A new anti-arrhythmic for the treatment of AF

Dronedarone is a benzofuran derivative with an electropharmacological profile similar to amiodarone but with different effects on individual ion channels. In two previous randomised controlled trials dronedarone was shown to be more effective than placebo in maintaining sinus rhythm and controlling ventricular rate during recurrences of AF.

The ATHENA (A Placebo Controlled Double Blind Parallel Arm Trial to Assess the Efficacy of Dronedarone 400mg bid for the Prevention of Cardiovascular Hospitalisation or Death from Any Cause in Patients with Atrial Fibrillation/Atrial Flutter) trial was a multicentre trial conducted in 37 countries and which involved 4628 patients. 2301 were randomised to receive dronedarone and 2327 were assigned to receive placebo. In light of the results from the ANDROMEDA trial (which looked at dronedarone in patients with advanced heart failure and was terminated because of an excess of deaths in the treatment arm) patients with recent decompensated heart failure or NYHA Class IV heart failure were excluded. The primary outcome was the first hospitalisation due to cardiac events or death from any cause. Secondary outcomes were death from any cause, death from cardiovascular causes and first hospitalisation due to cardiovascular events.

Patients were followed up for a mean of 21 +/-5 months. The study drug was discontinued prematurely in 30.2% of patients n the dronedarone arm an 30.8% in the placebo arm, mostly because of adverse events. The primary outcome occurred in 734 patients (31.9%) in the dronedarone group and 917 patients (39.4%) in the placebo group, hazard ratio for dronedarone 0.76 (95%CI 0.69-0.84, p<0.001). There were 116 deaths (5.0%) in the dronedarone group and 139 (6.0%) in the placebo group (HR 0.84, 95%CI 0.66-1.08, p=0.18). There were 63 deaths from cardiovascular causes (2.7%) in the dronedarone group and 90 (3.9%) in the placebo group (HR 0.71, 95%CI 0.51-0.98, p=0.03), predominantly due to a reduction of death from arrhythmia with dronedarone. Higher rates of bradycardia, QT-interval prolongation, nausea, diarrhoea, rash and increase in serum creatinine level occurred in the dronedarone group. Rates of thyroid and pulmonary related adverse events were not significantly different between the 2 groups although this should be interpreted with caution as the mean follow-up was 21 months and patients treated with amiodarone an develop such side effects >2 years from initiation of therapy.

It is likely that a combination of prevention of recurrence of AF and rate control during arrhythmic episodes were responsible for reducing the rates of hospitalization. The difference in outcome between ATHENA and ANDROMEDA is probably due to the differing enrollment criteria. It would appear that dronedarone increases cardiovascular mortality among patients with advanced and decompensated heart failure but reduces mortality among patients with less severe heart failure. The increase in creatinine level which was also seen in ANDROMEDA may not reflect a deterioration in renal function. It would appear that dronedarone reduces creatinine clearance without affecting glomerular filtration rate as a result of a specific partial inhibition of tubular organic-cation transporters. There was a relatively high rate of discontinuation of the study drug (30.2% in the dronedarone group) which may have underestimated both the benefit of dronedarone but also the likelihood of an increase in adverse events. The efficacy and tolerability of dronedarone and amiodarone as used to prevent the recurrence of AF are currently being evaluated in an ongoing clinical trial.

  • Hohnloser SH, Crijns HJGM, Van Eickels M et al. Effect of dronedarone on Cardiovascular Events in Atrial Fibrillation. N Engl J Med 2009; 360:668-78

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