Safety Of Dronedarone In Patients Research Articles

The impact of dronedarone on patients with atrial fibrillation and diabetes – a sub-analysis of the ATHENA and EURIDIS/ADONIS trials

Abstract Background Diabetes is a well-established risk factor for the development of atrial fibrillation (AF), and is associated with worse outcomes. Both the ATHENA (NCT00174785) and EURIDIS (NCT00259428)/ADONIS (NCT00259376) were randomized, double-blind, placebo-controlled clinical trials, that evaluated dronedarone 400 mg BID vs placebo (2:1 ratio) in patients with AF and atrial flutter (AFL). The aim of this post-hoc analysis was to evaluate the efficacy and safety of dronedarone in patients with or without diabetes. Methods Patients from the ATHENA trial with diabetes, and from the EURIDIS/ADONIS trials with diabetes, >1 elevated glucose level during trial (unfasted ≥11; fasted ≥7 mmol/L) or presence of diabetes medications were identified and categorized according to diabetes status at baseline. Descriptive analyses of baseline characteristics in patients with and without diabetes receiving dronedarone or placebo were assessed, and time to occurrence of the primary outcomes, CV hospitalization or death in ATHENA and AF/AFL recurrence within 12 months in EURIDIS/ADONIS, were estimated using the Kaplan–Meier method. Log-rank test was used to assess the statistical differences of the survival curves. Results A total of 945 (20.4%; dronedarone [N=482], placebo [N=463]) patients of 4628 patients in ATHENA, and 215 (17.4%; dronedarone [N=148], placebo [N=67]) of 1237 patients in EURIDIS/ADONIS had type 2 diabetes. Patients with diabetes were more likely to have coronary heart disease, hypertension, or structural heart disease in both trials. In ATHENA, there were higher rates of CV hospitalization or death in patients with diabetes (39.5%) than without (34.7%). The proportion of patients with diabetes with first CV hospitalization or death was lower with dronedarone versus placebo (35.1 vs 44.1%) and the time to first event occurred significantly later with dronedarone than placebo (log-rank p=0.005; Figure 1). In ATHENA, median time to first AF/AFL recurrence occurred significantly later with dronedarone vs placebo consistently in patients with diabetes (722 vs 527 days; log-rank p=0.004) or without diabetes (741 vs 492 days; log-rank p<0.001). In EURIDIS/ADONIS, the median time to first AF/AFL recurrence occurred later with dronedarone versus placebo in both patients with diabetes (100 vs 23 days; log-rank p non-significant) and without (120 vs 59 days; log-rank p<0.001; Figure 2). Occurrence of any treatment-emergent adverse event [TEAE] (ATHENA: 74.9 vs 71.2%; EURIDIS/ADONIS: 77.7 vs 68.1%) and serious TEAEs (ATHENA 23.8 vs 18.9%; EURIDIS/ADONIS 25.7 vs 18.5%) with dronedarone were similar for patients with or without diabetes. Conclusion Diabetic patients had shorter time to AF recurrences and higher rates of CV hospitalization than patients without diabetes. Dronedarone was equally safe, decreasing the risk of CV hospitalization or death, and effective, delaying AF/AFL recurrences, in patients with and without diabetes. Funding Acknowledgement Type of funding sources: Private grant(s) and/or Sponsorship. Main funding source(s): Sanofi

Efficacy and safety of dronedarone vs placebo in patients with atrial fibrillation or atrial flutter across a spectrum of renal function: post hoc analyses of the EURIDIS-ADONIS trials

Abstract Background/Introduction The use of antiarrhythmic drugs 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. Since CKD commonly co-occurs with atrial fibrillation/atrial flutter (AF/AFL), it is important to establish efficacy and safety for such drugs when used in AF/AFL patients with CKD. Purpose To evaluate the efficacy and safety of dronedarone in patients with AF or AFL across different levels of renal function. Methods This post hoc analysis evaluated pooled data from two multicentre, double-blind, randomised (2:1) trials of rhythm control with dronedarone 400 mg twice daily vs placebo. Primary endpoint was time to first recurrence of AF or AFL. Renal function (estimated glomerular filtration rate [eGFR]) was assessed with the CKD-Epidemiology Collaboration equation. Patients were grouped by eGFR strata. Log-rank testing and Cox regression were used to compare time to events between treatment groups. Results Most (85%) patients had mild or mild-to-moderate decrease in eGFR (Table 1). Median time to first AF recurrence was significantly longer in the dronedarone vs placebo group for all eGFR subgroups except the 30–44 mL/min group (Figure 1), where the trend was consistent; however, the small population size may have precluded meaningful analyses in this subgroup. Serious adverse events, deaths, and treatment discontinuations did not differ notably between each group irrespective of eGFR strata. Conclusions This analysis confirms the efficacy and safety of dronedarone in patients with AF across a wide spectrum of renal function. Figure 1 Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Sanofi

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

Abstract Background The use of antiarrhythmic drugs in patients with chronic kidney disease (CKD) is challenging due to issues with renal clearance, drug accumulation and increased proarrhythmic risks. Since CKD is a common comorbidity with atrial fibrillation (AF), it is important to establish the efficacy and safety for antiarrhythmic drug treatment in patients with CKD. Purpose To evaluate the efficacy and safety of dronedarone in patients with AF or atrial flutter (AFL) across different stages of renal impairment. Methods In this post-hoc analysis of ATHENA (NCT00174785), a randomised, double-blind trial of dronedarone 400 mg BID vs placebo in patients with AF or AFL plus additional risk factors for death and a calculated glomerular filtration rate ≥10 mL/min, the primary outcome was time to first cardiovascular (CV) hospitalisation or death. Renal function (estimated glomerular filtration rate [eGFR]) was assessed using CKD Epidemiology Collaboration equation and patients were grouped by eGFR (10–44, 45–59, ≥60 mL/min). Log-rank testing and Cox regression were used to compare time to events between treatment groups. Results In ATHENA, 43.6% of placebo and 42.2% of dronedarone patients had mild-to-moderate CKD (Table). Median time to CV hospitalisation/death was longer in all strata for dronedarone vs placebo, reaching significance in the 45–59 and ≥60 mL/min groups (Figure 1). There was a trend towards more treatment-emergent adverse events (TEAEs), deaths and discontinuations due to TEAEs in patients with eGFR 10–44 mL/min. No clear difference in safety was seen between treatment arms except for discontinuations, which were higher with dronedarone. Conclusions This analysis confirms the efficacy of dronedarone, demonstrated in ATHENA, across different stages of renal impairment. Further assessment of safety will require larger populations of patients with CKD. Figure 1 Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Sanofi

P1034Impact of ablation status on the efficacy and safety of dronedarone in patients with atrial fibrillation/flutter: a post-hoc analysis of the ATHENA trial

Abstract Background Despite increasing use of ablation for atrial fibrillation/flutter (AF/AFL), few systematic data exist on the use of dronedarone and other antiarrhythmic drugs after ablation. Purpose To assess efficacy and safety of dronedarone after ablation in patients with paroxysmal/persistent AF/AFL randomized to dronedarone or placebo in the ATHENA trial (NCT00174785). Methods In ATHENA, 196 patients (dronedarone 90, placebo 106) had an ablation for AF/AFL prior to study entry. AF/AFL recurrence was evaluated in patients in sinus rhythm at baseline (dronedarone 63, placebo 65) by ECG during study visits or symptom recurrence. Results Ablated vs non-ablated patients were more likely to be male, have an implantable cardioverter defibrillator or pacemaker implanted, or be receiving an oral anticoagulant. Fewer ablated patients had an AF/AFL recurrence with dronedarone (36 [57%]) than with placebo (46 [71%]). Median time to first AF/AFL recurrence was significantly longer with dronedarone versus placebo (561 versus 180 days; hazard ratio 0.65 [95% CI 0.42–1.00], p<0.05; Fig 1). Time to first cardiovascular hospitalization or death was similar with dronedarone versus placebo (hazard ratio 0.98 [0.62–1.53]). On-treatment rates of treatment-emergent adverse events with dronedarone versus placebo were 83.1 versus 75.5%, serious treatment-emergent adverse events were 27.0 versus 18.9%, permanent drug discontinuations were 10.1 versus 15.1%, and deaths were 0 versus 1.9%. Conclusions Dronedarone delayed AF/AFL recurrence in patients with a prior AF/AFL ablation. Safety outcomes were consistent with the overall ATHENA trial. Adequately sized prospective studies are needed to confirm these observations. Given the sparsity of data for antiarrhythmic drugs after ablation, this retrospective analysis has merit and is useful for hypothesis generation. Acknowledgement/Funding Sanofi, New York, New York, Unites States of America

Efficacy and safety of dronedarone in patients with amiodarone-induced hyperthyroidism: a clinical study.

The aim of the study was to examine the safety and efficacy of dronedarone in patients with a history of atrial fibrillation and amiodarone-induced hyperthyroidism. We conducted a prospective study to evaluate the use of amiodarone and dronedarone in 124 patients with a history of paroxysmal atrial fibrillation who had no additional structural heart disease. All patients received amiodarone 200 mg qd. Out of 124 patients, 56 (45%) switched to dronedarone 400 mg bid due to amiodarone-induced hyperthyroidism and the remaining 68 patients (55%), with normal thyroid function, continued to receive amiodarone. The follow-up period was 12 months, and the patients were regularly monitored. The primary outcome after 6 months dronedarone and amiodarone group was 56 and 68, including 38 (68%) and 54 (79.4%) (Odds ratio [OR] = 1.17, 95% confidence interval [95% CI] = 0.68-2.02) patients with sinus rhythm (SR) and 18 (32.14%) and 14 (28.6%) (odds ratio [OR] = 0.64, confidence interval [95% CI] = 0.29-1.40) patients with atrial fibrillation (AF). The secondary outcome after 12 months showed significant difference in thyroid function in the dronedarone group. Out of 46 patients, 24 (56.18%) patients reduced hyperthyroidism compared to the amiodarone group; out of 68, 6 (8.9%) patients were observed to have hyperthyroidism. At 12 months, there were 24 (43%) and 22 (62%) (odds ratio [OR] = 0.75, confidence interval [95% CI] = 0.38-1.49) patients with SR, and 32 (57%) and 26 (38%) (odds ratio [OR] = 0.67, confidence interval [95% CI] = 0.36-1.25) patients with AF. In our study, dronedarone appears to be a good therapeutic option in the treatment of atrial fibrillation in patients with amiodarone-induced hyperthyroidism. However, long-term studies are needed to estimate the efficacy and toxicity of both drugs.

Efficacy and safety of dronedarone in patients previously treated with other antiarrhythmic agents.

Currently available antiarrhythmic drugs (AADs) for the prevention of atrial fibrillation (AF)/atrial flutter (AFL) suffer from incomplete efficacy and poor tolerability. Dronedarone could represent an effective and safe option in patients previously treated with AADs, especially class Ic AADs and sotalol. 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. 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. 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.

Evaluation of dronedarone as a therapeutic option for patients with atrial fibrillation.

Atrial fibrillation (AF) is the predominant dysrhythmia affecting approximately 2·4 million people in the United States and over 6 million Europeans. Dronedarone is a benzofuran derivative of amiodarone newly approved in 2009 for the treatment of AF. Here, we comment on the efficacy and safety of dronedarone in patients with AF. Eight randomized controlled trials were analysed in this article. Several trials showed that dronedarone therapy delayed AF recurrence, controlled ventricular rate and reduced incidences of hospitalization or death. However, some of the studies were terminated early due to an excess mortality rate. Further studies on long-term safety and trials on direct comparison to rate controlling medications are suggested to obtain additional insight of dronedarone. Dronedarone reduces the incidence of AF recurrences, hospitalization and death in patients with paroxysmal or persistent AF. However, dronedarone should not be used in high-risk patients with permanent AF or patients with unstable chronic heart failure (HF) due to safety concerns.

Dronedarone

Atrial fibrillation (AF), the most common cardiac arrhythmia, is associated with substantial morbidity and mortality. Dronedarone is an amiodarone-like benzofuran which lacks the iodine moiety and presents a methane sulfonyl group that decreases its lipophilicity, thus shortening the half-life and decreasing tissue accumulation. Like amiodarone, dronedarone blocks multiple cardiac ion channels and β-adrenoceptors, presenting electrophysiological characteristics of all four Vaughan Williams classes of antiarrhythmic drugs. In clinical trials, dronedarone has been found effective for both rhythm and rate control. Dronedarone was more effective than placebo in maintaining sinus rhythm in patients with paroxysmal and/or persistent AF and was also effective for ventricular rate control during AF recurrences, providing incremental rate control on top of standard drugs in permanent AF. Furthermore, in the ATHENA trial, dronedarone reduced the incidence of hospitalization due to cardiovascular events or death in patients with nonpermanent AF. Even when dronedarone was less effective than amiodarone in decreasing AF recurrence, it had a better safety profile, being devoid of thyroid, pulmonary and neurological toxicity. This review analyzes the electrophysiological and pharmacological properties, as well as the efficacy and safety of dronedarone in patients with atrial fibrillation.