1. 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
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2. 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

3. 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

4. ATHENA Trial: Study Design
4,628 patients >75 years with atrial fibrillation or 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
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JCE 2008; 19.1/Heart Rhythm 2008

5. 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.
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JCE 2008; 19.1/Heart Rhythm 2008

6. 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
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JCE 2008; 19.1/Heart Rhythm 2008

7. 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
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JCE 2008; 19.1/Heart Rhythm 2008

8. 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
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JCE 2008; 19.1/Heart Rhythm 2008

9. 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)
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JCE 2008; 19.1/Heart Rhythm 2008

10. 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.
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JCE 2008; 19.1 /Heart Rhythm 2008

11. 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%.
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JCE 2008; 19.1/Heart Rhythm 2008

12. 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.
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JCE 2008; 19.1/Heart Rhythm 2008

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

14. 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).
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JCE 2008; 19.1/Heart Rhythm 2008

15. 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.
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JCE 2008; 19.1/Heart Rhythm 2008

16. 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 (%)
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JCE 2008; 19.1/Heart Rhythm 2008 16

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

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

19. 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

20. 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