Use Of Dronedarone Research Articles

Translating regulatory advice into practice: use of dronedarone and older anti-arrhythmics in AF management

Translating regulatory advice into practice: use of dronedarone and older anti-arrhythmics in AF management

Managing atrial fibrillation in the elderly: critical appraisal of dronedarone

Atrial fibrillation is the most commonly seen arrhythmia in the geriatric population and is associated with increased cardiovascular morbidity and mortality. Treatment of the elderly with atrial fibrillation remains challenging for physicians, because this unique subpopulation is characterized by multiple comorbidities requiring chronic use of numerous medications, which can potentially lead to severe drug interactions. Furthermore, age-related changes in the cardiovascular system as well as other physiological changes result in altered drug pharmacokinetics. Dronedarone is a new drug recently approved for the treatment of arrhythmias, such as atrial fibrillation and/or atrial flutter. Dronedarone is a benzofuran amiodarone analog which lacks the iodine moiety and contains a methane sulfonyl group that decreases its lipophilicity. These differences in chemical structure are responsible for making dronedarone less toxic than amiodarone which, in turn, results in fewer side effects. Adverse events for dronedarone include gastrointestinal side effects and rash. No dosage adjustments are required for patients with renal impairment. However, the use of dronedarone is contraindicated in the presence of severe hepatic dysfunction.

Management of atrial fibrillation: focus on the role of dronedarone.

Background: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.Objective: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.Results: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.Conclusion: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.

Elevated International Normalized Ratio Associated with Use of Dronedarone and Warfarin

To describe a case of elevated international normalized ratio (INR) after addition of dronedarone to warfarin therapy. A 72-year-old white female with a history of tinnitus, gastroesophageal reflux disease, and permanent pacemaker implantation was taking warfarin (target INR 2-3) and sotalol for chronic atrial fibrillation; atorvastatin for hyperlipidemia; and risedronate for osteopenia. Her warfarin therapy had been managed by a nurse-run anticoagulation clinic for several years. During the prior year, her INR had been stable with a weekly dose of warfarin 25 mg. After persistent episodes of atrial fibrillation, the antiarrhythmic agent was changed from sotalol to dronedarone 400 mg twice daily. Approximately 10 days after starting dronedarone, the INR was 4.8; she stated that there was no bleeding. The warfarin dose was decreased to 20 mg/wk, and the INR remained stable with that dosage for the next 11 months. Postmarketing surveillance has revealed cases of increased INR values with or without bleeding in patients taking warfarin who were started on dronedarone. In this case, the Horn Drug Interaction Probability Scale suggested a probable causality for an interaction between dronedarone and warfarin. Based on current knowledge, this interaction may involve an indirect gastrointestinal mechanism and/or a direct pharmacokinetic mechanism. Clinicians should monitor patients who are taking warfarin and dronedarone for INR changes and bleeding episodes about 1 week after initiation of dronedarone. If a significant interaction is noted, the warfarin dosage should be decreased and the patient should be monitored within 2 weeks to assess the need for further adjustments.

Effect of Dronedarone on Cardiovascular Events in Atrial Fibrillation

Background: Dronedarorie is a new antiarrhythniie drug that is being developed (or the treatment of patients with alnal iihrillalion. Methods: We conducted a multiceuter trial to evaluate the use of dronedarone in 4628 patienls with atrial fibrillation who had additional risk factors for death. Patients wen.' randomly assigned lo receive dronedarone, 400 mg twice a day, or placebo. The primary outcome was the first hospitalization due to cardiovascular e\ents or death. Secondary outcomes were death from any cause, death from cardiovascular causes, and hospilahzalion 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 9i7 patients (39.4%) in the placebo group, with a hazard ratio for dronedarone ol 0.76 (95% confidence interval [CIJ. 0.69 to 0.84; P<0.001). There were 1 16 deaths (5.0%) in the dronedarone group and 139 (6.0%) in the placebo group (hazard ratio, 0.84; 95% Cl. 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 ihe placebo group (hazard ratio. 0.71; 95% CI. 0.51 to 0.98; P = 0.03). largely due to a reduction in (he rale 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. Hales of ihyroid- and pulmonary-related adverse events were nol significantly different between the two groups. (Conclusion: Dronedarone reduced the incidence of. hospitalization due to cardiovascular events or death in patients with atrial fibrillation. (ChnicalTrials.gov number. NCTOO 174785.).

Dronedarone for the management of atrial fibrillation

Atrial fibrillation is a common arrhythmia associated with increased cardiovascular mortality and morbidity including stroke, heart failure and hospitalisations. Major studies on atrial fibrillation have shown no significant difference between rhythm and rate control in terms of mortality. However, rate control treatment may be insufficient to prevent morbidity in a number of patients. Amiodarone is generally considered the agent with the best efficacy for maintaining normal sinus rhythm. Despite amiodarone's efficacy, its use is often limited by its side effect profile and it is not currently recommended as the first choice antiarrhythmic agent, except in patients with heart failure or congenital heart disease. Dronedarone is a noniodinated benzofuran derivative of amiodarone that has been recently approved by Swissmedic for management of patients with atrial fibrillation or atrial flutter. Structural modification of dronedarone was introduced to decrease lipophilicity, shorten the half-life and minimise non-cardiovascular toxicity as compared to amiodarone. This article reviews the pharmacology, adverse effects and clinical evidence available to date on the use of dronedarone in the management of atrial fibrillation.

Comparing the 2010 North American and European Atrial Fibrillation Guidelines

This article compares the important differences in the American College of Cardiology Foundation (ACCF)/American Heart Association (AHA)/Heart Rhythm Society (HRS), Canadian Cardiovascular Society (CCS), and European Society of Cardiology (ESC) 2010 guidelines on atrial fibrillation (AF). All guidelines recommend more lenient targets for ventricular rate control although the CCS guidelines recommend a target heart rate at rest <100 bpm whereas the the ACCF/AHA/HRS and ESC guidelines accept a target heart rate at rest <110 bpm with provisos. All the guidelines recommend that the choice of antiarrhythmic drug for maintenance of sinus rhythm be based on the underlying cardiovascular disease state. However, the CCS guidelines do not recommend that the use of Class IC drugs or sotalol be restricted in the presence of left ventricular hypertrophy alone. All the guidelines have incorporated dronedarone into their recommendations of antiarrhythmic drug therapy for maintenance of sinus rhythm. However, the CCS guidelines do not make a specific recommendation that the use of dronedarone is reasonable to decrease the risk of hospitalization for cardiovascular causes in patients with AF. The ACCF/AHA/HRS update makes a strong recommendation for catheter ablation in patients with paroxysmal AF who have failed a single anti-arrhythmic drug whereas the CCS and ESC guidelines make this a conditional recommendation. The CCS guidelines are the only guidelines at present that recommend dabigitran for prevention of stroke in high risk patients and suggest that dabigatran is preferred to warfarin for stroke prevention in most patient groups.

A Review of the Appropriate and Inappropriate Use of Dronedarone: Lessons Learned From Controlled Studies and Regulatory Submission

Dronedarone is a multichannel blocker with electrophysiologic effects similar to amiodarone. Dronedarone has been documented to prevent atrial fibrillation recurrences and also has efficacy in slowing the ventricular response during episodes of atrial fibrillation. However, in the ANDROMEDA trial, dronedarone was associated with increased mortality when tested in New York Heart Association (NYHA) III/IV patients with left ventricular ejection fractions of less than 35%, who also had a recent hospitalization for decompensated heart failure. When such high-risk patients with heart failure were excluded in the ATHENA trial, dronedarone treatment resulted in a statistical reduction in the composite primary end point of all-cause mortality or cardiovascular hospitalization. In ATHENA, dronedarone reduced cardiovascular hospitalizations even though in the DIONY-SOS trial dronedarone had less effect than amiodarone on suppressing atrial fibrillation recurrences. The most appropriate patients for treatment with dronedarone would be patients with a recent history of paroxysmal or persistent atrial fibrillation/atrial flutter (AF/AFL) that have associated risk factors per the inclusion criteria of ATHENA. Inappropriate patients would be those with class IV heart failure or recently hospitalized for heart failure within the last month from an acute decompensation, the main inclusion criteria in ANDROMEDA. Dronedarone is a novel, multichannel blocking antiarrhythmic agent that may have some pleiotropic effects in addition to its ability to suppress and maintain sinus rhythm and control the rate during AF/AFL recurrences.

Dronedarone: An Alternative to Amiodarone?

To review the safety and efficacy of the newly approved, mixed-activity antiarrhythmic dronedarone (classes I-IV) versus its parent compound comparator, amiodarone (class III, with mixed activity). A MEDLINE/PUBMED (January 1966 to March 2010) and International Pharmaceutical Abstract (January 1975 to March 2010) search of English language papers in addition to a bibliographic search of retrieved papers. All human studies of dronedarone, alone or in combination with amiodarone, were reviewed. Approved in July 2009, dronedarone is a new antiarrhythmic agent indicated to reduce the risk of hospitalization for cardiac events in patients with paroxysmal or persistent atrial fibrillation or atrial flutter. Dronedarone has been viewed as a potential therapeutic alternative for amiodarone because of a lower risk for pulmonary, thyroid, and dermatologic adverse effects. Compared with amiodarone, dronedarone has poor bioavailability and a shorter terminal disposition half-life, which dictates a twice-daily dosing regimen. Furthermore, dronedarone failed to demonstrate superiority over amiodarone with respect to recurrence of atrial fibrillation in a comparative efficacy analysis. Dronedarone therapy is more costly and increases overall tablet burden. No dosage adjustments are required with dronedarone for renal impairment. Use of dronedarone is contraindicated in the presence of severe hepatic impairment. No serious organ-related toxicities (i.e., thyroid and pulmonary system) have been reported with use of dronedarone. Dronedarone as a niche drug may be a reasonable theoretical alternative for patients who cannot tolerate amiodarone or have underlying comorbidities that contraindicate amiodarone use (e.g., pulmonary, thyroid disease). However, dronedarone has not been studied in the vast majority of indications and patient populations in which amiodarone has been studied.

Dronedarone: A Safety Comparison to Amiodarone

Dronedarone is an oral Class III antiarrhythmic agent which was recently approved by the US Food and Drug Administration for use in nonpermanent atrial fibrillation. Structurally similar to amiodarone, dronedarone is a benzofuran derivative but it lacks the iodine moiety attached to amiodarone. Based upon the investigational clinical trials to date, it appears that dronedarone has an established efficacy when compared to placebo along with exhibiting a minimal adverse effect profile. The efficacy of dronedarone will need to be further evaluated in comparison trials with established antiarrhythmics for atrial fibrillation. The adverse profile of dronedarone appears to be substantially safer in comparison to amiodarone, although there is still little data available. The adverse effect profile of amiodarone necessitates close and extensive monitoring. Although a risk of pulmonary toxicity was identified in animals, long term studies in humans are needed to determine the significance of this adverse effect with dronedarone. One noted effect of dronedarone is an isolated increase in serum creatinine levels, and the clinical relevance of this effect needs further evaluation. Based on supporting evidence, the use of dronedarone is contraindicated in advanced or decompensated heart failure. Some clinically significant dronedarone drug interactions have been identified. Although the potential differences between dronedarone and amiodarone have been evaluated there have been no direct comparison trials published to date. This article reviews the chemistry, antiarrhythmic effects, pharmacokinetics, efficacy, adverse effects and drug interactions of dronedarone.

Dronedarone

Atrial fibrillation (AF) is a common arrhythmia associated with increased cardiovascular mortality, stroke, and hospitalization in the United States. Amiodarone is generally considered as the agent with the best efficacy for maintaining normal sinus rhythm. Despite its efficacy, amiodarone use is often limited by its extensive side effect profile. Dronedarone is a noniodinated benzofuran derivative of amiodarone that has been recently approved by the Food and Drug Administration to reduce cardiovascular hospitalization in patients with AF or atrial flutter. Structural modification of dronedarone was introduced to shorten the half-life, decrease lipophilicity, and minimize noncardiovascular toxicity as compared to amiodarone. This article reviews the pharmacology, adverse effects, and clinical evidence available to date of the use of dronedarone in the management of AF.

Significant Sirolimus and Dronedarone Interaction in a Kidney Transplant Recipient

To report the potential clinically significant pharmacokinetic interaction between sirolimus and dronedarone. A 67-year-old man status post-kidney transplant in 2004 was maintained on an immunosuppressive regimen consisting of sirolimus, mycophenolate mofetil, and prednisone. He had been maintained for more than 1 year on a stable dose of sirolimus (5 mg/day), with concentrations ranging between 5 and 13.5 ng/mL. The patient was admitted to the hospital with a complaint of bloody diarrhea; shortly after admission, he developed atrial fibrillation for which dronedarone 400 mg twice daily was initiated. Sirolimus concentrations obtained 3 days after initiation of dronedarone revealed a trough concentration that was increased by more than 3-fold (38.6 ng/mL) from his baseline trough concentration. After sirolimus was held for 6 days, the trough concentration was 7.8 ng/mL. The dosage was reduced to 1 mg/day; there was no need for further adjustment. While the potential for an interaction between sirolimus and dronedarone is listed in the package insert of dronedarone, there are no documented reports of this interaction in the peer-reviewed literature. Since sirolimus is a narrow therapeutic index medication, information about the severity and magnitude of the interaction with dronedarone may help clinicians avoid therapeutic misadventures when this combination is employed. Our case clearly demonstrates a significant pharmacokinetic interaction between sirolimus and dronedarone. The Horn Drug Interaction Probability Scale indicates that the occurrence of an interaction between sirolimus and dronedarone in our case is probable. Due to the potential for sirolimus toxicity and excessive immunosuppression, the concurrent use of dronedarone and sirolimus should be avoided when possible. If concurrent administration cannot be avoided, we suggest close monitoring and a 50-75% dose reduction of sirolimus prior to dronedarone initiation.

Dronedarone: an emerging therapy for atrial fibrillation

Atrial fibrillation (AF) is a common arrhythmia, with a prevalence ranging from 0.1% to 9.0% at different ages, and is associated with increased cardiovascular events and mortality. A significant increase in the prevalence of the disease is expected to occur in the coming years as a consequence of the aging of the population and advances in the management of coronary artery disease and heart failure. Effective rhythm control may be difficult to obtain in a significant proportion of patients with AF. The limited efficacy and the possible adverse effects of antiarrhythmic drugs has led researchers to focus their attention on new molecules, in a search of compounds with antiarrhythmic efficacy and a more favourable safety profile. Among several new drugs developed for the management of AF, dronedarone, a benzofuran derivative that shares many of the antiarrhythmic properties of amiodarone, but with a more favourable safety profile, seems particularly promising. The drug is noniodinated, has less lipophilicity, reaches therapeutic concentrations over a shorter period of time and has lower tissue accumulation. Dronedarone, similarly to amiodarone, exhibits electrophysiologic characteristics of all 4 Vaughan Williams classes. Clinical studies have shown that dronedarone effectively reduces ventricular rate, may prevent or delay the recurrence of AF, and may reduce cardiovascular morbidity and mortality in patients with AF or atrial flutter. The drug has an overall good safety profile, in particular with low pulmonary and thyroid toxicity. An important exception is represented by patients with unstable haemodynamic conditions, in which the use of dronedarone has been found to be associated with an increase in mortality. Dronedarone has been recently approved for clinical use by the Food and Drug Administration and by the European Medicines Agency. Further results from trials and clinical use will better define the efficacy and safety profile of dronedarone in AF compared with other antiarrhythmic drugs and its role in the management of patients with AF.

Effect of Dronedarone on Cardiovascular Events in Atrial Fibrillation

Dronedarone is a new antiarrhythmic drug that is being developed for the treatment of patients with atrial fibrillation. 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. 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. Dronedarone reduced the incidence of hospitalization due to cardiovascular events or death in patients with atrial fibrillation. (ClinicalTrials.gov number, NCT00174785.)

In Vitro Effects of Acute Amiodarone and Dronedarone on Epicardial, Endocardial, and M Cells of the Canine Ventricle

Amiodarone (AM) is an antiarrhythmic agent widely used in the treatment of ventricular and supraventricular arrhythmias. Dronedarone (DR) is a new compound with a pharmacological profile similar to that of AM, but iodine free. We previously demonstrated that chronic AM treatment reduces transmural dispersion of repolarization (TDR) in the canine heart. We used standard microelectrode technique to evaluate the effects of acute AM (100 microM) and DR (30 microM) on epicardial (EPI), endocardial (ENDO), and M region tissues obtained from the left ventricular wall of the canine heart. Amiodarone (100 microM, 120 min of exposure) produced little change in the action potential duration of ENDO and EPI tissues, but it shortened the action potential of M cells, especially at slow rates, leading to a decrease in TDR. Similar results were observed with DR. Acute AM (100 microM) and DR (30 microM) eliminated d-sotalol-induced early afterdepolarizations (EADs) and triggered activity in 3 of 3 and 2 of 6 M cell preparations, respectively. The reduction of TDR and the elimination of EAD-induced triggered activity differentiates AM and DR from other class III agents. These effects may explain the efficacy and low arrhythmogenicity of acute AM and suggest a potential safe use of DR as an antiarrhythmic agent.