenhuis

Almere Stad, Netherlands

Location

OLVG oost

Amsterdam, Netherlands

Location

SLAZ

Amsterdam, Netherlands

Location

VU medical center

Amsterdam, Netherlands

Location

Gelre Ziekenhuizen

Apeldoorn, Netherlands

Location

Rijnstate hospital

Arnhem, Netherlands

Location

Wilhelmina Ziekenhuis

Assen, Netherlands

Location

Rode Kruis Ziekenhuis

Beverwijk, Netherlands

Location

Amphia ziekenhuis

Breda, Netherlands

Location

Reinier de Graaf Groep

Delft, Netherlands

Location

Deventer Ziekenhuis

Deventer, Netherlands

Location

Slingeland

Doetinchem, Netherlands

Location

Albert Schweitzer

Dordrecht, Netherlands

Location

Gelderse Vallei

Ede, Netherlands

Location

Admiraal de Ruijter Ziekenhuis

Goes, Netherlands

Location

Groene Hart Ziekenhuis

Gouda, Netherlands

Location

Martini Ziekenhuis

Groningen, Netherlands

Location

UMCG

Groningen, Netherlands

Location

Spaarne Gasthuis

Haarlem, Netherlands

Location

St Jansdal

Harderwijk, Netherlands

Location

Atrium MC

Heerlen, Netherlands

Location

MC Leeuwarden

Leeuwarden, Netherlands

Location

LUMC

Leiden, Netherlands

Location

MUMC

Maastricht, Netherlands

Location

Canisius-Wilhelmina Ziekenhuis

Nijmegen, Netherlands

Location

St. Radboud UMC

Nijmegen, Netherlands

Location

Erasmus MC

Rotterdam, Netherlands

Location

Bronovo ziekenhuis

The Hague, Netherlands

Location

HAGA ziekenhuis

The Hague, Netherlands

Location

TweeSteden

Tilburg, Netherlands

Location

Diakonessen Utrecht

Utrecht, Netherlands

Location

UMCU

Utrecht, Netherlands

Location

Máxima MC

Veldhoven, Netherlands

Location

Oslo University Hospital

Oslo, Norway

Location

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

Moscow, Russia

Location

Vall d'Hebron Hospital

Barcelona, Spain

Location

Related Publications (18)

• 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.

  PMID: 10217099 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.

  PMID: 12130523 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.

  PMID: 18690344 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.

  PMID: 22315276 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.

  PMID: 15811953 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.

  PMID: 20464719 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.

  PMID: 10365733 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.

  PMID: 11762651 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.

  PMID: 15869590 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.

  PMID: 21232006 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.

  PMID: 21314819 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.

  PMID: 22102641 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.

  PMID: 20335572 BACKGROUND

• 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.

  PMID: 36695396 DERIVED

• 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.

  PMID: 36354038 DERIVED

• 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.

  PMID: 33779986 DERIVED

• 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.

  PMID: 25903529 DERIVED

• 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.

  PMID: 24768093 DERIVED

MeSH Terms

Conditions

Venous Thrombosis; Pulmonary Embolism

Interventions

Nadroparin; Enoxaparin; Dalteparin; Tinzaparin

Condition Hierarchy (Ancestors)

Thrombosis; Embolism and Thrombosis; Vascular Diseases; Cardiovascular Diseases; Lung Diseases; Respiratory Tract Diseases; Embolism

Intervention Hierarchy (Ancestors)

Heparin, Low-Molecular-Weight; Heparin; Glycosaminoglycans; Polysaccharides; Carbohydrates

Study Officials

• Saskia Middeldorp, MD PhD

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

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: prof.dr. S. Middeldorp

Study Record Dates

• First Submitted: April 5, 2013
• First Posted: April 11, 2013
• Study Start: April 24, 2013
• Primary Completion: October 31, 2021
• Study Completion: October 31, 2021
• Last Updated: May 26, 2022

Record last verified: 2022-05

Locations

ES (1); BE (1); CA (1); RU (1); DK (2); FR (23); NL (35); IE (6); US (1); NO (1)