What studies demonstrate the benefit of Andexxa (andexanet alfa) in reversing the effects of Eliquis (apixaban) and Xarelto (rivaroxaban)?

From the Guidelines

Andexanet alfa (Andexxa) is the recommended agent for reversing the anticoagulant effects of factor Xa inhibitors like apixaban (Eliquis) and rivaroxaban (Xarelto) in patients with acute major bleeding, as demonstrated by the ANNEXA-4 trial 1. The ANNEXA-4 trial showed that Andexxa rapidly reversed anti-factor Xa activity in patients with acute major bleeding, with 82% of patients achieving excellent or good hemostatic efficacy at 12 hours. Key points about Andexxa include:

• It works by acting as a decoy protein that binds to factor Xa inhibitors, preventing them from inhibiting native factor Xa and thus restoring normal coagulation.
• Andexxa is administered as an initial IV bolus followed by a 2-hour infusion, with dosing based on the specific anticoagulant and when it was last taken.
• For apixaban or rivaroxaban taken within the last 8 hours at a dose ≥5mg or >10mg respectively, a high dose of Andexxa is recommended (800mg bolus followed by 960mg infusion).
• For lower doses or longer time since last dose, a lower dose of Andexxa is used (400mg bolus followed by 480mg infusion). While effective, Andexxa carries risks including thrombotic events in approximately 10% of patients, so clinical judgment regarding the risk-benefit ratio is essential when considering its use for anticoagulation reversal in life-threatening bleeding situations 1. The most recent and highest quality study, ANNEXA-4, provides the strongest evidence for the use of Andexxa in this context, and its findings should guide clinical decision-making 1.

From the FDA Drug Label

The safety and efficacy of ANDEXXA were evaluated in two prospective, randomized, placebo- controlled studies, conducted in healthy volunteers (Study 1 ANNEXA-A; Study 2 ANNEXA-R) Study 1 ANNEXA-A (NCT02207725) – apixaban reversal Study 2 ANNEXA-R (NCT02220725) – rivaroxaban reversal Study 3 ANNEXA-4 (NCT02329327) In a multinational, prospective, single-arm, open-label study, ANDEXXA was administered to 477 patients taking FXa inhibitors who presented with acute major bleeding

The studies that show benefit to andexxa in Eliquis (apixaban) and Xarelto (rivaroxaban) reversal are:

• Study 1 ANNEXA-A: apixaban reversal, which demonstrated a statistically significant reduction in anti-FXa activity in favor of the ANDEXXA group compared to placebo.
• Study 2 ANNEXA-R: rivaroxaban reversal, which also demonstrated a statistically significant reduction in anti-FXa activity in favor of the ANDEXXA group compared to placebo.
• Study 3 ANNEXA-4: a multinational, prospective, single-arm, open-label study that administered ANDEXXA to patients taking FXa inhibitors, including apixaban and rivaroxaban, who presented with acute major bleeding, and evaluated the percent change in anti-FXa activity and the rate of effective hemostasis within 12 hours after infusion 2.

Key findings:

• Statistically significant reduction in anti-FXa activity in favor of the ANDEXXA group compared to placebo in both Study 1 and Study 2.
• Effective hemostasis within 12 hours after infusion in Study 3 ANNEXA-4.

Note that Eliquis is another name for apixaban, and Xarelto is another name for rivaroxaban.

From the Research

Andexanet Alfa for Reversal of Factor Xa Inhibitors

• Andexanet alfa is a catalytically inactive recombinant modified human factor Xa molecule that reverses the anticoagulant effect of direct and indirect acting factor Xa inhibitors, such as apixaban and rivaroxaban 3.
• The ANNEXA-4 study showed that treatment with andexanet alfa was associated with a 92% reduction in median anti-Xa activity levels and excellent or good hemostasis in 82% of patients presenting with serious bleeding while receiving apixaban or rivaroxaban 3.

Comparison with Four-Factor Prothrombin Complex Concentrate (4F-PCC)

• A systematic review and meta-analysis compared the effectiveness of andexanet alfa and 4F-PCC for factor Xa inhibitor-associated bleeding, and found that the weighted mean effectiveness for andexanet alfa was 82% at 12 hours and 71% at 24 hours, while the weighted mean effectiveness for 4F-PCC was 88% at 12 hours and 76% at 24 hours 4.
• A propensity score-overlap weighted analysis found that andexanet alfa was associated with greater odds of achieving hemostatic effectiveness and decreased odds of mortality compared to 4F-PCC for apixaban- or rivaroxaban-associated intracranial hemorrhage 5.
• A retrospective, single-center case series found that excellent or good hemostasis occurred in 88.9% of andexanet alfa-treated patients and 60% of 4F-PCC-treated patients with rivaroxaban or apixaban-associated intracranial hemorrhages 6.

Clinical Outcomes

• A retrospective, single-center, case series evaluating hemostatic efficacy of patients receiving andexanet alfa or 4F-PCC for reversal of apixaban or rivaroxaban after intracranial hemorrhage found that hemostatic efficacy occurred in 64.7% of patients receiving andexanet alfa and 54.8% of receiving 4F-PCC 7.
• Thirty-day all-cause mortality was 45.2% for 4F-PCC and 30% for andexanet alfa, and thrombotic events were higher with 4F-PCC (31.4%) compared to andexanet alfa (14.3%) 7.