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Effects of Amiodarone Therapy on Thyroid Function: Dronedarone


Dronedarone was approved by the FDA in July of 2009 for the treatment of atrial fibrillation. Dronedarone is, like amiodarone, a benzofuran derivative and was developed with the goal of replicating the antiarrhythmic effects of amiodarone while limiting the associated toxic effects. Dronedarone is structurally related to amiodarone but does not contain iodine atoms (Figure 1). Dronedarone has a very short half-life compared with amiodarone (30 h versus 40 days) and is less lipophilic because of its additional methane-sulfonamyl group.[20,54] The bio-availability of dronedarone is 15% owing to substantial first-pass metabolism, and peak plasma concentrations of dronedarone are achieved within 3-6 h.[20] At an average dose of 400 mg twice daily, steady state is reached within 4-8 days of treatment. The metabolites of dronedarone are excreted primarily in the feces, with renal excretion playing a minor role in elimination (6%).[20] Dronedarone demonstrates similar electrophysiologic properties to those of amiodarone.[54]

Safety and Efficacy

To assess the safety and efficacy of dronedarone, six multi-center studies were conducted. In these studies, over 3,000 patients were treated with dronedarone at doses of 400 mg twice daily for an average of 12 months. The EURIDIS and ADONIS trials were identical, multicenter, double-blind, randomized trials with the goals of assessing the 1-year efficacy of dronedarone to maintain sinus rhythm after electrical, pharmacological, or spontaneous conversion of atrial fibrillation or atrial flutter, compared with placebo.[55] These trials demonstrated that 1 year of treatment with dronedarone significantly decreased the risk of first recurrence of atrial fibrillation or atrial flutter, reduced the time of first recurrence of either state, slowed ventricular response in patients whose atrial fibrillation or atrial flutter recurred, and was associated with lower risk of hospitalization for cardiovascular events.[20,55] The ERATO trial[56] was a multicenter, double-blind, randomized trial comparing the efficacy of taking 400 mg dronedarone twice daily with that of placebo in controlling the ventricular rate in patients with symptomatic atrial fibrillation.[20,56] The authors concluded that dronedarone reduces the ventricular rate of patients with permanent atrial fibrillation.[56]

ANDROMEDA,[57] the first outcome trial of dronedarone, was a randomized double-blind, placebo-controlled trial that evaluated the risk of hospitalization for worsening heart failure or death in patients hospitalized for decompensated heart failure.[20,56-58] This study was terminated prematurely when taking dronedarone was associated with increased risk of death.[57] ATHENA[59] was developed to focus on the excess morbidity and mortality reported in ANDROMEDA. It was a randomized, double-blind, placebo-controlled trial to evaluate the long-term effect of dronedarone versus placebo on the combined risk of cardiovascular hospitalizations and all-cause mortality in patients with recent or current history of atrial fibrillation and/or flutter.[20,55,59] In marked contrast to ANDROMEDA, ATHENA reported a 24% reduction in the combined end point in the dronedarone group compared with the placebo group. The discrepancy between the results of the ANDROMEDA and the ATHENA studies has been attributed to differences in patient stability, to use of inhibitors of angiotensin-converting enzyme and of angiotensin receptor blockers in the ANDROMEDA trial and to the reliability of the findings.[20]

Toxic Effects

The major adverse effects associated with dronedarone are gastrointestinal (diarrhea, nausea and/or vomiting), elevated serum creatinine concentrations (caused by inhibition of creatinine excretion at the tubular level, with no change in glomerular filtration rate),[60] rash and cardiac effects known to be associated with this class of antiarrhythmic (bradycardia and QT interval prolongation).[20,54,55] The incidence of serious adverse events is similar to that among patients receiving placebo.[20]

In the EURIDIS and ADONIS trials, the incidence of clinical hyperthyroidism was 8.4% in the dronedarone group versus 14.1% in the placebo group (P = 0.002) and the incidence of hypothyroidism was 5.5% in the dronedarone group versus 3.5% in the placebo group (P = 0.15).[54] One of the causes of atrial fibrillation, a study entry criteria, is thyrotoxicosis, which may explain the high incidence of hyperthyroidism in the placebo group. The incidence of hyperthyroidism or hypothyroidism did not differ significantly between the placebo and dronedarone groups in the ATHENA trial, for unknown reasons.[54] These studies suggest that, in marked contrast to the experience with amiodarone, there is no increase in clinical thyroid disease in patients treated with dronedarone.

The DIONYSOS study[20] was a double-blind trial designed to compare the ability of dronedarone and amiodarone to maintain sinus rhythm in 504 patients (249 and 255 patients, respectively) with atrial fibrillation, followed up for at least 6 months. In contrast to prior studies, all patients had serial measures of thyroid function. At baseline, 5% of patients in both the amiodarone and the dronedarone groups had hypothyroidism and <1% of patients had hyperthyroidism. The study showed that 79% of patients treated with dronedarone and 50% of those treated with amiodarone had normal thyroid function at baseline, which was maintained during treatment. Overall, 105 (41%) amiodarone-treated patients, euthyroid at baseline, demonstrated changes in thyroid function consistent with an alteration in thyroid hormone metabolism and the development of hypothyroidism, compared with 30 patients (12%) treated with dronedarone and also euthyroid at baseline (P <0.001). For the most severe amiodarone-related adverse effect, AIT, the incidence was 6% in the amiodarone group and 1% in the dronedarone group, in previously euthyroid patients.