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

Pulmonary Embolism Clinical Trial

— Highlow  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01828697
• Other study ID #: Highlow study
• Secondary ID: 2012-001505-24NL
• Status: Completed
• Phase: Phase 4
• Start date: April 24, 2013
• Est. completion date: October 31, 2021

Study information

• Verified date: May 2022
• Source: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1110
• Est. completion date: October 31, 2021
• Est. primary completion date: October 31, 2021
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years to 50 Years

Eligibility

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.

Related Conditions & MeSH terms

• Deep Venous Thrombosis
• Embolism
• Pulmonary Embolism
• Thrombosis
• Venous Thrombosis

Intervention

Drug:
• Low dose nadroparin
Fixed low dose nadroparin: < 100 kg: 2850 IU subcutaneously once-daily 100 kg and above: 3800 IU subcutaneously once-daily
• 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.
• Low dose enoxaparin
Fixed low dose enoxaparin: < 100 kg: 40 mg subcutaneously once-daily 100 kg and above: 60 mg subcutaneously once-daily
• 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.
• Low dose dalteparin
Fixed low dose dalteparin: < 100 kg: 5000 IU subcutaneously once-daily 100 kg and above: 7500 IU subcutaneously once-daily
• 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.
• Fixed low dose tinzaparin
Fixed low dose tinzaparin: < 100 kg: 3500 IU subcutaneously once-daily 100 kg and above: 4500 IU subcutaneously once-daily
• 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.

Locations

Country	Name	City	State
Belgium	KU Leuven	Leuven
Canada	The Ottawa Hospital	Ottawa
Denmark	Aalborg University Hospital	Aalborg
Denmark	Aarhus University Hospital	Aarhus
France	CHU de Besancon	Besançon
France	CHU de Bordeaux	Bordeaux
France	CHU de Brest	Brest
France	CHU de Caen	Caen
France	CHU de Clermont - Ferrand	Clermont-Ferrand
France	APHP Louis Mourier	Colombes
France	CHU de Grenoble	Grenoble
France	CHU de Limoges	Limoges
France	Hopiteaux de Marseille	Marseille
France	Marseille St Joseph	Marseille
France	CHU de Nancy	Nancy
France	CHU de Nice	Nice
France	CHU de Nîmes	Nîmes
France	APHP Antoine Béclère	Paris
France	APHP Port Royal	Paris
France	CHU de Poitiers	Paris
France	Centra Hospitalier de Roanne	Roanne
France	Hopital Nord, CHU de Saint Etienne	Saint Etienne
France	La Réunion - Saint-Denis	Saint-Denis
France	La Réunion deSt Pierre	Saint-Pierre
France	Polyclinique de Sète	Sète
France	CHIC de Toulon	Toulon
France	CHU de Tours	Tours
Ireland	Corke University Hospital	Cork
Ireland	Coombe Women's Hospital	Dublin
Ireland	Rotunda Hospital	Dublin
Ireland	The National Maternity Hospital	Dublin
Ireland	Letterkenny University Hospital	Letterkenny
Ireland	University Hospital Limerick	Limerick
Netherlands	Jeroen Bosch Ziekenhuis	's-Hertogenbosch
Netherlands	Flevoziekenhuis	Almere
Netherlands	Academic Medical Center	Amsterdam	Noord-Holland
Netherlands	OLVG oost	Amsterdam
Netherlands	SLAZ	Amsterdam
Netherlands	VU medical center	Amsterdam
Netherlands	Gelre Ziekenhuizen	Apeldoorn
Netherlands	Rijnstate hospital	Arnhem
Netherlands	Wilhelmina Ziekenhuis	Assen
Netherlands	Rode Kruis Ziekenhuis	Beverwijk
Netherlands	Amphia ziekenhuis	Breda
Netherlands	Reinier de Graaf Groep	Delft
Netherlands	Bronovo ziekenhuis	Den Haag
Netherlands	HAGA ziekenhuis	Den Haag
Netherlands	Deventer Ziekenhuis	Deventer
Netherlands	Slingeland	Doetinchem
Netherlands	Albert Schweitzer	Dordrecht
Netherlands	Gelderse Vallei	Ede
Netherlands	Admiraal de Ruijter Ziekenhuis	Goes
Netherlands	Groene Hart Ziekenhuis	Gouda
Netherlands	Martini Ziekenhuis	Groningen
Netherlands	UMCG	Groningen
Netherlands	Spaarne Gasthuis	Haarlem
Netherlands	St Jansdal	Harderwijk
Netherlands	Atrium MC	Heerlen
Netherlands	MC Leeuwarden	Leeuwarden
Netherlands	LUMC	Leiden
Netherlands	MUMC	Maastricht
Netherlands	Canisius-Wilhelmina Ziekenhuis	Nijmegen
Netherlands	St. Radboud UMC	Nijmegen
Netherlands	Erasmus MC	Rotterdam
Netherlands	TweeSteden	Tilburg
Netherlands	Diakonessen Utrecht	Utrecht
Netherlands	UMCU	Utrecht
Netherlands	Máxima MC	Veldhoven
Norway	Oslo University Hospital	Oslo
Russian Federation	Federal State Institution "Research Center for Obstetrics, Gynecology and Perinatology"	Moscow
Spain	Vall d'Hebron Hospital	Barcelona
United States	Weill Cornell Medicine | NewYork-Presbyterian	New York	New York

Sponsors (5)

Lead Sponsor	Collaborator
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)	Aspen Pharma, CHU of Saint Etienne: French Ministry of Health Grant (sponsor of the French part of the study), Netherlands Organisation for Scientific Research, Rotunda Hospital: Definitive Interventions and Feasibility Awards (DIFA) 2017 (sponsor of the Irish part of the study))

Countries where clinical trial is conducted

United States,  Belgium,  Canada,  Denmark,  France,  Ireland,  Netherlands,  Norway,  Russian Federation,  Spain, 

References & Publications (13)

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. — View Citation

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. — View Citation

Greer IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet. 1999 Apr 10;353(9160):1258-65. Review. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 13 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Major bleeding	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	During pregnancy until 3 months postpartum
Other	Composite of major bleeding and clinically relevant non-major bleeding	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	During pregnancy until 3 months postpartum
Other	Early postpartum hemorrhage	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.	Within 24 hours of delivery
Other	Blood transfusion < 6 weeks after delivery		Within 6 weeks of delivery
Other	Blood transfusion < 24 hours postpartum		Within 24 hours of delivery
Other	Late postpartum hemorrhage	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.	From 24 hours postpartum to 6 weeks postpartum
Other	Mortality		During pregnancy until 3 months postpartum
Other	Minor bleeding	Minor bleeding is defined as all other overt bleeding episodes not meeting the criteria for major or clinically relevant bleeding or postpartum haemorrhage.	During pregnancy until 3 months postpartum
Other	Skin complications	e.g. itching, swelling, pain	During pregnancy until 3 months postpartum
Other	Easy bruising		During pregnancy until 3 months postpartum
Other	Necessity to switch to other LMWH		During pregnancy until 6 weeks postpartum
Other	Heparin-induced thrombocytopenia	Heparin-induced thrombocytopenia is defined according to the criteria of the ACCP guidelines.	During pregnancy until 3 months postpartum
Other	Congenital anomalies or birth defects		During pregnancy until 3 months postpartum
Primary	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
Primary	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	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
Secondary	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

External Links

•   Study website