Highlow: Comparison of Low and Intermediate Dose Low-molecular-weight Heparin to Prevent Recurrent Venous Thromboembolism in Pregnancy
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 |
---|---|---|
|
Phase 4 |
Study Design
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:
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:
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:
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:
|
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:
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:
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:
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:
|
Outcome Measures
Primary Outcome Measures
- 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 Outcome Measures
- 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 Outcome Measures
- 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.
- 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]
- 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.
- 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.
- Congenital anomalies or birth defects [During pregnancy until 3 months postpartum]
Eligibility Criteria
Criteria
Inclusion Criteria:
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Age: 18 years or older, and;
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Pregnancy confirmed by urinary pregnancy test, and;
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Gestational age < 14 weeks, and;
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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:
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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;
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Indication for treatment with therapeutic dose anticoagulant therapy (e.g. treatment of acute VTE; permanent use of therapeutic anticoagulants outside of pregnancy), or;
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Inability to provide informed consent, or;
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Any contraindication listed in the local labelling of LMWH.
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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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
- Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012 Feb;141(2 Suppl):e691S-e736S. doi: 10.1378/chest.11-2300.
- Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood. 2005 Jul 15;106(2):401-7. Epub 2005 Apr 5. Review.
- Greer IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet. 1999 Apr 10;353(9160):1258-65. Review.
- Kaandorp SP, Goddijn M, van der Post JA, Hutten BA, Verhoeve HR, Hamulyák K, Mol BW, Folkeringa N, Nahuis M, Papatsonis DN, Büller HR, van der Veen F, Middeldorp S. Aspirin plus heparin or aspirin alone in women with recurrent miscarriage. N Engl J Med. 2010 Apr 29;362(17):1586-96. doi: 10.1056/NEJMoa1000641. Epub 2010 Mar 24.
- Lepercq J, Conard J, Borel-Derlon A, Darmon JY, Boudignat O, Francoual C, Priollet P, Cohen C, Yvelin N, Schved JF, Tournaire M, Borg JY. Venous thromboembolism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies. BJOG. 2001 Nov;108(11):1134-40.
- Lindqvist PG, Bremme K, Hellgren M; Working Group on Hemostatic Disorders (Hem-ARG), Swedish Society of Obstetrics and Gynecology. Efficacy of obstetric thromboprophylaxis and long-term risk of recurrence of venous thromboembolism. Acta Obstet Gynecol Scand. 2011 Jun;90(6):648-53. doi: 10.1111/j.1600-0412.2011.01098.x. Epub 2011 Apr 15.
- Pabinger I, Grafenhofer H, Kaider A, Kyrle PA, Quehenberger P, Mannhalter C, Lechner K. Risk of pregnancy-associated recurrent venous thromboembolism in women with a history of venous thrombosis. J Thromb Haemost. 2005 May;3(5):949-54.
- Pabinger I, Grafenhofer H, Kyrle PA, Quehenberger P, Mannhalter C, Lechner K, Kaider A. Temporary increase in the risk for recurrence during pregnancy in women with a history of venous thromboembolism. Blood. 2002 Aug 1;100(3):1060-2.
- Roeters van Lennep JE, Meijer E, Klumper FJ, Middeldorp JM, Bloemenkamp KW, Middeldorp S. Prophylaxis with low-dose low-molecular-weight heparin during pregnancy and postpartum: is it effective? J Thromb Haemost. 2011 Mar;9(3):473-80. doi: 10.1111/j.1538-7836.2011.04186.x.
- Roshani S, Cohn DM, Stehouwer AC, Wolf H, van der Post JA, Büller HR, Kamphuisen PW, Middeldorp S. Incidence of postpartum haemorrhage in women receiving therapeutic doses of low-molecular-weight heparin: results of a retrospective cohort study. BMJ Open. 2011 Nov 14;1(2):e000257. doi: 10.1136/bmjopen-2011-000257. Print 2011.
- Sanson BJ, Lensing AW, Prins MH, Ginsberg JS, Barkagan ZS, Lavenne-Pardonge E, Brenner B, Dulitzky M, Nielsen JD, Boda Z, Turi S, Mac Gillavry MR, Hamulyák K, Theunissen IM, Hunt BJ, Büller HR. Safety of low-molecular-weight heparin in pregnancy: a systematic review. Thromb Haemost. 1999 May;81(5):668-72. Review.
- Tooher R, Gates S, Dowswell T, Davis LJ. Prophylaxis for venous thromboembolic disease in pregnancy and the early postnatal period. Cochrane Database Syst Rev. 2010 May 12;(5):CD001689. doi: 10.1002/14651858.CD001689.pub2. Review. Update in: Cochrane Database Syst Rev. 2014;2:CD001689.
- White RH, Chan WS, Zhou H, Ginsberg JS. Recurrent venous thromboembolism after pregnancy-associated versus unprovoked thromboembolism. Thromb Haemost. 2008 Aug;100(2):246-52.
- Highlow study
- 2012-001505-24
- NL40326.018.12
- NTR3894