Dronedarone vs. placebo in patients with atrial fibrillation or atrial flutter across a range of renal function: a post hoc analysis of the ATHENA trial

Mate Vamos, Jonas Oldgren, Gi-Byoung Nam, Gregory Y H Lip, Hugh Calkins, Jun Zhu, Kwo-Chang Ueng, Ulf Ludwigs, Mattias Wieloch, John Stewart, Stefan H Hohnloser, Mate Vamos, Jonas Oldgren, Gi-Byoung Nam, Gregory Y H Lip, Hugh Calkins, Jun Zhu, Kwo-Chang Ueng, Ulf Ludwigs, Mattias Wieloch, John Stewart, Stefan H Hohnloser

Abstract

Aims: Use of antiarrhythmic drugs (AADs) in patients with chronic kidney disease (CKD) is challenging owing to issues with renal clearance, drug accumulation, and increased proarrhythmic risks. Because CKD is a common comorbidity in patients with atrial fibrillation/atrial flutter (AF/AFL), it is important to establish the efficacy and safety of AAD treatment in patients with CKD.

Methods and results: Dronedarone efficacy and safety in individuals with AF/AFL and varying renal functionality [estimated glomerular filtration rate (eGFR): ≥60, ≥45 and <60, and <45 mL/min] was investigated in a post hoc analysis of ATHENA (NCT00174785), a randomized, double-blind trial of dronedarone vs. placebo in patients with paroxysmal or persistent AF/AFL plus additional cardiovascular (CV) risk factors. Log-rank testing and Cox regression were used to compare the incidence of endpoints between treatments. Overall, 4588 participants were enrolled from the trial. There was no interaction between treatment group and baseline eGFR assessed as a continuous variable (P = 0.743) for the first CV hospitalization or death from any cause (primary outcome). This outcome was lower with dronedarone vs. placebo across a wide range of renal function. First CV hospitalization and first AF/AFL recurrence were both lower in the two least renally impaired subgroups with dronedarone vs. placebo. Treatment emergent adverse events leading to treatment discontinuation were more frequent with dronedarone vs. placebo and occurred more often in patients with severe renal impairment.

Conclusion: Dronedarone is an effective AAD in patients with AF/AFL and CV risk factors across a wide range of renal function.

Keywords: ATHENA; Atrial fibrillation; Atrial flutter; Chronic kidney disease; Dronedarone; Safety.

© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.

Figures

Graphical Abstract
Graphical Abstract
Post-hoc analysis of the ATHENA trial demonstrates the efficacy of dronedarone across a wide range of renal function
Figure 1
Figure 1
Hazard ratio (95% confidence interval) for first cardiovascular hospitalization or death from any cause related to treatment with dronedarone vs. placebo according to baseline estimated glomerular filtration rate. Hazard ratio and 95% confidence interval (dotted lines) shown. Test of interaction between treatment group and estimated glomerular filtration rate (Chronic Kidney Disease-Epidemiology Collaboration) as a continuous variable: P-value = 0.7434. CI, confidence interval; eGFR, estimated glomerular filtration rate; and HR, hazard ratio.
Figure 2
Figure 2
Number of patients experiencing first cardiovascular hospitalization or death from any cause. The ‘ATHENA primary analysis’ data are from Hohnloser et al.*Probability of interaction between the treatment group and the subgroup. Total patients in dronedarone and placebo subgroups—≥60 mL/min: 1320 and 1301; ≥45 and <60 mL/min: 649 and 683; <45 mL/min: 313 and 322. CKD-EPI, Chronic Kidney Disease-Epidemiology Collaboration; CI, confidence interval; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HR, hazard ratio; and PBO, placebo.
Figure 3
Figure 3
Number of patients with (A) first cardiovascular hospitalization, (B) death from any cause, and (C) first atrial fibrillation / atrial flutter recurrence. The ‘ATHENA primary analysis’ data are from Hohnloser et al. *Probability of interaction between the treatment group and the subgroup. Total patients in dronedarone and placebo subgroups—≥60 mL/min: 1320 and 1301; ≥45 and <60 mL/min: 649 and 683; <45 mL/min: 313 and 322. AF, atrial fibrillation; AFL, atrial flutter; CKD-EPI, Chronic Kidney Disease-Epidemiology Collaboration; CI, confidence interval; CV, cardiovascular; eGFR, estimated glomerular filtration rate; HR, hazard ratio; and PBO, placebo.
Figure 4
Figure 4
Percentage change from baseline in creatinine by estimated glomerular filtration rate category, with study time displayed on the x-axis.

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