Transcript IntraCoronary Treatment with Integrilin To Improve

ATHENA Trial
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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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.
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ATHENA Trial: Dronedarone
• Dronedarone (Multaq®) manufactured by Sanofiaventis 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.
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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
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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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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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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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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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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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ATHENA Trial: Baseline Characteristics
Characteristic
Patient age
<65 years
65-74 years
≥75 years
Female gender
Hypertension
Mean systolic blood pressure
AF at baseline*
History of cardioversion
Incidence/Mean Value
19%
40%
42%
47%
86%
134 mmHg
25%
34%
*AF at baseline: according to the stratification factor at randomization.
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ATHENA Trial: Baseline Characteristics
Characteristic
Structural heart disease**
Incidence/Mean Value
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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ATHENA Trial: Baseline Characteristics
Characteristic
Structural heart disease cont.**
Incidence/Mean Value
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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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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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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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 proarrhythmia 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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Gastro-intestinal Effects (%)
ATHENA Trial: Adverse Events
30%
25%
26.0%
22.0%
20%
15%
• There was a higher
frequency of reported
gastro-intestinal
complications in the
Multaq® (dronedarone)
group than in the placebo
arm.
10%
5%
0%
Placebo
Multaq®
(dronedarone)
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Skin disorders (mainly rash) (%)
ATHENA Trial: Adverse Events
10.0%
10%
8.0%
5%
• Multaq® (dronedarone)
was associated with a
more frequent
occurrence of skin
disorders as compared to
placebo.
0%
Placebo
Multaq®
(dronedarone)
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Increased Blood Creatinine (%)
ATHENA Trial: Adverse Events
4.7%
5%
4%
3%
• Patients treated with
Multaq® (dronedarone)
demonstrated increased
serum creatinine more
frequently than those
given placebo.
2%
1.0%
1%
0%
Placebo
Multaq®
(dronedarone)
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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.
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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.
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