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Completed

NCT Number: NCT01828697

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

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.

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Key information

Conditions

Deep Venous Thrombosis Cardiovascular Diseases Embolism Embolism and Thrombosis Lung Diseases Pulmonary Embolism Respiratory Tract Diseases Thrombosis Vascular Diseases Venous Thrombosis

Age range

18 year–50 year

Sex eligibility

Female

Study type

Interventional

Phase

Phase 4

Primary location

KU Leuven, Leuven, Belgium

Loading trial locations.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

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.

Treatment and study plan

Low dose nadroparin

Drug

Fixed low dose nadroparin:

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

Other names: nadroparin, Fraxiparin

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.

Other names: nadroparin, Fraxiparin

Low dose enoxaparin

Drug

Fixed low dose enoxaparin:

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

Other names: enoxaparin, Clexane

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.

Other names: enoxaparin, Clexane

Low dose dalteparin

Drug

Fixed low dose dalteparin:

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

Other names: dalteparin, Fragmin

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.

Other names: dalteparin, Fragmin

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

Other names: tinzaparin, Innohep

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.

Other names: tinzaparin, Innohep

Primary outcomes

  1. Symptomatic confirmed deep venous thrombosis

    Time frame: From date of randomization up to 6 weeks postpartum

    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.

  2. Symptomatic confirmed pulmonary embolism

    Time frame: From date of randomization up to 6 weeks postpartum

    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)

Secondary outcomes

  1. Symptomatic confirmed deep venous thrombosis

    Time frame: From date of randomization up to 3 months postpartum

    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.

  2. Symptomatic confirmed pulmonary embolism

    Time frame: From date of randomization up to 3 months postpartum

    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)

Other outcomes

  1. Major bleeding

    Time frame: During pregnancy until 3 months postpartum

    Major bleeding is defined as overt bleeding and:

    • Associated with a fall in hemoglobin of 2 g/dL or more, or
    • Leading to a transfusion of 2 or more units of packed red blood cells or whole blood, or
    • Occurring in a critical site: intracranial, intraspinal, intraocular, pericardial, intra-articular, intramuscular with compartment syndrome, retro-peritoneal, or
    • Contributing to death

  2. Composite of major bleeding and clinically relevant non-major bleeding

    Time frame: During pregnancy until 3 months postpartum

    See 'Major bleeding' for the definition.

    Clinically relevant non-major bleeding is defined as overt bleeding not meeting the criteria for major bleeding but associated with medical intervention, unscheduled contact (visit or telephone call) with a physician, (temporary) cessation of study treatment, or associated with discomfort such as pain, or impairment of activities of daily life.

    • Hematuria if it is macroscopic, and either spontaneous or lasts for more than 24 hours after instrumentation (e.g. catheter placement or surgery) of the urogenital tract, or
    • Macroscopic gastro-intestinal haemorrhage: at least one episode of melena/hematemesis, if clinically apparent, or
    • Rectal blood loss, if more than a few spots, or
    • Hemoptysis, if more than a few speckles in the sputum, or
    • Intramuscular hematoma, or
    • Subcutaneous hematoma if the size is larger than 25 cm2, or larger than 100 cm2 if provoked, or
    • Multiple source bleeding

  3. Early postpartum hemorrhage

    Time frame: Within 24 hours of delivery

    Postpartum haemorrhage is defined as blood loss of more than 500 mL within 24 hours of delivery (WHO-criteria). Severe postpartum haemorrhage is defined as blood loss of more than 1000 mL within 24 hours of delivery.

  4. Blood transfusion < 6 weeks after delivery

    Time frame: Within 6 weeks of delivery

  5. Blood transfusion < 24 hours postpartum

    Time frame: Within 24 hours of delivery

  6. Late postpartum hemorrhage

    Time frame: From 24 hours postpartum to 6 weeks postpartum

    Postpartum haemorrhage is defined as blood loss of more than 500 mL within 24 hours of delivery (WHO-criteria). Severe postpartum haemorrhage is defined as blood loss of more than 1000 mL within 24 hours of delivery.

  7. Mortality

    Time frame: During pregnancy until 3 months postpartum

  8. Minor bleeding

    Time frame: During pregnancy until 3 months postpartum

    Minor bleeding is defined as all other overt bleeding episodes not meeting the criteria for major or clinically relevant bleeding or postpartum haemorrhage.

  9. Skin complications

    Time frame: During pregnancy until 3 months postpartum

    e.g. itching, swelling, pain

  10. Easy bruising

    Time frame: During pregnancy until 3 months postpartum

  11. Necessity to switch to other LMWH

    Time frame: During pregnancy until 6 weeks postpartum

  12. Heparin-induced thrombocytopenia

    Time frame: During pregnancy until 3 months postpartum

    Heparin-induced thrombocytopenia is defined according to the criteria of the ACCP guidelines.

  13. Congenital anomalies or birth defects

    Time frame: During pregnancy until 3 months postpartum

Sponsors and collaborators

Lead sponsor

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

Other

Collaborators

  • Aspen Pharma
  • CHU of Saint Etienne: French Ministry of Health Grant (sponsor of the French part of the study)
  • Netherlands Organisation for Scientific Research
  • Rotunda Hospital: Definitive Interventions and Feasibility Awards (DIFA) 2017 (sponsor of the Irish part of the study))

Registry information

Official study title

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

Acronym: Highlow

Important dates

Study start
2013
Primary completion
2021
Study completion
2021
First posted
Apr 11, 2013
Registry last updated
May 26, 2022

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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