113342211

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)

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

ATHENA Trial

Copyleft Clinical Trial Results. You Must Redistribute Slides


ATHENA Trial: BackgroundATHENA 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


• 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.

ATHENA Trial: DronedaroneATHENA Trial: Dronedarone


ATHENA Trial: Study DesignATHENA Trial: Study Design

Primary Endpoint: composite of all-cause mortality combined with cardiovascular hospitalization

Secondary Endpoint: death from any cause, cardiovascular death, hospitalization for cardiovascular reasons

Multaq® (dronedarone)400 mg BID

Placebo

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

12-30 mos. follow-up


ATHENA Trial: Inclusion CriteriaATHENA 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.



ATHENA Trial: Inclusion Criteria Cont.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



ATHENA Trial: Exclusion CriteriaATHENA 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.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


ATHENA Trial: Exclusion Criteria cont.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)


Characteristic 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%

ATHENA Trial: Baseline CharacteristicsATHENA Trial: Baseline Characteristics

JCE 2008; 19.1 /Heart Rhythm 2008Copyleft Clinical Trial Results. You Must Redistribute Slides

*AF at baseline: according to the stratification factor at randomization.

*AF at baseline: according to the stratification factor at randomization.


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%.

**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%.


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.***Lone atrial fibrillation: patients without hypertension and without structural heart disease.

ATHENA Trial: Primary Endpoint ResultsATHENA Trial: Primary Endpoint Results

Multaq® (dronedarone) decreased the risk of cardiovascular hospitalizations or death from any cause by 24% (p<0.001).


ATHENA Trial: Secondary Endpoint ResultsATHENA 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).


ATHENA Trial: Other OutcomesATHENA 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.


Placebo Multaq® (dronedarone)

0%

5%

10%

15%

20%

25%

30%

22.0%26.0%

• There was a higher frequency of reported gastro-intestinal complications in the Multaq® (dronedarone) group than in the placebo arm.

Gas

tro-

inte

stin

al E

ffect

s (

%)

ATHENA Trial: Adverse EventsATHENA Trial: Adverse Events



0%

5%

10%8.0%

10.0% • Multaq® (dronedarone) was associated with a more frequent occurrence of skin disorders as compared to placebo.

Ski

n di

sord

ers

(mai

nly

rash

) (

%)

ATHENA Trial: Adverse EventsATHENA Trial: Adverse Events



0%

1%

2%

3%

4%

1.0%

4.7%• Patients treated with

Multaq® (dronedarone) demonstrated increased serum creatinine more frequently than those given placebo.

Incr

ease

d B

lood

Cre

atin

ine

(%

)ATHENA Trial: Adverse EventsATHENA Trial: Adverse Events



ATHENA Trial: LimitationsATHENA 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.



ATHENA Trial: SummaryATHENA 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.


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