Munich, Germany - Add stroke to the list of clinical events that dronedarone (Multaq, Sanofi-Aventis) may favorably influence in patients with atrial fibrillation. In a post hoc analysis of the ATHENA trial, presented here at the European Society of Cardiology Congress 2008, the antiarrhythmic agent, seen as a potential alternative to amiodarone, was associated with a 34% drop (p=0.027) in adjusted risk of stroke compared with placebo over a follow-up averaging 21 months [1].

Dr Stuart J Connolly

"This reduction occurred in patients who were generally receiving appropriate antithrombotic therapy. The effect was consistent in higher-risk patients with different risk factors," coprincipal investigator Dr Stuart J Connolly (McMaster University, Hamilton, ON) said when presenting the findings. "No previous antiarrhythmic therapy has been shown to reduce stroke in this way."

ATHENA had already shown a 24% decline (p<0.001) in time to first CV hospitalization or any-cause death, which was its primary end point, as well as cuts in risk of CV mortality (29%, p=0.034), CV hospitalization (25%, p<0.001), and arrhythmic death (45%, p=0.01) associated with dronedarone, as reported by heartwire in May from the Heart Rhythm Society 2008 Scientific Sessions.

Largely on the strength of ATHENA, one of the largest antiarrhythmic drug trials ever conducted, with 4628 randomized patients, dronedarone is under review by regulators in both the US and Europe. Observers have noted that the drug has so far shown a fairly benign safety profile, putting it in stark contrast to amiodarone. The two drugs are biochemically similar, but dronedarone lacks its molecular cousin's iodine component primarily responsible for an infamous array of end-organ toxicities.

Tempering glee over the prospect of ditching amiodarone for dronedarone in AF rhythm control are several caveats. As reported before by heartwire, AF recurrence rates for patients taking dronedarone were only modestly better than those for placebo in the twin trials EURIDIS and ADONIS and seem a bit worse than what amiodarone can achieve. But as yet, there is no completed trial directly comparing the two drugs, although at least one, called DIONYSUS, is ongoing.

Another hitch with dronedarone is a possible adverse effect in patients with AF and heart failure, which are frequently seen together. A trial called ANDROMEDA had been halted early due to an apparent mortality increase associated with the drug in the trial's "high-risk" patients with systolic heart failure, heartwire reported in 2003.

As the discussant for Connolly's presentation, Dr Karl-Heinz Kuck (Asklepios Clinic St Georg, Hamburg, Germany) reviewed these issues and some other remaining reservations about dronedarone and ATHENA. The trial, he said, enrolled few patients with heart failure and primarily patients with paroxysmal AF, pointing to the need for studies in broader patient groups, he said. Also, dronedarone's long-term safety needs exploring, especially given ATHENA's finding of a somewhat higher incidence of elevated creatinine associated with the drug—although there were few such cases overall.

"When we have all these questions answered, we may know what place there may be for dronedarone for maintaining sinus rhythm and to prevent stroke and for other indications in patients with atrial fibrillation," Kuck said.

ATHENA had enrolled hemodynamically stable patients >75 years old or >70 to <75 years if they had at least one CV risk factor, such as hypertension, diabetes, prior stroke or transient ischemic attack, left atrial dilatation, or an LVEF <40%. About equal proportions of the 2301 randomized to dronedarone (400 mg twice daily) and 2327 to placebo were on beta blockers, calcium-channel blockers, ACE inhibitors (or angiotensin-receptor blockers), digoxin, statins, and oral anticoagulation.

Annual rates of stroke and other end points in ATHENA over a mean of 21 months and hazard ratios (HR) for dronedarone vs placebo

End point	Placebo (%/y)	Dronedarone (%/y)	HR (95% CI)	p
Stroke	1.79	1.19	0.66 (0.46-0.96)	0.027
Stroke or TIA	2.05	1.37	0.67 (0.47-0.94)	0.020
Fatal stroke	0.54	0.36	0.67 (0.34-1.32)	0.247
Stroke, ACS, or CV death	5.52	3.80	0.68 (0.55-0.84)	<0.001
Stroke, ACS, or all-cause death	6.70	5.06	0.75 (0.62-0.90)	0.002

"My personal view is that the stroke reduction by more than 30% is one of the most important findings of this trial," Kuck said. "I won't care too much, as a doctor who treats thousands of patients with atrial fibrillation, when the patient comes back to me with a recurrence that might be important to the patient's quality of life and the economic situation of our healthcare system. But a stroke reduction of 34% is more than important to the patient and also to the healthcare system. It's a significant benefit for patients with atrial fibrillation."

Multivariate predictors of stroke in ATHENA, adjusted relative risk (RR)

Predictor	RR (95% CI)	p
Dronedarone (vs placebo)	0.63 (0.43-0.91)	0.015
Age >75	1.04 (1.02-1.07)	0.001
Prior stroke/TIA	2.12 (1.38-3.26)	<0.001

ATHENA was sponsored by Sanofi-Aventis, from which Connolly reports receiving consulting fees and research grants. Other members of the trial's steering committee and coauthors variously report receiving research grants and/or fees for consulting or lecturing from Sanofi-Aventis, Bristol-Myers Squibb, Proctor & Gamble, ARYx, Cardiome, St Jude Medical, AstraZeneca, Chugai Pharmaceuticals, Astellas, and Pfizer. At least two coauthors are employees of Sanofi-Aventis. Kuck presented no disclosures.