ANNEXA-4: Factor Xa Antidote Continues to Show Promise

Marlene Busko

March 21, 2018

ORLANDO — The investigational factor Xa reversal agent andexanet alfa (AndexXa, Portola Pharmaceuticals) quickly stopped the bleeding in patients who had an acute major bleed while being treated with a factor Xa inhibitor, with an acceptable safety profile, researchers report.

Stuart J Connolly, MD, McMaster University, Hamilton, Ontario, Canada, presented these latest interim results from the ongoing Andexanet Alfa, a Novel Antidote to the Anticoagulation Effects of Factor Xa Inhibitors (ANNEXA-4) phase 3b/4 trial here at the American College of Cardiology (ACC) 2018 Annual Scientific Sessions.

"Andexanet very rapidly reverses anti–factor Xa activity in actively bleeding patients," he reported, and out to12 hours, "effective clinical hemostasis is achieved in 83% of patients."

Thrombotic events and mortality rates at 30 days, meanwhile, were consistent with the high-risk profile of this patient population.

And although the trial did not have a control arm, "andexanet reversal of factor Xa inhibitor bleeding has similar efficacy and safety as has been reported with other recently approved reversal agents," he noted.

The patients had developed acute bleeding while taking one of four factor Xa inhibitors — apixaban (Eliquis, Bristol-Myers Squibb), rivaroxaban (Xarelto, Bayer/Janssen Pharmaceuticals), edoxaban (Savaysa, Lixiana, Daiichi-Sankyo) or enoxaparin — to prevent a thrombotic event.

The interim findings with this reversal agent in 227 patients build on earlier promising results in 67 patients that were reported at the European Society of Cardiology (ESC) 2016 Congress and published in the New England Journal of Medicine.

Andexanet alfa is being reviewed by the US Food and Drug Administration (FDA), with an assigned action date of May 4, 2018, and by the European Medicines Agency (EMA), with an expected decision in 2019.

The FDA delayed approval of the drug in 2016 as a reversal agent for the four factor Xa inhibitors, requesting more data for edoxaban and enoxaparin

If regulatory bodies give the thumbs up to this reversal agent, it will be the first approved antidote to reverse acute major bleeding associated with several factor Xa inhibitors. An agent specific for reversal of dabigatran idarucizumab (Praxbind, Boehringer Ingelheim) was approved in 2015.

"The drug is being developed by a relatively small pharmaceutical company that needs to have a positive response from regulatory agencies," Connolly told theheart.org | Medscape Cardiology.

"So [there's] lot's more work to be done with andexanet, but a positive regulatory response is awaited and will be critical."

"If approved, andexanet will provide clinicians with an effective and safe tool for reversing the anticoagulant effect in patients receiving direct factor Xa inhibitors who present with severe or life-threatening bleeding," study discussant Gregory Piazza, MD, Brigham and Women's Hospital and Harvard University, Boston, Massachusetts, told the theheart.org | Medscape Cardiology in an email.

Although "severe or life-threatening bleeding is infrequent with the direct factor Xa inhibitors, andexanet will be an important agent for the small population of patients who present with this complication."

This trial also highlights that "when we reverse anticoagulation, we have to be looking for an opportunity to reinstate anticoagulation when it's safe," he said, because these patients have a high risk for thrombosis.

"Angst" vs Confidence in the Results

One panelist at the session was concerned about the lack of a control group, but others nevertheless see the results as very promising.

"I have no way to interpret how good these results are without a control group," said panelist Gregg W Stone, MD, Columbia University Medical Center and New York-Presbyterian Hospital, New York City, during the discussion.

"It's a limitation of the study. I can't deny that," Connolly agreed. However, the data align well with findings in randomized trials of other reversal agents that received regulatory approval. "But I understand your angst about not having a control group," he said. "I have the same angst."

"You guys might have that, but I personally do not," said session co-chair Roxana Mehran, MD, Mount Sinai Medical Center, New York City.  "Because if I'm a bleeding patient and you know that you have an agent that might reverse my bleeding or relieve the worsening of the expanding hematoma in my brain, I'd like you to use it, and you showed that you were able to do that."

"I think it's nice to say as a trialist that we all want randomized controlled trials," she continued. "But this is an unmet need, an incredibly important area of investigation, and you should be congratulated."  

Session chair, Duane S Pinto, MD, Beth Israel Deaconess Medical Center, Boston, Massachusetts, agreed with Mehran. He said he uses a lot of these medications in high-risk patients undergoing percutaneous coronary intervention with atrial fibrillation, "and it's often difficult to unlock bleeding from ischemic risk, but I expect to be using more of these agents in light of the COMPASS trial results," with rivaroxaban.

"Having a [reversal] agent, if it works — these are very promising results that are going to be very important in our armamentarium."

The final word went to Connolly: "It does work. There's no doubt that the anti–factor Xa activity is sharply and rapidly reduced," he said. "That part, there's no doubt."

Decoy Binding

Factor Xa inhibitors are used increasingly, but they can precipitate major bleeding that requires hospitalization and has a fatality rate of 15% to 20%.  

Andexanet is a protein that was designed to act as a decoy to bind molecules that inhibit factor Xa, and it was effective, with no thrombotic events, in 400 healthy volunteers.

The ANNEXA-4 trial is being conducted at 60 sites in the United States, Canada, and Europe, and the current results are from patients enrolled until October 2017.

Most patients had had an intracranial hemorrhage (61%), and the rest had a major gastrointestinal bleed (27%) or bleed from another site (12%) within 18 hours of taking apixaban (117 patients), rivaroxaban (90 patients), enoxaparin (17 patients), or edoxaban (3 patients).

The patients had a mean age of 77 years, and about half were male. Most (78%) had atrial fibrillation and a quarter had venous thromboembolic disease. About a quarter had heart failure, 21% had a prior stroke, and 14% had a prior myocardial infarction (MI).

"In a word, this was a high-risk population," Connolly emphasized.

Most patients received a 400-mg intravenous bolus of andexanet followed by a 2-hour, 480-mg infusion of andexanet since they had been taking apixaban or had taken a dose of rivaroxaban (<7 hours previously); the other patients received twice this dose.

Efficacy was assessed in the 132 patients who had sufficiently high anti–factor Xa levels at baseline.

After patients taking rivaroxaban or apixaban received a bolus of the antidote, their median anti–factor Xa levels dropped by 88% and 91%, respectively, and these levels remained until the end of the infusion. Then their anti–factor Xa levels increased somewhat before tapering off out to 12 hours.

The pattern was similar in patients who had been receiving enoxaparin or edoxaban.

As assessed by an independent adjudication committee, 109 of 132 patients (83%) achieved "excellent" or "good" hemostasis through 12 hours.

Efficacy was similar across different subgroups. For example, the reversal agent did a good or excellent job of stopping the bleeding in 82% and 83% of patients receiving apixaban and rivaroxaban, respectively, and 86% and 81% of patients with gastrointestinal bleeding or intracranial bleeding, respectively.   

Safety was assessed out to 30 days in the entire cohort.

Of the 227 patients, 6 patients (2.6%) had a thrombotic event within 3 days of taking andexanet and 24 patients (11%) had an event, including ischemic stroke, MI, and venous thromboembolic events, within 30 days.

Notably, there was no cluster of events immediately after the reversal agent was stopped.

Anticoagulation was restarted in 129 patients (57%) by 30 days.

Also at 30 days, 27 of the 227 patients (12%) had died, and 16 of the 139 patients with intracranial hemorrhage (12%) had died.

The hemostatic efficacy and the thrombotic event rate in ANNEXA-4 were similar to those in the REVERSE AD trial of idarucizumab for dabigatran, and the Sarode 2013 trial of the reversal agent 4-factor-prothrombin complex concentrate (Kcentra, CSL Behring) for warfarin, Connolly pointed out.

Notably, ANNEXA-4 enrolled more patients with intracranial hemorrhage (61%) than in these other trials (33% and 12%), he said.

The study was funded by Portola. Connolly has received consultant fees/honoraria from Sanofi-Aventis, Bristol-Myers Squibb, Boehringer-Ingelheim, Bayer, and Portola, and research grants from Bayer and Portola. Piazza has received consultant fees/honoraria from Agile, BCRI, BIO2, eXithera, and Optum and research grants from Bristol-Myers Squibb, Daiichi, EKOS, Janssen Pharmaceuticals Inc, and the Thrombosis Research Institute. Mehran has received consultant fees/honoraria from Abbott Vascular, Abiomed, Boston Scientific, Cardiovascular Systems Inc, The Medicines Company, Medscape, and Shanghai Bracco Sine Pharmaceutical Corp. She has been on the data safety monitoring board of Watermark Research Partners and has associations with Bristol-Myers Squibb, Claret Medical, Elixir Medical, Janssen Pharmaceuticals, Osprey Medical, WebMD, and Wiley Blackwell publishing company, She has received research grants from AstraZeneca, Bayer, Beth Israel Deaconess Medical Center, CSL Behring, Eli Lilly/DSI, Medtronic, Novartis Pharmaceuticals, OrbusNeich, and The Medicines Company. Stone has received consultant fees/honoraria from BackBeat Medical, Claret, Guided Delivery Systems, Matrizyme, Miracor, Neovasc, Reva, SIRtex, TherOx, Valfix, Vascular Dynamics, and V-Wave. He has a fiduciary role with Spectrawave and has ownership interest in Aria, Biostar family funds, Cagent, Caliber, Medfocus family funds, micardia and Qool Therapeutics. Pinto has received consultant fees/honoraria from Abiomed, Boston Scientific, Chiesi, Medtronic, and UpToDate and research grants from Boston Scientific.

American College of Cardiology (ACC) 2018 Annual Scientific Session. Abstract 409-14. Presented March 12, 2018.

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