ATHENA Published, FDA Readies to Hear Advisory Panel on Dronedarone for AF

Steve Stiles

February 12, 2009

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February 12, 2009 (Washington, DC) — Almost at the same time, the ATHENA randomized, controlled trial of dronedarone (Multaq, Sanofi-Aventis) for atrial fibrillation (AF) is formally published [1], and the US Food and Drug Administration has announced that an advisory panel will consider the antiarrhythmic agent's approvability next month [2].

The trial's finding of a 24% drop in death from any cause and other improved outcomes over a mean of 21 months among patients taking the drug, envisioned as a safer alternative to amiodarone, had been reported at the Heart Rhythm Society 2008 Scientific Sessions and was covered then by heartwire . Patients who received dronedarone or placebo experienced similarly low rates of thyroid, pulmonary, neurologic, and skin-related adverse effects and other toxicities for which amiodarone is well known.

However, "in many cases patients treated with amiodarone have such side effects (especially pulmonary toxic effects) later than two years after initiating therapy," beyond the average follow-up time in the dronedarone trial, write the ATHENA authors, led by Dr Stefan H Hohnloser (JW Goethe University, Frankfurt, Germany), in the February 12, 2009 issue of the New England Journal of Medicine.

Importantly, dronedarone has never actually been tested against amiodarone for efficacy or safety in a large trial of patients with AF. But on the strength of ATHENA and other dronedarone studies, likely including the EURIDIS and ADONIS trials, the FDA Cardiovascular and Renal Drugs Advisory Committee will consider the drug's approvability for "patients with a history of or current atrial fibrillation or atrial flutter, for the reduction of the risk of cardiovascular hospitalization or death."

The panel is slated to meet March 18, 2009, according to an FDA document made public on February 10.

ATHENA randomized 4628 patients with AF and at least one other CV risk factor, which could include age >70, drug-resistant hypertension, diabetes, history of stroke or transient ischemic attack, atrial enlargement, or LVEF <40%, to receive placebo or dronedarone at 400 mg twice daily. Patients had to be hemodynamically stable and not in NYHA class 4 heart failure.

Hazard Ratios for Outcomes, Dronedarone vs Placebo Groups, Over a Mean of 21 Months

End point

HR (95% CI)

p

Death or CV hospitalization*

0.76 (0.69–0.84)

<0.001

Death from any cause

0.84 (0.66–1.08)

0.18

CV death

0.71 (0.51–0.98)

0.03

CV hospitalization

0.74 (0.67–0.82)

<0.001

size="1">*Primary end point

About as many patients in one group as the other, 30.2% of those on dronedarone and 30.8% receiving placebo, discontinued the randomized agent prematurely, primarily due to adverse events.

An ongoing randomized trial is comparing dronedarone and amiodarone for the prevention of AF recurrences, the authors write. As previously reported by heartwire , the trial is called DIONYSUS.

ATHENA was funded by Sanofi-Aventis. Two of the coauthors are employees of and have equity interest in the company; other disclosures are listed in the paper.

  1. Hohnloser SH, Crijns HJGM, van Eickels M, et al. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009; 360:668-678.

  2. Food and Drug Administration. Cardiovascular and Renal Drugs Advisory Committee; Notice of meeting. February 10, 2009. Available at: http://www.fda.gov/OHRMS/DOCKETS/98fr/2009-4417-nm.pdf.



face="Verdana" size="1">The complete contents of Heartwire , a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

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