Low-Molecular-Weight Heparin for Thromboprophylaxis in Pregnancy: What Dose Is Best?

A low dose of low-molecular-weight heparin for thromboprophylaxis during pregnancy is the best dose to prevent a pregnancy-related recurrence of venous thromboembolism.

Weight-adjusted, intermediate-dose, low-molecular-weight heparin in the antepartum and postpartum periods was not associated with a lower risk for recurrence of venous thromboembolism compared with fixed low-dose, low-molecular-weight heparin in women with a history of venous thromboembolism. These are the findings of a study published in The Lancet.

For the open-label, randomized controlled Highlow study, researchers evaluated the efficacy and safety of intermediate-dose vs low-dose low-molecular-weight heparin in pregnant women with a history of venous thromboembolism at 70 international hospitals.

The women were aged 18 years and older with a history of objectively confirmed venous thromboembolism either unprovoked or provoked by hormonal or minor risk factors and a gestational age of 14 weeks or less. The researchers randomly assigned participants 1:1, stratified by center, to weight-adjusted, intermediate-dose or fixed low-dose, low-molecular-weight heparin once daily.

The intermediate-dose, low-molecular-weight heparin regimen was about half of a therapeutic dose based on actual body weight and adjusted as necessary in pregnancy or postpartum. The fixed low-dose regimen was based on body weight at randomization (<100 kg or ≥100 kg).

The primary efficacy outcome was symptomatic, objectively confirmed, venous thromboembolism up to 6 weeks postpartum, defined as new deep vein thrombosis, pulmonary embolism, or unusual site venous thrombosis. Major bleeding was the primary safety outcome.

For individual clinicians, counselling of pregnant women who are challenged by a history of venous thromboembolism will, for the first time, be supported by high-quality data.

A total of 1339 women were screened from April 24, 2013, to October 31, 2020, of whom 1110 were randomly assigned to the intermediate-dose (n = 555) or low-dose (n = 555) low-molecular-weight heparin group (intention-to-treat population). Participants’ overall mean age was 32.0 years (SD, 4.8), and their median body mass index was 25.0 kg/m2 (interquartile range, 22.0-30.0).

Symptomatic venous thromboembolism occurred in 11 (2%) women in the weight-adjusted, intermediate-dose, low-molecular-weight heparin group and in 16 (3%) women in the fixed low-dose, low-molecular-weight heparin group (relative risk [RR] 0.69; 95% CI, 0.32-1.47; P =.33).

In the antepartum period, 5 (1%) women in each group had venous thromboembolism. In the postpartum period, 6 (1%) women in the intermediate-dose group and 11 (2%) women in the low-dose group had venous thromboembolism in the post hoc analysis.

According to the on-treatment analysis of the per-protocol population, symptomatic venous thromboembolism up to 6 weeks postpartum occurred in 5 (1%) of 481 women in the intermediate-dose group and in 12 (2%) of 491 women in the low-dose group (RR 0.43; 95% CI, 0.15-1.20).

Major bleeding occurred in 23 (4%) of 520 women in the intermediate-dose, low-molecular-weight heparin group and in 20 (4%) of 525 who received low-dose, low-molecular-weight heparin (RR 1.16; 95% CI, 0.65-2.09; P =.63).

Study limitations include the lack of a placebo group, and a number of protocol deviations occurred in the postpartum period. In addition, the researchers relied on self-reported adherence instead of a syringe count for each visit, and the absence of race and ethnicity data could affect the generalizability of the results. Furthermore, the targeted number of centrally adjudicated and confirmed venous thromboembolism events was not met, with 27 adjudicated events occurring.

Overall, the findings suggest that a low dose of low-molecular-weight heparin for thromboprophylaxis during pregnancy is best to prevent a pregnancy-related recurrence of venous thromboembolism.

The researchers noted that “For individual clinicians, counselling of pregnant women who are challenged by a history of venous thromboembolism will, for the first time, be supported by high-quality data.”

“Post-hoc analyses suggest intermediate-dose low-molecular-weight heparin might be more effective than low-dose low-molecular-weight heparin in the post-partum period, but this finding will need confirmation in future randomised controlled studies,” they concluded.

Disclosure: This research was supported in part by GSK/Aspen and Pfizer. Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.

References:

Bistervels IM, Buchmüller A, Wiegers HMG, et al. Intermediate-dose versus low-dose low-molecular-weight heparin in pregnant and post-partum women with a history of venous thromboembolism (Highlow study): an open-label, multicentre, randomised, controlled trial. Lancet. 2022;400(10365):1777-1787. doi: 10.1016/S0140-6736(22)02128-6