New heart failure data from ATHENA

Dronedarone is a derivative of amiodarone that has different effects on individual ion channels. The ATHENA trial evaluated dronedarone against placebo in patients with atrial fibrillation who had additional risk factors for death.

ATHENA (1) (a placebo-controlled, double-blind, parallel arm trial to assess the efficacy of dronedarone 400 mg bid for the prevention of cardiovascular hospitalisation or death from any cause in patients with atrial fibrillation/atrial flutter) was designed to find out whether dronedarone would reduce the rate of the composite outcome of hospitalisation due to cardiovascular events or death.

It was conducted at 551 centres in 37 countries. Eligible patients had atrial fibrillation or flutter plus at least one other risk factor such as age over 70 years, hypertension, diabetes mellitus or previous stroke. Patients in New York Heart Association (NYHA) class IV heart failure or bradycardia <50 beats per minute were excluded from the trial.

In all, 4,628 patients were enrolled: 2,301 were assigned to dronedarone and 2,327 to placebo. Mean age was 71.6 years, and just under half of study participants were female. Twenty-five percent had atrial fibrillation at randomisation. Mean duration of follow-up was 21 months.

Of the patients treated with dronedarone, 734 (31.9%) had a primary outcome event, compared with 917 (39.4%) of patients in the placebo group (hazard ratio 0.76, p<0.001). These included 675 patients (29.3%) in the dronedarone group and 859 patients (36.9%) in the placebo group (hazard ratio 0.74, p<0.001) who had a first hospitalisation for cardiovascular events. This was driven mainly by a reduction in the number of hospitalisations for atrial fibrillation.

Deaths from any cause were not significantly reduced by dronedarone compared to placebo (5% versus 6%, p=0.18) but deaths classified as cardiovascular in origin were significantly reduced by dronedarone (63 patients, 2.7% versus 90 patients, 3.9%, p=0.03). The death rate from cardiac arrhythmia was significantly reduced (1.1% versus 2.1%, hazard ratio 0.55, p=0.01).

Patient discontinuations occurred in a high proportion (30% in both groups) but pulmonary symptoms and abnormalities of thyroid function were not more common in the dronedarone group compared to the placebo group. Bradycardia, prolongation of the QT interval, diarrhoea, rash and a raised serum creatinine level were seen more often in the dronedarone group. The latter finding was expected and “did not necessarily indicate a decline in renal function” in the view of the study authors. They also note that, there was no significant increase in the rates of thyroid or pulmonary disorders, which “may suggest that dronaderone has a more benign side-effect profile than amiodarone”.

A recent post-hoc analysis, presented at the Heart Rhythm Society (HRS) 2009 Scientific Sessions recently in Boston, looked at trial patients with New York Heart Association (NYHA) class III heart failure (91 dronedarone patients versus 109 controls), as well as patients with baseline ejection fractions (EF) <35% at baseline (92 versus 87 patients respectively). In the NYHA III patients there was a significant 44% (p=0.0028) reduction in the primary end point, predominantly from a 43% reduction in risk of cardiovascular hospitalisation. There was no significant reduction in clinical end points in the patients with reduced EF at baseline however.

Dronaderone was not associated with with any significantly increased risk of first heart failure hospitalisation. The latest results appear to be consistent with the overall ATHENA findings, and that dronaderone may improve clinical end points in patients with stable congestive heart failure.

Further details of the recent ATHENA data will be be presented in a future edition of Arrhythmia Watch.

The Cardiovascular and Renal Drugs Advisory Committee recently voted 10 to 3 in favour of the Approval of Dronedarone (Multaq) by the U.S. Food and Drug Administration (FDA) to treat patients with atrial fibrilation (AF).

Reference

1. Hohnloser SH, Crijns HJGM, van Eickels M et al for the ATHENA Investigators. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009; 360: 668-78.