AzTrials
AzTrials

Deep Venous ThrombosisPhase 4HighlowNCT01828697

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

A Phase 4 study testing Low dose nadroparin, Intermediate dose nadroparin and Low dose enoxaparin in people with Deep Venous Thrombosis and Pulmonary Embolism, run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) at 72 sites in 10 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial 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). Read more about this study

Who is it for?
Ages 18 to 50 years, women only
Conditions the study is for
Deep Venous Thrombosis, Pulmonary Embolism
What is being tested?
Low dose nadroparin, Intermediate dose nadroparin and Low dose enoxaparin
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
1,110 participants
Where
72 sitesin 10 countries
Study dates
24 Apr 2013to 31 Oct 2021
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 50 years
  • Women only
  • No healthy volunteers
  • Adult

Who may be able to join

  • 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).

Who cannot join

  • 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.

Trial locations and contacts

72 sites in 10 countries.

72 sites in 10 countries

Netherlands35 sites

  • Jeroen Bosch Ziekenhuis

    's-Hertogenbosch

  • Flevoziekenhuis

    Almere Stad

  • Academic Medical Center

    Amsterdam, North Holland, 1105 AZ

  • OLVG oost

    Amsterdam

  • SLAZ

    Amsterdam

  • VU medical center

    Amsterdam

  • Gelre Ziekenhuizen

    Apeldoorn

  • Rijnstate hospital

    Arnhem

  • Wilhelmina Ziekenhuis

    Assen

  • Rode Kruis Ziekenhuis

    Beverwijk

  • Amphia ziekenhuis

    Breda

  • Reinier de Graaf Groep

    Delft

  • Deventer Ziekenhuis

    Deventer

  • Slingeland

    Doetinchem

  • Albert Schweitzer

    Dordrecht

  • Gelderse Vallei

    Ede

  • Admiraal de Ruijter Ziekenhuis

    Goes

  • Groene Hart Ziekenhuis

    Gouda

  • Martini Ziekenhuis

    Groningen

  • UMCG

    Groningen

  • Spaarne Gasthuis

    Haarlem

  • St Jansdal

    Harderwijk

  • Atrium MC

    Heerlen

  • MC Leeuwarden

    Leeuwarden

  • LUMC

    Leiden

  • MUMC

    Maastricht

  • Canisius-Wilhelmina Ziekenhuis

    Nijmegen

  • St. Radboud UMC

    Nijmegen

  • Erasmus MC

    Rotterdam

  • Bronovo ziekenhuis

    The Hague

  • HAGA ziekenhuis

    The Hague

  • TweeSteden

    Tilburg

  • Diakonessen Utrecht

    Utrecht

  • UMCU

    Utrecht

  • Máxima MC

    Veldhoven

Other trials in Netherlands

France23 sites

  • CHU de Besancon

    Besançon

  • CHU de Bordeaux

    Bordeaux

  • CHU de Brest

    Brest

  • CHU de Caen

    Caen

  • CHU de Clermont - Ferrand

    Clermont-Ferrand

  • APHP Louis Mourier

    Colombes

  • CHU de Grenoble

    Grenoble

  • CHU de Limoges

    Limoges

  • Hopiteaux de Marseille

    Marseille

  • Marseille St Joseph

    Marseille

  • CHU de Nancy

    Nancy

  • CHU de Nice

    Nice

  • CHU de Nîmes

    Nîmes

  • APHP Antoine Béclère

    Paris

  • APHP Port Royal

    Paris

  • CHU de Poitiers

    Paris

  • Centra Hospitalier de Roanne

    Roanne

  • La Réunion - Saint-Denis

    Saint-Denis

  • Hopital Nord, CHU de Saint Etienne

    Saint-Etienne

  • La Réunion deSt Pierre

    Saint-Pierre

  • Polyclinique de Sète

    Sète

  • CHIC de Toulon

    Toulon

  • CHU de Tours

    Tours

Other trials in France

Ireland6 sites

  • Corke University Hospital

    Cork

  • Coombe Women's Hospital

    Dublin

  • Rotunda Hospital

    Dublin

  • The National Maternity Hospital

    Dublin

  • Letterkenny University Hospital

    Letterkenny

  • University Hospital Limerick

    Limerick

Other trials in Ireland

Denmark2 sites

  • Aalborg University Hospital

    Aalborg

  • Aarhus University Hospital

    Aarhus

Other trials in Denmark

United States1 site

  • Weill Cornell Medicine | NewYork-Presbyterian

    New York, New York

Other trials in United States

Belgium1 site

  • KU Leuven

    Leuven

Other trials in Belgium

Canada1 site

  • The Ottawa Hospital

    Ottawa

Other trials in Canada

Norway1 site

  • Oslo University Hospital

    Oslo

Other trials in Norway

Russia1 site

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

    Moscow

Other trials in Russia

Spain1 site

  • Vall d'Hebron Hospital

    Barcelona

Other trials in Spain

About this study

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

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.

Being tested
Low dose nadroparin, Intermediate dose nadroparin, Low dose enoxaparin, Intermediate dose enoxaparin, Low dose dalteparin
Keywords
Low-molecular-weight heparin, Pregnancy, Venous thrombosis
Medical subject headings
Venous Thrombosis, Pulmonary Embolism

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Low dose nadroparinDrug

    Also called nadroparin, Fraxiparin

    Fixed low dose nadroparin:

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

  • Intermediate dose nadroparinDrug

    Also called nadroparin, Fraxiparin

    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.

  • Low dose enoxaparinDrug

    Also called enoxaparin, Clexane

    Fixed low dose enoxaparin:

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

  • Intermediate dose enoxaparinDrug

    Also called enoxaparin, Clexane

    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.

  • Low dose dalteparinDrug

    Also called dalteparin, Fragmin

    Fixed low dose dalteparin:

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

  • Intermediate dose dalteparinDrug

    Also called dalteparin, Fragmin

    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.

  • Fixed low dose tinzaparinDrug

    Also called tinzaparin, Innohep

    Fixed low dose tinzaparin:

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

  • Intermediate dose tinzaparinDrug

    Also called tinzaparin, Innohep

    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.
Study groups in NCT01828697
Study groupRoleWhat they receive
Low dose LMWHActive comparatorFixed 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.
Receives: Drug: Low dose nadroparin; Drug: Low dose enoxaparin; Drug: Low dose dalteparin; Drug: Fixed low dose tinzaparin
Intermediate dose LMWHActive comparatorIntermediate 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.
Receives: Drug: Intermediate dose nadroparin; Drug: Intermediate dose enoxaparin; Drug: Intermediate dose dalteparin; Drug: Intermediate dose tinzaparin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: From date of randomization up to 6 weeks postpartum

  2. 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)

    Measured: From date of randomization up to 6 weeks postpartum

Secondary outcomes (2)

  1. 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 3 months 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.

    Measured: From date of randomization up to 3 months postpartum

  2. Symptomatic confirmed pulmonary embolism

    All events of symptomatic pulmonary embolism in subjects will be recorded from the the date of randomization up to 3 months 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)

    Measured: From date of randomization up to 3 months postpartum

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted11 Apr 2013 (estimated)
  2. Study start24 Apr 2013
  3. Primary completion31 Oct 2021
  4. Study completion31 Oct 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Prevention
Allocation
Randomised
Intervention model
Parallel groups
Masking
None (open label)
Enrolment
1,110 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01828697
Sponsor's protocol ID
Highlow study
Other IDs
2012-001505-24, NL40326.018.12, NTR3894
Acronym
Highlow
Status last verified
May 2022
First submitted
5 Apr 2013
Last updated
26 May 2022
Results posted
No
Data monitoring committee
Yes

Publications

  • 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.

    PubMed 10217099

  • 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.

    PubMed 12130523

  • 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.

    PubMed 18690344

  • 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.

    PubMed 22315276

  • 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.

    PubMed 15811953

  • 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.

    PubMed 20464719

  • 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.

    PubMed 10365733

  • 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.

    PubMed 11762651

  • 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.

    PubMed 15869590

  • 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.

    PubMed 21232006

  • 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.

    PubMed 21314819

  • 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.

    PubMed 22102641

  • 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.

    PubMed 20335572

  • 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.

    PubMed 36695396

  • 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.

    PubMed 36354038

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Low dose nadroparin, Intermediate dose nadroparin and Low dose enoxaparin in people with Deep Venous Thrombosis and Pulmonary Embolism, run by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) at 72 sites in 10 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 4 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 26 May 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 72 sites in Netherlands, France, Ireland, Denmark, United States and 5 more countries. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Symptomatic confirmed deep venous thrombosis (time frame: From date of randomization up to 6 weeks postpartum). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01828697, which also lists 18 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 May 2022.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in