Deep Venous Thrombosis, Pulmonary Embolism
Conditions
Keywords
Low-molecular-weight heparin, Pregnancy, Venous thrombosis
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.
Interventions
DRUGLow dose nadroparin
Fixed low dose nadroparin: * \< 100 kg: 2850 IU subcutaneously once-daily * 100 kg and above: 3800 IU subcutaneously once-daily
DRUGIntermediate 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.
Fixed low dose enoxaparin: * \< 100 kg: 40 mg subcutaneously once-daily * 100 kg and above: 60 mg subcutaneously once-daily
DRUGIntermediate 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.
DRUGLow dose dalteparin
Fixed low dose dalteparin: * \< 100 kg: 5000 IU subcutaneously once-daily * 100 kg and above: 7500 IU subcutaneously once-daily
DRUGIntermediate 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.
DRUGFixed low dose tinzaparin
Fixed low dose tinzaparin: * \< 100 kg: 3500 IU subcutaneously once-daily * 100 kg and above: 4500 IU subcutaneously once-daily
DRUGIntermediate 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.
Sponsors
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))
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 50 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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
| Measure | Time frame | Description |
|---|---|---|
| Blood transfusion < 6 weeks after delivery | Within 6 weeks of delivery | — |
| Blood transfusion < 24 hours postpartum | Within 24 hours of delivery | — |
| 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. |
| Mortality | During pregnancy until 3 months postpartum | — |
| Congenital anomalies or birth defects | During pregnancy until 3 months postpartum | — |
| Skin complications | During pregnancy until 3 months postpartum | e.g. itching, swelling, pain |
| Easy bruising | During pregnancy until 3 months postpartum | — |
| Necessity to switch to other LMWH | During pregnancy until 6 weeks postpartum | — |
| Heparin-induced thrombocytopenia | During pregnancy until 3 months postpartum | Heparin-induced thrombocytopenia is defined according to the criteria of the ACCP guidelines. |
| 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. |
| 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 |
| 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 |
| 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. |
Countries
Belgium, Canada, Denmark, France, Ireland, Netherlands, Norway, Russia, Spain, United States
Outcome results
None listed