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Stefan H. Hohnloser - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of Dronedarone in patients with a prior ablation for atrial fibrillation flutter insights from the athena study
Clinical Cardiology, 2020Co-Authors: Peter R. Kowey, Christian Torppedersen, Hugh Calkins, Mate Vamos, Valerie Corp Dit Genti, Mattias Wieloch, Andrew Koren, Stefan H. HohnloserAbstract: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 <.05) as well as the median time to first AF/AFL recurrence (561 vs 180 days) compared with placebo. The HR for first CV hospitalization/all-cause death with Dronedarone vs placebo was 0.98 (95% CI: 0.62, 1.53; P =.91). Rates of treatment-emergent adverse events were 83.1% vs 75.5% and rates of serious TEAEs were 27.0% vs 18.9% in the Dronedarone and placebo groups, respectively. One death occurred with Dronedarone (not treatment-emergent) and five occurred with placebo. Conclusion: In patients with prior ablation for AF/AFL, Dronedarone reduced the risk of AF/AFL recurrence compared with placebo, but not the risk of first CV hospitalization/all-cause death. Safety outcomes were consistent with those of the overall ATHENA study. (Less)
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safety and efficacy of Dronedarone from clinical trials to real world evidence implications for its use in atrial fibrillation
Europace, 2019Co-Authors: Giuseppe Boriani, Stefan H. Hohnloser, Carina Blomstromlundqvist, Lennart Bergfeldt, Giovanni Luca Botto, Alessandro Capucci, Ignacio Fernandez Lozano, Andreas Goette, Carsten W IsraelAbstract:Efficacy and safety of Dronedarone was shown in the ATHENA trial for paroxysmal or persistent atrial fibrillation (AF) patients. Further trials revealed safety concerns in patients with heart failure and permanent AF. This review summarizes insights from recent real-world studies and meta-analyses, including reports on efficacy, with focus on liver safety, mortality risk in patients with paroxysmal/persistent AF, and interactions of Dronedarone with direct oral anticoagulants. Reports of rapidly progressing liver failure in Dronedarone-prescribed patients in 2011 led to regulatory cautions about potential liver toxicity. Recent real-world evidence suggests Dronedarone liver safety profile is similar to other antiarrhythmics and liver toxicity could be equally common with many Class III antiarrhythmics. Dronedarone safety concerns (increased mortality in patients with permanent AF) were raised based on randomized controlled trials (RCT) (ANDROMEDA and PALLAS), but comedication with digoxin may have increased the mortality rates in PALLAS, considering the Dronedarone-digoxin pharmacokinetic (PK) interaction. Real-world data on apixaban-Dronedarone interactions and edoxaban RCT observations suggest no significant safety risks for these drug combinations. Median trough plasma concentrations of dabigatran 110 mg during concomitant use with Dronedarone are at acceptable levels, while PK data on the rivaroxaban-Dronedarone interaction are unavailable. In RCTs and real-world studies, Dronedarone significantly reduces AF burden and cardiovascular hospitalizations, and demonstrates a low risk for proarrhythmia in patients with paroxysmal or persistent AF. The concerns on liver safety must be balanced against the significant reduction in hospitalizations in patients with non-permanent AF and low risk for proarrhythmias following Dronedarone treatment.
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Efficacy and safety of Dronedarone in patients previously treated with other antiarrhythmic agents.
Clinical cardiology, 2014Co-Authors: Federico Guerra, Peter R. Kowey, Stefan H. Hohnloser, David Radzik, Stuart J. Connolly, Harry J.g.m. Crijns, Etienne Aliot, Denis Roy, Alessandro CapucciAbstract: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.
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interaction between digoxin and Dronedarone in the pallas trial
Circulation-arrhythmia and Electrophysiology, 2014Co-Authors: Stefan H. Hohnloser, Jonathan L. Halperin, Peggy Gao, David Radzik, John A Camm, Stuart J. ConnollyAbstract:BACKGROUND: Elevated serum digoxin concentration can cause toxicity, including death. Dronedarone increases digoxin concentration by P-glycoprotein interaction. In Permanent Atrial Fibrillation Outcome Study Using Dronedarone On Top Of Standard Therapy Trial (PALLAS), Dronedarone was associated with both increased cardiovascular death and heart failure in patients with permanent atrial fibrillation. The present analysis examines whether the Dronedarone-digoxin interaction might explain these adverse outcomes. METHODS AND RESULTS: Subgroup analysis was performed to compare outcomes of patients on digoxin at baseline or not. In PALLAS, 1619 patients were randomized to Dronedarone and 1617 to placebo, of whom 544 (33.6%) and 526 (32.5%) were receiving digoxin, respectively. Median (Q1,Q3) digoxin serum concentration on day 7 was 1.1 (0.7,1.5) ng/mL on Dronedarone and 0.7 (0.5,1.1) ng/mL on placebo (P<0.001). Among patients on digoxin, there were 15 (8.6%/year) cardiovascular deaths on Dronedarone and 2 (1.2%/year) on placebo (adjusted hazard ratio, 7.31; 95% confidence interval, 1.66-32.20; P=0.009). Among patients not on digoxin, there were 6 cardiovascular deaths on Dronedarone (1.7%/year) and 8 on placebo (2.2%/year; adjusted hazard ratio, 0.67; 95% confidence interval, 0.23-1.95; P=0.46; interaction P value 0.01). In patients on digoxin, there were 11 arrhythmic deaths on Dronedarone and none on placebo; and in patients not on digoxin, there were 2 arrhythmic deaths on Dronedarone and 4 on placebo (P value for interaction 0.002). There was no interaction between baseline digoxin use and the adverse effect of Dronedarone on heart failure events. CONCLUSIONS: In PALLAS, there was a strong effect of concurrent digoxin use on the adverse effect of Dronedarone on cardiovascular death, but not on occurrence of heart failure. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01151137.
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Interaction between digoxin and Dronedarone in the PALLAS trial
Circulation. Arrhythmia and electrophysiology, 2014Co-Authors: Stefan H. Hohnloser, Jonathan L. Halperin, A. John Camm, Peggy Gao, David Radzik, Stuart J. ConnollyAbstract:Elevated serum digoxin concentration can cause toxicity, including death. Dronedarone increases digoxin concentration by P-glycoprotein interaction. In Permanent Atrial Fibrillation Outcome Study Using Dronedarone On Top Of Standard Therapy Trial (PALLAS), Dronedarone was associated with both increased cardiovascular death and heart failure in patients with permanent atrial fibrillation. The present analysis examines whether the Dronedarone-digoxin interaction might explain these adverse outcomes. Subgroup analysis was performed to compare outcomes of patients on digoxin at baseline or not. In PALLAS, 1619 patients were randomized to Dronedarone and 1617 to placebo, of whom 544 (33.6%) and 526 (32.5%) were receiving digoxin, respectively. Median (Q1,Q3) digoxin serum concentration on day 7 was 1.1 (0.7,1.5) ng/mL on Dronedarone and 0.7 (0.5,1.1) ng/mL on placebo (P<0.001). Among patients on digoxin, there were 15 (8.6%/year) cardiovascular deaths on Dronedarone and 2 (1.2%/year) on placebo (adjusted hazard ratio, 7.31; 95% confidence interval, 1.66-32.20; P=0.009). Among patients not on digoxin, there were 6 cardiovascular deaths on Dronedarone (1.7%/year) and 8 on placebo (2.2%/year; adjusted hazard ratio, 0.67; 95% confidence interval, 0.23-1.95; P=0.46; interaction P value 0.01). In patients on digoxin, there were 11 arrhythmic deaths on Dronedarone and none on placebo; and in patients not on digoxin, there were 2 arrhythmic deaths on Dronedarone and 4 on placebo (P value for interaction 0.002). There was no interaction between baseline digoxin use and the adverse effect of Dronedarone on heart failure events. In PALLAS, there was a strong effect of concurrent digoxin use on the adverse effect of Dronedarone on cardiovascular death, but not on occurrence of heart failure. http://www.clinicaltrials.gov. Unique identifier: NCT01151137. © 2014 American Heart Association, Inc.
Stuart J. Connolly - One of the best experts on this subject based on the ideXlab platform.
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Efficacy and safety of Dronedarone in patients previously treated with other antiarrhythmic agents.
Clinical cardiology, 2014Co-Authors: Federico Guerra, Peter R. Kowey, Stefan H. Hohnloser, David Radzik, Stuart J. Connolly, Harry J.g.m. Crijns, Etienne Aliot, Denis Roy, Alessandro CapucciAbstract: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.
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interaction between digoxin and Dronedarone in the pallas trial
Circulation-arrhythmia and Electrophysiology, 2014Co-Authors: Stefan H. Hohnloser, Jonathan L. Halperin, Peggy Gao, David Radzik, John A Camm, Stuart J. ConnollyAbstract:BACKGROUND: Elevated serum digoxin concentration can cause toxicity, including death. Dronedarone increases digoxin concentration by P-glycoprotein interaction. In Permanent Atrial Fibrillation Outcome Study Using Dronedarone On Top Of Standard Therapy Trial (PALLAS), Dronedarone was associated with both increased cardiovascular death and heart failure in patients with permanent atrial fibrillation. The present analysis examines whether the Dronedarone-digoxin interaction might explain these adverse outcomes. METHODS AND RESULTS: Subgroup analysis was performed to compare outcomes of patients on digoxin at baseline or not. In PALLAS, 1619 patients were randomized to Dronedarone and 1617 to placebo, of whom 544 (33.6%) and 526 (32.5%) were receiving digoxin, respectively. Median (Q1,Q3) digoxin serum concentration on day 7 was 1.1 (0.7,1.5) ng/mL on Dronedarone and 0.7 (0.5,1.1) ng/mL on placebo (P<0.001). Among patients on digoxin, there were 15 (8.6%/year) cardiovascular deaths on Dronedarone and 2 (1.2%/year) on placebo (adjusted hazard ratio, 7.31; 95% confidence interval, 1.66-32.20; P=0.009). Among patients not on digoxin, there were 6 cardiovascular deaths on Dronedarone (1.7%/year) and 8 on placebo (2.2%/year; adjusted hazard ratio, 0.67; 95% confidence interval, 0.23-1.95; P=0.46; interaction P value 0.01). In patients on digoxin, there were 11 arrhythmic deaths on Dronedarone and none on placebo; and in patients not on digoxin, there were 2 arrhythmic deaths on Dronedarone and 4 on placebo (P value for interaction 0.002). There was no interaction between baseline digoxin use and the adverse effect of Dronedarone on heart failure events. CONCLUSIONS: In PALLAS, there was a strong effect of concurrent digoxin use on the adverse effect of Dronedarone on cardiovascular death, but not on occurrence of heart failure. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01151137.
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Interaction between digoxin and Dronedarone in the PALLAS trial
Circulation. Arrhythmia and electrophysiology, 2014Co-Authors: Stefan H. Hohnloser, Jonathan L. Halperin, A. John Camm, Peggy Gao, David Radzik, Stuart J. ConnollyAbstract:Elevated serum digoxin concentration can cause toxicity, including death. Dronedarone increases digoxin concentration by P-glycoprotein interaction. In Permanent Atrial Fibrillation Outcome Study Using Dronedarone On Top Of Standard Therapy Trial (PALLAS), Dronedarone was associated with both increased cardiovascular death and heart failure in patients with permanent atrial fibrillation. The present analysis examines whether the Dronedarone-digoxin interaction might explain these adverse outcomes. Subgroup analysis was performed to compare outcomes of patients on digoxin at baseline or not. In PALLAS, 1619 patients were randomized to Dronedarone and 1617 to placebo, of whom 544 (33.6%) and 526 (32.5%) were receiving digoxin, respectively. Median (Q1,Q3) digoxin serum concentration on day 7 was 1.1 (0.7,1.5) ng/mL on Dronedarone and 0.7 (0.5,1.1) ng/mL on placebo (P<0.001). Among patients on digoxin, there were 15 (8.6%/year) cardiovascular deaths on Dronedarone and 2 (1.2%/year) on placebo (adjusted hazard ratio, 7.31; 95% confidence interval, 1.66-32.20; P=0.009). Among patients not on digoxin, there were 6 cardiovascular deaths on Dronedarone (1.7%/year) and 8 on placebo (2.2%/year; adjusted hazard ratio, 0.67; 95% confidence interval, 0.23-1.95; P=0.46; interaction P value 0.01). In patients on digoxin, there were 11 arrhythmic deaths on Dronedarone and none on placebo; and in patients not on digoxin, there were 2 arrhythmic deaths on Dronedarone and 4 on placebo (P value for interaction 0.002). There was no interaction between baseline digoxin use and the adverse effect of Dronedarone on heart failure events. In PALLAS, there was a strong effect of concurrent digoxin use on the adverse effect of Dronedarone on cardiovascular death, but not on occurrence of heart failure. http://www.clinicaltrials.gov. Unique identifier: NCT01151137. © 2014 American Heart Association, Inc.
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impact of Dronedarone on hospitalization burden in patients with atrial fibrillation results from the athena study
Europace, 2011Co-Authors: Christian Torppedersen, Stuart J. Connolly, Christophe Gaudin, Richard L Page, Harry J.g.m. Crijns, Stefan H. HohnloserAbstract:Aims Cardiovascular (CV) hospitalization is a predictor of CV mortality and has a negative impact on patients’ quality of life. The primary endpoint of 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 (ATHENA), a composite of first CV hospitalization or death from any cause, was significantly reduced by Dronedarone. This post hoc analysis evaluated the secondary endpoint of CV hospitalization and the clinical benefit of Dronedarone on the number and duration of CV hospitalizations in patients with atrial fibrillation (AF). Methods and results ATHENA was a double-blind, parallel group study in 4628 patients with a history of paroxysmal/persistent AF and additional risk factors, treated with placebo or Dronedarone. Dronedarone treatment significantly reduced the risk of first CV hospitalization ( P < 0.0001 vs. placebo), while the risk of first non-CV hospitalization was similar in both groups ( P = 0.77). About half of the CV hospitalizations were AF-related, with a median duration of hospital stay of four nights. The risk of any hospitalization for AF [hazard ratio (95% confidence interval) 0.626 (0.546−0.719)] and duration of hospital stay were significantly reduced by Dronedarone ( P < 0.0001 vs. placebo). Dronedarone treatment reduced total hospitalizations for acute coronary syndrome ( P = 0.0105) and the time between the first AF/atrial flutter recurrence and CV hospitalization/death ( P = 0.0048). Hospitalization burden was significantly reduced across all levels of care ( P < 0.05). Cumulative incidence data indicated that the effects of Dronedarone persisted for at least 24 months. Conclusion Dronedarone reduced the risk for CV hospitalization and the total hospitalization burden in this patient group. The trial is registered under ClinicalTrials.gov #NCT 00174785.
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rhythm and rate controlling effects of Dronedarone in patients with atrial fibrillation from the athena trial
American Journal of Cardiology, 2011Co-Authors: Richard L Page, Stuart J. Connolly, Martin Van Eickels, Christophe Gaudin, Christian Torppedersen, Harry J.g.m. Crijns, Stefan H. HohnloserAbstract:Dronedarone is a multi-channel-blocking drug for the treatment of patients with atrial fibrillation (AF) or atrial flutter (AFL) with rate- and rhythm-controlling properties. A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg b.i.d. for the Prevention of Cardiovascular Hospitalization or Death from Any Cause in Patients With Atrial Fibrillation/Atrial Flutter (ATHENA) demonstrated that Dronedarone reduced the risk for first cardiovascular hospitalization or death from any cause. The aim of this post hoc analysis was to evaluate the rhythm- and rate-controlling properties of Dronedarone in the ATHENA trial. Patients were randomized to Dronedarone 400 mg twice daily (n = 2,301) or placebo (n = 2,327). Electrocardiographic tracings were classified for AF or AFL or sinus rhythm. Patients with AF or AFL on every postbaseline electrocardiogram were classified as having permanent AF or AFL. All electrical cardioversions were documented. The use of rate-controlling medications was equally distributed in the 2 treatment groups. The median time to first AF or AFL recurrence of patients in sinus rhythm at baseline was 498 days in placebo patients and 737 days in Dronedarone patients (hazard ratio 0.749, 95% confidence interval 0.681 to 0.824, p <0.001). In the Dronedarone group, 339 patients (15%) had ≥1 electrical cardioversion, compared to 481 (21%) in the placebo group (hazard ratio 0.684, 95% confidence interval 0.596 to 0.786, p <0.001). The likelihood of permanent AF or AFL was lower with Dronedarone (178 patients [7.6%]) compared to placebo (295 patients [12.8%]) (p <0.001). At the time of first AF or AFL recurrence, the mean heart rates were 85.3 and 95.5 beats/min in the Dronedarone and placebo groups, respectively (p <0.001). In conclusion, Dronedarone demonstrated both rhythm- and rate-controlling properties in ATHENA. These effects are likely to contribute to the reduction of important clinical outcomes observed in this trial.
Gerald V. Naccarelli - One of the best experts on this subject based on the ideXlab platform.
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Outcomes Associated with Dronedarone Use in Patients with Atrial Fibrillation.
The American journal of cardiology, 2020Co-Authors: Earl L. Goehring, Rhonda L. Bohn, John C. Pezzullo, Arlene Tave, Judith Jones, Sylvie Bozzi, Ret. Capt Sally G. Tamayo, Nicholas Sicignano, Gerald V. NaccarelliAbstract:The antiarrhythmic drug Dronedarone was designed to reduce the extra-cardiac adverse effects associated with amiodarone use in treatment of patients with atrial fibrillation / atrial flutter (AF/AFL). This epidemiological study used a retrospective cohort design to compare risk of cardiovascular-related hospitalizations and death in AF/AFL patients treated with Dronedarone versus other antiarrhythmic drugs (AADs). AF/AFL patients with incident Dronedarone fills were matched by propensity score (PS) to incident users of other AADs. The primary study outcome was hospitalization for cardiovascular (CV) causes within 24 months after the first study drug fill. A secondary composite outcome comprised hospitalization for CV causes or all-cause mortality during follow-up. In the AF/AFL patient cohort meeting eligibility criteria, 6,964 incident users of Dronedarone and 25 607 incident users of other AADs were identified. The PS-matched cohort comprised 6,349 Dronedarone users (91.2% of all eligible) and 12,698 other AAD users. Dronedarone patients had a significantly lower risk of hospitalization for a CV event compared to Other AAD users (hazard ratio = 0.87; 95% confidence interval = 0.79 to 0.96). This was consistent with results for the composite outcome (hazard ratio=0.86; 95% confidence interval = 0.78 to 0.95). In conclusion, AF/AFL patients initiated on Dronedarone versus other AADs had significantly lower risk of CV hospitalizations as well as the composite CV hospitalization / death from any cause.
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the role of Dronedarone in the treatment of atrial fibrillation flutter in the aftermath of pallas
Current Cardiology Reviews, 2014Co-Authors: Gerald V. Naccarelli, Peter R. KoweyAbstract: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.
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The role of Dronedarone in the treatment of atrial fibrillation/flutter in the aftermath of PALLAS.
Current cardiology reviews, 2014Co-Authors: Gerald V. Naccarelli, Peter R. KoweyAbstract: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.
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Appropriate and Inappropriate Use of Dronedarone in 2013
Current treatment options in cardiovascular medicine, 2013Co-Authors: Gerald V. NaccarelliAbstract:Dronedarone is a multichannel blocking antiarrhythmic agent that has been shown to prevent atrial fibrillation/flutter (AF/AFl) recurrences in several multi-center trials. In the ANDROMEDA trial, Dronedarone treatment increased mortality and cardiovascular hospitalizations patients with decompensated heart failure. In the ATHENA trial, Dronedarone was used in elderly high risk patients with paroxysmal or persistent AF/AFl, excluding those with advanced heart failure, cardiovascular hospitalizations were significantly reduced. Dronedarone increased mortality and cardiovascular hospitalizations in a different patient group with permanent AF/AFl. Although organic toxicity from the drug is very rare, post-marketing data has reported rare hepatic toxicity associated with Dronedarone use. Current guidelines position Dronedarone as a front-line antiarrhythmic in many patients with AF/Fl. However, Dronedarone should not be used in patients with advanced heart failure or in permanent AF. Clinical trial results have helped us define appropriate and inappropriate candidates for Dronedarone.
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Safety and Efficacy of Dronedarone in the Treatment of Atrial Fibrillation/Flutter
Clinical Medicine Insights. Cardiology, 2011Co-Authors: Gerald V. Naccarelli, Deborah L. Wolbrette, Vadim Levin, Soraya Samii, Javier E. Banchs, Erica Penny-peterson, Mario D. GonzalezAbstract:Dronedarone is an amiodarone analog but differs structurally from amiodarone in that the iodine moiety was removed and a methane-sulfonyl group was added. These modifications reduced thyroid and other end-organ adverse effects and makes Dronedarone less lipophilic, shortening its 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 and slows the ventricular response during AF. Dronedarone is approved in Europe for rhythm and rate control indications. In patients with decompensated heart failure, Dronedarone treatment increased mortality and cardiovascular hospitalizations. However, when Dronedarone was used in elderly high risk AF/AFl patients excluding such high risk heart failure, cardiovascular hospitalizations were significantly reduced and the drug was approved in the USA for this indication in 2009 by the Food and Drug Administration. Updated guidelines suggest Dronedarone as a front-line antiarrhythmic in many patients with AF/Fl but caution that the drug should not be used in patients with advanced heart failure. In addition, the recent results of the PALLAS trial suggest that Dronedarone should not be used in the long-term treatment of patients with permanent AF.
Christian Torppedersen - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of Dronedarone in patients with a prior ablation for atrial fibrillation flutter insights from the athena study
Clinical Cardiology, 2020Co-Authors: Peter R. Kowey, Christian Torppedersen, Hugh Calkins, Mate Vamos, Valerie Corp Dit Genti, Mattias Wieloch, Andrew Koren, Stefan H. HohnloserAbstract: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 <.05) as well as the median time to first AF/AFL recurrence (561 vs 180 days) compared with placebo. The HR for first CV hospitalization/all-cause death with Dronedarone vs placebo was 0.98 (95% CI: 0.62, 1.53; P =.91). Rates of treatment-emergent adverse events were 83.1% vs 75.5% and rates of serious TEAEs were 27.0% vs 18.9% in the Dronedarone and placebo groups, respectively. One death occurred with Dronedarone (not treatment-emergent) and five occurred with placebo. Conclusion: In patients with prior ablation for AF/AFL, Dronedarone reduced the risk of AF/AFL recurrence compared with placebo, but not the risk of first CV hospitalization/all-cause death. Safety outcomes were consistent with those of the overall ATHENA study. (Less)
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impact of Dronedarone on hospitalization burden in patients with atrial fibrillation results from the athena study
Europace, 2011Co-Authors: Christian Torppedersen, Stuart J. Connolly, Christophe Gaudin, Richard L Page, Harry J.g.m. Crijns, Stefan H. HohnloserAbstract:Aims Cardiovascular (CV) hospitalization is a predictor of CV mortality and has a negative impact on patients’ quality of life. The primary endpoint of 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 (ATHENA), a composite of first CV hospitalization or death from any cause, was significantly reduced by Dronedarone. This post hoc analysis evaluated the secondary endpoint of CV hospitalization and the clinical benefit of Dronedarone on the number and duration of CV hospitalizations in patients with atrial fibrillation (AF). Methods and results ATHENA was a double-blind, parallel group study in 4628 patients with a history of paroxysmal/persistent AF and additional risk factors, treated with placebo or Dronedarone. Dronedarone treatment significantly reduced the risk of first CV hospitalization ( P < 0.0001 vs. placebo), while the risk of first non-CV hospitalization was similar in both groups ( P = 0.77). About half of the CV hospitalizations were AF-related, with a median duration of hospital stay of four nights. The risk of any hospitalization for AF [hazard ratio (95% confidence interval) 0.626 (0.546−0.719)] and duration of hospital stay were significantly reduced by Dronedarone ( P < 0.0001 vs. placebo). Dronedarone treatment reduced total hospitalizations for acute coronary syndrome ( P = 0.0105) and the time between the first AF/atrial flutter recurrence and CV hospitalization/death ( P = 0.0048). Hospitalization burden was significantly reduced across all levels of care ( P < 0.05). Cumulative incidence data indicated that the effects of Dronedarone persisted for at least 24 months. Conclusion Dronedarone reduced the risk for CV hospitalization and the total hospitalization burden in this patient group. The trial is registered under ClinicalTrials.gov #NCT 00174785.
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rhythm and rate controlling effects of Dronedarone in patients with atrial fibrillation from the athena trial
American Journal of Cardiology, 2011Co-Authors: Richard L Page, Stuart J. Connolly, Martin Van Eickels, Christophe Gaudin, Christian Torppedersen, Harry J.g.m. Crijns, Stefan H. HohnloserAbstract:Dronedarone is a multi-channel-blocking drug for the treatment of patients with atrial fibrillation (AF) or atrial flutter (AFL) with rate- and rhythm-controlling properties. A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg b.i.d. for the Prevention of Cardiovascular Hospitalization or Death from Any Cause in Patients With Atrial Fibrillation/Atrial Flutter (ATHENA) demonstrated that Dronedarone reduced the risk for first cardiovascular hospitalization or death from any cause. The aim of this post hoc analysis was to evaluate the rhythm- and rate-controlling properties of Dronedarone in the ATHENA trial. Patients were randomized to Dronedarone 400 mg twice daily (n = 2,301) or placebo (n = 2,327). Electrocardiographic tracings were classified for AF or AFL or sinus rhythm. Patients with AF or AFL on every postbaseline electrocardiogram were classified as having permanent AF or AFL. All electrical cardioversions were documented. The use of rate-controlling medications was equally distributed in the 2 treatment groups. The median time to first AF or AFL recurrence of patients in sinus rhythm at baseline was 498 days in placebo patients and 737 days in Dronedarone patients (hazard ratio 0.749, 95% confidence interval 0.681 to 0.824, p <0.001). In the Dronedarone group, 339 patients (15%) had ≥1 electrical cardioversion, compared to 481 (21%) in the placebo group (hazard ratio 0.684, 95% confidence interval 0.596 to 0.786, p <0.001). The likelihood of permanent AF or AFL was lower with Dronedarone (178 patients [7.6%]) compared to placebo (295 patients [12.8%]) (p <0.001). At the time of first AF or AFL recurrence, the mean heart rates were 85.3 and 95.5 beats/min in the Dronedarone and placebo groups, respectively (p <0.001). In conclusion, Dronedarone demonstrated both rhythm- and rate-controlling properties in ATHENA. These effects are likely to contribute to the reduction of important clinical outcomes observed in this trial.
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effect of Dronedarone on cardiovascular events in atrial fibrillation
The New England Journal of Medicine, 2009Co-Authors: Stefan H. Hohnloser, Martin Van Eickels, Christophe Gaudin, Richard L Page, Christian Torppedersen, Stuart J. ConnollyAbstract:Background Dronedarone is a new antiarrhythmic drug that is being developed for the treatment of patients with atrial fibrillation. Methods We conducted a multicenter trial to evaluate the use of Dronedarone in 4628 patients with atrial fibrillation who had additional risk factors for death. Patients were randomly assigned to receive Dronedarone, 400 mg twice a day, or placebo. The primary outcome was the first hospitalization due to cardiovascular events or death. Secondary outcomes were death from any cause, death from cardiovascular causes, and hospitalization due to cardiovascular events. Results The mean follow-up period was 21±5 months, with the study drug discontinued prematurely in 696 of the 2301 patients (30.2%) receiving Dronedarone and in 716 of the 2327 patients (30.8%) receiving placebo, mostly because of adverse events. The primary outcome occurred in 734 patients (31.9%) in the Dronedarone group and in 917 patients (39.4%) in the placebo group, with a hazard ratio for Dronedarone of 0.76 (95% confidence interval [CI], 0.69 to 0.84; P<0.001). There were 116 deaths (5.0%) in the Dronedarone group and 139 (6.0%) in the placebo group (hazard ratio, 0.84; 95% CI, 0.66 to 1.08; P = 0.18). There were 63 deaths from cardiovascular causes (2.7%) in the Dronedarone group and 90 (3.9%) in the placebo group (hazard ratio, 0.71; 95% CI, 0.51 to 0.98; P = 0.03), largely due to a reduction in the rate of death from arrhythmia with Dronedarone. The Dronedarone group had higher rates of bradycardia, QT-interval prolongation, nausea, diarrhea, rash, and an increased serum creatinine level than the placebo group. Rates of thyroid- and pulmonary-related adverse events were not significantly different between the two groups. Conclusion Dronedarone reduced the incidence of hospitalization due to cardiovascular events or death in patients with atrial fibrillation. (ClinicalTrials.gov number, NCT00174785.)
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analysis of stroke in 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 atria
Circulation, 2009Co-Authors: Stuart J. Connolly, Martin Van Eickels, Christophe Gaudin, Richard L Page, Christian Torppedersen, Harry J.g.m. Crijns, Stefan H. HohnloserAbstract:Background—Many patients with atrial fibrillation are at high risk for stroke and require antithrombotic therapy. Antiarrhythmic drugs have not previously been shown to reduce the risk of stroke in atrial fibrillation. The effect of Dronedarone, a new multichannel-blocking antiarrhythmic drug, on stroke has been evaluated in a randomized, double-blind clinical trial, 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). Methods and Results—Patients with persistent or paroxysmal atrial fibrillation and at least 1 risk factor for cardiovascular hospitalization were randomized to receive Dronedarone (400 mg BID) or double-blind matching placebo and followed up for a minimum of 1 year to a common termination at 30 months. All strokes that occurred during the study were included in the present post hoc analysis. There were 4628 patients randomized to placebo or Dronedarone. The baseline risk factors for stroke were well balanced between the 2 groups, and the baseline mean CHADS2 score was 2. The baseline use of either oral anticoagulant therapy or antiplatelet agent alone was 60%. Dronedarone reduced the risk of stroke from 1.8% per year to 1.2% per year (hazard ratio 0.66, 95% confidence interval 0.46 to 0.96, P0.027). The effect of Dronedarone was similar whether or not patients were receiving oral anticoagulant therapy, and there was a significantly greater effect of Dronedarone in patients with higher CHADS2 scores. Conclusions—In this post hoc analysis, a reduction in stroke was observed in patients with atrial fibrillation who were receiving usual care, which included antithrombotic therapy and heart rate control, who were randomized to Dronedarone. Further studies to investigate the effect of Dronedarone and other antiarrhythmic agents on stroke are indicated. (Circulation. 2009;120:1174-1180.)
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safety of apixaban in combination with Dronedarone in patients with atrial fibrillation
International Journal of Cardiology, 2018Co-Authors: Leif FribergAbstract:Abstract Background There have been concerns about bleeding risks for patients with atrial fibrillation treated with Dronedarone in combination with new oral anticoagulants (NOACs). The aim of the study was to compare the bleeding risks with the apixaban + Dronedarone and warfarin + Dronedarone combinations. Method Retrospective study of Swedish nationwide health registers. All patients with atrial fibrillation who used Dronedarone in combination with apixaban or warfarin during 2013–2016 were identified. Two propensity matched cohorts of each 1681 patients were compared. The main endpoint included intracranial bleeding, bleedings with hospitalization and fatal bleedings. Results Bleedings thus defined occurred at rates of 1.31 and 2.14 per 100 years at risk with the apixaban and warfarin combinations respectively (p = 0.121). The hazard ratio with the apixaban combination was 0.66 (CI 0.35–1.23) compared to the warfarin combination. No significant differences were seen regarding secondary endpoints. Conclusion Major bleedings were rare among patients with atrial fibrillation treated with Dronedarone in combination with apixaban or warfarin. No significant differences in favour of either drug combination were found.
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safety of Dronedarone in routine clinical care
Journal of the American College of Cardiology, 2014Co-Authors: Leif FribergAbstract:Objectives The aim of this study was to examine mortality and liver disease among patients exposed to Dronedarone. Background There has been concern about the safety of Dronedarone, especially for patients with heart failure and permanent atrial fibrillation (AF). There have also been suspicions about liver toxicity. Methods All 174,995 patients with a diagnosis of AF during 2010 to 2012 were identified in the Swedish Patient Register. Of these, 4,856 patients had received Dronedarone according to the Swedish Drug Register, and 170,139 patients who had not were used as a control population. Mean follow-up was 1.6 years, with a minimal follow-up of 6 months. Results Patients prescribed Dronedarone were younger (age 65.5 years vs. 75.7 years, p Conclusions Dronedarone, as prescribed to AF patients in Sweden, has not exposed patients to increased risks of death or liver disease.
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Safety of Dronedarone in routine clinical care.
Journal of the American College of Cardiology, 2014Co-Authors: Leif FribergAbstract:The aim of this study was to examine mortality and liver disease among patients exposed to Dronedarone. There has been concern about the safety of Dronedarone, especially for patients with heart failure and permanent atrial fibrillation (AF). There have also been suspicions about liver toxicity. All 174,995 patients with a diagnosis of AF during 2010 to 2012 were identified in the Swedish Patient Register. Of these, 4,856 patients had received Dronedarone according to the Swedish Drug Register, and 170,139 patients who had not were used as a control population. Mean follow-up was 1.6 years, with a minimal follow-up of 6 months. Patients prescribed Dronedarone were younger (age 65.5 years vs. 75.7 years, p < 0.0001) and healthier than control patients. The annual mortality rate among patients who received Dronedarone was 1.3% compared with 14.0% in the control population. There were no sudden cardiac deaths and no deaths related to liver failure among patients who received treatment with Dronedarone. After propensity score matching and adjustment for cofactors, patients who received Dronedarone had lower mortality than other AF patients (hazard ratio [HR]: 0.41; 95% confidence interval [CI]: 0.33 to 0.51). Dronedarone patients with heart failure had lower mortality than other heart failure patients (HR: 0.40; 95% CI: 0.30 to 0.53). They also had lower mortality than expected from the general population (standardized mortality ratio: 0.67; 95% CI: 0.55 to 0.78), which indicates the selection of low-risk patients. The risk of liver disease was not increased (HR: 0.57; 95% CI: 0.34 to 0.92). Dronedarone, as prescribed to AF patients in Sweden, has not exposed patients to increased risks of death or liver disease. Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.
