Pleiotropic effects of antiarrhythmic agents: dronedarone in the treatment of atrial fibrillation.
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ABSTRACT:
SUBMITTER: Heijman J
PROVIDER: S-EPMC3747997 | biostudies-literature | 2013
REPOSITORIES: biostudies-literature
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Pleiotropic effects of antiarrhythmic agents: dronedarone in the treatment of atrial fibrillation.
Heijman Jordi J Heusch Gerd G Dobrev Dobromir D
Clinical Medicine Insights. Cardiology 20130811
Atrial fibrillation remains the most common arrhythmia in clinical practice. Dronedarone is an antiarrhythmic drug for the maintenance of sinus rhythm in patients with atrial fibrillation. Dronedarone is an amiodarone derivative developed to reduce the number of extracardiovascular side effects. Dronedarone has undergone extensive experimental and clinical testing during the last decade. On the aggregate, these studies have highlighted a complex set of pleiotropic actions that may contribute to ...[more]
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Project description:Atrial fibrillation (AF), the most common cardiac arrhythmia worldwide, is driven by complex mechanisms that differ between subgroups of patients. This complexity is apparent from the different forms in which AF presents itself (post-operative, paroxysmal and persistent), each with heterogeneous patterns and variable progression. Our current understanding of the mechanisms responsible for initiation, maintenance and progression of the different forms of AF has increased significantly in recent years. Nevertheless, antiarrhythmic drugs for the management of AF have not been developed based on the underlying arrhythmia mechanisms and none of the currently used drugs were specifically developed to target AF. With the increased knowledge on the mechanisms underlying different forms of AF, new opportunities for developing more effective and safer AF therapies are emerging. In this review, we provide an overview of potential novel antiarrhythmic approaches based on the underlying mechanisms of AF, focusing both on the development of novel antiarrhythmic agents and on the possibility of repurposing already marketed drugs. In addition, we discuss the opportunity of targeting some of the key players involved in the underlying AF mechanisms, such as ryanodine receptor type-2 (RyR2) channels and atrial-selective K+-currents (IK2P and ISK) for antiarrhythmic therapy. In addition, we highlight the opportunities for targeting components of inflammatory signaling (e.g., the NLRP3-inflammasome) and upstream mechanisms targeting fibroblast function to prevent structural remodeling and progression of AF. Finally, we critically appraise emerging antiarrhythmic drug principles and future directions for antiarrhythmic drug development, as well as their potential for improving AF management.
| S-EPMC9029767 | biostudies-literature
Project description:BackgroundCurrently available antiarrhythmic drugs (AADs) for the prevention of atrial fibrillation (AF)/atrial flutter (AFL) suffer from incomplete efficacy and poor tolerability.HypothesisDronedarone could represent an effective and safe option in patients previously treated with AADs, especially class Ic AADs and sotalol.MethodsRetrospective analysis of 2 double-blind, parallel-group trials (EURIDIS [European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm] and ADONIS [American-Australian-African Trial With Dronedarone in Atrial Fibrillation or Flutter Patients for the Maintenance of Sinus Rhythm]) comparing the efficacy and safety of dronedarone with placebo over 12 months. The primary end point was AF/AFL recurrence in patients previously treated with another AAD that was discontinued for whatever reason prior to randomization.ResultsIn patients previously treated with any AADs, dronedarone decreased the risk of AF recurrence by 30.4% vs placebo (hazard ratio [HR]: 0.70; 95% confidence interval [CI]: 0.59-0.82; P < 0.001). In patients previously treated with a class Ic agent, dronedarone decreased the risk of recurrence by 31.4% (HR: 0.69; 95% CI: 0.53-0.89; P = 0.004), whereas in patients previously treated with sotalol, dronedarone showed a trend toward a decrease of risk of recurrence (HR: 0.86; 95% CI: 0.67-1.11; P = 0.244). Dronedarone was equally effective irrespective of whether class Ic or sotalol were stopped for lack of efficacy or adverse events (AEs). Discontinuation rates were similar in the 2 groups (55.9% vs 43.1%), as were incidence of AEs and serious AEs.ConclusionsDronedarone seems to be effective in preventing AF recurrences in patients without permanent AF previously treated with other AADs, even if those were discontinued for lack of efficacy. Dronedarone appears to be well tolerated even in patients who already had tolerability issues with AADs.
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Project description:Atrial fibrillation (AF) is a supraventricular arrhythmia that leads to a decrease in cardiac output and impairs cardiac function and quality of life. Dronedarone has an atrial-selective property and has been used for management of AF in humans, but limited information is available in dogs. This study was designed to evaluate efficacy of dronedarone in attenuating the duration of AF in dog model of sustained AF. Six beagle dogs were anesthetized with isoflurane and instrumented to measure atrial action potential duration (aAPD) and atrial effective refractory period (AERP). Then AF was induced by rapid right atrial pacing (20 V, 40 Hz) simultaneously with infusion of phenylephrine (2 µg/kg/min, intravenously) for 20 min. The duration of sustained AF was recorded, and the animals were allowed to recover. Dronedarone was given at a dose of 20 mg/kg, BID, orally for 7 days. On the last day, the dogs were anesthetized again to record aAPD and AERP, and AF was induced with the same procedure as described above. The results showed that after dronedarone administration the aAPD was lengthened significantly from 76.4 ± 4.2 ms to 91.2 ± 3.9 ms (P<0.05) and AERP was prolonged significantly from 97.5 ± 2.8 ms to 120 ± 4.8 ms (P<0.05). The duration of sustained AF was also significantly attenuated after receipt of dronedarone (P<0.05). It can be suggested that oral dronedarone attenuates the duration of sustained AF in a dog model of AF by extending the AERP more than the aAPD, causing post-repolarization refractoriness. Hence, dronedarone may be useful for management of AF in dogs.
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Project description:BackgroundThe ATHENA (A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg bid for the Prevention of Cardiovascular Hospitalization or Death from Any Cause in Patients with Atrial Fibrillation/Atrial Flutter) trial demonstrated a significant reduction (26%) in the rate of first cardiovascular (CV) hospitalization in dronedarone-treated patients with paroxysmal or persistent atrial fibrillation/flutter (AF/AFL). ATHENA was the first trial to demonstrate a CV outcomes benefit, specifically reduced CV hospitalizations, with an antiarrhythmic drug. The objective of this study was to assess the impact of dronedarone treatment on healthcare resource utilization among real-world patients with AF/AFL in United States clinical practice.MethodsThis retrospective cohort study used claims data from the MarketScan® databases (Truven Health, Durham, NC, USA) to identify patients with ≥2 concurrent de novo pharmacy claims for dronedarone (≥180 days' total supply) between June 2009 and March 2011, and with an AF/AFL diagnosis and no heart failure-related hospitalization during the 12 months preceding the initial (index) dronedarone claim. Annualized inpatient and outpatient resource utilization were compared between the pre-index (baseline) and post-index (follow-up) periods.ResultsIn total, 5,656 AF/AFL patients were prescribed dronedarone for ≥6 months and were followed for mean (standard deviation) 11.9 (4.7) months. Reductions in mean numbers of annualized all-cause, CV- and AF-related hospitalizations (~40-45%), and emergency department visits (~30-45%) were realized. These benefits were offset by increases in office visits (~10-30%) and AF-related prescription claims (74%) after dronedarone initiation. The sub-cohort of patients switching to dronedarone from Prior Rhythm-Control therapy (n=2,080) showed similar reductions in hospital and emergency department events.ConclusionsThis study suggests that dronedarone use in real-world practice, as in the ATHENA trial, results in substantial reductions in hospital admissions, both in first-line and second-line antiarrhythmic treatment settings.
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Project description:In patients with recurrent atrial fibrillation (AF), the hallmark of treatment has been the use of antiarrhythmic drugs (AADs). Goals of therapy include reduction in the frequency and duration of episodes of arrhythmia as well an emerging goal of reducing mortality and hospitalizations associated with AF. Safety and efficacy are important factors when choosing an antiarrhythmic drug for the treatment of AF, hence, if AAD are required for maintenance of sinus rhythm, their safety profi le, together with individual patient characteristics, should be of utmost concern. In the next paragraphs we would like to review some aspects (electrophysiologic effects, metabolism, side effects, current evidence and indication) of the most commonly used AAD for the management of patients with AF, following the Vaughan-Williams classification. However, this system is mainly based on ventricular activity, therefore, and due to its relatively atrial selective actions, some agents will not readily fit in the Vaughan Williams AAD classification. For that reason, in the final part of the manuscript, new promising agents will be reviewed separately.
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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.
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Project description: Not available
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Project description:Background. Atrial fibrillation (AF) is the most common form of arrhythmia. Several trials have suggested that acupuncture may prevent AF. However, the efficacy of acupuncture for AF prevention has not been well investigated. Therefore, we designed a prospective, two-parallel-armed, participant and assessor blinded, randomized, sham-controlled clinical trial to investigate acupuncture in persistent AF (ACU-AF). Methods. A total of 80 participants will be randomly assigned to active acupuncture or sham acupuncture groups in a 1 : 1 ratio. Both groups will take the same antiarrhythmic medication during the study period. Patients will receive 10 sessions of acupuncture treatment once a week for 10 weeks. The primary endpoint is AF recurrence rate. Secondary endpoints are left atrium (LA) and left atrial appendage (LAA) changes in function and volume, and inflammatory biomarker changes. Ethics. This study protocol was approved by the institutional review boards (IRBs) of Kyung Hee University Hospital (number 1335-04). This trial is registered with clinicaltrials.gov NCT02110537.
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