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

Pregnancy-related venous thrombo-embolism (VTE), i.e. deep-vein thrombosis
(DVT) and pulmonary embolism (PE), is one of the leading causes of maternal
mortality in western countries. Women with a history of VTE have a 3 to 4 fold
higher risk of recurrent VTE during subsequent pregnancies than outside of
pregnancy, and the absolute risk without thrombosis prophylaxis is estimated
between 2 and 10%. Thus, thrombosis prophylaxis with low-molecular-weight
heparin (LMWH), that is safe for the fetus, is indicated in most women with a
history episode of VTE throughout pregnancy and the 6 weeks postpartum period.
However, the optimal dose of LMWH is unknown, since only two very small trials
(n=40, n=16) with methodological limitations have been performed in this group
of patients. Most centers use a prophylactic dose of LMWH in women who have an
indication for thrombosis prophylaxis in pregnancy and the postpartum period.
However, numerous treatment failures have been reported. Recent reports, have
indicated that the risk of recurrent VTE despite the use of low-dose LMWH is as
high as 5 to 6%, although another observational report suggests a high
efficacy. Some centers use therapeutic dose LMWH to prevent recurrent VTE in
pregnancy. A recent retrospective study showed no recurrences, whereas the risk
of serious bleeding was not increased compared to women who had delivered in
the same hospital without LMWH use. However, such an approach is not widely
accepted, because of bleeding risks associated with delivery and neuraxial
anesthesia, and the guidelines of the ACCP suggest either a prophylactic or an
intermediate dose of LMWH to prevent recurrent VTE in pregnancy and the
postpartum period.

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

Multicenter randomized controlled phase IV parallel group study.
Randomisation (1:1) to:
3. Nadroparine intermediate dose qd
4. Nadroparine low dose qd.
Treatment from week de 4-14 of pregnancy until week 6 after delivery.
Follow-up until 3 months after devlivery.
Independent DSMB.
850-1100 patients.

Treatment with LMWH in low or intermediate dose.

Risk: Adverse effects of study treatment.
Burden: Visits 2 after initiation of treatment and 20th and 30th week of
pregnancy and 1, 6 weeks and 3 months after delivery. These visits wil coincide
with the standard visits for pregnancy.
1-3 x safety blood tests (10 ml).
1x compression ultrasonography lower legs.