Apixaban-Calibrated Anti-FXa Activity in Relation to Outcome Events and Clinical Characteristics in Patients with Atrial Fibrillation: Results from the AVERROES Trial

Abstract

Background In patients with nonvalvular atrial fibrillation (AF), apixaban is given in doses of 5 or 2.5 mg twice daily, according to clinical characteristics. The usual on-treatment range of apixaban drug levels, as determined by apixaban-calibrated anti-factor Xa (anti-Xa) activity, has previously been measured in small cohorts; however, the association between anti-Xa activity and clinical outcomes and the predictors of variability in anti-Xa activity have not been well studied in the AF population. Methods and Results Anti-Xa activity was measured before taking the morning dose, 3 months after enrollment in the AVERROES study using a calibrated anti-Xa assay (Rotachrom). Patients with two of the following criteria-age >80; weight <60 kg; or creatinine >133 μg/L-received 2.5 mg twice daily ( n = 145), while all others received 5 mg twice daily ( n = 2,247). A total of 2,392 patients were included, with median follow-up of 1.1 years. Median apixaban anti-Xa activity was 122 ng/mL (interquartile range [IQR]: 63-198 ng/mL) for the entire group; 99 ng/mL (IQR: 60-146 ng/mL) for the 2.5-mg group; and 125 ng/mL (IQR: 64-202 ng/mL) for the 5-mg group ( p = 0.003). A relationship was evident between bleeding and anti-Xa activity ( p = 0.01), which was driven by minor bleeding. No relationship was evident between major bleeding or stroke/systemic embolism and anti-Xa activity. In those receiving the 5-mg dose, estimated glomerular filtration rate, sex, and age had the strongest association with anti-Xa activity. Conclusion There is considerable variability in anti-Xa activity among AF patients receiving apixaban. Rates of major bleeding and stroke/systemic embolism were low irrespective of anti-Xa activity. Clinical Trial Registration ClinicalTrials.gov NCT00496769; https://clinicaltrials.gov/ct2/show/NCT00496769 .

Keywords: apixaban; fibrillation; hemorrhage; systemic embolism.

Fig. 1

Apixaban-calibrated anti-Xa activity by dose. Blood samples were drawn immediately prior to the morning dose of apixaban. Boxes represent median and interquartile range, whiskers represent 10th to 90th centiles, and points represent minimum and maximum.

Fig. 2

Stroke/systemic embolism and bleeding versus anti-Xa activity. Predicted probability of ( A ) stroke/systemic embolism; or ( B ) bleeding of any severity (minor, clinically relevant nonmajor, or major) versus anti-Xa activity. The shaded region represents the 95% confidence interval.