Low-molecular-weight heparin to prevent recurrent venous thromboembolism in pregnancy: Rationale and design of the Highlow study, a randomised trial of two doses.

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. 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. 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.

Bleker SM ，Buchmüller A ，Chauleur C ，Ní Áinle F ，Donnelly J ，Verhamme P ，Jacobsen AF ，Ganzevoort W ，Prins M ，Beyer-Westendorf J ，DeSancho M ，Konstantinides S ，Pabinger I ，Rodger M ，Decousus H ，Middeldorp S ... -  《-》

Venous thromboembolism, thrombophilia, antithrombotic therapy, and pregnancy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).

Bates SM ，Greer IA ，Pabinger I ，Sofaer S ，Hirsh J ... -  《CHEST》

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.

Pregnancy-related venous thromboembolism is a leading cause of maternal morbidity and mortality, and thromboprophylaxis is indicated in pregnant and post-partum women with a history of venous thromboembolism. The optimal dose of low-molecular-weight heparin to prevent recurrent venous thromboembolism in pregnancy and the post-partum period is uncertain. In this open-label, randomised, controlled trial (Highlow), pregnant women with a history of venous thromboembolism were recruited from 70 hospitals in nine countries (the Netherlands, France, Ireland, Belgium, Norway, Denmark, Canada, the USA, and Russia). Women were eligible if they were aged 18 years or older with a history of objectively confirmed venous thromboembolism, and with a gestational age of 14 weeks or less. Eligible women were randomly assigned (1:1), before 14 weeks of gestational age, using a web-based system and permuted block randomisation (block size of six), stratified by centre, to either weight-adjusted intermediate-dose or fixed low-dose low-molecular-weight heparin subcutaneously once daily until 6 weeks post partum. The primary efficacy outcome was objectively confirmed venous thromboembolism (ie, deep-vein thrombosis, pulmonary embolism, or unusual site venous thrombosis), as determined by an independent central adjudication committee, in the intention-to-treat (ITT) population (ie, all women randomly assigned to treatment). 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), assessed in all women who received at least one dose of assigned treatment and had a known end of treatment date. This study is registered with ClinicalTrials.gov, NCT01828697, and is now complete. Between April 24, 2013, and Oct 31, 2020, 1339 pregnant women were screened for eligibility, of whom 1110 were randomly assigned to weight-adjusted intermediate-dose (n=555) or fixed low-dose (n=555) low-molecular-weight heparin (ITT population). Venous thromboembolism occurred in 11 (2%) of 555 women in the weight-adjusted intermediate-dose group and in 16 (3%) of 555 in the fixed low-dose group (relative risk [RR] 0·69 [95% CI 0·32-1·47]; p=0·33). Venous thromboembolism occurred antepartum in five (1%) women in the intermediate-dose group and in five (1%) women in the low-dose group, and post partum in six (1%) women and 11 (2%) women. On-treatment major bleeding in the safety population (N=1045) occurred in 23 (4%) of 520 women in the intermediate-dose group and in 20 (4%) of 525 in the low-dose group (RR 1·16 [95% CI 0·65-2·09]). In women with a history of venous thromboembolism, weight-adjusted intermediate-dose low-molecular-weight heparin during the combined antepartum and post-partum periods was not associated with a lower risk of recurrence than fixed low-dose low-molecular-weight heparin. These results indicate that low-dose low-molecular-weight heparin for thromboprophylaxis during pregnancy is the appropriate dose for the prevention of pregnancy-related recurrent venous thromboembolism. French Ministry of Health, Health Research Board Ireland, GSK/Aspen, and Pfizer.

Bistervels IM ，Buchmüller A ，Wiegers HMG ，Ní Áinle F ，Tardy B ，Donnelly J ，Verhamme P ，Jacobsen AF ，Hansen AT ，Rodger MA ，DeSancho MT ，Shmakov RG ，van Es N ，Prins MH ，Chauleur C ，Middeldorp S ，Highlow Block writing committee ，Highlow Investigators ... -  《-》

[Thromboprophylaxis with low-molecular-weight heparin insufficient in high-risk pregnancy].

Roeters van Lennep JE ，Meijer E ，Klumper FJ ，Middeldorp JM ，Bloemenkamp KW ，Middeldorp S ... -  《-》

The incidence and risk factors of recurrent venous thromboembolism during pregnancy.

Recurrent venous thromboembolism (VTE) during pregnancy is a challenging topic with relatively few publications. The aim of this study was to identify the incidence and the risk factors of recurrent antepartum VTE in women with a history of at least one previous VTE episode. This observational cohort study involved 270 pregnant women (369 pregnancies) with at least one previous episode of VTE. The risk factors of recurrent antepartum VTE were identified by using group A (women without recurrent venous thromboembolism VTE) as a control group for group B (women with recurrent VTE despite LMWH (low molecular weight heparin) prophylaxis) and C (women with VTE recurrence in early pregnancy before the planned initiation of LMWH prophylaxis). The incidence of recurrent VTE was 7.6% (n=28). Twelve recurrent VTEs in ten women (3.3%) developed during early pregnancy before initiation of LMWH and sixteen recurrent VTEs (4.3%) developed in 15 women despite LMWH prophylaxis. In women with recurrent antepartum VTE, the incidence of a history of two or more previous VTEs (group A vs. B: 5.7% vs. 40.0%, p<0.001; group A vs. C: 5.7% vs. 30.0%, p=0.022), previous VTE in connection with antiphospholipid antibody syndrome (group A vs. B: 2.6% vs. 20.0%, p=0.012) and a history of VTE related to hormonal risk factors (group A vs. B: 60.4% vs. 93.3%, p=0.011) was significantly higher compared to those with successful LMWH-prophylaxis. The percentage of the women with long-term anticoagulation was also significantly higher among the women with recurrent antepartum VTE (group A vs. B: 7.6% vs. 46.7%, p<0.001) compared to those with successful LMWH-prophylaxis. The risk of antepartum recurrent VTE is considerable in women with a history of two or more previous VTEs, antiphospholipid antibody syndrome or long-term anticoagulation. The antepartum prophylaxis with prophylactic dose of LMWH or even with intermediate dose of LMWH might not be sufficient in this high-risk population.

Galambosi PJ ，Ulander VM ，Kaaja RJ 《-》