A Trial With Dronedarone to Prevent Hospitalization or Death in Patients With Atrial Fibrillation (ATHENA)

• Death From Any Cause [ Time Frame: minimum follow-up duration: 1 year ; maximum: 2.5 years ] [ Designated as safety issue: No ]
• First Hospitalization for Cardiovascular Reason [ Time Frame: minimum follow-up duration: 1 year ; maximum: 2.5 years ] [ Designated as safety issue: No ]
• Cardiovascular Death [ Time Frame: minimum follow-up duration: 1 year ; maximum: 2.5 years ] [ Designated as safety issue: No ]

• Secondary criteria are:
• - Death from any cause
• - Cardiovascular death
• - Hospitalization for cardiovascular reasons

To assess the efficacy of dronedarone in preventing cardiovascular hospitalization or death from any cause in a population of high-risk patients with atrial fibrillation/atrial flutter (AF/AFL).

To assess that dronedarone is well tolerated in this population.

This is a prospective, multinational, double-blind, randomized, multi-center, placebo-controlled, parallel-group trial evaluating the effects of dronedarone versus placebo (ratio 1:1) over a minimum treatment duration of 12 months and a mean follow-up duration of 1.75 years (in AF/AFL patients). Patients can be included in the study while in atrial fibrillation/flutter or in sinus rhythm if conversion has occurred either spontaneously or following a procedure such as electrical cardioversion (or overdrive pacing) or administration of an antiarrhythmic drug.After randomization all patients will be followed until the common study end date; the last patient included in the study will be followed for 1 year. Visits will be at baseline, after 7 days, after 14 days, after one month, after three months and then every three months until end of the study. At each visit patients will be asked for the occurrence of hospitalizations or other events since the last visit. The study will be monitored by an independent Data Monitoring Committee (DMC) for safety, tolerability and efficacy.

• Atrial Fibrillation
• Atrial Flutter

• Drug: dronedarone (SR33589)
  oral administration (tablets)
  Other Name: Multaq®
• Drug: placebo
  oral administration (tablets)

• Experimental: Dronedarone 400mg bid
  Dronedarone 400mg tablets twice daily (bid)
  Intervention: Drug: dronedarone (SR33589)
• Placebo Comparator: Placebo
  matching placebo tablets
  Intervention: Drug: placebo

• Hohnloser SH, Connolly SJ, Crijns HJ, Page RL, Seiz W, Torp-Petersen C. Rationale and design of 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. J Cardiovasc Electrophysiol. 2008 Jan;19(1):69-73. Epub 2007 Nov 21.
• Hohnloser SH, Crijns HJ, van Eickels M, Gaudin C, Page RL, Torp-Pedersen C, Connolly SJ; ATHENA Investigators. Effect of dronedarone on cardiovascular events in atrial fibrillation. N Engl J Med. 2009 Feb 12;360(7):668-78. doi: 10.1056/NEJMoa0803778. Erratum in: N Engl J Med. 2009 Jun 4;360(23):2487. N Engl J Med. 2011 Apr 14;364(15):1481.
• Åkerborg Ö, Nilsson J, Bascle S, Lindgren P, Reynolds M. Cost-effectiveness of dronedarone in atrial fibrillation: results for Canada, Italy, Sweden, and Switzerland. Clin Ther. 2012 Aug;34(8):1788-802. doi: 10.1016/j.clinthera.2012.06.007. Epub 2012 Jul 6.
• Torp-Pedersen C, Crijns HJ, Gaudin C, Page RL, Connolly SJ, Hohnloser SH; ATHENA Investigators. Impact of dronedarone on hospitalization burden in patients with atrial fibrillation: results from the ATHENA study. Europace. 2011 Aug;13(8):1118-26. doi: 10.1093/europace/eur102. Epub 2011 May 15.
• Page RL, Connolly SJ, Crijns HJ, van Eickels M, Gaudin C, Torp-Pedersen C, Hohnloser SH; ATHENA Investigators. Rhythm- and rate-controlling effects of dronedarone in patients with atrial fibrillation (from the ATHENA trial). Am J Cardiol. 2011 Apr 1;107(7):1019-22. doi: 10.1016/j.amjcard.2010.11.028. Epub 2011 Feb 4.
• Hohnloser SH, Crijns HJ, van Eickels M, Gaudin C, Page RL, Torp-Pedersen C, Connolly SJ; ATHENA Investigators. Dronedarone in patients with congestive heart failure: insights from ATHENA. Eur Heart J. 2010 Jul;31(14):1717-21. doi: 10.1093/eurheartj/ehq113. Epub 2010 Apr 30.

Inclusion Criteria:

• 1. Patients aged 75 years or older (70 years before protocol amendment 1), or patients aged at least 70 years (any age before protocol amendment 1) with one or more of the following risk factors at baseline:

  • Hypertension (taking antihypertensive drugs of at least two different classes)
  • Diabetes
  • Prior cerebrovascular accident (stroke or transient ischemic attack) or systemic embolism
  • Left atrium diameter greater than or equal to 50 mm by echocardiography
  • Left ventricular ejection fraction less than 0.40 by 2D-echocardiography (two-dimensional echocardiography)
• 2. Availability of one electrocardiogram (ECG) within the last 6 months, showing that the patient was or is in AF/AFL
• 3. Availability of one ECG within the last 6 months, showing that the patient was or is in sinus rhythm

Exclusion Criteria:

General criteria:

• 1. Refusal or inability to give informed consent to participate in the study
• 2. Any non cardiovascular illness or disorder that could preclude participation or severely limit survival including cancer with metastasis and organ transplantation requiring immune suppression
• 3. Pregnant women (pregnancy test must be negative) or women of childbearing potential not on adequate birth control: only women with a highly effective method of contraception [oral contraception or intra-uterine device (IUD)] or sterile can be randomized.
• 4. Breastfeeding women
• 5. Previous (2 preceding months) or current participation in another clinical trial with an investigational drug (under development) or with an investigational device
• 6. Previous participation in this trial

Criteria Related to a cardiac condition:

• 7. Patients in permanent atrial fibrillation
• 8. Patients in unstable hemodynamic condition such as acute pulmonary edema within 12 hours prior to start of study medication; cardiogenic shock; treatment with intra-venous pressor agents; patients on respirator; congestive heart failure of stage NYHA IV (New York Heart Association classification) within the last 4 weeks; uncorrected, hemodynamically significant primary obstructive valvular disease; hemodynamically significant obstructive cardiomyopathy; a cardiac operation or revascularization procedure within 4 weeks preceding randomization
• 9. Planned major non-cardiac or cardiac surgery or procedures including surgery for valvular heart disease, coronary artery bypass graft (CABG) , percutaneous coronary intervention (PCI) , or on urgent cardiac transplantation list
• 10. Acute myocarditis or constrictive pericarditis
• 11. Bradycardia < 50 bpm and/or PR-interval > 0.28 sec on the last 12-lead ECG
• 12. Significant sinus node disease (documented pause of 3 seconds or more) or 2nd or 3rd degree atrioventricular block (AV-block) unless treated with a pacemaker

Criteria Related to Concomitant Medications:

• 13. Need of a concomitant medication that is prohibited in this trial, including the requirement for Vaughan Williams Class I and III anti-arrhythmic drugs, that would preclude the use of study drug during the planned study period

Criteria Related to Laboratory Abnormalities:

• 14. Plasma potassium < 3.5 mmol/l (as anti-arrhythmic drugs can be arrhythmogenic in patients with hypokalemia, this must be corrected prior to randomization)
• 15. A calculated Glomerular Filtration Rate (GFR) at baseline <10 ml/min using the Cockroft Gault formula