Low-molecular-weight heparin to prevent recurrent venous thromboembolism in pregnancy: Rationale and design of the Highlow study, a randomised trial of two doses.
BACKGROUND
Women with a history of venous thromboembolism (VTE) have a 2% to 10% absolute risk of VTE recurrence during subsequent pregnancies. Therefore, current guidelines recommend that all pregnant women with a history of VTE receive pharmacologic thromboprophylaxis. The optimal dose of low-molecular-weight heparin (LMWH) for thromboprophylaxis is unknown. In the Highlow study (NCT 01828697; www.highlowstudy.org), we compare a fixed low dose of LMWH with an intermediate dose of LMWH for the prevention of pregnancy-associated recurrent VTE. We present the rationale and design features of this study.


METHODS
The Highlow study is an investigator-initiated, multicentre, international, open-label, randomised trial. Pregnant women with a history of VTE and an indication for ante- and postpartum pharmacologic thromboprophylaxis are included before 14weeks of gestation. The primary efficacy outcome is symptomatic recurrent VTE during pregnancy and 6weeks postpartum. The primary safety outcomes are clinically relevant bleeding, blood transfusions before 6weeks postpartum and mortality. Patients are closely monitored to detect cutaneous reactions to LMWH and are followed for 3months after delivery. A central independent adjudication committee adjudicates all suspected outcome events.


CONCLUSIONS
The Highlow study is the first large randomised controlled trial in pregnancy that will provide high-quality evidence on the optimal dose of LWMH thromboprophylaxis for the prevention of recurrent VTE in pregnant women with a history of VTE.
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands. Electronic address: s.m.bleker@amc.uva.nl.
Suzanne M
SM
Bleker
INSERM, CIC 1408 - F Crin, INNOVTE; CHU Saint-Etienne, Hôpital Nord, Service Médecine Vasculaire et Thérapeutique, F-42055 Saint Etienne, France.
Andrea
A
Buchmüller
INSERM, U1059, F-42023, CHU Saint-Etienne, Hôpital Nord, Service de Gynéco-Obstétrique, F-42055 Saint Etienne, France.
Céline
C
Chauleur
Mater Misericordiae University Hospital and Rotunda Hospital, Dublin, Ireland; SPHERE Research Group, University College Dublin School of Medicine.
Fionnuala
F
Ní Áinle
Mater Misericordiae University Hospital and Rotunda Hospital, Dublin, Ireland; SPHERE Research Group, University College Dublin School of Medicine.
Jennifer
J
Donnelly
University Hospital Leuven, Center for Molecular and Vascular Biology, Leuven, Belgium.
Peter
P
Verhamme
Oslo University Hospital, Oslo, Norway.
Anne Flem
AF
Jacobsen
Department of Obstetrics and Gynaecology, Academic Medical Center, Amsterdam, The Netherlands.
Wessel
W
Ganzevoort
Department of Clinical Epidemiology, Maastricht University, Maastricht, The Netherlands.
Martin
M
Prins
Center for Vascular Diseases, Division "Thrombosis Research", University Hospital "Carl Gustav Carus", Dresden, Germany.
Jan
J
Beyer-Westendorf
Weill Cornell Medical Center New York, New York, United States.
Maria
M
DeSancho
Center for Thrombosis and Haemostasis, Johannes Gutenberg University of Mainz, Germany.
Stavros
S
Konstantinides
Clinical Division of Haematology and Haemostaseology, Medical University of Vienna, Vienna, Austria.
Ingrid
I
Pabinger
Departments of Medicine, Epidemiology and Community Medicine, University of Ottawa, Ottawa, Canada; Department of Obstetrics and Gynecology, University of Ottawa, Ottawa, Canada.
Marc
M
Rodger
INSERM, CIC 1408 - F Crin, INNOVTE; CHU Saint-Etienne, Hôpital Nord, Service Médecine Vasculaire et Thérapeutique, F-42055 Saint Etienne, France.
Hervé
H
Decousus
Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands.
Saskia
S
Middeldorp
D000328:Adult; D000925:Anticoagulants / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced; D006495:Heparin, Low-Molecular-Weight / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006801:Humans; D049590:Postpartum Period; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular / Q000517:prevention & control*; D012008:Recurrence; D055502:Secondary Prevention; D016896:Treatment Outcome; D054556:Venous Thromboembolism / Q000517:prevention & control*; D055815:Young Adult
D000925:Anticoagulants; D006495:Heparin, Low-Molecular-Weight
Clinical trials; LMWH; Pregnancy; Prophylaxis; Venous thrombosis