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ARTICLE CONTRIBUTORS

Dr Anish George

Dr Joseph John

Dr Sudipta Chattopadhyay

Clinical Articles, News & Views

Dronedarone: a new therapeutic option for atrial fibrillation

Lincolnshire cardiologists review the new antiarrhythmic agent, dronedarone, which is indicated for the maintenance of sinus rhythm after successful cardioversion in adult clinically stable patients with paroxysmal or persistent atrial fibrillation (AF).

Atrial fibrillation (AF) is a common cardiac arrhythmia, and is associated with significant morbidity and mortality. Amiodarone, one of the most widely used antiarrhythmic agents, is however associated with various adverse effects. Dronedarone is a new non-iodinated benzofuran derivative with a sulphonamide group which, while similar to amiodarone in structure and properties, has a better safety profile.
During the initial clinical trials dronedarone was noted to significantly reduce the recurrence and ventricular rate in patients with non-permanent AF. One of the studies however noted that dronedarone should not be considered in patients with severe New York Heart Failure (NYHA III or IV) symptoms or left ventricular ejection fraction (LVEF) of <35%, due to increased mortality risk in this group. Following its introduction into the market, reports of liver injury and increased mortality in patients with permanent AF has resulted in some element of ambiguity in its role in clinical practice.

Atrial fibrillation (AF) is a common cardiac arrhythmia, and is associated with significant morbidity and mortality. Amiodarone, one of the most widely used antiarrhythmic agents, is however associated with various adverse effects. Dronedarone is a new non-iodinated benzofuran derivative with a sulphonamide group which, while similar to amiodarone in structure and properties, has a better safety profile.

During the initial clinical trials dronedarone was noted to significantly reduce the recurrence and ventricular rate in patients with non-permanent AF. One of the studies however noted that dronedarone should not be considered in patients with severe New York Heart Failure (NYHA III or IV) symptoms or left ventricular ejection fraction (LVEF) of <35%, due to increased mortality risk in this group. Following its introduction into the market, reports of liver injury and increased mortality in patients with permanent AF has resulted in some element of ambiguity in its role in clinical practice.

Introduction

AF is the most common sustained cardiac arrhythmia, and is associated with considerable morbidity and mortality. Despite improvements in the primary and secondary care for coronary disease, and its risk factors, the prevalence of AF continues to increase. Each year nearly 50,000 new cases of AF are diagnosed in the UK. The prevalence of AF in the general UK population is around 1%; however this increases significantly with age, affecting more than one in 10 people above the age of 85.1 AF increases the risk of stroke by four to five fold and death by twofold, resulting in considerable burden to the heath services.2,3

There are two fundamental strategies for AF management: rhythm and rate control. Although rate control with anticoagulation therapy offers considerable reduction in arrhythmia related symptoms and thrombo-embolic strokes, maintaining patients in sinus rhythm (SR) is considered to have the added advantage of improving the quality of life and exercise tolerance.4,5,6

Among the established pharmacological agents available for rhythm control, amiodarone remains the mainstay of therapy for the management of AF. Unfortunately amiodarone is associated with a number of serious side effects and drug interactions. Furthermore, pharmacologically, it has a prolonged half-life and large volume of distribution.7 There is hence a demand for safer and more effective antiarrhythmic agents. The majority of the deleterious effects associated with amiodarone has been blamed on its high iodine content which, in addition to causing thyroid dysfunction, makes it lipophilic and causes it to accumulate in highly vascular organs like the liver, lungs, skin etc.8

Dronedarone is a new antiarrhythmic agent with multiple channel blocking and anti-adrenergic properties which, while being similar to amiodarone in structure and function, is not associated with the serious side effects seen with amiodarone. The National Institute for Health and Clinical Excellence (NICE) has recently approved the use of dronedarone as a second line drug in patients with non-permanent AF, who meet the appropriate criteria.9

Clinical pharmacology

Dronedarone is similar to amiodarone in structure, and can be considered to be a non-iodinated benzofuran derivative with a methane sulfonyl group. In vitro studies have shown that in addition to being structurally related, the electrophysiological properties of dronedarone are also similar to amiodarone. They both exhibit multiple transmembrane channel blocking properties, including Na channel blocking at rapid pacing (class I effect), non-competitive antiadrenergic effects (class II effect), prolonged cardiac action potential and refractoriness (class III effect), and Ca channel blocking (class IV effect).10,11

Dronedarone has shown even less reverse use-dependence for repolarisation compared to amiodarone, and may hence be associated with a better cardiac safety profile.12 Furthermore, following chronic treatment with dronedarone for four weeks, the prolongation of the QTc and the cardiac action potential duration in papillary muscles were not as significant as the changes seen following chronic treatment with amiodarone.13

Preclinical animal studies showed that the antiarrhythmic properties of dronedarone were similar to those of amiodarone. In animal studies looking at the antiarrhythmic properties in the context of ischaemia and reperfusion induced arrhythmia, dronedarone was found to be more effective than amiodarone in reducing ventricular fibrillation (VF) and mortality. In rat studies, during a 20 minute period of ischaemia, dronedarone reduced the incidence of VF from 80% to 30% (p<0.05) at 3 mg/kg iv, and eliminated VF and mortality completely at a dose of 10 mg/kg iv. In contrast amiodarone, at 10 mg/kg iv, only reduced the incidence of mortality during ischaemia (from 60% to 0%, p<0.01), while having no effect at 3 mg/kg iv.14

Similarly during reperfusion (post five minute period of ischaemia) dronedarone reduced mortality significantly (from 90% to 20%, p<0.05) at 1 mg/kg, and eliminated VF and mortality completely at 3 mg/kg, while amiodarone required a higher dose of 10 mg/kg to produce a similar result.14

Pharmacokinetics

Dronedarone is well absorbed orally (70%100%), and reaches steady state serum level within 57 days. However due to extensive first-pass metabolism more than four fifths of the drug gets eliminated, hence requiring a twice daily regime. Like amiodarone its bioavailability increases by two to threefold when taken with food. The absence of the iodine moiety makes it less lipophilic, resulting in lower tissue accumulation, and a shorter half-life of about 24 hours, compared to amiodarone which has an average half-life of 58 days.10,11

Dronedarone is metabolised via the cytochrome (CYP) P450 3A4 isoenzyme system, and eliminated predominantly in faeces. Only around 5% of the drug is excreted via the kidneys, hence its drug levels remain largely unaffected in renal impairment. Dronedarone and its active metabolites can cross the blood brain barrier, the placenta, and can be secreted in breast milk, and hence are better avoided in pregnant or breastfeeding females.8 Dronedarone partially inhibits the tubular transport of creatinine thereby increasing the serum levels of creatinine; however this is not associated with any deterioration in the glomerular filtrations rate.15

Clinical trials

Over the last few years various double blinded, placebo controlled randomised trials have been conducted, looking at the therapeutic response and adverse effects associated with dronedarone, involving patients with AF. The results of these studies have been summarised below.

DAFNE study

Of the early clinical trials, the Dronedarone Atrial Fibrillation Study after Electrical Cardioversion (DAFNE) which is a phase IIb double-blinded, randomised, placebo controlled trial, is probably the most relevant.16 The study involved 270 patients with persistent AF who underwent pharmacological or electrical cardioversion. From amongst this group, primary analysis was performed on the 199 patients in whom SR was restored. These patients (n=199) were randomly allocated to 400 mg bd, 600 mg bd, or 800 mg bd doses of dronedarone or placebo and were followed up for six months. The primary end point was the time to the first episode of documented AF. It is worth noting that heart failure (NYHA III-IV or LVEF< 35%) was one of the exclusion criteria for the study.

The results at the end of the six month period showed that the median time period to the first documented AF recurrence in the placebo group was 5.3 days, compared to 60 days in the 400 mg bd dronedarone group (p=0.001). Furthermore, in the event of recurrence, patients who received dronedarone had a lower ventricular rate compared to the placebo group (p=0.0001). No significant benefit was seen at higher doses. Also the recurrence of AF was lower among the dronedarone group, with 35% still in SR after the six month period compared to 10% with the placebo group.

The overall premature drug discontinuation due to adverse events among the dronedarone group was 10.8% (22 patients), while there were no premature discontinuations in the placebo group.  The 400 mg bd, 600 mg bd, and 800 mg bd groups were associated with discontinuation rates of 3.9%, 7.6%, and 22.6% respectively, with the most common cause being gastrointestinal side effects. There were no episodes of arrhythmia, including torsades de pointes; and statistically significant QTc prolongation was only noted in the 800 mg bd group. Furthermore no evidence of thyroid, pulmonary or ocular toxicity was noted. While there were a few cases of heart failure they were statistically insignificant. The study hence showed that dronedarone 400 mg bd, appeared to be effective and safe for the prevention of AF relapses after successful cardioversion during a six month follow-up.

EURIDIS/ADONIS studies

The European Trial in Atrial Fibrillation or Flutter Patients Receiving Dronedarone for the Maintenance of Sinus Rhythm (EURIDIS) and the American-Australian-African Trial with Dronedarone in Atrial Fibrillation or Flutter Patients for the Maintenance of Sinus Rhythm (ADONIS) were two identical phase III, multi-national, placebo-controlled, double blind studies that compared the efficacy of dronedarone in maintaining SR in patients with paroxysmal AF or atrial flutter (AFl).17

The studies which were carried out in 12 European countries (EURIDIS in 65 centers), USA, Canada, Australia, South Africa and Argentina (ADONIS in 101 centers) and involved patients above the age of 21 years, with at least one electrocardiogram (ECG) documented episode of AF/ AFl within the last three months, and who were in SR for at least an hour at the time of randomisation. Eligible patients (n= 612 in EURIDIS, and n= 625 in ADONIS) were randomised in 2:1 ratio to receive dronedarone 400 mg bd, or placebo for 12 months. The primary end point was the time from randomisation to the first documented episode of AF/AFl recurrence lasting for 10 minutes or more. As seen with DAPHNE study, heart failure (NYHA III-IV) and permanent AF were among the exclusion criteria.

In the ADONIS trial, the median time to recurrence was 158 days in the dronedarone group compared to 59 days in the placebo group, while in the EURIDIS study the median time was 96 days for the dronedarone group compared to 41 days for the placebo group. Combined results for secondary endpoints showed that after 12 months the incidence of recurrence was lower in the dronedarone group compared to placebo (64.1% vs 78.15%, p<0.001). As noted with DAFNE, in patients with recurrence, the ventricular rate was lower in the dronedarone group. A post hoc analysis showed that 22.8% patients in the dronedarone group had been hospitalised or had died at the end of the 12 month period compared to 30.9% in the placebo group (p=0.01). The incidence of heart failure, while slightly higher in the dronedarone group, was not statistically significant (2.4% vs 1%, p: 0.12).

The main side effect noted with dronedarone was gastrointestinal. Also, the serum creatinine levels were raised in the dronedarone group (2.4% vs 0.2%, p=0.004). However there was no significant variation in the incidence of serious side effects in the dronedarone group compared to the placebo group. Furthermore as noted with DAFNE trial there was no evidence of pulmonary or thyroid toxicity in the dronedarone group. The study concluded that dronedarone was significantly more effective than placebo in maintaining SR and in reducing the ventricular rate during recurrence of arrhythmia.

The ANDROMEDA trial

The Antiarrhythmic Trial with Dronedarone in Moderate to Severe Congestive heart failure Evaluating Morbidity Decrease (ANDROMEDA) was a multi-center, randomised, double blind, placebo controlled study looking at the efficacy of the antiarrhythmic properties of dronedarone in patients with congestive heart failure. Eligibility included an NYHA class of III-IV, or paroxysmal nocturnal dyspnoea within the last one month, or LVEF≤35% (wall motion index ≤1.2).18 It is worth mentioning that this was not an AF study and presence of AF was not required for participating in the study. This was the first study to look at the effect of dronedarone in heart failure patients.18

The initial plan was to enrol 1,000 patients, who would then be randomised on 1:1 ratio to receive dronedarone 400 mg bd or the placebo for a minimum period of 12 months. The primary end point was the composite of death from any cause or hospitalisation for heart failure. However, the study was terminated prematurely after the inclusion of 627 patients (310 in the dronedarone group and 317 in the placebo group) and a median follow up period of two months, following the recommendations of the safety monitoring board due to the presence of increased mortality in the dronedarone group. During a median follow up of two months, 25 patients in the dronedarone group (8.1%) and 12 patients in the placebo group (3.8%) died (p=0.03, hazard ratio in the dronedarone group 2.13, 95% confidence interval 1.074.25). The main cause for the excess mortality was exacerbation of heart failure (10 in the dronedarone group, and two in the placebo group) and arrhythmia.

The overall conclusion of the study was that treatment with dronedarone in patients with severe heart failure, and left ventricular systolic dysfunction was associated with increased early mortality due to worsening of heart failure.

ATHENA study

ATHENA (Assess the Efficacy of Dronedarone for the Prevention of Cardiovascular Hospitalisation or Death from any cause in patients with Atrial Fibrillation or Flutter) was a multi-center randomised, double blind, placebo controlled trial, which evaluated the efficacy of dronedarone, on top of standard AF therapy, in reducing morbidity and mortality in patients with AF or AFl with additional risk factors for death. The primary end point was the first hospitalisation due to cardiovascular events or death.19,20

The study involved 4,628 patients, who were randomised to receive dronedarone 400 mg bd (n=2,301), or placebo (n=2,327). The eligibility for enrolment in the study was a history of paroxysmal or persistent AF or AFl, with risk factors for death or cardiac events. This risk was defined as age ≥75 or the presence of at least one of the following: hypertension, diabetes, prior stroke or transient ischaemic attack or systemic embolism, enlarged left atrium (≥5.0 cm), or LVEF of ≤40%. Among the exclusion criteria the key ones to note are permanent AF, recent decompensated heart failure and NYHA IV heart failure.

The results, after a mean follow up period of 21 months, showed that the incidence of first hospitalisation due to a cardiovascular cause or death was significantly lower in the dronedarone group compared to the placebo group (31.9% vs 39.4%, p<0.001). There were 63 deaths from cardiovascular causes in the dronedarone group compared to 90 in the placebo group (hazard ratio 0.71, 95% CI 0.510.98, p=0.03). This was largely due to a reduction in the arrhythmia related death with dronedarone (p=0.01). It is however worth noting that the all-cause mortality, although numerically lower in the dronedarone group, was not statistically significant (116 vs 139, p=0.18, hazard ratio 0.84; 95% CI 0.661.08).

There were 1,649 treatment-emergent adverse event in the dronedarone group (vs 1,603, placebo group, p=0.048), including gastrointestinal effects, bradycardia, QT prolongation, skin-related events including rash, and raised serum creatinine, all of which were statistically more common in the dronedarone group. There was no evidence of any significant pulmonary or thyroid toxicity in the dronedarone group.

Post-hoc analysis from the ATHENA study revealed that dronedarone reduced the number of days of hospital stay by 28% (p<0.001).21 A second post-hoc analysis showed that dronedarone reduced the mean heart rate in AF 75 bpm compared to 84 bpm for placebo (p<0.001). Furthermore fewer patients developed permanent AF during the study in the dronedarone group (7.7% vs 12.7%, p< 0.001).22 The study concluded that dronedarone reduced the incidence of hospitalisation and mortality due to cardiovascular events in patients with non-permanent AF. While the study included patients with LVEF<45% (12%), and NYHA II-III (21%), and the results did not reveal any worsening of heart failure, in view of the ANDROMEDA trial results, they recommended avoidance in patients with severe heart failure.

DIONYSUS study

The DIONYSUS (Dronedarone vs Amiodarone for the Maintenance of Sinus Rhythm in Patients with Atrial Fibrillation) is a randomised, double blind study comparing the safety and efficacy of dronedarone with amiodarone. The study involved 504 patients who were known to have persistent AF and to have had documented AF for more than 72 hours, who were then randomised on a 1:1 ratio to receive dronedarone 400 mg bd or amiodarone 600 mg daily for 28 days and then 200 mg daily. The median study duration was seven months.23 Patients with NYHA III-IV and severe heart failure were excluded.

The enrolled patients were amiodarone naïve, and were on oral anticoagulation. In patients who failed to convert to SR by day ten, electrical cardioversion were performed. The primary composite endpoint measured was recurrence of AF or premature study discontinuation, while the main safety endpoint was occurrence of thyroid, pulmonary, hepatic, skin, ocular or gastrointestinal events or premature study drug withdrawal following an adverse event.

The results of the study showed that the composite primary endpoint was 75.1% with dronedarone and 58.8% with amiodarone at twelve months (p<0.0001), which was mainly due to increased incidence of AF recurrence in the dronedarone group (63.5% vs 42.0%). Furthermore AF recurrence after successful cardioversion was also higher in the dronedarone group (36.5% vs 24.3%).

Main safety endpoint was 39.3% with the dronedarone group when compared to 44.5% with the amiodarone group (hazard ratio: 0.80, 95% CI 0.601.07, p=0.129) which was largely due to fewer thyroid, neurological, skin and ocular effects. The main adverse effect associated with dronedarone was gastrointestinal, and if this were excluded from the safety endpoint analysis, the difference becomes statistically significant (61 vs 99, p=0.002). Also the incidence of bradycardia (8 vs 22) and QT (27 vs 52) prolongation was less common in the dronedarone group.

The study concluded that dronedarone was less effective than amiodarone in decreasing AF recurrence, but had a better safety profile, specifically with regard to thyroid and neurological events and a lack of interaction with oral anticoagulants.23

PALLAS study

The PALLAS (Permanent Atrial fibrillation outcome study using Dronedarone on top of standard therapy) study is a randomised, double blinded, placebo controlled trial evaluating the effects of dronedarone (400 mg bd) on top of standard therapy in patients with permanent AF. This was the first major trial looking at the effects of dronedarone on permanent AF. The primary end points were time to the occurrence of major cardiovascular event (stroke, myocardial infarction (MI), systemic arterial embolism or cardiovascular mortality) and time to the first unscheduled cardiovascular hospitalisation or death from any cause.

The study included patients aged ≥65 years, with permanent AF (defined as presence of AF or AFl for at least six months prior to randomisation, with no plans to restore SR) and at least one additional cardiovascular risk factor (table 1). Patients with NYHA III-IV were excluded. The co-primary end points included, stroke, thrombo-embolic phenomena, MI, cardiovascular death and all-cause mortality or cardiovascular readmission. The study was originally expected to enrol 10,800 patients, but was discontinued after 3,236 patients (1,619 in dronedarone and 1,617 in placebo group), due to significantly higher incidence of cardiovascular events in the dronedarone group (table 2). It is, however, worth noting that patients in the dronedarone group were more likely to stay in SR at follow-up (3.5% vs 1.4%, p=0.01), with better reduction in the mean heart rate (7.6 vs 1.7, p<0.001). However, dronedarone was also associated with a higher rate of drug discontinuation (21% vs 11%, p<0.001).

Table 1. Additional risk factors for PALLAS study

Table 1. Additional risk factors for PALLAS study

Table 2. Results of the PALLAS study

Table 2. Results of the PALLAS study

The study concludes that dronedarone is associated with an increased risk of death, heart failure and stroke in high risk patients with permanent AF, and would not be recommended for use in these patients. There was also an increased rate of discontinuation due to adverse effects in this group.24,25

Hepatocellular toxicity

Following introduction into market, dronedarone has been associated with reports of hepatocellular injury, including two cases with acute liver failure requiring transplant. In view of these reports, it has now been advised that liver function tests (LFT) should be performed prior to initiation of treatment with dronedarone. This is followed by further monitoring of the LFTs after one week, one month, and then repeated monthly for the next six months, at nine and 12 months, and then periodically thereafter.

If alanine aminotransferase (ALT) levels are elevated by ≥3 x upper normal limit, it has to be rechecked in 2448 hours. If repeat ALT levels are also elevated then the treatment with dronedarone has to be discontinued, and hepatic function has to be closely monitored using appropriate tests. Any symptom suggestive of liver injury should be promptly investigated.26

Patient monitoring

In light of the recent reports of liver injury, and concerns regarding cardiovascular safety following premature termination of the PALLAS study European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) has recommended new monitoring requirements for the safe use of dronedarone. This involves:

  • Regular cardiovascular examination including an ECG at least every six months. If AF recurs, discontinuation of dronedarone should be considered, while if patient goes into permanent AF, the drug should be discontinued.
  • Patients should be monitored for any symptoms of heart failure, while on the drug.
  • Liver functions should be monitored as previously stated.
  • International normalised ratio (INR) monitored closely after commencing dronedarone, in patients anticoagulated with vitamin K antagonists.
  • Serum creatinine measured prior to and seven days post initiation.
  • Symptoms suggestive of pulmonary toxicity should be promptly investigated and, if proved, dronedarone should be discontinued.26

NICE recommendations and recent EMA recommendation

NICE guidelines, published recently, recommended the use of dronedarone as a second line drug for the management of non-permanent AF. The NICE recommended indications are as shown in table 3.

Table 3: NICE recommended indication for the management of patients with non-permanent atrial fibrillation (lasting for ≤1 year)9

Table 3: NICE recommended indication for the management of patients with non-permanent atrial fibrillation (lasting for ≤1 year)9

However it has to be noted that these guidelines were published prior to the results of PALLAS study and reports of liver injury and hence it would be recommended to consider the recent EMA recommendation and the subsequent EMA-approved modified summary of product characteristics, prior to initiating dronedarone therapy. These are as detailed below.

Dronedarone is now only recommended in adult clinically stable patients with paroxysmal or persistent AF for the maintenance of SR, after successful cardioversion. All other therapeutic options should be considered prior to starting a patient on dronedarone, in view of its safety profile. The treatment should be initiated only under specialist supervision and it should be monitored on a routine basis.27

Dronedarone is now contraindicated in patients with unstable haemodynamic conditions; history of, or concurrent heart failure or LV systolic dysfunction; permanent AF (AF duration ≥6 months or unknown, with no plans to restore SR), liver and lung toxicity related to previous amiodarone therapy.26 Figure 1 shows the algorithm for the medical management of persistent AF and the position of dronedarone in it.9,10,11

Figure 1. Algorithm for the medical management of persistent AF.

Figure 1. Algorithm for the medical management of persistent atrial fibrillation.9,25

The recommended oral dose for dronedarone is 400 mg twice a day. Dronedarone is not available in intravenous preparations. The guidelines do not specifically mention the use of dronedarone in patients who are already on amiodarone. This decision would be up to the clinician, and would involve taking into account the duration of antiarrhythmic therapy, implications of possible side effects and the opinion of patients involved.9

Conclusion

Dronedarone is a benzofuran class of antiarrhythmic agent, which has structural and functional similarity to amiodarone. Unlike amiodarone, dronedarone is not associated with any significant pulmonary, thyroid or ocular toxicity; however dronedarone is associated reports of hepatocellular toxicity. Moreover it is also associated with adverse cardiovascular outcome in patients with heart failure and/or permanent AF. While a small percentage of patients on dronedarone were noted to have elevated serum creatinine and prolonged QTc interval, this has not been found to result in renal impairment or arrhythmia.

At the time of introduction into the market, dronedarone was considered as an alternative to amiodarone, with better safety profile even though not as effective. However, in light of the recent findings, dronedarone appears to be more of an alternative to drugs like flecainide and sotalol. It should however be noted that dronedarone remains an efficient antiarrhythmic agent that when considered in the appropriate patient group is effective in reducing the incidence of relapse in patients with AF.

Conflict of interest

None declared.

References

1 Majeed A, Moser K, Carroll K. Trends in the prevalence and management of atrial fibrillation in general practice in England and Wales, 19941998: analysis of data from the general practice research database. Heart 2001;86:2848.

2 Feinberg WM, Blackshear JL, Laupacis A et al. Prevalence, age distribution and gender of patients with atrial fibrillation. Arch Intern Med 1995; 155:46973.

3 Wattigney WA, Mensah GA, Croft JB, Increasing trends in hospitalization for atrial fibrillation in the United States, 1985 through 1999: implications for primary prevention. Circulation 2003;108:7116.

4 Singh BN, Singh SN, Reda DJ, et al. Sotalol Amiodarone Atrial Fibrillation Efficacy Trial (SAFE-T) Investigators. Amiodarone versus sotalol for atrial fibrillation. N Engl J Med 2005;352:186172.

5 Nattel S, Singh BN. Evolution, mechanisms, and classification of antiarrhythmic drugs: focus on class III actions. Am J Cardiol 1999;84:11R19R.

6 Singh BN. Atrial fibrillation: epidemiologic considerations and rationale for conversion and maintenance of sinus rhythm. J Cardiovasc Pharmacol Ther 2003;8 Suppl 1: S13S26.

7 McNamara RL, Tamariz LJ, Segal JB, Bass EB. Management of atrial fibrillation: Review of the evidence for the role of pharmacologic therapy, electrical cardioversion, and echocardiography. Ann Intern Med 2003;139:1018–33.

8 Hans TS, Williams GR, Vanderpump MP. Benzofuran derivatives and the thyroid. Clin Endocrinol (Oxf).2009;70:213.

9 National Institute of Health and Clinical Excellence. Dronedarone for the treatment of non-permanent atrial fibrillation (TA 197). Available at www.nice.org.uk/guidance/TA197. Last accessed on the 18th January, 2012.

10 Tafreshi MJ, Rowles J. A review of the investigational antiarrhythmic agent dronedarone. J Cardiovasc Pharmacol Ther 2007;12:15–26.

11 Watanabe Y, Kimura J. Acute inhibitory effect of dronedarone, a noniodinated benzofuran analogue of amiodarone, on Na+/Ca2+ exchange current in guinea pig cardiac ventricular myocytes. Naunyn Schmiedebergs Arch Pharmacol 2008;377:371–6.

12 Finance O, Manning A, Chatelain P. Effects of a new amiodarone like agent, SR33589, in comparison to amiodarone, D,L-sotalol and lignocaine, on ischaemia induced ventricular arrhythmias in anesthetized pigs. J Cardiovasc Pharmacol 1995;26:5706.

13 Varro A, Takacs J, Nemeth M, et al. Electrophysiological effects of dronedarone (SR 33589), a noniodinated amiodarone derivative in the canine heart: comparison with amiodarone. B J Pharmacol 2001;133:62534.

14 Manning AS, Bruyninckx C, Ramboux J, et al. SR 33589, a new amiodarone-like agent: effect on ischaemia- and reperfusion- induced arrhythmias in anesthetised rats. J Cardiovasc Pharmacol 1995;26:453–61.

15 Tschuppert Y, Buclin T, Rothuizen LE, Decosterd LA, Galleyrand J, Gaud C, Biollaz J. Effect of dronedarone on renal function in healthy subjects. Br J Clin Pharmacol. 2007;64:785–91

16 Touboul P, Brugada J, Capucci A, Crijns HJ, Edvardsson N, Hohnloser SH. Dronedarone for prevention of atrial fibrillation: A dose-ranging study. Eur Heart J 2003;24:1481–7.

17 Singh BN, Connolly SJ, Crijns HJ, et al. Dronedarone for Maintenance of Sinus Rhythm in Atrial Fibrillation or Flutter. N Engl J Med 2007;357:98799.

18 Kober L, Torp-Pedersen C, McMurray JJ, et al. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med 2008;358:267887.

19 Hohnloser SH, Connolly SJ, Crijns HJ et al. Rationale and design of ATHENA: A placebo controlled, double blind parallel arm trial to assess the efficacy of dronedarone 400mg bid for the prevention of cardiovascular hospitalization or death from any cause in patients with atrial fibrillation/ atrial flutter. J Cardiovasc Electrophysiol 2008;19:6973.

20 Hohnloser SH, Crijns HJ, van Eickels M et al. The effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009;360:66878.

21 Torp-Pedersen C, Page RL, Connolly SJ, et al. The effect of dronedarone on hospitalizations in patients with atrial fibrillation. Results from the ATHENA study. American Heart Association 2008 Scientific Sessions; November 8–12, 2008; New Orleans, LA. Abstract 4101.

22 Page RL, Connolly SJ; Crijns HJ, et al. Rhythm- and rate-controlling effects of dronedarone in patients with atrial fibrillation: Insights from the ATHENA trial. American Heart Association 2008 Scientific Sessions; November 8–12, 2008; New Orleans, LA. Abstract 4097.

23 Le Heuzey JY, De Ferrari GM, Radzik D, et al. A short term randomised, double blind, parallel group study to evaluate the efficacy and safety of dronedarone versus amiodarone in patients with persistent atrial fibrillation. J Cardiovasc Electrophysiol 2010;21:597605.

24 Connolly SJ, Camm AJ, et al. Dronedarone in high-risk permanent atrial fibrillation. N Engl J Med 2011;365:226876.

25 Food and drug administration, USA. Available at www.fda.gov/Drugs/DrugSafety/ucm264059.htm, and last accessed on 18th of January, 2012.

26 European Medicines Agency. Available at www.ema.europa.eu. Last accessed on 18th of January, 2012.

27 Summary of Product Characteristics, available from: http://www.medicines.org.uk/emc/medicine/22894/SPC/Multaq+400mg+tablets/

IMAG0137

Dr Anish George, research registrar in Cardiology

Authors
Dr Anish George
Research registrar in Cardiology
(
anish.george@nlg.nhs.uk)

Dr Joseph John
Consultant Cardiologist
(
joseph.john@nlg.nhs.uk)

Dr Sudipta Chattopadhyay
Consultant Cardiologist
(
sudipta.chattopadhyay@nhs.net)

Scunthorpe General Hospital, Cliff Gardens, Scunthorpe, North Lincolnshire DN15 7BH

Citation

George A, John J, Chattopadhyay S.  Dronedarone: a new therapeutic option for atrial fibrillation.  BJC Arrhythmia Watch 2012;Issue 21 (Feb)

Published on: February 7, 2012

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