Dronedarone Versus Sotalol in Antiarrhythmic Drug-Naive Veterans With Atrial Fibrillation.

BACKGROUND: Sotalol and dronedarone are both used for maintenance of sinus rhythm for patients with atrial fibrillation. However, while sotalol requires initial monitoring for QT prolongation and proarrhythmia, dronedarone does not. These treatments can be used in comparable patients, but their safety and effectiveness have not been compared head to head. Therefore, we retrospectively evaluated the effectiveness and safety using data from a large health care system. METHODS: Using Veterans Health Administration data, we identified 11 296 antiarrhythmic drug-naive patients with atrial fibrillation prescribed dronedarone or sotalol in 2012 or later. We excluded patients with prior conduction disease, pacemakers or implantable cardioverter-defibrillators, ventricular arrhythmia, cancer, renal failure, liver disease, or heart failure. We used natural language processing to identify and compare baseline left ventricular ejection fraction between treatment arms. We used 1:1 propensity score matching, based on patient demographics, comorbidities, and medications, and Cox regression to compare strategies. To evaluate residual confounding, we performed falsification analysis with nonplausible outcomes. RESULTS: The matched cohort comprised 6212 patients (3106 dronedarone and 3106 sotalol; mean [±SD] age, 71±10 years; 2.5% female; mean [±SD] CHA2DS2-VASC, 2±1.3). The mean (±SD) left ventricular ejection fraction was 55±11 and 58±10 for dronedarone and sotalol users, correspondingly. Dronedarone, compared with sotalol, did not demonstrate a significant association with risk of cardiovascular hospitalization (hazard ratio, 1.03 [95% CI, 0.88-1.21]) or all-cause mortality (hazard ratio, 0.89 [95% CI, 0.68-1.16]). However, dronedarone was associated with significantly lower risk of ventricular proarrhythmic events (hazard ratio, 0.53 [95% CI, 0.38-0.74]) and symptomatic bradycardia (hazard ratio, 0.56 [95% CI, 0.37-0.87]). The primary findings were stable across sensitivity analyses. Falsification analyses were not significant. CONCLUSIONS: Dronedarone, compared with sotalol, was associated with a lower risk of ventricular proarrhythmic events and conduction disorders while having no difference in risk of incident cardiovascular hospitalization and mortality. These observational data provide the basis for prospective efficacy and safety trials.

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.

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.

Amiodarone, Unlike Dronedarone, Activates Inflammasomes via Its Reactive Metabolites: Implications for Amiodarone Adverse Reactions.

Amiodarone is a benzofuran derivative used to treat arrhythmias, but its use is limited by adverse reactions. There is evidence that some of the severe adverse reactions such as liver injury and interstitial lung disease are immune-mediated; however, details of the mechanism have not been elucidated. We tested the ability of amiodarone to induce the release of danger-associated molecular patterns (DAMPs) that activate inflammasomes. Human hepatocarcinoma functional liver cell-4 (FLC-4) cells were used for drug bioactivation, and the detection of inflammasome activation was performed with the human macrophage cell line, THP-1 cells. Amiodarone is known to be oxidized to reactive quinone metabolites. The supernatant from the incubation of amiodarone with FLC-4 cells for 7 days increased caspase-1 activity and production of IL-1ß by THP-1 cells. In the supernatant of FLC-4 cells with amiodarone, the heat shock protein (HSP) 40 was significantly increased. Addition of a cytochrome P450 inhibitor to the FLC-4 cells prevented the release of HSP40 from the FLC-4 cells and activation of THP-1 inflammasomes by the FLC-4 supernatant. These results suggested that the reactive quinone metabolites of amiodarone can cause the release of DAMPs from hepatocytes which can activate inflammasomes. Dronedarone, a safer analog of amiodarone, did not activate inflammasomes. Inflammasome activation may be an important step in the activation of the immune system by amiodarone, which in some patients, can cause immune-related adverse events. In addition, our data suggest that drugs that block the effects or the formation of IL-1ß would provide better treatment of amiodarone-induced immune-related adverse reactions.