Dronedarone associated with increased mortality in patients with severe heart failure

Key Points

In the Antiarrhythmic Trial with Dronedarone in Moderate to Severe CHF Evaluating Morbidity Decrease (ANDROMEDA), which was published in the New England Journal of Medicine, investigators observed that dronedarone, an anti-arrhythmic agent related to amiodarone, was associated with increased mortality in patients who were hospitalized for symptomatic heart failure (HF) (New York Heart Association [NYHA] class II, III, or IV) and left ventricular systolic dysfunction.

Study investigators had theorized that dronedarone could potentially reduce the risk of death from any cause or hospitalization for HF in patients with symptomatic HF because of the agent's ability to prevent the occurrence of both atrial and ventricular arrhythmias. Instead, the trial had to be terminated by the data and safety monitoring board after only approximately two-thirds of the intended participants had been enrolled (n=627; followed for a median of 2 mo) because of an unexpected finding of greater mortality in patients taking dronedarone compared with those taking placebo (HR=2.13; 95% CI, 1.07–4.25; P=.03). An increased risk of the primary end point of death from any cause or hospitalization for HF was also observed (HR=1.38; 95% CI, 0.92–2.09; P=.12); however, this finding did not reach statistical significance, likely because there was an insufficient number of enrolled patients to properly evaluate this end point.

Upon closer evaluation of the data, study investigators discovered that the majority of excess deaths observed in patients taking dronedarone were caused by worsening HF, with the greatest risk of death in patients with the worst left ventricular systolic function.

An additional interesting finding of the ANDROMEDA study was that patients taking dronedarone were more likely to develop significant increases in serum creatinine levels (2.6%) compared with those taking placebo (0). However, as it is thought that the increases in serum creatinine observed with dronedarone may be caused by its ability to inhibit tubular transporters, it is unknown whether co-administration of dronedarone will decrease the renal elimination of other drugs.

SOURCES

Kober L, Torp-Pedersen C, McMurray JJV, et al; for the Dronedarone Study Group. Increased mortality after dronedarone therapy for severe heart failure. N Engl J Med. 2008;358:2678–2687.

Singh BN, Connolly SJ, Crijns HG, et al; EURIDIS and ADONIS Investigators. Dronedarone for maintenance of sinus rhythm in atrial fibrillation or flutter. N Engl J Med. 2007;357:987–999.