Dronedarone: NICE enough?

Keywords::

• antiarrhythmic drugs
• atrial fibrillation
• dronedarone
• hospitalizations
• outcomes

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia in clinical practice, and is associated with increased risk of morbidity and mortality. Studies indicate increasing prevalence of AF [1–5], in part linked to the aging population, and healthcare costs associated with this arrhythmia are projected to increase accordingly. Approximately 1% of the UK NHS costs can be attributed to AF, an economic burden similarly reported in other developed countries [6–8].

Despite the emergence of catheter ablation of AF, pharmacological treatment remains central to the management of AF. The strategy of pharmacological rhythm control, although intuitively attractive, is hampered by limited efficacy and significant toxicity associated with antiarrhythmic agents. Class I antiarrhythmic agents have been shown to increase mortality in patients with structural heart disease. Similarly, class III agents can result in repolarization abnormalities and increased risk of ventricular arrhythmias. Although the risk of proarrhythmia appears to be lower with amiodarone, the risk of thyroid dysfunction and potentially fatal hepatic and pulmonary toxicity restricts its long-term use [9]. Indeed, the failure of antiarrhythmic drugs to safely and effectively maintain sinus rhythm in the long term, and over-enthusiastic discontinuation of anticoagulation therapy, are widely acknowledged as the reasons for the failure of pharmacological rhythm control to outperform rate control in randomized trials of patients with AF [10,11].

Buoyed by indications of better survival in patients in whom maintenance of sinus rhythm is successful [12], investigators have continued the search for safer and more effective strategies for rhythm control. As ongoing clinical trials evaluate the precise role of catheter ablation of AF, a new antiarrhythmic drug, dronedarone, has recently emerged as a promising antiarrhythmic agent for rhythm control, which also reduces hospitalizations in high-risk patients with AF.

Dronedarone is an amiodarone analogue free of the iodine moiety, and possesses class I–IV antiarrhythmic properties without the major adverse effects associated with amiodarone. Compared to placebo, dronedarone increases the time to AF recurrence in patients with paroxysmal AF [13]. The addition of dronedarone to standard rate-limiting agents (b-blockers, calcium antagonists and digoxin) in patients with permanent AF also significantly reduced the ventricular rate in the Efficacy and Safety of Dronedarone for the Control of Ventricular Rate During Atrial Fibrillation (ERATO) trial [14]. More recently, A Placebo-Controlled, Double-Blind, Parallel Arm Trial to Assess the Efficacy of Dronedarone 400 mg twice-daily. for the Prevention of Cardiovascular Hospitalization or Death from Any Cause in Patients with Atrial Fibrillation/Atrial Flutter (ATHENA) showed a 24% relative risk reduction in hospitalization due to cardiovascular events or deaths from any cause in patients taking dronedarone compared with placebo. However, this result was driven predominantly by reduction in hospitalization related to AF. There was no significant difference in all-cause mortality between dronedarone and placebo [15]. Has dronedarone answered the call for a safe and effective treatment for AF?

The safety and efficacy of dronedarone must be considered in the context of currently available therapy. Data from a randomized, double-blind trial to evaluate the efficacy and safety of dronedarone (400 mg twice-daily) versus amiodarone (600 mg once-daily for 28 days, then 200 mg once daily thereafter) for at least 6 months for the maintenance of sinus rhythm in patients with AF (DIONYSOS) and a recent indirect meta-analysis suggest that dronedarone is less effective at preventing the recurrence of AF and may not reduce AF-related morbidity and mortality compared with amiodarone [16]. Furthermore, although free from significant pulmonary, hepatic and thyroid toxicity, dronedarone is associated with increased mortality in patients with severe congestive or unstable heart failure [17]. Therefore, safety in patients with milder heart failure or asymptomatic left ventricular dysfunction with dronedarone cannot be assumed. By contrast, amiodarone does not appear to be associated with increased mortality in patients with heart failure [18].

In this regard, the recent draft appraisal guidance by NICE on the use of dronedarone in nonpermanent AF appears to be consistent with available data [101]. The NICE technology appraisal recommended dronedarone as an optional second-line treatment for nonpermanent AF patients who have at least one of the following cardiovascular risk factors: hypertension requiring at least two different classes of drugs; diabetes mellitus; previous stroke, thromboembolism or transient ischemic attack; left atrial diameter of more than 50 mm; left ventricular ejection fraction of less than 40%; age 70 years or older (based on inclusion criteria of the ATHENA trial). Dronedarone is not recommended in patients with unstable New York Heart Association class III or IV symptoms. This draft recommendation is currently undergoing further consultation and is subject to further appraisal.

Hence, dronedarone represents a valuable addition to the limited armamentarium of antiarrhythmic drugs for the treatment of AF, but added safety over amiodarone comes at the expense of less efficacy (and perhaps financial cost). Existing antiarrhythmic drugs have major limitations; for example, the adverse effects associated with amiodarone, and the contraindications for Class 1c agents in patients with coronary artery or structural heart disease. The availability of dronedarone provides another option for an antiarrhythmic drug to be used for AF, with moderate efficacy similar to sotalol and Class 1c agents, but less so compared with amiodarone. Clearly, dronedarone is better tolerated and perhaps safer than amiodarone (and probably also sotalol and Class 1c agents). We may also be concentrating too much on symptoms and the arrhythmia, and given that hospitalizations related to AF are a major health economic cost, the reduction of hospitalizations with dronedarone would also be an added advantage. Overall, dronedarone is probably quite nice. Time will tell.

Financial & competing interests disclosure

Gregory Lip has received funding for research, educational symposia, consultancy and lecturing from different manufacturers of drugs used for the treatment of atrial fibrillation, including Sanofi-Aventis, who market dronedarone. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.