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

Background: 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. Methods: 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 6 weeks postpartum. The primary safety outcomes are clinically relevant bleeding, blood transfusions before 6 weeks postpartum and mortality. Patients are closely monitored to detect cutaneous reactions to LMWH and are followed for 3 months after delivery. A central independent adjudication committee adjudicates all suspected outcome events. Conclusion: 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.