Study information Highlow study

Please click here for the patient information of the Rotunda Hospital in Dublin, Ireland

 

Please click here for the patient information of the CHU de Saint-Étienne, France

 

Low-molecular-weight heparin to prevent recurrent VTE in pregnancy: a randomized controlled trial of two doses

 

Objective
To evaluate the efficacy and safety of intermediate dose LMWH versus fixed low dose LMWH in pregnant women with a history of previous VTE.

 

Study design
This is a randomized-controlled open-label trial comparing two different doses of LMWH in pregnant patients with a history of previous VTE. Patients enter the study as soon as a home test confirms pregnancy. LWMH 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.

 

Study population
The study population consists of women with a history of previous VTE who are pregnant and have an indication for LMWH to prevent recurrent VTE during pregnancy or the postpartum period.
Inclusion criteria
- Age 18 years and older
- Pregnancy confirmed by urinary pregnancy test, gestational age < 14 weeks since first day of last menstrual period
- 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
- Indication for treatment with therapeutic dose anticoagulant therapy (e.g. treatment of acute VTE; permanent use of therapeutic anticoagulants outside of pregnancy)
- Inability to provide informed consent
- Any contraindication listed in the local labelling of LMWH

 

Intervention
The intervention is subcutaneously injected intermediate dose LMWH (nadroparin), adjusted to actual body weight during pregnancy. The comparator treatment is fixed low-dose LMWH, that is nadroparin 2850 IE (if the patient weighs < 100kg) or 3800IE (if the patient weighs >= 100kg). Postpartum doses are similar to the last dose given antepartum, but will be decreased according to weight loss. Study medication will be discontinued 6 weeks after delivery.

 

Outcome measures
1) Efficacy outcomes
Primary
- Symptomatic DVT during pregnancy and 6 weeks postpartum
- Symptomatic PE during pregnancy and 6 weeks postpartum

Secondary
- Symptomatic DVT during pregnancy until 3 months postpartum
- Symptomatic PE during pregnancy until 3 months postpartum

2) Safety outcomes
Primary
- Major bleeding
- Composite of major bleeding and clinically relevant non-major bleeding
- Postpartum haemorrhage
- Blood transfusion < 24 hours postpartum
- Blood transfusion < 6 weeks after delivery
- Median peripartum blood loss
- Mortality

Secondary
- Minor bleeding
- Skin complications (e.g. itching, swelling, pain)
- Bruises
- Necessity to switch to other LMWH
- Heparin-induced thrombocytopenia
- Congenital anomalies or birth defects

 

Power/data analysis
An event-driven sample size has been chosen because of the uncertainty about the event rate. Assuming a 65% relative risk reduction with the intermediate dose, a total of 29 events would provide a power of 80% to demonstrate that intermediate dose is superior to low dose (two-sided alpha=0.05). Based on the available literature an incidence of 4 to 5% in the Low group is expected, leading to a proposed sample size of 859 to 1074 women.

 

Time schedule
For the inclusion of patients, 48 months are expectedly needed.

 

Projectleader
Prof. dr. S. Middeldorp, Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands

 

Subsidy
This study is sponsored by the AMC and partially supported by an unrestricted grant from Aspen.

In France, a grant has been acquired from the French Ministry of Health to support the French part of the Highlow study (PHRC national 2014)

 

Contact (researcher)
Prof. dr. S. Middeldorp, Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
E:
s.middeldorp@amc.uva.nl
Drs. S.M. Bleker, Department of Vascular Medicine, Academic Medical Center, Amsterdam, the Netherlands.
E:
s.m.bleker@amc.uva.nl