Efficacy and safety of dronedarone in patients with a prior ablation for atrial fibrillation/flutter: Insights from the ATHENA study.
ABSTRACT: BACKGROUND:The role of antiarrhythmic drugs for atrial fibrillation/atrial flutter (AF/AFL) after catheter ablation is not well established. HYPOTHESIS:We hypothesized that changing the myocardial substrate by ablation may alter the responsiveness to dronedarone. METHODS:We assessed the efficacy and safety of dronedarone in the treatment of paroxysmal/persistent atrial fibrillation/atrial flutter (AF/AFL) post-ablation, based on a post hoc analysis of the ATHENA study. A total of 196 patients (dronedarone 90, placebo 106) had an ablation for AF/AFL before study entry. In these patients, the effect of treatment on the first hospitalization because of cardiovascular (CV) events/all-cause death was assessed, as was AF/AFL recurrence in individuals with sinus rhythm at baseline. The safety of dronedarone vs placebo was also determined. RESULTS:In patients with prior ablation, dronedarone reduced the risk of AF/AFL recurrence (hazard ratio [HR]: 0.65 [95% confidence interval [CI]: 0.42, 1.00]; P
Project description:<b>Background: </b>Atrial fibrillation/atrial flutter (AF/AFL) burden increases with increasing duration of AF/AFL history.<br><br><b>Hypothesis: </b>Outcomes with dronedarone may also be impacted by duration of AF/AFL history.<br><br><b>Methods: </b>In this post hoc analysis of ATHENA, efficacy and safety of dronedarone vs placebo were assessed in groups categorized by time from first known AF/AFL episode to randomization (ie, duration of AF/AFL history): <3 months (short), 3 to <24?months (intermediate), and???24?months (long).<br><br><b>Results: </b>Of 2859 patients with data on duration of AF/AFL history, 45.3%, 29.6%, and 25.1% had short, intermediate, and long histories, respectively. Patients in the long history group had the highest prevalence of structural heart disease and were more likely to be in AF/AFL at baseline. Placebo-treated patients in the long history group also had the highest incidence of AF/AFL recurrence and cardiovascular (CV) hospitalization during the study. The risk of first CV hospitalization/death from any cause was lower with dronedarone vs placebo in patients with short (hazard ratio, 0.79 [95% confidence interval: 0.65-0.96]) and intermediate (0.72 [0.56-0.92]) histories; a trend favoring dronedarone was also observed in patients with long history (0.84 [0.66-1.07]). A similar pattern was observed for first AF/AFL recurrence. No new drug-related safety issues were identified.<br><br><b>Conclusions: </b>Patients with long AF/AFL history had the highest burden of AF/AFL at baseline and during the study. Dronedarone significantly improved efficacy vs placebo in patients with short and intermediate AF/AFL histories. While exploratory, these results support the potential value in initiating rhythm control treatment early in patients with AF/AFL.
Project description:The 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.This 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.In 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.This 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.
Project description:INTRODUCTION:The phase 3 EURIDIS and ADONIS studies evaluated dronedarone for atrial fibrillation (AF)/atrial flutter (AFL) recurrence in patients with nonpermanent AF. Here we assessed whether patient characteristics and/or treatment outcomes in these studies differed based on the need for cardioversion before randomization. METHODS:Time to adjudicated first AF/AFL recurrence, symptomatic recurrence, cardiovascular hospitalization/death, and AF hospitalization, and safety were assessed by cardioversion status. RESULTS:Of 1237 patients randomized (2:1 dronedarone:placebo), 364 required baseline cardioversion (dronedarone 243, placebo 121). Patients requiring cardioversion had a greater prevalence of cardiovascular comorbidities and shorter times to first AF/AFL recurrence compared with those not requiring cardioversion. Dronedarone was associated with longer median time to first AF/AFL recurrence vs placebo regardless of cardioversion status (cardioversion: 50 vs 15 days, hazard ratio [HR] 0.76; 95% confidence interval [CI], 0.59-0.97; P?=?.02; non-cardioversion: 150 vs 77 days, HR 0.76; 95% CI, 0.64-0.90; P?<?.01). Dronedarone was similarly associated with prolonged median time to symptomatic recurrence vs placebo in the cardioversion (347 vs 87 days, HR 0.65; 95% CI, 0.49-0.87) and non-cardioversion (288 vs 120 days, HR 0.74; 95% CI, 0.62-0.90) populations. Risk of cardiovascular hospitalization/death and first AF hospitalization was lower with dronedarone vs placebo regardless of cardioversion status, but differences were not statistically significant. The safety of dronedarone was similar in both groups. CONCLUSION:Patients requiring baseline cardioversion represent a distinct population, having more underlying cardiovascular disease and experiencing a shorter time to AF/AFL recurrences. Dronedarone was associated with improved efficacy vs placebo regardless of cardioversion status.
Project description:BACKGROUND:Currently available antiarrhythmic drugs (AADs) for the prevention of atrial fibrillation (AF)/atrial flutter (AFL) suffer from incomplete efficacy and poor tolerability. HYPOTHESIS:Dronedarone could represent an effective and safe option in patients previously treated with AADs, especially class Ic AADs and sotalol. METHODS:Retrospective 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. RESULTS:In 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. CONCLUSIONS:Dronedarone 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.
Project description:<h4>Background and objectives</h4>Cavotricuspid isthmus (CTI) block is easily achieved, and prophylactic ablation can be performed during atrial fibrillation (AF) ablation. However, the previous study was too small and short-term to clarify the efficacy of this block.<h4>Methods</h4>Patients who underwent catheter ablation for paroxysmal AF were enrolled, and patients who had previous or induced atrial flutter (AFL) were excluded. We randomly assigned 366 patients to pulmonary vein isolation (PVI) only and prophylactic CTI ablation (PVI vs. PVI+CTI).<h4>Results</h4>There was no significant difference in procedure time between the two groups because most CTI blocks were performed during the waiting time after the PVI (176.8±72.6 minutes in PVI vs. 174.2±76.5 minutes in PVI+CTI, p=0.75). All patients were followed up for at least 18 months, and the median follow-up was 3.4 years. The recurrence rate of AF or AFL was not different in the 2 groups (25.7% in PVI vs. 25.7% in PVI+CTI, p=0.92). The recurrence rate of any AFL was not significantly different in the 2 groups (3.3% in PVI vs. 1.6% in PVI+CTI, p=0.31). The recurrence rate of typical AFL also was not different (0.5% in PVI vs. 0.5% in PVI+CTI, p=0.99).<h4>Conclusions</h4>In this large and long-term follow-up study, prophylactic CTI ablation had no benefit in patients with paroxysmal AF without typical AFL.<h4>Trial registration</h4>ClinicalTrials.gov Identifier: NCT02031705.
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:To study the influence of age on the clinical presentation and long-term outcome of patients referred for atrial flutter (AFL) ablation. Age-related differences have been reported regarding the prognosis of arrhythmias.A total of 1187 patients with a mean age 65±12 years consecutively referred for AFL ablation were retrospectively analyzed in the study.445 (37.5%) patients were aged ≥70 (range 70 to 93) among which 345 were aged 70 to 79 years (29.1%) and 100 were aged ≥80 (8.4%). In multivariable analysis, AFL-related rhythmic cardiomyopathy and presentation with 1/1 AFL were less frequent (respectively adjusted OR = 0.44, 0.27-0.74, p = 0.002 and adjusted OR = 0.29, 0.16-0.52, p<0.0001). AFL ablation-related major complications were more frequent in patients ≥70 although remained lower than 10% (7.4% in ≥70 vs. 4.2% in <70, adjusted OR = 1.74, 1.04-2.89, p = 0.03). After 2.1±2.7 years, AFL recurrence was less frequent in patients ≥70 (adjusted OR = 0.54, 0.37-0.80, p = 0.002) whereas atrial fibrillation (AF) occurrence was as frequent in the 70-79 and ≥80 age subsets. As expected, cardiac mortality was higher in older patients. Patients aged ≥80 also had a low probability of AFL recurrence (5.0%) and AF onset (19.0%).Older patients represent 37.5% of patients referred for AFL ablation and displayed a <10% risk of ablation-related complications. Importantly, AFL recurrences were less frequent in patients ≥70 while AF occurrence was as frequent as in patients <70. Similar observations were made in patients ≥80 years. AFL ablation appears to be safe and efficient and should not be ruled out in elderly patients.
Project description:Dronedarone is an amiodarone analog that differs structurally from amiodarone in that the iodine moiety was removed and a methane-sulfonyl group was added. These modifications reduce thyroid and other end-organ adverse effects and makes dronedarone less lipophilic, with a shorter half-life. Dronedarone has been shown to prevent atrial fibrillation/ flutter (AF/AFl) recurrences in several multi-center trials. In addition to its rhythm control properties, dronedarone has rate control properties. In patients with decompensated heart failure, dronedarone treatment increased mortality and cardiovascular hospitalizations. When dronedarone was used in elderly high risk AF/AFl patients, excluding those with advanced heart failure, cardiovascular hospitalizations were significantly reduced. The results of the PALLAS trial suggest that dronedarone should not be used in the long-term treatment of patients with permanent AF. Post-marketing data have demonstrated rare hepatic toxicity to be associated with dronedarone use. Updated practice and regulatory guidelines have positioned dronedarone as a front-line antiarrhythmic in many patients with AF/Fl. However, the drug should not be used in patients with advanced heart failure and in patients who develop permanent AF.
Project description:OBJECTIVE:To use novel statistical methods for analyzing the effect of lesion set on (long-standing) persistent atrial fibrillation (AF) in the Cardiothoracic Surgical Trials Network trial of surgical ablation during mitral valve surgery (MVS). METHODS:Two hundred sixty such patients were randomized to MVS + surgical ablation or MVS alone. Ablation was randomized between pulmonary vein isolation and biatrial maze. During 12 months postsurgery, 228 patients (88%) submitted 7949 transtelephonic monitoring (TTM) recordings, analyzed for AF, atrial flutter (AFL), or atrial tachycardia (AT). As previously reported, more ablation than MVS-alone patients were free of AF or AF/AFL at 6 and 12 months (63% vs 29%; P < .001) by 72-hour Holter monitoring, without evident difference between lesion sets (for which the trial was underpowered). RESULTS:Estimated freedom from AF/AFL/AT on any transmission trended higher after biatrial maze than pulmonary vein isolation (odds ratio, 2.31; 95% confidence interval, 0.95-5.65; P = .07) 3 to 12 months postsurgery; estimated AF/AFL/AT load (ie, proportion of TTM strips recording AF/AFL/AT) was similar (odds ratio, 0.90; 95% confidence interval, 0.57-1.43; P = .6). Within 12 months, estimated prevalence of AF/AFL/AT by TTM was 58% after MVS alone, and 36% versus 23% after pulmonary vein isolation versus biatrial maze (P < .02). CONCLUSIONS:Statistical modeling using TTM recordings after MVS in patients with (long-standing) persistent AF suggests that a biatrial maze is associated with lower AF/AFL/AT prevalence, but not a lower load, compared with pulmonary vein isolation. The discrepancy between AF/AFL/AT prevalence assessed at 2 time points by Holter monitoring versus weekly TTM suggests the need for a confirmatory trial, reassessment of definitions for failure after ablation, and validation of statistical methods for assessing atrial rhythms longitudinally.
Project description:Dronedarone is a benzofuran derivative with a pharmacological profile similar to amiodarone but has a more rapid onset of action and a much shorter half-life (13-19 h). Our goal was to evaluate the efficacy of dronedarone in atrial fibrillation (AF) patients using dual-chamber pacemakers capable of quantifying atrial fibrillation burden.Pacemakers were adjusted to optimize AF detection. Patients with AF burden >1% were randomized to dronedarone 400 mg twice daily (BID) or placebo. Pacemakers were interrogated after 4 and 12 weeks of treatment. The primary endpoint was the change in AF burden from baseline over the 12-week treatment period. Patients with permanent AF, severe/recently decompensated heart failure, and current use of antiarrhythmic drugs were excluded. AF burden was assessed by a core laboratory blinded to treatment assignment.From 285 patients screened, 112 were randomized (mean age 76 years, 60% male, 84% hypertensive, 65% with sick sinus syndrome, 26% with diabetes mellitus type II, 15% with heart failure). Baseline mean (SEM) AF burden was 8.77% (0.16) for placebo and 10.14% (0.17) for dronedarone. Over the 12-week study period, AF burden compared to baseline decreased by 54.4% (0.22) (P = 0.0009) with dronedarone and trended higher by 12.8% (0.16) (P = 0.450) with placebo. The absolute change in burden was decreased by 5.5% in the dronedarone group and increased by 1.1% in the placebo group. Heart rate during AF was reduced to approximately 4 beats/min with dronedarone (P = 0.285). Adverse events were higher with dronedarone compared to placebo (65 vs 56%).Dronedarone reduced pacemaker-assessed the relative AF burden compared to baseline and placebo by over 50% during the 12-week observation period.