ReviewInterventions for the treatment of atrial fibrillation: A systematic literature review and meta-analysis
Introduction
Atrial fibrillation (AF) is the most common cardiac arrhythmia, and is associated with high rates of hospitalisation and death — often resulting from co-morbid events such as heart failure, stroke and other embolic complications [1], [2], [3], [4], [5], [6]. In the United States, AF represents a huge public health burden; reportedly affecting over 2.5 million people [4].
Management of AF may involve ‘rate’ control strategy (where tachycardia is reduced) or ‘rhythm’ control strategy (where the patient is converted to normal sinus rhythm (SR)) and the optimum treatment strategy is determined by AF classification (permanent versus paroxysmal versus persistent) and patient-specific, underlying medical considerations (e.g. hypertension, diastolic heart failure) [7], [8], [9], [10], [11], [12]. Anti-arrhythmic drugs (AADs) have been widely used for the long-term management of AF, and are grouped into four classes according to their mechanism of action (Vaughn–Williams classification): Class I, sodium channel blockers; Class II, sympatholytic drugs; Class III, repolarisation prolonging drugs; Class IV, calcium channel blockers [13]. Current recommendations as to the choice between the AADs are largely dependent on the type of AF, the severity of underlying structural disease and toxicity profile of the available agents [14], [15].
In 2007, a systematic review of randomised controlled trials (RCTs) was undertaken to assess AADs for the treatment of AF [16]. Unlike previous reviews in AF, the investigators assessed the effect of long-term drug therapy on the recurrence of AF and mortality rates, as well as other clinically important outcomes including embolic complications and withdrawals due to adverse events (AEs) [16]. The investigators concluded that amiodarone (Class III) was the most effective AAD for the maintenance of SR, although the agent's usefulness may be limited by its toxicity profile [16]. One further important conclusion was to highlight the lack of data on clinically relevant morbidity outcomes. Such outcomes impact negatively on AF patients' quality of life [17] and are associated with a significant economic burden on healthcare systems [18].
Since the publication of this previous review, several phase III RCTs have been published reporting the efficacy and safety of dronedarone (Class III) in the management of AF: three placebo-controlled trials — EURIDIS/ADONIS [19], DAFNE [20], and ATHENA [21] and one active-controlled study versus amiodarone — DIONYSOS [22]. Only provisional results from the EURIDIS/ADONIS RCTs were included in the previous systematic review.
Therefore, the aim of the current systematic review and meta-analysis was to expand upon the previous review in order to facilitate the therapeutic positioning of the novel Class III AAD, dronedarone, via an evaluation of the efficacy and safety of treatments for AF. In addition to efficacy and safety, outcomes of interest also included morbidity outcomes, persistence/compliance and health-related quality of life (HRQoL). Results reported in the present publication will focus on Class Ic (flecainide and propafenone) and Class III (amiodarone, dronedarone, sotalol and dofetilide) AADs.
Section snippets
Search strategy
On April 8th 2009, we systematically searched the Cochrane library, Medline, and EMBASE electronic databases using Medical Subjects Headings (MeSH) and free text terms. The search strategy included, but was not limited to, atrial fibrillation/flutter, anti-arrhythmic drugs, ablation, prospective clinical study, and randomised controlled trial (RCT). There were no restrictions by date of publication or language. The following conference proceedings were hand-searched (2003–2008 inclusive):
Data extraction and assessment of study quality
Inclusion and exclusion criteria were applied by two independent reviewers, and discrepancies were resolved by a third party. Data were extracted from eligible publications by a reviewer into an Excel® spreadsheet. A second reviewer checked the extracted data and discrepancies were resolved through discussion.
Methods detailed in the Cochrane Reviewer's handbook version 4.2.6, were used to assess the quality of included studies [25]. Briefly, this included the assessment of bias according to the
Systematic literature review
Searches of the Cochrane library, Medline and EMBASE identified 10,743 publications which were reviewed for relevancy based on pre-defined inclusion/exclusion criteria. In total 113 separate publications met the pre-defined inclusion criteria in the current systematic review (Fig. 1). The dataset was supplemented with data from the clinical study report from the DIONYSOS RCT, which was provided by sanofi-aventis.1 A total of 74
Discussion
The current systematic review aimed to evaluate the efficacy and safety of treatments for AF. Recent updates to both the European Society of Cardiology and American Heart Association guidelines on the management of atrial fibrillation now include dronedarone as a recommended treatment for the initial management of AF in patients without significant structural heart disease [14], [15]. The restoration and maintenance of sinus rhythm has historically been the main aim of treatment for AF [16].
Conclusions
The benefit of AADs in the treatment of patients with AF is clearly demonstrated, when considering the reduction of AF recurrences. On the basis of the evidence identified, although amiodarone remains one of the most effective AADs for the prevention of AF recurrence, a trend towards lower incidences of SAEs and withdrawals due to AEs was noted with sotalol, dronedarone and propafenone. Proarrhythmia occurred less frequently with dronedarone versus amiodarone and there was evidence of a trend
Acknowledgments
The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology.
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