Inventing OFF After Pushing ON: Progressing Toward Reversing Factor Xa Inhibitor Anticoagulants

Although the factor Xa (FXa) inhibitor oral anticoagulants have fewer drug interactions and are without burdens associated with warfarin, such as blood test monitoring, dosage adjustment, and diet restriction, they also lack an approved antidote to their anticoagulant effect.

A possible solution is underway as andexanet alfa (AndexXa, Portola Pharmaceuticals) is demonstrating safety and efficacy in reversing FXa inhibitors in phase 3 trials. Additionally, ciraparantag (PER977, Perosphere) is in phase 2 trials as an antidote to both oral FXa inhibitor anticoagulants and subcutaneous low-molecular weight heparin (LMWH), as well as to factor IIa (FIIa, thrombin) inhibition.

Risk Remains With Direct-Acting Anticoagulants

Ciraparantag, is likely to be valued more as an antidote to multiple classes of anticoagulants rather than for including effects against the FIIa inhibitor dabigatran (Pradaxa, Boehringer Ingelhiem), as idarucizumab (Praxbind, Boehringer Ingelhiem) was approved as the specific antidote to dabigatran in 2015.Even without available antidotes, the direct-acting anticoagulants were welcomed as alternatives to the vitamin K antagonist warfarin, not only for relative ease of use, but for evidencing comparable or better efficacy in preventing stroke from nonvalvular atrial fibrillation and preventing and treating venous thromboembolism, with less likelihood of a major bleed.¹

Although, less is not absence of risk, as the anticoagulant effect intended as therapeutic also increases patient vulnerability to spontaneous, traumatic, and perioperative bleeding. Protocols for reversing direct-acting anticoagulants in the event of a severe bleed have varied in the absence of controlled trial data and specific antidotes; however, sharing supportive measures such as fluid replacement, blood transfusions, topical hemostatic measures, and the administration of activated charcoal in event of recent overdose has been used.

Products that have been considered for use in protocols against bleeding with direct-acting anticoagulants are those that have also been used in efforts to reverse warfarin, other than vitamin K. These include 4-factor prothrombin complex concentrate (PCC), and, in hemophiliacs, recombinant activated factor VII and/or activated PCC (aPCC).

Progress Toward Reversing with Specific Antidotes

In a recent study evaluating the effectiveness of these products against anticoagulation from rivaroxaban (Xarelto, Janssen), the thrombin generation assay and thromboelastometry parameters affected by rivaroxaban were improved to different degrees by each of the products. The investigators deemed that the aPCC reversed anticoagulation from rivaroxaban more efficiently than the other 2 products. They cautioned about the potential for prothombotic effect and the importance of dosing within guidelines.²Andexanet alfa (andexanet) was created through recombinant genetic technology as a “decoy” FXa molecule to reduce binding of the direct inhibitor anticoagulants to the endogenous clotting factor. The decoy mechanism is effective against the oral direct FXa inhibitors and the LMWH and fondaparinux (Arixtra, GlaxoSmithKline) that inhibit FXa through antithrombin.

Two phase 3 trials, ANNEXA-A and ANNEXA-R, evidenced efficacy of andexanet in reversing anticoagulant activity of apixaban (Elquis, Bristol-Myers Squibb) and rivaroxaban, respectively. The studies recruited subjects aged 50 to 75 years, to correspond to the typical anticoagulant patient population, and healthy subjects rather than treated patients to gauge andexanet effect against controlled anticoagulant dosing and levels.

The 2 trials, reported concurrently, demonstrated rapid and significant reduction in both the anti-FXa activity and the mean plasma concentrations of the direct-acting anticoagulants.³ The dose of andexanet needed to reverse apixaban was different from that required against rivaroxaban, which prompted a commentator to express concern about how the antidote will be applied in practice.

“The different doses are based on both the type of factor Xa inhibitor ingested and the time from last dose, which has the potential to make its use in the busy emergency department challenging; it also raises concerns about underdosing the bleeding patient if clinically obtained information is incorrect,” wrote Jean Connors, MD, an internist in the Hematology Division at Brigham and Women's Hospital and Harvard Medical School, in Boston, Massachusetts.⁴

The opportunity to assess andexanet in such clinical settings was provided in the subsequent phase 3b-4 ANNEXA-4 trial. A published interim report of that trial documented the outcome with 67 patients who had acute major bleeding within 18 hours after the administration of a FXa inhibitor.⁵ The efficacy subgroup comprised 47 patients confirmed to have had baseline anti-FXa activity >75ng/ml, with the remaining patients serving to provide additional safety data on the andexanet administration. In the efficacy group, 26 were receiving rivaroxaban, 20 were on apixaban, and 1 received enoxaparin (Lovenox, Sanofi-Aventis).

Stuart Connolly, MD, FRCPC, of the Population Health Research Institute, and professor emeritus of medicine at McMaster University, in Hamilton, Ontario, Canada, and the ANNEXA-4 investigators reported that an initial bolus and subsequent 2-hour infusion of andexanet substantially reduced anti-FXa activity in patients with acute major bleed after receiving an FXa inhibitor, with effective hemostasis measured 12 hours after infusion in 79% of patients, consistent across subgroups.

“This finding supports the idea that prolonged reversal of factor Xa inhibition may not be necessary to achieve a good hemostatic response,” Connolly and colleagues noted.⁵

In an editorial accompanying the ANNEXA-4 report.⁶, Beverley J. Hunt, MD, FRCP, FRCPath, a professor of thrombosis and haemostasis and the director of the Haemostasis Research Unit at the Thrombosis and Haemophilia Centre of St. Thomas’ Hospital, in London, England, and Marcel Levi, MD, PhD, a professor of medicine and the chairman of the Department of Medicine at the University of Amsterdam’s Academic Medical Center, in the Netherlands, commented on the impact of andexanet in terms of factor Xa inhibition.

Ciraparantag Continues Antidote Story

“The advent of andexanet completes the story of direct oral anticoagulants, since there are now effective and relatively safe antidotes,” Hunt said.Rather than the story being completed with andexanet, as Hunt and Levi suggested, it is likely to continue with development of ciraparantag adding a different mechanism and spectrum of action.

Ciraparantag was initially developed as an antidote to heparin, LMWH, and fondaparinux through noncovalent binding with those target molecules. The binding through hydrogen bonding and charge-charge interaction was subsequently found to also occur with both FXa and FIIa inhibitor anticoagulants.

The efficacy of ciraparantag in reversing anticoagulant effects of LWMH was demonstrated in a phase 1/2 trial involving 4 cohorts of 10 healthy volunteers who received escalating doses of ciraparantag approximately 4 hours after a single subcutaneous 1.5-mg/kg dose of enoxaparin.⁷

Enoxaparin increased clotting time by a mean of 30% over baseline, and a single intravenous dose of 100, 200 or 300 mg of ciraparantag reduced the clotting time to within 20% over baseline within 1 hour, and maintained that for 24 hours. The reversal of enoxaparin was assayed through whole blood clotting time, as ciraparantag also binds to calcium chelators such as sodium citrate, which then interferes with collection of blood samples for routine coagulations tests.

A phase 1/2 trial of ciraparantag efficacy in reversing edoxaban (Savaysa, Daiichi-Sankyo) anticoagulation was conducted in 80 healthy volunteers receiving an intravenous dose of 100 to 300 mg, 3 hours after receiving edoxaban 60 mg.⁸ The anticoagulation effect was fully reversed within 10 to 30 minutes and sustained for 24 hours. The researchers reported no evidence of procoagulant activity following ciraparantag, as assessed by D-dimer, prothrombin fragments 1.2, and tissue factor pathway inhibitor levels.

Jeffrey Weitz, MD, FRCPC, FACP, a professor of medicine and biochemistry and the director of the Thrombosis & Atherosclerosis Research Institute at McMaster University in Ontario, Canada, and John Eikelboom, MBBS, an associate professor at McMaster University, have considered the data on both andexanet and ciraparantag, and although andexanet has progressed further in clinical testing, they anticipate that ciraparantag will find a place in the anticoagulant antidote armamentarium.

“The availability of andexanet alfa will be restricted to start and it is likely to cost substantially more than ciraparantag,” Weitz and Eikelboom said. “In addition, by binding tissue factor pathway inhibitor to form a nonproductive complex that fails to inhibit the tissue factor-factor VIIa complex, andexanet alfa produces a transient hypercoagulable state characterized by an increase in the levels of D-dimer and prothrombin fragment.”⁹

Weitz and Eikelboom acknowledged that there were no thrombotic complications with andexanet alfa in the healthy volunteers, but indicated that “studies are needed to exclude this potential complication.”

They noted that additional studies with ciraparantag will also be needed to answer their question: “Could ciraparantag serve as a cheaper and simpler-to-administer alternative to andexanet alfa?”

REFERNCES

1. Raval A, Cigarroa J, Chung, M, et al; American Heart Association. Management of patients on non-vitamin K antagonist oral anticoagulants in the acute care and periprocedural setting: a scientific statement from the American Heart Association Circulation. 2017; 135.

doi

: /10.1161/CIR.000000000000047.

2. Schultz NH, Tran HTT, Bjørnsen S, Henriksson CE, KSandset PM, Holme PA. The reversal effect of prothrombin complex concentrate (PCC), activated PCC and recombinant activated factor VII against anticoagulation of Xa inhibitor. Thromb J. 2017;15(6).

doi

: 10.1186/s 12959-017-0129-1. 3. Siegal DM, Curnutte JT, Connolly SJ, et al. Andexanet alfa for the reversal of factor Xa inhibitor activity. N Engl J Med. 2015;373(25):2413-2424.

doi

:10.1056/NEJMoa1510991.4. Connors JM.

Antidote

for factor Xa anticoagulants. N Engl J Med. 2015;373(25):2471-2472.

doi

: 10.1056/NEJMe1513258.

5. Connolly SJ, Milling TJ, Eikelboom JW, et al; ANNEXA-4 Investigators. Andexanet alfa for acute major bleeding associated with factor Xa

inibitors

. N Engl J Med. 2016;375(12):1131-1141.

doi

: 10.1056/NEJMoa1607887. 6. Hunt BJ and Levi M. Engineering reversal—finding an antidote for direct oral anticoagulants. N Engl J Med. 2016;375(12):1185-1186.

doi

: 10.1056/NEJMoa1607887.

7. Ansell JE, Laulicht BE, Bakhru SH, Hoffman M, Steiner SS, Costin JC. Ciraparantag safely and completely reverses the anticoagulant effects of low molecular weight heparin. Thromb Res. 2016;146:113-118.

doi

: 10.1016/j.thromres.2016.07.008.

8. Ansell JE, Bakhru SH, Laulicht BE, et al. Single-dose

ciraparantag

safely and completely reverses anticoagulant effects of edoxaban. Thromb Haemost. 2017;117(2):238-245.

doi

: 10.1160/TH16-03-0224.

9. Weitz JI, Eikelboom JW. Ciraparantag for enoxaparin reversal: Adding to the evidence. Thromb Res. 2016;146:106-107.

doi

: 10.1016/j.thromres.2016.08.013.