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

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.

Rapid Detection of Apixaban by a ROTEM-Based Approach and Reversibility with Andexanet Alfa or DOAC-Stop

“…Thus, in a “real-world” study of a U.S. population, major bleedings on apixaban were almost 5% per year 12 and even higher, close to 8%, in a Korean population. 13 Furthermore, bleeding complications in apixaban-treated patients which require actions from health care may occur in up to one-third of treated patients per year, according to data from U.S. 12 On the other side, there are now effective antidotes approved 14 or under clinical evaluation 15 for the reversal of apixaban. Of note, andexanet alfa (AA) (coagulation factor Xa [FXa] [recombinant] inactivated-zhzo), a FXa decoy, has been approved for patients treated with a direct FXa inhibitor (apixaban or rivaroxaban) when reversal of anticoagulation is needed, due to life-threatening bleeding or uncontrolled bleeding.…”

Pharmacology of Heparin and Related Drugs: An Update

“…Ciraparantag (formerly PER977) also neutralizes the activity of heparin (see Section IV.B), and that of the DOACs, through charge-charge interactions, without affecting physiologic coagulation factors or the efficacy of other commonly used (nonanticoagulant) drugs (Ansell et al, 2022). Ciraparantag was found to reverse the effects of apixaban and rivaroxaban in a dose-related manner, in dose-ranging trials in healthy elderly subjects, and was well tolerated (Ansell et al, 2022;Chan and Weitz, 2022). Ciraparantag was also demonstrated to reverse the bleeding effects induced by UFH and a LMWH (enoxaparin) in a preclinical (rat) model, whereas protamine did not (Ansell et al, 2021).…”

“…However, protamine did restore the APTT to control levels whereas ciraparantag had no effect on this measurement, with similarly contradictory effects on an anti-FXa assay (Ansell et al, 2021;Siegal, 2021). Hence, standard plasma-based assays are not suitable tools to assess the effect of ciraparantag on anticoagulant reversal (Ansell et al, 2022), with whole-blood clotting time being used successfully for this purpose in animal and human studies (Ansell et al, 2014(Ansell et al, , 2016(Ansell et al, , 2021(Ansell et al, , 2022.…”

A Historical Perspective on the Reversal of Anticoagulants

“…A follow-up substudy looked at healthy elderly subjects and found similar results where there was complete reversal of WBCT within 1hour post-ciraparantag and sustained up to 6 hours in a dosedependent manner. 193 A phase I study showed ciraparantag to induce full reversal of edoxaban within 10 minutes and sustained for 24 hours. 33 The aforementioned studies suggest that ciraparantag may be a safe and efficacious reversal agent for DOACs.…”