Dataset Information

Efficacy and safety of dronedarone versus placebo in patients with atrial fibrillation stratified according to renal function: Post hoc analyses of the EURIDIS-ADONIS trials.

ABSTRACT:

Background

The use of antiarrhythmic drugs (AADs) in patients with chronic kidney disease (CKD) is complex because impaired renal clearance can cause increased drug levels, and risk of intolerance or adverse events. Due to the propensity for CKD to occur alongside atrial fibrillation/atrial flutter (AF/AFL), it is essential that AAD safety and efficacy are assessed for patients with CKD.

Hypothesis

Dronedarone, an approved AAD, may present a suitable therapeutic option for patients with AF/AFL and concomitant CKD.

Methods

EURIDIS-ADONIS (EURIDIS, NCT00259428; ADONIS, NCT00259376) were identically designed, multicenter, double-blind, parallel-group trials investigating AF/AFL control with dronedarone 400 mg twice daily versus placebo (randomized 2:1). In this post hoc analysis, the primary endpoint was time to first AF/AFL. Patients were stratified according to renal function using the CKD-Epidemiology Collaboration equation and divided into estimated glomerular filtration rate (eGFR) subgroups of 30-44, 45-59, 60-89, and ≥90 ml/min. Time-to-events between treatment groups were compared using log-rank testing and Cox regression.

Results

At baseline, most (86%) patients demonstrated a mild or mild-to-moderate eGFR decrease. Median time to first AF/AFL recurrence was significantly longer with dronedarone versus placebo for all eGFR subgroups except the 30 to 44 ml/min group, where the trend was similar but statistical power may have been limited by the small population. eGFR stratification had no significant effect on serious adverse events, deaths, or treatment discontinuations.

Conclusions

This analysis suggests that dronedarone could be an effective therapeutic option for AF with an acceptable safety profile in patients with impaired renal function.

SUBMITTER: Thind M

PROVIDER: S-EPMC8799050 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Publications

Efficacy and safety of dronedarone versus placebo in patients with atrial fibrillation stratified according to renal function: Post hoc analyses of the EURIDIS-ADONIS trials.

Thind Munveer M Zareba Wojciech W Atar Dan D Crijns Harry J G M HJGM Zhu Jun J Pak Hui-Nam HN Reiffel James J Ludwigs Ulf U Wieloch Mattias M Stewart John J Kowey Peter P

Clinical cardiology 20220112 1

<h4>Background</h4>The use of antiarrhythmic drugs (AADs) in patients with chronic kidney disease (CKD) is complex because impaired renal clearance can cause increased drug levels, and risk of intolerance or adverse events. Due to the propensity for CKD to occur alongside atrial fibrillation/atrial flutter (AF/AFL), it is essential that AAD safety and efficacy are assessed for patients with CKD.<h4>Hypothesis</h4>Dronedarone, an approved AAD, may present a suitable therapeutic option for patient ...[more]

PMID: 35019175

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Project description:Dronedarone is an amiodarone derivative that was approved in the US in July 2009 to reduce the risk of cardiovascular hospitalization in patients with paroxysmal or persistent atrial fibrillation (AF), who are in sinus rhythm (SR), or who will be cardioverted.This article reviews the pharmacology, adverse effects, and clinical evidence available to date on the use of dronedarone in the management of AF and its potential role in the emergency department setting.In the EURIDIS and ADONIS studies evaluating the efficacy of dronedarone in maintaining SR, dronedarone significantly reduced the risk of recurrence of AF compared to placebo, by 22% and 27%, respectively. The ERATO study examined the ability of dronedarone to control ventricular rate in permanent AF. The DIONYSOS study demonstrated that recurrences of AF were more frequent with dronedarone. However, discontinuation of therapy due to intolerance was more frequent with amiodarone. Furthermore, the ATHENA study demonstrated that dronedarone reduced mortality and cardiovascular hospitalization by 24% (P < 0.05) in patients in SR but with other associated risks and a history of AF. However, the ANDROMEDA study, evaluating the use of dronedarone in patients with recent decompensated heart failure, and the PALLAS study, evaluating the use of dronedarone in patients with chronic AF, were both terminated prematurely due to a trend toward an increased risk of cardiovascular events.Dronedarone has been demonstrated to be effective in reducing the incidence of AF recurrence. It appears to be less effective but better tolerated than amiodarone. Dronedarone appears to have a low proarrhythmic risk and is the first anti-arrhythmic that has been demonstrated to reduce cardiovascular mortality and cardiovascular hospitalization in clinically stable patients with other risk factors for recurrent AF. Therefore, dronedarone can be recommended as an anti-arrhythmic of choice in clinically stable patients for maintaining SR. If dronedarone is to be used in a patient with chronic stable heart failure, the patient must be monitored closely for any worsening of heart failure symptoms. The drug must be discontinued should the heart failure symptoms worsen.

Project description:ObjectivesThe aim of this study was to evaluate the effectiveness of a combination of dronedarone and ranolazine in suppression of atrial fibrillation (AF).BackgroundSafe and effective pharmacological management of AF remains one of the greatest unmet medical needs.MethodsThe electrophysiological effects of dronedarone (10 μmol/l) and a relatively low concentration of ranolazine (5 μmol/l) separately and in combination were evaluated in canine isolated coronary-perfused right and left atrial and left ventricular preparations as well as in pulmonary vein preparations.ResultsRanolazine caused moderate atrial-selective prolongation of action potential duration and atrial-selective depression of sodium channel-mediated parameters, including maximal rate of rise of the action potential upstroke, leading to the development of atrial-specific post-repolarization refractoriness. Dronedarone caused little or no change in electrophysiological parameters in both atrial and ventricular preparations. The combination of dronedarone and ranolazine caused little change in action potential duration in either chamber but induced potent use-dependent atrial-selective depression of the sodium channel-mediated parameters (maximal rate of rise of the action potential upstroke, diastolic threshold of excitation, and the shortest cycle length permitting a 1:1 response) and considerable post-repolarization refractoriness. Separately, dronedarone or a low concentration of ranolazine prevented the induction of AF in 17% and 29% of preparations, respectively. In combination, the 2 drugs suppressed AF and triggered activity and prevented the induction of AF in 9 of 10 preparations (90%).ConclusionsLow concentrations of ranolazine and dronedarone produce relatively weak electrophysiological effects and weak suppression of AF when used separately but when combined exert potent synergistic effects, resulting in atrial-selective depression of sodium channel-dependent parameters and effective suppression of AF.

Project description:BackgroundSeveral studies have investigated the effect of direct oral anticoagulants (DOACs) in Latin American patients with atrial fibrillation (AF), but the results remain controversial. Therefore, we aimed to compare the efficacy and safety of DOACs vs. warfarin in Latin American patients with AF.MethodsWe systematically searched the PubMed and Embase databases until November 2021 for studies that compared the effect of DOACs vs. warfarin in Latin patients with AF. Adjusted hazard ratios (HRs) and 95% CIs were pooled by a random-effects model using an inverse variance method.ResultsFour post-hoc analyses of randomized clinical trials (RCTs) involving 42,411 DOACs and 29,270 warfarin users were included. In Latin American patients with AF, for the effectiveness outcomes, the use of DOACs compared with warfarin was significantly associated with decreased risks of stroke or systemic embolism (SSE) (HR = 0.78; 95%CI.64-0.96), stroke (HR = 0.75; 95%CI.57-0.99), hemorrhagic stroke (HR = 0.14; 95%CI.05-0.36), all-cause death (HR = 0.89; 95% CI.80-1.00), but not ischemic stroke and cardiovascular death. For the safety outcomes, compared with warfarin, the use of DOACs was associated with reduced risks of major or non-major clinically relevant (NMCR) bleeding (HR = 0.70; 95% CI.57-0.86), major bleeding (HR = 0.70; 95%CI.53-0.92), intracranial hemorrhage (ICH) (HR = 0.42; 95%CI.24-0.74), or any bleeding (HR = 0.70;95% CI.62-0.78), but not gastrointestinal bleeding. In non-Latin American patients with AF, for the effectiveness outcomes, the use of DOACs compared with warfarin was significantly associated with decreased risks of SSE (HR = 0.87; 95%CI.75-1.00), hemorrhagic stroke (HR = 0.41; 95%CI.28-0.60), cardiovascular death (HR = 0.87; 95% CI.81-0.94), all-cause death (HR = 0.90; 95% CI.85-0.94). Conversely, the risk of myocardial infarction increased (HR = 1.34; 95% CI 1.13-1.60), but not ischemic stroke. For the safety outcomes, compared with warfarin, the use of DOACs was associated with reduced risks of major or NMCR bleeding (HR = 0.75; 95%CI.61-0.92), major bleeding (HR = 0.76; 95%CI.63-0.92), ICH (HR = 0.42; 95%CI.36-0.52), and any bleeding (HR = 0.81; 95% CI.71-0.92), but not gastrointestinal bleeding.ConclusionCurrent pooled data from the four post-hoc analyses of RCTs suggested that compared with warfarin, DOACs appeared to have significant reductions in SSE, stroke, hemorrhagic stroke, all-cause death, major or NMCR bleeding, major bleeding, ICH, and any bleeding, but comparable risks of ischemic stroke, cardiovascular death, and gastrointestinal bleeding in Latin American patients with AF. DOACs appeared to have significant reductions in SSE, hemorrhagic stroke, all-cause death, cardiovascular death, major or NMCR bleeding, major bleeding, ICH, and any bleeding, and increased the risk of myocardial infarction, but comparable risks of stroke, ischemic stroke, and gastrointestinal bleeding in non-Latin American patients with AF.

Dataset Information

Efficacy and safety of dronedarone versus placebo in patients with atrial fibrillation stratified according to renal function: Post hoc analyses of the EURIDIS-ADONIS trials.

Background

Hypothesis

Methods

Results

Conclusions

Publications

Efficacy and safety of dronedarone versus placebo in patients with atrial fibrillation stratified according to renal function: Post hoc analyses of the EURIDIS-ADONIS trials.

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