"Reversal of Anticoagulation". The New England Journal of Medicine. 2015. 373:2413-2424.
Links to original sources: Wiki Journal Post Full Journal Article
Does andexanet rapidly reverse the anticoagulation effects of apixaban and rivaroxaban in older healthy participants without causing serious adverse or thrombotic events?
Andexanet rapidly reversed the anticoagulation effect of apixaban and rivaroxaban in older participants with no evidence of serious adverse events or clinical thrombosis.
Andexanet alfa (andexanet) is a factor Xa inhibitor reversal agent designed to neutralize the anticoagulant effects of both direct and indirect factor Xa inhibitors. The ANNEXA-A (andexanet for apixaban) and ANNEXA-R (andexanet for rivaroxaban) randomized controlled trials demonstrated that andexanet effectively reversed anticoagulation as assessed by anti–factor Xa activity, restored thrombin generation, and reduced unbound anticoagulant concentrations within minutes after administration.
At the time of study publication, there were no existing guidelines for the reversal of factor Xa inhibitors with andexanet alfa. Further clinical trials in patients with acute major bleeding on factor Xa inhibitors are required to provide data for formal guideline recommendations.
Two part, randomized, double-blind, placebo-controlled studies in healthy older volunteers receiving apixaban or rivaroxaban. - ANNEXA-A (N=65) for apixaban. - ANNEXA-R (N=80) for rivaroxaban. Mean age: 57.9 years - 39% female
Healthy volunteers aged 50 to 75 years.
Inclusion Criteria: - Participants who received the highest approved doses of apixaban (5 mg twice daily) or rivaroxaban (20 mg daily) to steady-state levels.
Exclusion Criteria: Not explicitly defined in the summary, but typically would include allergies to study drugs or active bleeding.
Andexanet given as an intravenous bolus or bolus plus a 2-hour infusion after steady state dosing of either apixaban or rivaroxaban to achieve maximum anticoagulation effect.
Primary Outcome: - Mean percent change in anti–factor Xa activity from baseline to nadir significantly reduced with andexanet compared to placebo in both ANNEXA-A and ANNEXA-R studies (P<0.001).
- At least 80% reversal of anti–factor Xa activity in nearly all participants given andexanet (P<0.001 compared to placebo). - Restoration of thrombin generation to normal range in 100% of andexanet recipients in ANNEXA-A and 96% in ANNEXA-R (all above the lower limit of normal range, P<0.001 compared to placebo). - Significant reduction of unbound apixaban and rivaroxaban concentrations with andexanet compared to placebo (P<0.001).
- The study population consisted of healthy older adults, which may not accurately represent the characteristics of patients typically receiving anticoagulation therapy. - The efficacy of andexanet for urgent reversal in the context of active bleeding events or emergencies requiring rapid anticoagulant reversal was not assessed. - There were transient increases in d-dimer and prothrombin fragments 1 and 2, potential signs of coagulopathy, which could be concerning although no clinical thrombosis occurred.
Supported by Portola Pharmaceuticals, Bayer, Bristol-Myers Squibb, Johnson & Johnson, and Pfizer.
ANNEXA-A (NCT02207725) and ANNEXA-R (NCT02220725) ClinicalTrials.gov numbers, ongoing ANNEXA-4 study (NCT02329327).