"Andexanet Alfa for Reversing Anticoagulation from Factor Xa Inhibitors".The New England Journal of Medicine. 2016. 375:1131-1141.PubMed•Full text•PDFContents1Clinical Question2Bottom Line3Major Points4Design5Population5.1Inclusion Criteria5.2Exclusion Criteria5.3Baseline Characteristics6Interventions7Outcomes7.1Primary Outcomes7.2Secondary Outcome8Criticisms9Funding10Further ReadingClinical QuestionIn patients with acute major bleeding within 18 hours after the administration of a factor Xa inhibitor, does administration of Andexanet Alfa reverse anticoagulation and improve outcomes?Bottom LineAndexanet Alfa reduces anti-factor Xa activity in patients with acute major bleeding within 18 hours after administration of a factor Xa inhibitor, with clinical hemostasis being achieved in 79% of cases. However, thrombotic events occurred in 18% of patients during 30-day follow-up.Major PointsFactor Xa inhibitors, used for the treatment and prevention of venous thromboembolism and for stroke prevention in patients with atrial fibrillation, are associated with major and potentially fatal bleeding. Until recently, there was no reversal agent available for these anticoagulants. Andexanet Alfa, a recombinant modified human factor Xa decoy protein, was designed to reverse anticoagulation by factor Xa inhibitors. This study showed that an initial bolus and subsequent 2-hour infusion of Andexanet Alfa rapidly reduced anti-factor Xa activity and resulted in effective hemostasis in a majority of patients.DesignMulticenter, prospective, open-label, single-group study.N=67 patients with acute major bleeding after a factor Xa inhibitor.Interventions involved a bolus of Andexanet followed by a 2-hour infusion.PopulationInclusion CriteriaPatients at least 18 years old.Acute major bleeding within 18 hours after administration of a factor Xa inhibitor (apixaban, rivaroxaban, edoxaban, or enoxaparin).Exclusion CriteriaSurgery scheduled within less than 12 hours.Intracranial hemorrhage with Glasgow Coma Scale score <7 or estimated intracerebral hematoma volume >60 ml.Expected survival <1 month.Major thrombotic event within 2 weeks prior.Excluded if received certain anticoagulants within 7 days prior to screening.Baseline CharacteristicsMean age: 77 years.Most patients had substantial cardiovascular disease.Bleeding predominantly gastrointestinal or intracranial.InterventionsAndexanet bolus and subsequent infusion.Dosage was determined by timing and type of factor Xa inhibitor last received.OutcomesPrimary OutcomesReduction in anti-factor Xa activity.Excellent or good clinical hemostatic efficacy 12 hours after the infusion of Andexanet Alfa.Secondary OutcomeThrombotic events and deaths within 30 days.CriticismsThe study used a single-group cohort design, lacking a placebo or comparator group.Strict eligibility criteria may limit the generalizability of findings.The efficacy population excluded patients with baseline anti-factor Xa activity below certain levels.Further analysis is required to detail the relationship between reduction in anti–factor Xa activity and clinical hemostatic outcomes.FundingSupported by Portola Pharmaceuticals.Further ReadingAdditional information can be found in the supplementary material provided, including the full text, and a complete list of the investigators involved in the study (available at NEJM.org).