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Randomized Controlled Trial
. 2022 Mar 7;43(10):985-992.
doi: 10.1093/eurheartj/ehab637.

Ciraparantag reverses the anticoagulant activity of apixaban and rivaroxaban in healthy elderly subjects

Jack Ansell  1 , Sasha Bakhru  2 , Bryan E Laulicht  3 , Gregory Tracey  4 , Stephen Villano  5 , Daniel Freedman  5
Affiliations
Randomized Controlled Trial

Ciraparantag reverses the anticoagulant activity of apixaban and rivaroxaban in healthy elderly subjects

Jack Ansell et al. Eur Heart J. .

Abstract

Aims: Ciraparantag is a reversal agent for anticoagulants including direct oral anticoagulants. The aim was to evaluate the efficacy and safety of ciraparantag to reverse anticoagulation induced by apixaban or rivaroxaban in healthy elderly adults.

Methods and results: Two randomized, placebo-controlled, dose-ranging trials conducted in healthy subjects aged 50-75 years. Subjects received apixaban (Study 1) 10 mg orally twice daily for 3.5 days or rivaroxaban (Study 2) 20 mg orally once daily for 3 days. At steady-state anticoagulation subjects were randomized 3:1 to a single intravenous dose of ciraparantag (Study 1: 30, 60, or 120 mg; Study 2: 30, 60, 120, or 180 mg) or placebo. Efficacy was based on correction of the whole blood clotting time (WBCT) at multiple timepoints over 24 h. Subjects and technicians performing WBCT testing were blinded to treatment. Complete reversal of WBCT within 1 h post-dose and sustained through 5 h (apixaban) or 6 h (rivaroxaban) was dose related and observed with apixaban in 67%, 100%, 100%, and 17% of subjects receiving ciraparantag 30 mg, 60 mg, 120 mg, or placebo, respectively; and with rivaroxaban in 58%, 75%, 67%, 100%, and 13% of subjects receiving ciraparantag 30 mg, 60 mg, 120 mg, 180 mg, or placebo, respectively. Adverse events related to ciraparantag were mild, transient hot flashes or flushing.

Conclusions: Ciraparantag provides a dose-related reversal of anticoagulation induced by steady-state dosing of apixaban or rivaroxaban. Sustained reversal was achieved with 60 mg ciraparantag for apixaban and 180 mg ciraparantag for rivaroxaban. All doses of ciraparantag were well tolerated.

Keywords: Anticoagulant; Antidote; Apixaban; Ciraparantag; Rivaroxaban.

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Figures

Graphical Abstract
Graphical Abstract
Percent change from baseline in whole blood clotting time over time. The first displayed timepoint represents the time of peak anticoagulant effect, measured ∼15 min prior to study drug infusion. Time 0 represents the end of study drug infusion. CI, confidence interval; WBCT, whole blood clotting time.
Figure 1
Figure 1
Subject disposition. AE, adverse event; WBCT, whole blood clotting time.
Figure 2
Figure 2
Correction of whole blood clotting time vs. dose. Proportion of subjects with complete and sustained reversal of steady-state anticoagulation induced by apixaban (Study 1) or rivaroxaban (Study 2) based on manual whole blood clotting time vs. dose. In this analysis, complete and sustained reversal is a whole blood clotting time ≤10% above baseline within 1 h after ciraparantag/placebo dose and sustained through at least 5 or 6 h for apixaban or rivaroxaban, respectively.
Figure 3
Figure 3
Correction of whole blood clotting time vs. time. Proportion of subjects with complete reversal of steady-state anticoagulation induced by apixaban (Study 1) or rivaroxaban (Study 2) based on manual whole blood clotting time vs. time. In this analysis, complete reversal is defined as a whole blood clotting time ≤10% above baseline at any time point within 1 h of ciraparantag/placebo dose. The dose of ciraparantag for apixaban was 120 mg and for rivaroxaban was 180 mg.
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