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

Sponsor
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) (Other)
Overall Status
Completed
CT.gov ID
NCT01828697
Collaborator
Netherlands Organisation for Scientific Research (Other), Aspen Pharma (Other), CHU of Saint Etienne: French Ministry of Health Grant (sponsor of the French part of the study) (Other), Rotunda Hospital: Definitive Interventions and Feasibility Awards (DIFA) 2017 (sponsor of the Irish part of the study)) (Other)
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Study Details

Study Description

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
  • 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

Study Design

Study Type:
Interventional
Actual Enrollment :
1110 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 :
Apr 24, 2013
Actual Primary Completion Date :
Oct 31, 2021
Actual Study Completion Date :
Oct 31, 2021

Arms and Interventions

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
  • Outcome Measures

    Primary Outcome Measures

    1. Symptomatic confirmed deep venous thrombosis [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 [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 [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 [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 [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 [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 [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 [Within 6 weeks of delivery]

    5. Blood transfusion < 24 hours postpartum [Within 24 hours of delivery]

    6. Late postpartum hemorrhage [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 [During pregnancy until 3 months postpartum]

    8. Minor bleeding [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 [During pregnancy until 3 months postpartum]

      e.g. itching, swelling, pain

    10. Easy bruising [During pregnancy until 3 months postpartum]

    11. Necessity to switch to other LMWH [During pregnancy until 6 weeks postpartum]

    12. Heparin-induced thrombocytopenia [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 [During pregnancy until 3 months postpartum]

    Eligibility Criteria

    Criteria

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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Weill Cornell Medicine | NewYork-Presbyterian New York New York United States
    2 KU Leuven Leuven Belgium
    3 The Ottawa Hospital Ottawa Canada
    4 Aalborg University Hospital Aalborg Denmark
    5 Aarhus University Hospital Aarhus Denmark
    6 CHU de Besancon Besançon France
    7 CHU de Bordeaux Bordeaux France
    8 CHU de Brest Brest France
    9 CHU de Caen Caen France
    10 CHU de Clermont - Ferrand Clermont-Ferrand France
    11 APHP Louis Mourier Colombes France
    12 CHU de Grenoble Grenoble France
    13 CHU de Limoges Limoges France
    14 Hopiteaux de Marseille Marseille France
    15 Marseille St Joseph Marseille France
    16 CHU de Nancy Nancy France
    17 CHU de Nice Nice France
    18 CHU de Nîmes Nîmes France
    19 APHP Antoine Béclère Paris France
    20 APHP Port Royal Paris France
    21 CHU de Poitiers Paris France
    22 Centra Hospitalier de Roanne Roanne France
    23 Hopital Nord, CHU de Saint Etienne Saint Etienne France
    24 La Réunion - Saint-Denis Saint-Denis France
    25 La Réunion deSt Pierre Saint-Pierre France
    26 Polyclinique de Sète Sète France
    27 CHIC de Toulon Toulon France
    28 CHU de Tours Tours France
    29 Corke University Hospital Cork Ireland
    30 Coombe Women's Hospital Dublin Ireland
    31 Rotunda Hospital Dublin Ireland
    32 The National Maternity Hospital Dublin Ireland
    33 Letterkenny University Hospital Letterkenny Ireland
    34 University Hospital Limerick Limerick Ireland
    35 Academic Medical Center Amsterdam Noord-Holland Netherlands 1105 AZ
    36 Jeroen Bosch Ziekenhuis 's-Hertogenbosch Netherlands
    37 Flevoziekenhuis Almere Netherlands
    38 OLVG oost Amsterdam Netherlands
    39 SLAZ Amsterdam Netherlands
    40 VU medical center Amsterdam Netherlands
    41 Gelre Ziekenhuizen Apeldoorn Netherlands
    42 Rijnstate hospital Arnhem Netherlands
    43 Wilhelmina Ziekenhuis Assen Netherlands
    44 Rode Kruis Ziekenhuis Beverwijk Netherlands
    45 Amphia ziekenhuis Breda Netherlands
    46 Reinier de Graaf Groep Delft Netherlands
    47 Bronovo ziekenhuis Den Haag Netherlands
    48 HAGA ziekenhuis Den Haag Netherlands
    49 Deventer Ziekenhuis Deventer Netherlands
    50 Slingeland Doetinchem Netherlands
    51 Albert Schweitzer Dordrecht Netherlands
    52 Gelderse Vallei Ede Netherlands
    53 Admiraal de Ruijter Ziekenhuis Goes Netherlands
    54 Groene Hart Ziekenhuis Gouda Netherlands
    55 Martini Ziekenhuis Groningen Netherlands
    56 UMCG Groningen Netherlands
    57 Spaarne Gasthuis Haarlem Netherlands
    58 St Jansdal Harderwijk Netherlands
    59 Atrium MC Heerlen Netherlands
    60 MC Leeuwarden Leeuwarden Netherlands
    61 LUMC Leiden Netherlands
    62 MUMC Maastricht Netherlands
    63 Canisius-Wilhelmina Ziekenhuis Nijmegen Netherlands
    64 St. Radboud UMC Nijmegen Netherlands
    65 Erasmus MC Rotterdam Netherlands
    66 TweeSteden Tilburg Netherlands
    67 Diakonessen Utrecht Utrecht Netherlands
    68 UMCU Utrecht Netherlands
    69 Máxima MC Veldhoven Netherlands
    70 Oslo University Hospital Oslo Norway
    71 Federal State Institution "Research Center for Obstetrics, Gynecology and Perinatology" Moscow Russian Federation
    72 Vall d'Hebron Hospital Barcelona Spain

    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

    • Principal Investigator: Saskia Middeldorp, MD PhD, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)

    Study Documents (Full-Text)

    None provided.

    More Information

    Additional Information:

    Publications

    Responsible Party:
    S. Middeldorp, prof.dr. S. Middeldorp, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
    ClinicalTrials.gov Identifier:
    NCT01828697
    Other Study ID Numbers:
    • Highlow study
    • 2012-001505-24
    • NL40326.018.12
    • NTR3894
    First Posted:
    Apr 11, 2013
    Last Update Posted:
    May 26, 2022
    Last Verified:
    May 1, 2022
    Keywords provided by S. Middeldorp, prof.dr. S. Middeldorp, Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
    Additional relevant MeSH terms:

    Study Results

    No Results Posted as of May 26, 2022