Effect of Dronedarone on Cardiovascular Outcomes in High-Risk Patients With Atrial Fibrillation or Atrial Flutter - ATHENA

Sep 21, 2009
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Trial Sponsor:
Sanofi-Aventis
Date Presented:
01/01/2008
Date Published:
01/01/2009
Date Updated:
09/21/2009
Original Posted Date:
09/21/2009
References

Description:

ATHENA (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) was a double-blind randomized clinical trial designed to test the safety and efficacy of dronedarone in the treatment of atrial fibrillation (AF) and atrial flutter (Afl).

Hypothesis:

Dronedarone would be superior to placebo in reducing the occurrence of cardiovascular hospitalization or death from any cause in high-risk patients with paroxysmal or persistent AF or Afl.

Study Design

Patients Enrolled: 4,628
NYHA Class: I-III
Mean Follow Up: 21 months
Mean Patient Age: 71.6 years
Female: 47
Mean Ejection Fraction: <45% (12%), <35% (4.0%)

Patient Populations:

  • Age ≥75 years
  • Two 12-lead electrocardiograms available within the past 6 months: one demonstrating AF or Afl, and the other demonstrating normal sinus rhythm

Patients ages 70-75 years were included if they had at least one of the following risk factors:
  • Hypertension (being treated with at least two antihypertensive medications)
  • Diabetes mellitus
  • Prior stroke or transient ischemic attack, or evidence of systemic embolism
  • Left atrial diameter >50 mm by M-mode echocardiography
  • Left ventricular ejection fraction

Exclusions:

Specific:
  • Permanent AF
  • Unstable hemodynamics, including recent congestive heart failure
  • New York Heart Association class IV symptoms
  • Planned major surgery
  • Acute myocarditis
  • Bradycardia <50 bpm="" and/or="" a="" pr="" interval="">0.28 seconds
    General:
    • Use of other class I or III antiarrhythmic agents
    • Significant sinus node disease in the past, if not treated with a pacemaker
    • Known noncardiac disease limiting life expectancy
    • Nursing or pregnant women
    • Women of childbearing age not on adequate birth control
    • Calculated glomerular filtration rate <10>
    • Potassium level <3.5 if="">

    Primary Endpoints:

    First occurrence of cardiovascular hospitalization or death from any cause

    Secondary Endpoints:

    • Overall mortality
    • Cardiovascular deaths
    • Hospitalization for cardiovascular causes
    • Stroke
    • All adverse effects

    Drug/Procedures Used:

    Patients meeting inclusion and exclusion criteria received either dronedarone 400 mg twice daily or matching placebo, with a minimum treatment and follow-up duration of 1 year.

    Concomitant Medications:

    Beta-blockers (70.7%), digoxin (13.6%), statins (38.7%), vitamin K antagonists (60.3%), aspirin (44%)

    Principal Findings:

    A total of 4,628 patients were randomized from more than 550 sites in 37 countries: 2,301 to dronedarone and 2,327 to placebo. About 42% of the patients were ages 75 years or older. Patients were stratified based on the presence or absence of AF or Afl at baseline, which was present in one-quarter of the patients randomized; lone AF was present in about 6% of the patients. Only 12% of the patients had evidence of systolic dysfunction, with an ejection fraction of lower than 45%. About 30% of the patients had coexisting coronary artery disease. The baseline CHADS2 score was 2.05; about 64.5% of the patients had a CHADS2 score ≥2.

    The use of ancillary medications such as beta-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, or angiotensin-receptor blockers, digoxin, statins, and oral anticoagulation was similar between the two groups.

    Efficacy: Compared with placebo, patients receiving dronedarone had a significant 24% reduction in cardiovascular hospitalizations or death over the duration of follow-up (31.9% vs. 39.4%, hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.69-0.84, p

    Safety: The rate of drug discontinuation was similar between the two arms. The total adverse event rates were higher with dronedarone than with placebo (72% vs. 69.3%, p = 0.048). This included a higher incidence of any cardiac events (11.3% vs. 9.6%, p = 0.048), including bradycardia (3.5% vs. 1.2%, p

    Skin-related events such as rash were also higher in the dronedarone arm. Rates of side effects, such as thyroid dysfunction and respiratory complications, were similar between the two groups.

    Interpretation:

    The results of this landmark clinical trial, which is the largest antiarrhythmic drug trial conducted in patients with AF, indicate that dronedarone is effective in the chronic management of AF in high-risk patients, with a significant reduction in the incidence of cardiovascular hospitalizations or death, cardiovascular deaths (primarily death due to arrhythmias), and stroke at 21 months, compared with placebo. However, there was a higher incidence of treatment-related side effects including cardiac events such as bradycardia and QT-prolongation, as well as gastrointestinal events such as nausea and diarrhea. The incidence of respiratory and endocrine side effects was similar to placebo.

    Although this trial did not directly compare dronedarone to amiodarone, indirect comparisons from this trial suggest that dronedarone may be similar in efficacy to amiodarone, without being associated with some of its significant side effects.

    Results of this trial are similar to earlier studies such as EURIDIS and ADONIS, but contrary to ANDROMEDA, all of which were placebo-controlled trials. The results of ongoing trials comparing dronedarone to amiodarone (such as DIONYSOS) are eagerly awaited.

    References:

    Hohnloser SH, Crijns HJ, van Eickels M, et al., on behalf of the ATHENA Investigators. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med 2009;360:668-78.

    Connolly SJ, Crijns HJ, Torp-Pedersen C, et al., on behalf of the ATHENA Investigators. Analysis of Stroke in ATHENA: 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. Circulation 2009;Sep 14:[Epub ahead of print].

    ATHENA: The Effect of Dronedarone on Cardiovascular Outcomes and Stroke in Patients With Atrial Fibrillation. Presented by Dr. Stuart Connolly at the European Society of Cardiology Congress, Munich, Germany, August/September 2008.

    Also presented by Dr. Stefan H. Hohnloser at the Heart Rhythm Society Annual Scientific Sessions, San Francisco, CA, May 2008.

    Keywords: Ischemic Attack, Transient, Follow-Up Studies, Digoxin, Risk Factors, Electrocardiography, Calcium Channel Blockers, Stroke Volume, Confidence Intervals, Hypertension, Exanthema, Echocardiography, Nausea, Angiotensin Receptor Antagonists, Stroke, Diarrhea, Bradycardia, Embolism, Hospitalization, Diabetes Mellitus, Atrial Flutter


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