2012-001505-24

Amsterdamumc

Meibergdreef 9, Amsterdam, Netherlands,

Project leader, AmsterdamUMC, +31 205669111na, saskia.middeldorp@radboudumc.nl

Project leader, AmsterdamUMC, +31 205669111na, saskia.middeldorp@radboudumc.nl

No

No

No

Final

31 Oct 2021

Yes

31 Oct 2021

Yes

31 Oct 2021

No

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

Insurance

01 Jul 2013

Yes

Yes

Netherlands: 516

Norway: 28

Belgium: 42

Denmark: 15

Ireland: 99

France: 388

Canada: 12

United States: 7

Russian Federation: 3

1110

1088

0

0

0

0

0

0

1110

0

0

Overall trial (overall period)

Randomised - controlled

Eligible women were randomly assigned (1:1), using a web-based system and permuted block randomisation with a block size of six, stratified by centre, to weightadjusted intermediate-dose or fixed low-dose low molecular-weight heparin once daily. Physicians and participants were unmasked to treatment allocation because medication was supplied by local pharmacies in usual patient care settings or as study drug in accordance with national regulatory requirements.

Yes

Nadroparin, enoxaparin, dalteparin, tinzaparin

Fraxiparin, clexane, fragmin, innohep

Solution for infusion in pre-filled syringe

Subcutaneous use

Participants were instructed to self-administer their allocated dose of low-molecular-weight heparin once daily from pre-filled syringes subcutaneously. The intermediate-dose low-molecular-weight heparin regimen was approximately half of a therapeutic dose, categorised by actual bodyweight and adjusted if needed during pregnancy or post partum, with cutoffs of less than 50 kg, 50 kg to less than 70 kg, 70 kg to less than 100 kg, and 100 kg or more. Once-daily doses ranged from 3800 to 9500 international units (IU) for nadroparin, 6000 to 12 000 IU for enoxaparin, 7500 to 15 000 IU for dalteparin, or 4500 to 12 000 IU for tinzaparin (table 1). The fixed low-dose regimen was based on bodyweight at randomisation (<100 kg or ≥100 kg), per clinical practice in many centres and suggested by the Royal College of Obstetricians and Gynaecologists’ Green-top guideline and the dose was not changed throughout pregnancy or post partum.

Nadroparin, Dalteparin, Enoxaparin, Tinzaparin

Fraxiparin, Fragimin, Clexane, Innohep

Solution for injection in pre-filled syringe

Subcutaneous use

Participants were instructed to self-administer their allocated dose of low-molecular-weight heparin once daily from pre-filled syringes subcutaneously. The intermediate-dose low-molecular-weight heparin regimen was approximately half of a therapeutic dose, categorised by actual bodyweight and adjusted if needed during pregnancy or post partum, with cutoffs of less than 50 kg, 50 kg to less than 70 kg, 70 kg to less than 100 kg, and 100 kg or more. Once-daily doses ranged from 3800 to 9500 international units (IU) for nadroparin, 6000 to 12 000 IU for enoxaparin, 7500 to 15 000 IU for dalteparin, or 4500 to 12 000 IU for tinzaparin (table 1). The fixed low-dose regimen was based on bodyweight at randomisation (<100 kg or ≥100 kg), per clinical practice in many centres and suggested by the Royal College of Obstetricians and Gynaecologists’ Green-top guideline and the dose was not changed throughout pregnancy or post partum.

weight-adjusted intermediate dose LMWH

fixed low-dose LMWH

Intention to treat

We did the primary efficacy analysis in the intention-totreat (ITT) population, defined as all women randomly assigned to treatment, and included all data and adjudicated outcomes from randomisation up to 6 weeks post partum.

Safety analysis

We assessed safety in all women who received at least one dose of allocated study treatment and who had a known date of end of on-treatment period, and included in our analyses all data and adjudicated outcomes from randomisation up to 6 weeks post partum.

weight-adjusted intermediate dose LMWH

fixed low-dose LMWH

Intention to treat

We did the primary efficacy analysis in the intention-totreat (ITT) population, defined as all women randomly assigned to treatment, and included all data and adjudicated outcomes from randomisation up to 6 weeks post partum.

Safety analysis

We assessed safety in all women who received at least one dose of allocated study treatment and who had a known date of end of on-treatment period, and included in our analyses all data and adjudicated outcomes from randomisation up to 6 weeks post partum.

The primary efficacy outcome was symptomatic, objectively confirmed, venous thromboembolism (ie, a thromboembolism that is diagnosed by compression ultrasound examination, venography, CT or pulmonary angiography, or obduction and confirmed by the independent central adjudication committee)which was defined as an occurrence of new deep-vein thrombosis, pulmonary embolism, or unusual site venous thrombosis (eg, splanchnic vein or cerebral sinus thrombosis). After a diagnosis of recurrent thrombosis, patients were censored from the study.

Primary

Any time from randomization up to 6 weeks postpartum

We did the primary efficacy analysis in the intention-totreat (ITT) population, defined as all women randomly assigned to treatment, and included all data and adjudicated outcomes from randomisation up to 6 weeks post partum. Secondary efficacy analyses were also assessed in the ITT population. We also did prespecified analyses of the primary efficacy outcome from randomisation until 3 months post partum.

weight-adjusted intermediate dose LMWH v fixed low-dose LMWH

1110

Pre-specified

2-sided

Standard error of the mean

The primary safety outcome was major bleeding, which included antepartum, early post-partum (within 24 h after delivery), and late post-partum major bleeding (24 h or longer after delivery until 6 weeks post partum), based on population-specific definitions proposed by the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis (ISTH)

Primary

from randomisation up to 6 weeks postpartum

We assessed safety in all women who received at least one dose of allocated study treatment and who had a known date of end of on-treatment period, and included in our analyses all data and adjudicated outcomes from randomisation up to 6 weeks post partum. On-treatment was defined as the time from randomisation to the last day of allocated low-molecularweight heparin dose plus 2 days.

weight-adjusted intermediate dose LMWH v fixed low-dose LMWH

1045

Pre-specified

2-sided

Standard error of the mean

Secondary efficacy outcomes were the three components of the primary outcome, objectively confirmed superficial thrombophlebitis, and a composite of venous thromboembolism or superficial thrombophlebitis,

Secondary

, at any time from randomisation until 6 weeks post partum, and until 3 months post partum.

Secondary safety outcomes were a composite of major or clinically relevant non-major bleeding, clinically relevant non-major bleeding and minor bleeding using population-specific definitions, maternal mortality, bruises, skin reactions around the injection site (type IV allergy), type I allergic reaction to low-molecular weight heparin, heparin-induced thrombocytopenia and congenital anomalies or birth defects

Secondary

from randomization up to 6 weeks postpartum

from randomization to 6 weeks postpartum

This is a thromboprophylaxis study. SAE for the primary and secundary outcomes such as VTE mortality, congential abnormalities, and bleeding, we refer to the primary and secudary efficacy and safety outcomes of the study.

1