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 |
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Recruitment Status :
Completed
First Posted : April 11, 2013
Last Update Posted : May 26, 2022
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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 |
| Study Type : | Interventional (Clinical Trial) |
| 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 : | April 24, 2013 |
| Actual Primary Completion Date : | October 31, 2021 |
| Actual Study Completion Date : | October 31, 2021 |
| Arm | Intervention/treatment |
|---|---|
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Active Comparator: Low dose LMWH
Fixed low dose low-molecular-weight heparin:
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Drug: Low dose nadroparin
Fixed low dose nadroparin:
Other Names:
Drug: Low dose enoxaparin Fixed low dose enoxaparin:
Other Names:
Drug: Low dose dalteparin Fixed low dose dalteparin:
Other Names:
Drug: Fixed low dose tinzaparin Fixed low dose tinzaparin:
Other Names:
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Active Comparator: Intermediate dose LMWH
Intermediate dose low-molecular-weight heparin. Dosing is weight-adjusted according to the protocol.
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Drug: Intermediate dose nadroparin
Intermediate weight-adjusted dose nadroparin:
Other Names:
Drug: Intermediate dose enoxaparin Intermediate weight-adjusted dose enoxaparin:
Other Names:
Drug: Intermediate dose dalteparin Intermediate weight-adjusted dose dalteparin:
Other Names:
Drug: Intermediate dose tinzaparin Intermediate weight-adjusted dose tinzaparin:
Other Names:
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- 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.
- 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)
- 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.
- 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)
- 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
- 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
- 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.
- Blood transfusion < 6 weeks after delivery [ Time Frame: Within 6 weeks of delivery ]
- Blood transfusion < 24 hours postpartum [ Time Frame: Within 24 hours of delivery ]
- 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.
- Mortality [ Time Frame: During pregnancy until 3 months postpartum ]
- 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.
- Skin complications [ Time Frame: During pregnancy until 3 months postpartum ]e.g. itching, swelling, pain
- Easy bruising [ Time Frame: During pregnancy until 3 months postpartum ]
- Necessity to switch to other LMWH [ Time Frame: During pregnancy until 6 weeks postpartum ]
- Heparin-induced thrombocytopenia [ Time Frame: During pregnancy until 3 months postpartum ]Heparin-induced thrombocytopenia is defined according to the criteria of the ACCP guidelines.
- Congenital anomalies or birth defects [ Time Frame: During pregnancy until 3 months postpartum ]
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| Ages Eligible for Study: | 18 Years to 50 Years (Adult) |
| 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.
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
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| Principal Investigator: | Saskia Middeldorp, MD PhD | Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) |
Publications:
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
| 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 ( 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: | May 26, 2022 |
| Last Verified: | May 2022 |
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Low-molecular-weight heparin Pregnancy Venous thrombosis |
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Pulmonary Embolism Thrombosis Embolism Venous Thrombosis Embolism and Thrombosis Vascular Diseases Cardiovascular Diseases Lung Diseases Respiratory Tract Diseases Enoxaparin |
Dalteparin Tinzaparin Heparin, Low-Molecular-Weight Nadroparin Enoxaparin sodium Anticoagulants Fibrinolytic Agents Fibrin Modulating Agents Molecular Mechanisms of Pharmacological Action |