Safety and Efficacy of Dronedarone in the Treatment of Atrial Fibrillation/Flutter

Abstract

Dronedarone is an amiodarone analog but differs structurally from amiodarone in that the iodine moiety was removed and a methane-sulfonyl group was added. These modifications reduced thyroid and other end-organ adverse effects and makes dronedarone less lipophilic, shortening its half-life. Dronedarone has been shown to prevent atrial fibrillation/flutter (AF/AFl) recurrences in several multi-center trials. In addition to its rhythm control properties, dronedarone has rate control properties and slows the ventricular response during AF. Dronedarone is approved in Europe for rhythm and rate control indications. In patients with decompensated heart failure, dronedarone treatment increased mortality and cardiovascular hospitalizations. However, when dronedarone was used in elderly high risk AF/AFl patients excluding such high risk heart failure, cardiovascular hospitalizations were significantly reduced and the drug was approved in the USA for this indication in 2009 by the Food and Drug Administration. Updated guidelines suggest dronedarone as a front-line antiarrhythmic in many patients with AF/Fl but caution that the drug should not be used in patients with advanced heart failure. In addition, the recent results of the PALLAS trial suggest that dronedarone should not be used in the long-term treatment of patients with permanent AF.

Pleiotropic Effects of Antiarrhythmic Agents: Dronedarone in the Treatment of Atrial Fibrillation

“…As such, dronedarone may increase the bioavailability of other cardiovascular drugs including digoxin, simvastatin, and metropolol in some patients,10 and the pleiotropic effects of dronedarone may partly be due to effects on other drugs. Dosing of these drugs may need to be adjusted to prevent unwanted side effects 70. For example, it has been suggested that concomitant digoxin therapy contributed to the adverse outcomes with dronedarone in the PALLAS trial,22 and the combined use of both drugs is discouraged in the current guidelines 71…”

Inactivation of Human Cytochrome P450 3A4 and 3A5 by Dronedarone andN-Desbutyl Dronedarone

“…In fact, amiodarone has been shown to cause time-dependent inhibition of CYP3A4 (Ohyama et al, 2000) and CYP2C8 (Polasek et al, 2004), a key feature of irreversible or quasi-irreversible inactivation of CYP450. Although dronedarone has been reported to be a moderate inhibitor of CYP3A4 and a weak inhibitor of CYP2D6 (Naccarelli et al, 2011), the potential inactivation of CYP450 by dronedarone and NDBD has not been investigated. In-house preliminary findings demonstrated that dronedarone inhibits CYP3A4 and CYP3A5 in a timedependent manner (unpublished data).…”

Pleiotropic Effects of Dronedarone on Ischemia/Reperfusion Injury in Heart and Brain

“…While dronedarone can easily pass the blood-brain barrier [61], the mechanism(s) by which dronedarone exerts is neuroprotective function remain(s) to be elucidated but might relate to its acute inhibition of the sodium-calcium exchanger, potassium and/or sodium currents or the induction of HIF-1 (see above).…”