Idrabiotaparinux, a Biotinylated Long-Acting Anticoagulant, in the Treatment of Deep Venous Thrombosis (EQUINOX Study): Safety, Efficacy, and Reversibility by Avidin
Authors: Buller Harry Roger , Destors Jean-Michel , Gallus Alexander S. , Prins Martin H , Raskob Gary Edward 
Published: April 2020

Abstract
Idrabiotaparinux is a novel synthetic anticoagulant that links idraparinux, a specific, indirect factor Xa inhibitor, to biotin. The long half-life of idraparinux allows once-weekly (o.w.) subcutaneous (s.c.) injection. Avidin, a hen egg protein, specifically and tightly binds with biotin. When given by intravenous (i.v.) infusion, avidin (half life: 15-minutes) reverses the anti-factor Xa (a-Xa) activity of idrabiotaparinux by forming a complex that is rapidly cleared from the circulation. Idraparinux 2.5 mg s.c. o.w. was effective and safe in the van Gogh DVT trial of 2904 patients with deep vein thrombosis (DVT), when compared with standard anticoagulant therapy 1.
Methods: In EQUINOX, patients with symptomatic and confirmed DVT were randomised to receive weekly s.c. injection of equimolar amounts of idrabiotaparinux (3 mg) or idraparinux (2.5 mg) for 6 months. The aims of this multicentre, double-blind, study were to demonstrate, at the end of the 6 months of therapy, bioequipotency of idrabiotaparinux with idraparinux, to measure the effect of i.v. avidin on peak circulating a-Xa activity, and to document efficacy and safety. The main outcome events were clinically relevant bleeding (major or not), death, or symptomatic recurrent venous thromboembolism (VTE) within 6 months of randomisation, assessed by a blinded independent adjudication committee. Reversal of anticoagulant effect by 100 mg i.v. avidin infused over 30 minutes, and its safety, were assessed in a subset of patients re-randomised at 6 months and blindly allocated to receive avidin (idrabiotaparinux arm) or placebo (idrabiotaparinux and idraparinux arms, to preserve blinding). Avidin or placebo was infused 2–5 hours (around tmax) after the last injection of the 6 month treatment period; plasma a-Xa activity was measured just before avidin/placebo infusion, just after, and then for 5 days.
Results: Of 757 patients randomised, 385 received idrabiotaparinux and 370 idraparinux. Overall, 22.7% had previous venous thromboembolism (VTE), 5.2% had cancer within the past 6 months, 53.8% had apparently unprovoked thrombosis, and 36.2% were aged &gt;65. There was less clinically relevant bleeding (20 v. 27; 5.2% v. 7.3%) and less major bleeding (3 v. 14; 0.8% v. 3.8%) with idrabiotaparinux than with idraparinux. Rates of recurrent VTE and of fatal or non-fatal pulmonary embolism PE were similar with idrabiotaparinux and idraparinux (VTE: 9 v. 12; 2.3% v. 3.2%. PE: 6 v. 7; 1.6% v. 1.8%). Trough levels of a-Xa activity were identical in the treatment groups throughout 6 months. Of 52 idrabiotaparinux patients re-randomised at 6 months to receive i.v. avidin or placebo, 41 were analysable for reversal of a-Xa activity (23 avidin and 18 placebo). At the end of the 30 minute avidin infusion, mean anti-Xa activity was reduced by 77.8%, sustained for at least 5 days, compared with 2.4% after placebo (p = 3.45 × 10−15). No allergic reactions were observed to avidin.
Conclusion: A 6-month treatment period with idrabiotaparinux, compared to idraparinux in patients with DVT, showed a comparable efficacy with a trend to less bleeding. Trough a-Xa activity was identical in the two groups. Avidin infusion at around tmax after the last idrabiotaparinux injection led to rapid and substantial reversal of a-Xa activity, sustained for at least 5 days. Avidin infusion was well-tolerated.