Reversal Agent for Factor Xa Inhibitors Continues to Look Good: ANNEXA-4

ORLANDO, FL—A new interim analysis of the ongoing ANNEXA-4 study evaluating andexanet alfa (AndexXa; Portola Pharmaceuticals) affirms that the drug rapidly reverses the anticoagulant effects of the direct and indirect factor Xa inhibitors.

Moreover, good or excellent hemostasis was achieved in 83% of patients within 12 hours, Stuart Connolly, MD (Population Health Research Institute, Hamilton, Canada), reported at the American College of Cardiology 2018 Scientific Session here.

He said the safety and efficacy of the reversal agent compare favorably with the performance of idarucizumab (Praxbind), the antidote for the direct thrombin inhibitor dabigatran (Pradaxa; both Boehringer Ingelheim) that was approved by the US Food and Drug Administration (FDA) in October 2015.

Although it was expected that andexanet alfa would join idarucizumab on the market back in 2016, the FDA declined to approve it, citing the need for more information related to manufacturing and more data to support inclusion of all of the factor Xa inhibitors on the label. The agency continues its review and is expected to make a decision regarding the drug’s fate this spring.

Discussing the ANNEXA-4 results at a press conference, Gregory Piazza, MD (Brigham and Women’s Hospital, Boston, MA), noted that one of the obstacles to use of the non-vitamin K antagonist oral anticoagulants (NOACs) has been the question of whether the effects could be reliably reversed in the setting of major bleeding

“I think this combined with REVERSE-AD for the direct thrombin inhibitor really show that we now have tools at our disposal that can quickly reverse anticoagulation and return hemostasis to a level that provides patients the ability to recover from major bleeding,” Piazza said.

When questioned about what impact approval of andexanet alfa might have on prescription of the factor Xa inhibitors, Piazza pointed out that dabigatran prescriptions increased in the wake of the approval of its reversal agent.

“I would posit that with the approval of andexanet there might be one less obstacle to using a class of agents that by all accounts probably improves safety and [is] at least as effective [as] if not more effective than warfarin depending on the clinical setting,” he said.

ANNEXA-4 Continues

The factor Xa inhibitors—including the direct agents rivaroxaban (Xarelto; Bayer/Janssen), apixaban (Eliquis; Bristol-Myers Squibb), and edoxaban (Savaysa; Daiichi Sankyo), as well as the indirect agent enoxaparin—have been shown to be safe and effective, but they carry a risk of major bleeding. Major bleeding associated with the agents accounts for more than 100,000 hospitalizations in the United States each year, Connolly said.

Andexanet alfa was designed as a specific reversal agent. It is a recombinant modified human factor Xa molecule that acts as a decoy, binding with factor Xa inhibitors in the bloodstream to allow native factor Xa to resume its normal coagulant activity. It has been shown to rapidly reverse anticoagulant effects in healthy volunteers and in a previous interim analysis of ANNEXA-4.

The prospective, single-arm, phase IIIb/IV study is enrolling patients who present with acute major bleeding within 18 hours of the last dose of a factor Xa inhibitor. Andexanet alfa is administered as an IV bolus followed a 2-hour infusion.

Connolly presented an analysis of patients included in the study as of October 20, 2017; 227 were included in the safety population and 137 in the efficacy population. Overall, the population was elderly (mean age 77) with a high burden of comorbidities. About three-quarters were receiving anticoagulation for A-fib, with the rest being treated for venous thromboembolic disease; a handful of patients were being treated for both.

Initially, most patients presented with intracranial bleeding (61%), with GI bleeding in 27% and bleeding in other sites in 12%.

Andexanet alfa rapidly reversed the anticoagulant effects regardless of the factor Xa inhibitor patients were using. By the end of the infusion, effects were reduced by 87% in patients taking rivaroxaban, by 91% in those taking apixaban, and by 73% in those taking enoxaparin. Connolly did not report results with edoxaban because of low patient numbers.

After the infusion ended, anticoagulant activity increased slightly before tapering off as the factor Xa inhibitors were cleared from the body normally.

The rate of excellent or good hemostasis was 83% at 12 hours after andexanet alfa treatment, a finding that was consistent across subgroups.

Importance of Restarting Anticoagulation

In terms of safety, thrombotic events—including ischemic strokes, MIs, and venous thromboembolic events—occurred in 2.6% of patients within 3 days of being treated with andexanet alfa and 11% within 30 days. The mortality rate was 12% at 30 days.

While we have the benefit of having a reversal agent, that doesn’t give us the opportunity to really take our eyes off the ball. Gregory Piazza

Connolly said those rates are consistent with the high-risk profile of the patients included in the study and compare well with those seen in REVERSE-AD and a study evaluating use of four-factor prothrombin complex concentrate and plasma to reverse the effects of warfarin. He noted, too, that anticoagulation was stopped in all patients when they presented and was restarted in only 57% by 30 days.

Connolly said that andexanet alfa is not believed to be causing thrombotic events directly, pointing out that there was no clustering of events early after the drug was administered and that thrombotic events and deaths accumulated steadily throughout the 30-day follow-up period.

Piazza said an important concept highlighted by this analysis is the issue of thrombosis in patients who have had their anticoagulation discontinued and reversed.

“One thing that is very important is that when we reverse anticoagulation, we have to be looking for the opportunity to reinstitute anticoagulation when it’s safe, and failure to do so exposes our patients to an incredible hazard for thrombosis,” Piazza said. “While we have the benefit of having a reversal agent, that doesn’t give us the opportunity to really take our eyes off the ball.”

Connolly cautioned, however, that it’s not clear what to do in terms of restarting anticoagulation in a patient who has had an intracranial hemorrhage, noting that guidelines are vague.