, Volume 69, Issue 7, pp 757-774
Date: 17 Sep 2012

Novel Approaches for Pharmacological Management of Atrial Fibrillation

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Abstract

In the light of the progressively increasing prevalence of atrial fibrillation (AF), medical awareness of the need to develop improved therapeutic approaches for the arrhythmia has also risen over the last decade. AF reduces quality of life and is associated with increased morbidity and mortality. Despite several setbacks as a result of negative results from rhythm control trials, the potential advantages of sinus-rhythm (SR) maintenance have motivated continued efforts to design novel pharmacological options aiming to terminate AF and prevent its recurrence, with a hope that optimized medical therapy will improve outcomes in AF patients.

Pathophysiologically, AF is associated with electrical and structural changes in the atria, which increase the propensity to arrhythmia perpetuation but may eventually allow for new modalities for therapeutic intervention.

Antiarrhythmic drug therapy has traditionally targeted ionic currents that modulate excitability and/or repolarization of cardiac myocytes. Despite efficacious suppression of ventricular and supraventricular arrhythmias, traditional antiarrhythmic drugs present problematic risks of pro-arrhythmia, potentially leading to excess mortality in the case of Na+-channel blockers or IKr (IKr = the rapid component of the delayed rectifier potassium current) blockers. New anti-AF agents in development do not fit well into the classical Singh and Vaughan-Williams formulation, and are broadly divided into ‘atrial-selective compounds’ and ‘multiple-channel blockers’.

The prototypic multiple-channel blocker amiodarone is the most efficient presently available compound for SR maintenance, but the drug has extra-cardiac adverse effects and complex pharmacokinetics that limit widespread application. The other available drugs are not nearly as efficient for SR maintenance and have a greater risk of proarrhythmia than amiodarone.

Two new antiarrhythmic drugs are on the cusp of introduction into clinical practice. Vernakalant affects several atrially expressed ion channels and has rapid unbinding Na+-channel blocking action along with promising efficacy for AF conversion to SR. Dronedarone is an amiodarone derivative with an electrophysiological profile similar to its predecessor but lacking most amiodarone-associated adverse effects. Furthermore, dronedarone has shown benefits for important clinical endpoints, including cardiovascular mortality in specific AF populations, the first AF-suppressing drug to do so in prospective randomized clinical trials.

Agents that modulate non-ionic current targets (termed ‘upstream’ therapies) may help to modify the substrate for AF maintenance. Among these, drugs such as angiotensin II type 1 (AT1) receptor antagonists, im-munosuppressive agents or HMG-CoA reductase inhibitors (statins) deserve mention. Finally, drugs that block atrial-selective ion-channel targets such as the ultra-rapid delayed rectifier current (IKur) and the acetylcholine-regulated K+-current (Ikach) are presently in development.

The introduction of novel antiarrhythmic agents for the management of AF may eventually improve patient outcomes. The potential value of a variety of other novel therapeutic options is currently under active investigation.