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

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ClinicalTrials.gov Identifier: NCT01828697
Recruitment Status : Recruiting
First Posted : April 11, 2013
Last Update Posted : July 3, 2019
Sponsor:
Collaborators:
Netherlands Organisation for Scientific Research
Aspen Pharma
CHU of Saint Etienne: French Ministry of Health Grant (sponsor of the French part of the study)
Rotunda Hospital: Definitive Interventions and Feasibility Awards (DIFA) 2017 (sponsor of the Irish part of the study))
Information provided by (Responsible Party):
S. Middeldorp, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

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.


Condition or disease Intervention/treatment Phase
Deep Venous Thrombosis Pulmonary Embolism Drug: 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 Phase 4

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1000 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Official Title: Low-molecular-weight Heparin to Prevent Recurrent VTE in Pregnancy: a Randomized Controlled Trial of Two Doses
Actual Study Start Date : April 2013
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: 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.
Drug: Low dose nadroparin

Fixed low dose nadroparin:

  • < 100 kg: 2850 IU subcutaneously once-daily
  • 100 kg and above: 3800 IU subcutaneously once-daily
Other Names:
  • nadroparin
  • Fraxiparin

Drug: Low dose enoxaparin

Fixed low dose enoxaparin:

  • < 100 kg: 40 mg subcutaneously once-daily
  • 100 kg and above: 60 mg subcutaneously once-daily
Other Names:
  • enoxaparin
  • Clexane

Drug: Low dose dalteparin

Fixed low dose dalteparin:

  • < 100 kg: 5000 IU subcutaneously once-daily
  • 100 kg and above: 7500 IU subcutaneously once-daily
Other Names:
  • dalteparin
  • Fragmin

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
Other Names:
  • tinzaparin
  • Innohep

Active Comparator: 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.
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.
Other Names:
  • nadroparin
  • Fraxiparin

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.
Other Names:
  • enoxaparin
  • Clexane

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.
Other Names:
  • dalteparin
  • Fragmin

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.
Other Names:
  • tinzaparin
  • Innohep




Primary Outcome Measures :
  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 Outcome Measures :
  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 Outcome Measures:
  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 ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 50 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01828697


Contacts
Layout table for location contacts
Contact: Ingrid M. Bistervels, MD +31205667516 i.m.bistervels@amc.nl
Contact: Saskia Middeldorp, MD PhD s.middeldorp@amc.nl

  Show 70 Study Locations
Sponsors and Collaborators
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Netherlands Organisation for Scientific Research
Aspen Pharma
CHU of Saint Etienne: French Ministry of Health Grant (sponsor of the French part of the study)
Rotunda Hospital: Definitive Interventions and Feasibility Awards (DIFA) 2017 (sponsor of the Irish part of the study))
Investigators
Layout table for investigator information
Principal Investigator: Saskia Middeldorp, MD PhD Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

Additional Information:
Publications:

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: S. Middeldorp, prof.dr. S. Middeldorp, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
ClinicalTrials.gov Identifier: NCT01828697     History of Changes
Other Study ID Numbers: Highlow study
2012-001505-24 ( EudraCT Number )
NL40326.018.12 ( Other Identifier: CCMO )
NTR3894 ( Registry Identifier: Netherlands Trial Register )
First Posted: April 11, 2013    Key Record Dates
Last Update Posted: July 3, 2019
Last Verified: July 2019
Keywords provided by S. Middeldorp, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA):
Low-molecular-weight heparin
Pregnancy
Venous thrombosis
Additional relevant MeSH terms:
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Pulmonary Embolism
Thrombosis
Embolism
Venous Thrombosis
Embolism and Thrombosis
Vascular Diseases
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Heparin
Calcium heparin
Heparin, Low-Molecular-Weight
Dalteparin
Tinzaparin
Nadroparin
Enoxaparin
Anticoagulants
Fibrinolytic Agents
Fibrin Modulating Agents
Molecular Mechanisms of Pharmacological Action