The Safety and Efficacy of Full Versus Reduced Dose Betrixaban in the Acute Medically Ill VTE (Venous Thromboembolism) Prevention with Extended Duration Betrixaban (APEX) Trial

• Published in: The American heart journal 2017-03, Vol.185, p.93-100
• Main Authors: Gibson, C. Michael, Halaby, Rim, Korjian, Serge, Daaboul, Yazan, Arbetter, Douglas F, Yee, Megan K, Goldhaber, Samuel Z, Hull, Russel, Hernandez, Adrian F, Gold, Alex, Wiens, Brian, Leeds, Janet, Harrington, Robert A, Cohen, Alexander T
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Anticoagulants; Anticoagulants - therapeutic use; Benzamides - administration & dosage; Bleeding; Cardiovascular; Clinical trials; Double-Blind Method; Drug dosages; Effectiveness; Embolism; Enoxaparin - therapeutic use; Factor Xa Inhibitors - administration & dosage; Female; Glycoproteins; Health risk assessment; Hemorrhage - chemically induced; Hospitalization; Humans; Kidney transplantation; Laboratories; Male; P-Glycoprotein; Pharmacokinetics; Pharmacology; Population; Prevention; Pulmonary Embolism - prevention & control; Pyridines - administration & dosage; Reduction; Renal insufficiency; Risk; Risk management; Risk reduction; Safety; Studies; Thromboembolism; Thrombosis; Venous Thromboembolism - prevention & control; Venous Thrombosis - prevention & control
• ISSN: 0002-8703; 1097-6744
• DOI: 10.1016/j.ahj.2016.12.004

Background The Acute Medically Ill VTE (Venous Thromboembolism) Prevention with Extended Duration Betrixaban (APEX) trial assessed the safety and efficacy of extended-duration thromboprophylaxis using betrixaban versus standard dosing of enoxaparin among acutely ill medical patients. The 80 mg betrixaban dose was halved to 40 mg among subjects with severe renal insufficiency and those receiving a concomitant strong P-glycoprotein (P-gp) inhibitor. Methods This analysis assessed the pharmacokinetics, efficacy and safety of full (80 mg) and reduced dose (40 mg) betrixaban relative to enoxaparin in the APEX trial. Results The median concentration of betrixaban among subjects administered the 80 mg dose was higher than that of the 40 mg dose (19 ng/ml vs 11 ng/ml, P < .001). In the primary analysis Cohort 1 (D-dimer ≥2X ULN), the primary efficacy outcome (PEO) (asymptomatic proximal DVT, symptomatic proximal or distal DVT, symptomatic nonfatal PE, or VTE-related death) was significantly reduced among subjects treated with 80 mg of extended dose betrixaban vs enoxaparin [6.27% (95/1516) vs 8.39% (130/1549), RRR = 0.26 (0.04–0.42), P = .023]; and similarly in the entire PEO population [4.87% (122/2506) vs 7.06% (181/2562), RRR = 0.30 (0.13–0.44), P = .001]. There was no difference in the primary outcome for subjects treated with 40 mg betrixaban dose vs enoxaparin across Cohorts. Additionally, there was no excess of major bleeding associated with either betrixaban dose compared with enoxaparin. Conclusions The 80 mg betrixaban dose achieves higher serum concentrations than the 40 mg dose and is associated with improved efficacy across all cohorts relative to standard dose enoxaparin, without an excess risk of major bleeding in the management of medically ill patients.