Efficacy and safety of edoxaban compared with warfarin according to the burden of diseases in patients with atrial fibrillation: insights from the ENGAGE AF-TIMI 48 trial

Abstract

Aims Non-vitamin K antagonist oral anticoagulants represent a new option for prevention of embolic events in patients with atrial fibrillation (AF). However, little is known about the impact of non-cardiac comorbidities on the efficacy and safety profile of these drugs. Methods and results In a post hoc analysis of the ENGAGE AF-TIMI 48 trial, we analysed 21 105 patients with AF followed for an average of 2.8 years and randomized to either a higher-dose edoxaban regimen (HDER), a lower-dose edoxaban regimen, or warfarin. We used the updated Charlson Comorbidity Index (CCI) to stratify the patients according to the burden of concomitant disease (CCI = 0, 1, 2, 3, and ≥4). The treatment groups were then compared for safety, efficacy, and net clinical outcomes across CCI categories. There were 32.0%, 7.3%, 42.1%, 12.7%, and 6.0% of patients with CCI scores of 0, 1, 2, 3, and ≥4, respectively. A CCI score ≥4 was associated with significantly higher rates of thromboembolic events, bleeding, and death compared to CCI = 0 (P < 0.05 for each). The annualized rates of the primary net clinical outcome (stroke/systemic embolism, major bleeding, or death) for CCI = 0, 1, 2, 3, or ≥4 were 5.9%, 8.7%, 6.6%, 10.3%, and 13.6% (Ptrend < 0.001). There were no significant interactions between treatment with HDER vs. warfarin and efficacy, safety, and net outcomes across the CCI groups (P-interaction > 0.10 for each). Conclusion Although increasing CCI scores are associated with worse outcomes, the efficacy, safety, and net clinical outcomes of edoxaban vs. warfarin were independent of the degree of comorbidity present.

Edoxaban versus Warfarin in Patients with Atrial Fibrillation at the Extremes of Body Weight: An Analysis from the ENGAGE AF-TIMI 48 Trial

“…It is noteworthy that poorer outcomes in patients with LBW occurred despite a lower mean Charlson comorbidity index as compared with the other two weight groups. 16,17 The complexity of the clinical status of patients with LBW is further underscored by the data on endogenous FXa, which are presented here for the first time for subgroups of patients at the extremes of weight. Patients with LBW had the lowest levels of endogenous FXa at baseline, which per se characterize a higher bleeding risk.…”

“…The proportion of time with an INR in the therapeutic range (2.0-3.0) differed according to weight categories, with median (interquartile range) values of 63.0% (49.0-73.0) for LBW patients, 69.3% (55.9-77.8) MBW, and 70.1% (61.0-79.9) HBW (P trend < 0.001). This difference was due to a greater proportion of time with a low INR (<2.0) in patients with LBW: INR < 2.0 in 22.6% (13.7-34.9) vs. 17.7% (10.7-28.3) vs. 16.3% (9.7-24.7) (P trend < 0.001). Smaller differences were present in the proportion of time with a high INR (>3.0): 11.2 vs. 10.9 vs. 10.9% (P trend ¼ 0.030).…”

“…The burden of comorbid illnesses was assessed by the updated Charlson comorbidity index, calculated for each patient. 16,17 Blood samples were collected at baseline prior to the first dose of study drug for endogenous FXa activity, at peak and trough 1 month after randomization for concentrations of edoxaban, exogenous anti-FXa activity, and % inhibition of baseline FXa activity measurements, and they were measured as previously described. 18,19 The time-in-therapeutic range (TTR) for the warfarin group was calculated as the percentage of days with an INR 2.0 to 3.0, using linear interpolation.…”

Unmet Clinical Needs in Elderly Patients Receiving Direct Oral Anticoagulants for Stroke Prevention in Non-valvular Atrial Fibrillation

“…In a more recent subanalysis of the ENGAGE-AF study, patients were stratified according to concomitant burden disease using the updated Charlson Comorbidity Index. The efficacy, safety, and net clinical benefit outcomes of edoxaban compared to warfarin were independent of the degree of comorbidity [ 16 ].…”

Direct Oral Anticoagulant Edoxaban in Patients with Non-Valvular Atrial Fibrillation: Results of Direct Comparison with Warfarin

“…Существенных различий по эффективности, безопасности и совокупному клиническому эффекту между варфарином и эдоксабаном в суточной дозе 60 / 30 мг у больных с разной суммой баллов по модифицированному индексу коморбидности Charlson (0, 1, 2, 3 и ≥4), а также у принимающих одновременно 0-3, 4 и ≥5 лекарственных средств, не отмечено [6].…”