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

Study Overview
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Brief Summary
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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.

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

Conditions
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Deep Venous Thrombosis, Pulmonary Embolism

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Low dose LMWH<br>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<br>* Fixed low dose nadroparin: < 100 kg: 2850 IU subcutaneously once-daily 100 kg and above: 3800 IU subcutaneously once-daily<br>* Other names: Fraxiparin;Drug: Low dose enoxaparin<br>* Fixed low dose enoxaparin: < 100 kg: 40 mg subcutaneously once-daily 100 kg and above: 60 mg subcutaneously once-daily<br>* Other names: Clexane;Drug: Low dose dalteparin<br>* Fixed low dose dalteparin: < 100 kg: 5000 IU subcutaneously once-daily 100 kg and above: 7500 IU subcutaneously once-daily<br>* Other names: Fragmin;Drug: Fixed low dose tinzaparin<br>* Fixed low dose tinzaparin: < 100 kg: 3500 IU subcutaneously once-daily 100 kg and above: 4500 IU subcutaneously once-daily<br>* Other names: Innohep;|
| Active Comparator: Intermediate dose LMWH<br>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<br>* 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.<br>* Other names: Fraxiparin;Drug: Intermediate dose enoxaparin<br>* 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.<br>* Other names: Clexane;Drug: Intermediate dose dalteparin<br>* 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.<br>* Other names: Fragmin;Drug: Intermediate dose tinzaparin<br>* 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.<br>* Other names: Innohep;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From date of randomization up to 6 weeks postpartum | 
| 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) | From date of randomization up to 6 weeks postpartum | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | From date of randomization up to 3 months postpartum | 
| 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) | From date of randomization up to 3 months postpartum | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Low-molecular-weight heparin, Pregnancy, Venous thrombosis