Enoxaparin

Safety analyses included all the patients who had received andexanet. The efficacy analysis population included only patients who retrospectively met both of two criteria: baseline anti-factor Xa activity of at least 75 ng per milliliter (or ≥0.25 IU per milliliter for patients receiving enoxaparin) and confirmed major bleeding at presentation, as determined by the adjudication committee. Initially, a sample of 250 patients was planned, which would provide 80% power to show that the percentage of patients with excellent or good hemostatic efficacy was more than 50%. The sample was adjusted to 350 patients in protocol amendment 4 (January 2017) to meet new regulatory requirements for sufficient numbers of patients for each factor Xa inhibitor and to have at least 120 patients with intracranial hemorrhage in the efficacy analysis population.
Continuous variables are summarized as mean and standard deviation or median and interquartile range; categorical variables are presented as frequencies. Percent change from baseline in anti-factor Xa activity was computed with a two-sided nonparametric confidence interval for the median.¹⁰ Percentages of patients with effective hemostasis are presented with a 95% confidence interval calculated with the binomial test. The association between hemostatic efficacy and change in anti-factor Xa activity was examined with the use of receiver-operating-characteristic (ROC) curves.^{11 (link)} Analyses were performed with the use of SAS software, version 9.4 (SAS Institute).

Patients were enrolled at 63 centers in North America and Europe. Patients were eligible if they were at least 18 years of age, presented with acute major bleeding, and had received within 18 hours one of the following: apixaban, rivaroxaban, or edoxaban at any dose or enoxaparin at a dose of at least 1 mg per kilogram of body weight per day. Acute major bleeding was defined as bleeding having one or more of the following features: potentially life-threatening bleeding with signs or symptoms of hemodynamic compromise (e.g., severe hypotension, poor skin perfusion, mental confusion, or low cardiac output that could not otherwise be explained); bleeding associated with a decrease in the hemoglobin level of at least 2 g per deciliter (or a hemoglobin level of ≤8 g per deciliter if no baseline hemoglobin level was available); or bleeding in a critical area or organ (e.g., retroperitoneal, intraarticular, pericardial, epidural, or intracranial bleeding or intramuscular bleeding with compartment syndrome). Written informed consent was obtained from all the patients, whether directly from the patient, by proxy consent from a legally authorized representative, or by emergency consent (as described in the Supplementary Appendix, available at NEJM.org).
Patients were enrolled from April 2015 through May 2018. From July 2016 through August 2017, only patients with intracranial hemorrhage were enrolled to enrich the study with these patients. After August 2017, patients with all types of bleeding except visible, musculoskeletal, or intraarticular bleeding were enrolled. Substantive amendments to the enrollment criteria during the trial are presented in the Supplementary Appendix.
Key exclusion criteria were planned surgery within 12 hours after andexanet treatment (with the exception of minimally invasive operations or procedures); intracranial hemorrhage in a patient with a score of less than 7 on the Glasgow Coma Scale (scores range from 15 [normal] to 3 [deep coma]) or an estimated hematoma volume of more than 60 cc; expected survival of less than 1 month; the occurrence of a thrombotic event within 2 weeks before enrollment; or use of any of the following agents within the previous 7 days: vitamin K antagonist, dabigatran, prothrombin complex concentrate, recombinant factor VIIa, whole blood, or plasma.