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

Overview

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.

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

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Parallel Assignment
    • Primary Purpose: Prevention
    • Masking: None (Open Label)
  • Study Primary Completion Date: October 31, 2021

Interventions

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

Arms, Groups and Cohorts

  • 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.
  • 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.

Clinical Trial Outcome Measures

Primary Measures

  • 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)

Secondary Measures

  • 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)

Participating in This Clinical Trial

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.

Gender Eligibility: Female

Minimum Age: 18 Years

Maximum Age: 50 Years

Are Healthy Volunteers Accepted: No

Investigator Details

  • Lead Sponsor
    • Academisch Medisch Centrum – Universiteit van Amsterdam (AMC-UvA)
  • Collaborator
    • Netherlands Organisation for Scientific Research
  • Provider of Information About this Clinical Study
    • Principal Investigator: S. Middeldorp, prof.dr. S. Middeldorp – Academisch Medisch Centrum – Universiteit van Amsterdam (AMC-UvA)
  • Overall Official(s)
    • Saskia Middeldorp, MD PhD, Principal Investigator, Academisch Medisch Centrum – Universiteit van Amsterdam (AMC-UvA)

References

Greer IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet. 1999 Apr 10;353(9160):1258-65. doi: 10.1016/S0140-6736(98)10265-9.

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. doi: 10.1182/blood-2002-01-0149.

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.

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. doi: 10.1182/blood-2005-02-0626. Epub 2005 Apr 5.

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.

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, Hamulyak K, Theunissen IM, Hunt BJ, Buller HR. Safety of low-molecular-weight heparin in pregnancy: a systematic review. Thromb Haemost. 1999 May;81(5):668-72.

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. doi: 10.1111/j.1471-0528.2003.00272.x.

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. doi: 10.1111/j.1538-7836.2005.01307.x.

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.

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.

Roshani S, Cohn DM, Stehouwer AC, Wolf H, van der Post JA, Buller 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.

Kaandorp SP, Goddijn M, van der Post JA, Hutten BA, Verhoeve HR, Hamulyak K, Mol BW, Folkeringa N, Nahuis M, Papatsonis DN, Buller 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.

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