November 19, 2008 (New Orleans, Louisiana) — Patients with atrial fibrillation (AF) who received dronedarone (Multaq, Sanofi-Aventis) were less often hospitalized for cardiovascular reasons regardless of whether the cause of hospital admission was AF or something else, in a large placebo-controlled trial that--researchers say--offered those hints and others that some of the drug's clinical benefits may derive from nonantiarrhythmic effects .
Moreover, as an antiarrhythmic agent, dronedarone displayed both rate- and rhythm-controlling properties in the trial, called ATHENA, which randomized >4500 "moderate- to high-risk" patients with AF .
Those secondary findings were reported here last week at the American Heart Association 2008 Scientific Sessions. In presentations earlier this year, as reported by heartwire , the trial had shown a 24% drop in the primary end point of CV hospitalization or death and a 34% decline in risk of stroke in the dronedarone group compared with placebo over its mean 21-month follow-up.
"The amazing thing about this data set is the consistency of the findings," Dr Richard L Page (University of Washington, Seattle), told heartwire , pointing to independent dronedarone-related declines in hospitalization rate of 37% when the cause of admission was AF and 14% when it wasn't AF (both significant), 30% when it was acute coronary syndromes (perhaps significant), and 14% (nonsignificant) when the cause was heart failure. The "intriguing but not definitive" risk decreases that fell short of significance, he said, "at least all go in the right direction."
The results of ATHENA can be interpreted only so far, as the drug has not been directly compared with the likeliest drug AF patients might now receive, amiodarone; a comparator trial called DIONYSUS is ongoing, observed Page, who reported ATHENA's secondary results at the meeting. But if the drug's benefits vs placebo seen in ATHENA are borne out in further studies, he noted, some AF patients who might not respond to or tolerate amiodarone could become candidates for dronedarone.
Observers of ATHENA agree that dronedarone has so far shown a fairly benign safety profile, with rates of clinically important adverse events similar to those seen with placebo. That contrasts it with its chemical cousin amiodarone, which is notorious for its potential end-organ toxicities.
But observers also note that dronedarone's ability to suppress AF doesn't seem quite as strong as that of amiodarone. Moreover, many have reservations about using the drug in patients with heart failure; the two conditions commonly coexist. As previously reported by heartwire , a trial called ANDROMEDA had been terminated early after an apparent mortality increase with the drug among the trial's "high-risk" patients with systolic heart failure. ATHENA excluded patients with NYHA class 4 heart failure.
The trial randomized patients with paroxysmal or persistent AF or atrial flutter to receive dronedarone (400 mg twice daily, n=2301) or placebo (n=2327); beta blockers, calcium-channel blockers, and digoxin were used as frequently in one group as the other. Participants were required to be older than 75 years or, in the presence of at least one other risk factor, older than 70 years; the other risk factors could be diabetes, hypertension, a history of stroke, reduced LVEF, or atrial enlargement.
HR (95% CI) for Cardiovascular Hospitalization Over Mean of 21 Months, Dronedarone vs Placebo, in ATHENA
|Reason for CV hospitalization||HR (95% CI)||p|
|Heart failure||0.86 (0.67–1.10)||0.221|
AF=atrial fibrillation; ACS=acute coronary syndromes; VT=ventricular tachycardia; VF=ventricular fibrillation
There was no significant difference in rate of non-CV hospitalizations.
Among patients in sinus rhythm at baseline, the median time to first recurrence of AF or atrial flutter was significantly improved in the active-therapy group: 737 days vs 498 days on placebo (hazard ratio 0.75, 95% CI 0.68–0.82; p<0.001).
At least one electrical cardioversion occurred in 14.7% and 20.7% of the patients, respectively (HR 0.68, 95% CI 0.60–0.79; p<0.001).
Associated with the significant observed dronedarone-related reductions in morbidity was significantly reduced hospitalization time for patients taking the drug, observed Page. Actively treated patients spent about 28% fewer days in the hospital and about 35% fewer when hospitalized for CV reasons (both differences p<0.001).
Rate of Hospitalization and Number of Hospitalization Days in ATHENA
|>1 hospitalization (%)||35||44||<0.001|
|Total hospital nights (n)||9995||13 986||<0.001|
|Total nights of CV hospitalization (n)||5875||9073||<0.001|
"That reduction of almost 4000 hospital days translates to a decrease of 1.26 hospitalization days per patient per year," according to Page. "Almost 500 of those days were in the CCU or ICU, and a good number were in medium care." That, he said, "would translate into significant savings."
Interestingly, heart rate during AF or atrial flutter also decreased significantly in the dronedarone group compared with placebo; the median and mean both fell by 9 bpm (p<0.001 for both). That and other observations, according to Page, suggest that dronedarone, like amiodarone, has cardiovascular effects that aren't directly antiarrhythmic but may contribute to clinical benefits.
For example, Page observed that systolic blood pressure dropped among ATHENA's actively treated patients compared with controls. "A little bit, by about 2 mm Hg, which may play a role when it's spread over this many patients." Also, as heartwire previously reported, dronedarone appeared to reduce the risk of stroke.
Moreover, according to Page, there were 473 patients in the trial, 178 on dronedarone and 295 in the placebo group (p<0.001), who never produced an ECG showing sinus rhythm and so were classified as having permanent AF--yet as a group showed a trend of a 26% drop in risk of CV hospitalization or death (p<0.10). "They had a hazard ratio [for the primary end point] almost identical to the overall study population," he said. "They did not reach a 0.05 p value because they were in the minority, but it suggests that there could be something going on here over and above the antiarrhythmic effect."
ATHENA was sponsored by Sanofi-Aventis. Page has disclosed being an advisor or consultant for Sanofi-Aventis and Astellas. At least two ATHENA coauthors are employees of Sanofi-Aventis.
Torp-Pedersen C, Page RL, Connolly SJ, et al. The effect of dronedarone on hospitalizations in patients with atrial fibrillation. Results from the ATHENA study. American Heart Association 2008 Scientific Sessions; November 8-12, 2008; New Orleans, LA. Abstract 4101.
Page RL, Connolly SJ; Crijns HJ, et al. Rhythm- and rate-controlling effects of dronedarone in patients with atrial fibrillation: Insights from the ATHENA trial. American Heart Association 2008 Scientific Sessions; November 8-12, 2008; New Orleans, LA. Abstract 4097.
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.
Heartwire from Medscape © 2008 Medscape
Cite this: Steve Stiles. AHA 2008: ATHENA Secondary Results: Dronedarone for AF May Cut Hospital Admissions Regardless of Cause - Medscape - Nov 19, 2008.