ATHENA Trial Presented at Heart Rhythm 2008 in San Francisco, USA ATHENA Trial (A placebo-controlled, double-blind, parallel arm Trial to assess the efficacy of dronedarone 400 mg bid for the prevention of cardiovascular Hospitalization or death from any cause in patiENts with Atrial fibrillation/atrial flutter) Presented at Heart Rhythm 2008 in San Francisco, USA Presented by Stefan H. Hohnloser, MD Copyleft Clinical Trial Results. You Must Redistribute Slides

ATHENA Trial: Background Atrial fibrillation (AF) impairs patients’ lives, leading to increased risks of cardiovascular complications. Over the course of 20 years of clinical drug trials in AF no drug has demonstrated a significant reduction in the risk of cardiac death. ATHENA set out to evaluate the effect of Multaq® (dronedarone), a multi-channel blocker with anti-adrenergic properties, on a composite primary endpoint of all-cause mortality and cardiovascular hospitalization in patients with AF. JCE 2008; 19.1/Heart Rhythm 2008

ATHENA Trial: Dronedarone Dronedarone (Multaq®) manufactured by Sanofi-aventis is a new multi-channel blocker that affects the calcium, potassium and sodium channels and has anti-adrenergic properties. Unlike amiodarone, this drug does not contain iodine radical and hence does not result in adverse effects on thyroid and lung functions. JCE 2008; 19.1/Heart Rhythm 2008

ATHENA Trial: Study Design 4,628 patients >75 years with atrial fibrillation or 70-75 years with atrial fibrillation and at least one additional cardiovascular risk factor prior to randomization. Double blind. Randomized. Placebo controlled. International multicenter. Mean follow-up 21 months. R Multaq® (dronedarone) 400 mg BID Placebo 12-30 mos. follow-up Primary Endpoint: composite of all-cause mortality combined with cardiovascular hospitalization Secondary Endpoint: death from any cause, cardiovascular death, hospitalization for cardiovascular reasons Copyleft Clinical Trial Results. You Must Redistribute Slides JCE 2008; 19.1/Heart Rhythm 2008

ATHENA Trial: Inclusion Criteria ≥75 yrs with or without additional risk factors ≥70 yrs with at least one of the following risk factors: arterial hypertension (ongoing therapy with at least two antihypertensive drugs of different classes), diabetes mellitus, prior stroke or transient ischemic attack or systemic embolism, left atrium diameter ≥ 50 mm by M-mode echocardiography, LVEF < 0.40 by 2D-echocardiography. Copyleft Clinical Trial Results. You Must Redistribute Slides JCE 2008; 19.1/Heart Rhythm 2008

ATHENA Trial: Inclusion Criteria Cont. Availability of one 12-lead ECG within the last 6 months, indicating prior or current AF/A flutter Access to a second 12-lead ECG within the last 6 months showing prior or current SR Copyleft Clinical Trial Results. You Must Redistribute Slides JCE 2008; 19.1/Heart Rhythm 2008

ATHENA Trial: Exclusion Criteria Presence of one of the following cardiac conditions: Permanent AF Unstable hemodynamic situation (i.e., recently decompensated heart failure) Congestive heart failure NYHA class IV Planned major non-cardiac or cardiac surgery Acute myocarditis Bradycardia < 50 bpm and/or a PR interval > 0.28 seconds Significant sinus node disease in the past, if not treated with a pacemaker Copyleft Clinical Trial Results. You Must Redistribute Slides JCE 2008; 19.1/Heart Rhythm 2008

ATHENA Trial: Exclusion Criteria cont. Refusal or inability to give informed consent Any non-cardiac severe illness limiting life expectancy Pregnancy and breast feeding Women of child-bearing potential without adequate birth control Participation in another clinical trial Copyleft Clinical Trial Results. You Must Redistribute Slides JCE 2008; 19.1/Heart Rhythm 2008

ATHENA Trial: Exclusion Criteria cont. A calculated GFR at baseline < 10mL/min using the Cockroft Gault formula Potassium level < 3.5 mmol/L if not corrected Need for concomitant medication prohibited within ATHENA (i.e., other antiarrhythmic drugs of Vaughan-Williams class I or III) Copyleft Clinical Trial Results. You Must Redistribute Slides JCE 2008; 19.1/Heart Rhythm 2008

ATHENA Trial: Baseline Characteristics Incidence/Mean Value Patient age <65 years 19% 65-74 years 40% ≥75 years 42% Female gender 47% Hypertension 86% Mean systolic blood pressure 134 mmHg AF at baseline* 25% History of cardioversion 34% *AF at baseline: according to the stratification factor at randomization. Copyleft Clinical Trial Results. You Must Redistribute Slides JCE 2008; 19.1 /Heart Rhythm 2008

ATHENA Trial: Baseline Characteristics Incidence/Mean Value Structural heart disease** 60% -History of coronary artery disease 30% -Ischemic dilated cardiomyopathy 5% -Nonischemic dilated cardiomyopathy 4% -Rheumatic valve disease 2% -Nonrheumatic valve disease 15% **Structural heart disease: coronary heart disease and/or ischemic dilated cardiomyopathy and/or nonischemic dilated cardiomyopathy and/or rheumatic valvular heart disease and/or nonrheumatic valvular heart disease and/or hypertrophic cardiomyopathy and/or history of congestive heart failure and/or left ventricular ejection fraction (LVEF) < 45%. Copyleft Clinical Trial Results. You Must Redistribute Slides JCE 2008; 19.1/Heart Rhythm 2008

ATHENA Trial: Baseline Characteristics Incidence/Mean Value Structural heart disease cont.** 60% - Hypertrophic cardiomyopathy 2% - History of congestive heart failure 29% - LVEF < 0.45 12% Lone atrial fibrillation*** 6% ***Lone atrial fibrillation: patients without hypertension and without structural heart disease. Copyleft Clinical Trial Results. You Must Redistribute Slides JCE 2008; 19.1/Heart Rhythm 2008

ATHENA Trial: Primary Endpoint Results Multaq® (dronedarone) decreased the risk of cardiovascular hospitalizations or death from any cause by 24% (p<0.001). Copyleft Clinical Trial Results. You Must Redistribute Slides JCE 2008; 19.1/Heart Rhythm 2008

ATHENA Trial: Secondary Endpoint Results Compared to placebo, Multaq® (dronedarone) significantly decreased the risk of cardiovascular death by 30% (p=0.034). Multaq® (dronedarone) was associated with numerically fewer deaths from any cause (16%, p=0.17). First cardiovascular hospitalization was reduced by 25% (p=<0.001). Copyleft Clinical Trial Results. You Must Redistribute Slides JCE 2008; 19.1/Heart Rhythm 2008

ATHENA Trial: Other Outcomes Death from arrhythmias was reduced by 45% (p=0.01) when patients were treated with Multaq® (dronedarone). Multaq® (dronedarone) demonstrated a lower risk of pro-arrhythmia than placebo and no excess of hospitalizations for congestive heart failure. The rate of study drug discontinuation was similar between the two study arms. Copyleft Clinical Trial Results. You Must Redistribute Slides JCE 2008; 19.1/Heart Rhythm 2008

ATHENA Trial: Adverse Events There was a higher frequency of reported gastro-intestinal complications in the Multaq® (dronedarone) group than in the placebo arm. Gastro-intestinal Effects (%) Copyleft Clinical Trial Results. You Must Redistribute Slides JCE 2008; 19.1/Heart Rhythm 2008 16

ATHENA Trial: Adverse Events Multaq® (dronedarone) was associated with a more frequent occurrence of skin disorders as compared to placebo. Skin disorders (mainly rash) (%) Copyleft Clinical Trial Results. You Must Redistribute Slides JCE 2008; 19.1/Heart Rhythm 2008 17

ATHENA Trial: Adverse Events Patients treated with Multaq® (dronedarone) demonstrated increased serum creatinine more frequently than those given placebo. Increased Blood Creatinine (%) Copyleft Clinical Trial Results. You Must Redistribute Slides JCE 2008; 19.1/Heart Rhythm 2008 18

ATHENA Trial: Limitations Future trials should consider patients under 75 years of age without additional cardiovascular risk factors and those with decompensated heart failure. The exclusion of these patients from this study limits the applicability of the results. JCE 2008; 19.1/Heart Rhythm 2008

ATHENA Trial: Summary Multaq® (dronedarone) has been discovered as the first safe drug to benefit patients with atrial fibrillation. Findings include decreased rates of cardiovascular hospitalization and mortality. JCE 2008; 19.1/Heart Rhythm 2008