Reversing anticoagulant effects of novel oral anticoagulants: role of ciraparantag, andexanet alfa, and idarucizumab

Figures & data

Table 1 General management of bleeding in patients on novel oral anticoagulant therapy

	Dabigatran	Rivaroxaban	Apixaban	Edoxaban
Minor bleeding	Mechanical compression, interrupt anticoagulation if appropriate
Major bleeding	IV fluids, correct anemia, thrombocytopenia, source control. Stop agent
Activated charcoal	Yes*	Unknown	Yes*	Unknown
Hemodialysis	Yes§	No	No	Unknown
Antifibrinolytics	Tranexamic acid and ε-aminocaproic acid∞
Plasma factors	PCC, aPCC and recombinant FVIIa

Notes:

* Activated charcoal may be useful in apixaban and dabigatran overdose if administered early, especially within 2–3 hours of ingestion;

§ dabigatran has low protein binding and can be dialyzed unlike rivaroxaban and apixaban;

∞ limited data but inexpensive and favorable safety profile.

Abbreviations: aPCC, activated prothrombin complex concentrate; FVIIa, recombinant factor VII activated; PCC, prothrombin complex concentrate; IV, intravenous.

Table 2 Antidotes for NOACs, ongoing and completed clinical trials

Antidote	Study	Study description	Enrollment (number of people)	Results/anticipated completion date	Clinical trial identifier
Perosphere	Phase I, non-randomized	Pharmacokinetic study of single-dose administration of PER977 in healthy subjects	6	August 2014	NCT02205905
	Phase I, RCT	Safety/efficacy of escalating doses of PER977 alone and following one dose of edoxaban	80 Randomized 8:2 to PER977 or placebo	Achieved baseline hemostasis within 10–30 minutes following administration (whole-blood clotting time); effects sustained for 24 hours	NCT01826266
	Phase II, RCT	Safety/efficacy of escalating reversal doses of PER977 following edoxaban. Additionally investigating effects of PER977 on re-anticoagulation with edoxaban and second PER977 reversal	69 Randomized 4:1 to PER977 or placebo	September 2015	NCT02207257
Andexanet alfa	Phase II, RCT	Pharmacokinetics/safety of andexanet alfa in reversing rivaroxaban, apixaban, edoxaban, enoxaparin, and betrixaban	144 Randomized 6:3	November 2013 Preliminary data: Immediate dose- dependent reduction in factor Xa activity that returned to placebo levels by 2 hours following treatment.	NCT01758432
	Phase III, RCT ANNEXA (Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of fXA Inhibitors)	ANNEX – A Safety/efficacy of andexanet alfa in reversal of apixaban in healthy 50–75 yo subjects	64	Preliminary data: Immediate reversal of anticoagulation lasting 1–2 hours. Anti-factor Xa activity decreased by 94% and near normalization of ACT	NCT02207725
		ANNEXA – R Safety/efficacy of andexanet alfa in reversal of rivaroxaban in healthy 50–75 yo subjects	79	November 2014
	Phase III, cohort study	Safety and efficacy of andexanet alfa in achieving hemostasis in patients with major bleeding on direct or indirect factor Xa inhibitors (except lovenox)	270	November 2022	NCT02329327
Idarucizumab	Phase I, RCT	Part 1: Rising dose assessment of idarucizumab in healthy subjects	110 Randomized 3:1 to idarucizumab or placebo	Safe and well tolerated. Rapid peak plasma exposure and elimination achieved	NCT01688830
		Part 2: Safety and efficacy of idarucizumab in dabigatran reversal in healthy subjects	47 Randomized 3:1 to idarucizumab or placebo	Immediate, complete, and sustained (72 hours) reversal of dabigatran-induced anticoagulation (dTT, ECT, aPTT, TT) in healthy subjects
	Phase III, cohort study RE- VERSE AD (A Study of the RE- VERSal Effects of Idarucizumab on Active Dabigatran)	Safety and efficacy of idarucizumab in dabigatran reversal in patients with serious bleeding (group A) or patients requiring urgent procedure (group B)	Estimated enrollment: 300	July 2017 Interim analysis of 90 patients who received idarucizumab: idarucizumab normalized dTT in $93% of patients, ECT in $88%, and unbound dabigatran concentration was reduced to minimal levels. Median cessation of bleeding in group A: 11.4 hours. Normal hemostasis achieved in 92% of patients undergoing surgery (92%) in group B	NCT02104947

Abbreviations: ACT, activated clotting time; RE-VERSE AD, Reversal Effects of Idarucizumab on Active Dabigatran; dTT, dilute thrombin time; ECT, ecarin-clotting time; NOACs, novel oral anticoagulants; TT, thrombin time; aPTT, activated partial thromboplastin time; RCT, randomized control trial; yo, years-old.

Figure 1 Coagulation cascade depicting site of action of anticoagulants and reversal agents.

Notes: Dark gray: Idarucizumab – potential reversal agent for direct thrombin inhibitor (dabigatran). Light gray: Perosphere – potential reversal agents for drugs in dashed box. White: Andexanet alfa – potential reversal agent for drugs in solid box.
Abbreviation: LMWH, low molecular weight heparin.

Table 3 Ciraparantag – a universal reversal agent undergoing FDA review

Ciraparantag (PER977) at a glance
Mechanism of action	Universal reversal agent
	Synthetic molecule binds:
	Direct Xa inhibitors (apixaban, rivaroxaban, and edoxaban)
	Direct thrombin inhibitors (dabigatran)
	Unfractionated and low molecular weight heparin
Proposed dose	Single 100 mg IV dose*
Time to effect	30 minutes: restoration of WBCT and mean fibrin–fibrin diameter**
Adverse effects	Mild perioral and facial flushing, dysgeusia**
	PT remains elevated
	Does not appear to be sensitive marker for PER977-mediated anticoagulation reversal*
	No prothrombotic effect§
Possible indications	Life threatening hemorrhage
	Emergent surgery
	Elective procedures to minimize time off anticoagulation

Notes:

* Dose being investigated in Phase II trial;

** data from Laulicht et al;⁵⁰

§ data from Ansell et al.³⁸

Abbreviations: FDA, Food and Drug Administration; PT, prothrombin time; WBCT, whole-blood clotting time; IV, intravenous.

Table 4 Andexanet alfa (PRT064445) – a factor Xa inhibitor antidote undergoing FDA review

Andexanet at a glance
Mechanism of action	Recombinant and inactivated form of factor Xa
	Binds factor Xa inhibitors: apixaban, rivaroxaban, and edoxaban
Proposed dose	400 mg IV bolus ±2 hours infusion at 4 mg/min*
Time to effect	2 minutes: 94% decrease in anti fXa activity§
	Effects of bolus last 1–2 hours
Adverse effects	No known prothrombotic effect – tissue factor pathway inhibitor interaction deserves further investigation
Possible indications	Life-threatening hemorrhage
	Emergent surgery

Notes:

* Dose currently being investigated in Phase III, part 2 trial;

§ data from Crowther et al.⁴⁴

Abbreviation: FDA, Food and Drug Administration; IV, intravenous.

Table 5 Idarucizumab – a direct thrombin (dabigatran) inhibitor undergoing FDA review

Idarucizumab at a glance
Mechanism of action	Binds free and thrombin-bound dabigatran
	Renal elimination of complex
Dose	Two 2.5 g 50 mL bolus IV infusions within 15 minutes: total 5 g*
Half-life	45 minutes, may require repeat dosing*
Time to effect	Normalization of dTT and ECT minutes after infusion*
	Median time to cessation of bleeding: 11.4 hours*
Adverse effects	Headache, nasopharyngitis, back pain, skin irritation – similar to placebo§
	No prothrombotic effect§
Possible indications	Life-threatening hemorrhage
	Emergent surgery
	Dabigatran overdose

Notes:

* Data from Pollack et al:⁴⁹ interim analysis of Phase III study;

§ data from Glund et al:^47,48 Phase I studies.

Abbreviations: dTT, dilute thrombin time; FDA, Food and Drug Administration; ECT, ecarin-clotting time; IV, intravenous.

LaulichtBBakhruSSteinerSPER977 (ciraparantag) reverses edoxaban anticoagulation at steady state and has no effect on reanticoagulation at the next scheduled doseEur Heart J201536 Abstract Supplement

 Web of Science ®Google Scholar

AnsellJEBakhruSHLaulichtBEUse of PER977 to reverse the anticoagulant effect of edoxabanN Engl J Med2014371222141214225371966

 PubMed Web of Science ®Google Scholar

CrowtherMGoldALuGANNEXA (TM)-A PART 2: a phase 3 randomized, double-blind, placebo-controlled trial demonstrating sustained reversal of apixaban-induced anticoagulation in older subjects by andexanet ALFA (PRT064445), a universal antidote for factor XA (FXA) inhibitorsJ Thromb Haemost2015138485

 Web of Science ®Google Scholar

PollackCVJrReillyPAEikelboomJIdarucizumab for dabigatran reversalN Engl J Med201537351152026095746

 PubMed Web of Science ®Google Scholar

GlundSStangierJSchmohlMSafety, tolerability, and efficacy of idarucizumab for the reversal of the anticoagulant effect of dabigatran in healthy male volunteers: a randomised, placebo-controlled, double-blind phase 1 trialLancet201538668069026088268

 PubMed Web of Science ®Google Scholar

GlundSMoschettiVNorrisSA randomised study in healthy volunteers to investigate the safety, tolerability and pharmacokinetics of idarucizumab, a specific antidote to dabigatranThromb Haemost2015113594395125789661

 PubMed Web of Science ®Google Scholar