Safety and Efficacy of Apixaban Versus Enoxaparin/Warfarin in Patients with Extremes of Body Weight: Post-Hoc Analysis of the AMPLIFY Trial

BACKGROUND: Guidelines recommend avoiding direct oral anticoagulants (DOACs) in patients who weigh >120 kg due to limited clinical data in this population. OBJECTIVES: The objective of this post-hoc analysis of the AMPLIFY trial was to evaluate the efficacy, safety, and exposure of apixaban for the treatment of VTE in patients across the following weight categories: ≤ 60 kg, >60 to <100 kg, ≥ 100 to < 120 kg and ≥ 120 kg. METHODS: This analysis evaluated the efficacy (VTE/VTE related deaths) and safety (Major and composite of Major and Clinically Relevant Non-Major [CRNM] bleeds) of apixaban versus enoxaparin/warfarin in patients for the following four body weight categories: ≤ 60 kg, >60 to <100 kg, ≥ 100 to < 120 kg and ≥ 120 kg. Patients were randomized to apixaban or enoxaparin /warfarin and treated for 6 months and were followed up 30 days after the end of the intended treatment period. The exposure of apixaban across the sub-groups of weight was also evaluated. RESULTS: Of the 5356 patients randomized and included in the safety analysis with body weights recorded, there were 473, 3844, 749, and 290 patients in body weight categories ≤ 60 kg, >60 to <100 kg, ≥ 100 to < 120 kg, and ≥ 120 kg, respectively. The rates of VTE/VTE-related death for apixaban versus enoxaparin/warfarin were similar across the sub-groups of weight with relative risks (RR) and 95% confidence intervals (CI) of 0.63 (95% CI: 0.23, 1.72), 0.99 (95% CI: 0.65, 1.50), 0.77 (95% CI: 0.34, 1.72), and 0.20 (95% CI: 0.02, 1.72) for ≤ 60 kg, >60 to <100 kg, ≥ 100 to < 120 kg, and ≥ 120 kg, respectively (treatment by weight interaction P-value = 0.44). There was a reduction in Major Bleeding events in the >60 to <100 kg sub-group on apixaban compared to enoxaparin/warfarin with RR=0.41 (95% CI; 0.21, 0.77). Due to the low numbers of Major Bleeding events (apixaban: 0/377, enoxaparin/warfarin: 7/372), the RR in the subgroup of weight ≥ 100 to < 120 kg was not estimable. The RRs for ≤ 60 kg, and ≥ 120 kg weight sub-groups were 0.15 (95% CI: 0.02, 1.15), and 0.34 (95% CI: 0.04, 3.22), respectively. For the composite end-point of Major and CRNM bleeds, apixaban-treated patients had less events compared to enoxaparin/warfarin-treated patients across sub-groups of weight [RR of 0.46 (95% CI: 0.24, 0.89) for ≤ 60 kg, RR of 0.49 (95% CI: 0.38, 0.63) for >60 to <100 kg, RR of 0.30 (95% CI: 0.16, 0.58) for ≥ 100 to < 120 kg, and RR of 0.28 (95% CI: 0.12, 0.66) for ≥ 120 kg weight categories (treatment by weight interaction P-value = 0.36)]. A total of 281 patients had apixaban plasma concentrations measured. There was a small non-clinically significant decrease (<30%) in the median predicted exposure across weight sub-groups (2990, 2734, 2239 and 2006 ng*hr/ml in the ≤ 60 kg, >60 to <100 kg, ≥ 100 to < 120 kg and ≥ 120 kg weight categories, respectively). The exposure range was similar among weight categories with overlapping quartiles. CONCLUSION: In this post-hoc analysis, the safety and efficacy of apixaban in patients with extremes of body weight are consistent with the main results of the AMPLIFY trial. Across sub-groups of body weight including extremes of body weight, apixaban compared with enoxaparin/warfarin resulted in similar rates of recurrent VTE/VTE-related death, and reductions in the rates of the composite of Major and CRNM bleeds. There were also no clinically significant differences in apixaban exposure in patients with extremes of body weight compared to those in the >60 to <100 kg weight category. Lee: Pfizer Inc.: Employment, Equity Ownership. Pan:Pfizer: Employment. Byon:Pfizer: Employment, Equity Ownership. Ilyas:Pfizer: Employment, Equity Ownership.