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

This study has been completed.
Sponsor:
Information provided by:
Sanofi
ClinicalTrials.gov Identifier:
NCT00174785
First received: September 13, 2005
Last updated: January 5, 2010
Last verified: January 2010
Results First Received: July 24, 2009  
Study Type: Interventional
Study Design: Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double (Participant, Investigator);   Primary Purpose: Prevention
Conditions: Atrial Fibrillation
Atrial Flutter
Interventions: Drug: dronedarone (SR33589)
Drug: placebo

  Participant Flow
  Hide Participant Flow

Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
Enrollment of patients started on June 29, 2005 and was completed on December 30, 2006. The study was conducted at 551 centers in 37 countries. The common study end date ensuring a minimum planned follow-up of one year was December 30th, 2007.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
No text entered.

Reporting Groups
  Description
Dronedarone 400mg Bid dronedarone tablets 400mg twice daily
Placebo matching placebo tablets

Participant Flow:   Overall Study
    Dronedarone 400mg Bid   Placebo
STARTED   2301 [1]   2327 [2] 
COMPLETED   1605 [3]   1611 [3] 
NOT COMPLETED   696   716 
Adverse Event                293                191 
Protocol Violation                14                14 
Withdrawal by Subject                173                175 
Atrial Fibrillation/Flutter recurrence                110                167 
Prohibited antiarrhythmic medication                39                88 
Other prohibited medication                5                3 
Family request                6                8 
Not pre-specified/Not coded                56                70 
[1] randomized patients; among them, 10 patients did not receive any study drug in the dronedarone group
[2] randomized patients; among them, 14 patients did not receive any study drug in the placebo group
[3] completed study drug



  Baseline Characteristics
  Hide Baseline Characteristics

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Dronedarone 400mg Bid dronedarone tablets 400mg twice daily
Placebo matching placebo tablets
Total Total of all reporting groups

Baseline Measures
   Dronedarone 400mg Bid   Placebo   Total 
Overall Participants Analyzed 
[Units: Participants]
 2301   2327   4628 
Age, Customized 
[Units: Participants]
     
18 to < 65 years   431   442   873 
65 to < 75 years   923   907   1830 
>= 75 years   947   978   1925 
Age 
[Units: Years]
Mean (Standard Deviation)
 71.6  (8.9)   71.7  (9.0)   71.6  (9.0) 
Gender 
[Units: Participants]
     
Female   1131   1038   2169 
Male   1170   1289   2459 


  Outcome Measures
  Hide All Outcome Measures

1.  Primary:   First Hospitalization for Cardiovascular Reason or Death From Any Cause   [ Time Frame: minimum follow-up duration: 1 year ; maximum: 2.5 years ]

Measure Type Primary
Measure Title First Hospitalization for Cardiovascular Reason or Death From Any Cause
Measure Description The primary event is the first hospitalization for cardiovascular reason or death from any cause, whichever is earlier, as assessed by the investigator. The primary efficacy analysis is performed on the time from randomization to this primary event. The Measured Values table below presents the numbers of patients with the event at the end of the study period.
Time Frame minimum follow-up duration: 1 year ; maximum: 2.5 years  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
All efficacy analyses were performed on the "all randomized patients" population including all patients randomized irrespective of whether the patient actually received any drug or complied with the study protocol.

Reporting Groups
  Description
Dronedarone 400mg Bid dronedarone tablets 400mg twice daily
Placebo matching placebo tablets

Measured Values
   Dronedarone 400mg Bid   Placebo 
Participants Analyzed 
[Units: Participants]
 2301   2327 
First Hospitalization for Cardiovascular Reason or Death From Any Cause 
[Units: Participants]
 734   917 


Statistical Analysis 1 for First Hospitalization for Cardiovascular Reason or Death From Any Cause
Groups [1] All groups
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Log Rank
P Value [4] <0.0001
Hazard Ratio (HR) [5] 0.76
95% Confidence Interval 0.69 to 0.84
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Cumulative incidence functions in each treatment group were calculated using non-parametric Kaplan-Meier estimates. Median time-to-event was not reached in any group. The primary comparison was performed at the 5% level using a 2-sided Log rank test.
[5] Other relevant estimation information:
  The hazard ratio was estimated by a Cox's proportional hazard model with treatment arm factor. It represents the relative hazard of first hospitalization for cardiovascular reason or death for the dronedarone group compared with the placebo group.



2.  Secondary:   Death From Any Cause   [ Time Frame: minimum follow-up duration: 1 year ; maximum: 2.5 years ]

Measure Type Secondary
Measure Title Death From Any Cause
Measure Description The considered event is death from any cause. The analysis is performed on the time from randomization to this event. The Measured Values table below presents the numbers of patients with the event at the end of the study period.
Time Frame minimum follow-up duration: 1 year ; maximum: 2.5 years  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
«All randomized patients» population

Reporting Groups
  Description
Dronedarone 400mg Bid dronedarone tablets 400mg twice daily
Placebo matching placebo tablets

Measured Values
   Dronedarone 400mg Bid   Placebo 
Participants Analyzed 
[Units: Participants]
 2301   2327 
Death From Any Cause 
[Units: Participants]
 116   139 


Statistical Analysis 1 for Death From Any Cause
Groups [1] All groups
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Log Rank
P Value [4] 0.18
Hazard Ratio (HR) [5] 0.84
95% Confidence Interval 0.66 to 1.08
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Cumulative incidences calculated in each group using non-parametric Kaplan-Meier estimates. Median time-to-event was not reached in any group. Hierarchical procedure applied to secondary efficacy endpoints testing to protect the global type I error.
[5] Other relevant estimation information:
  The hazard ratio was estimated by a Cox's proportional hazard model with treatment arm factor. It represents the relative hazard of death from any cause for the dronedarone group compared with the placebo group.



3.  Secondary:   First Hospitalization for Cardiovascular Reason   [ Time Frame: minimum follow-up duration: 1 year ; maximum: 2.5 years ]

Measure Type Secondary
Measure Title First Hospitalization for Cardiovascular Reason
Measure Description The considered event is the first hospitalization for cardiovascular reason, as assessed by the Investigator. The analysis is performed on the time from randomization to this event. The Measured Values table below presents the numbers of patients with the event at the end of the study period.
Time Frame minimum follow-up duration: 1 year ; maximum: 2.5 years  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
«All randomized patients» population

Reporting Groups
  Description
Dronedarone 400mg Bid dronedarone tablets 400mg twice daily
Placebo matching placebo tablets

Measured Values
   Dronedarone 400mg Bid   Placebo 
Participants Analyzed 
[Units: Participants]
 2301   2327 
First Hospitalization for Cardiovascular Reason 
[Units: Participants]
 675   859 


Statistical Analysis 1 for First Hospitalization for Cardiovascular Reason
Groups [1] All groups
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Log Rank
P Value [4] <0.0001
Hazard Ratio (HR) [5] 0.74
95% Confidence Interval 0.67 to 0.82
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Cumulative incidences calculated in each group using non-parametric Kaplan-Meier estimates. Median time-to-event was not reached in any group. Hierarchical procedure applied to secondary efficacy endpoints testing to protect the global type I error.
[5] Other relevant estimation information:
  The hazard ratio was estimated by a Cox's proportional hazard model with treatment arm factor. It represents the relative hazard of first hospitalization for cardiovascular reason for the dronedarone group compared with the placebo group.



4.  Secondary:   Cardiovascular Death   [ Time Frame: minimum follow-up duration: 1 year ; maximum: 2.5 years ]

Measure Type Secondary
Measure Title Cardiovascular Death
Measure Description The considered event is cardiovascular death, as assessed by the Investigator. The analysis is performed on the time from randomization to this event. The Measured Values table below presents the numbers of patients with the event at the end of the study period.
Time Frame minimum follow-up duration: 1 year ; maximum: 2.5 years  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
«All randomized patients» population

Reporting Groups
  Description
Dronedarone 400mg Bid dronedarone tablets 400mg twice daily
Placebo matching placebo tablets

Measured Values
   Dronedarone 400mg Bid   Placebo 
Participants Analyzed 
[Units: Participants]
 2301   2327 
Cardiovascular Death 
[Units: Participants]
 65   94 


Statistical Analysis 1 for Cardiovascular Death
Groups [1] All groups
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Log Rank
P Value [4] 0.025
Hazard Ratio (HR) [5] 0.70
95% Confidence Interval 0.51 to 0.96
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Cumulative incidences calculated in each group using non-parametric Kaplan-Meier estimates. Median time-to-event was not reached in any group. Hierarchical procedure applied to secondary efficacy endpoints testing to protect the global type I error.
[5] Other relevant estimation information:
  The hazard ratio was estimated by a Cox's proportional hazard model with treatment arm factor. It represents the relative hazard of cardiovascular death for the dronedarone group compared with the placebo group.



5.  Other Pre-specified:   Adjudicated Cardiovascular Death   [ Time Frame: minimum follow-up duration: 1 year ; maximum: 2.5 years ]

Measure Type Other Pre-specified
Measure Title Adjudicated Cardiovascular Death
Measure Description The considered event is cardiovascular death, as assessed by the blinded adjudication of the Steering Committee. The analysis is performed on the time from randomization to this event. The Measured Values table below presents the numbers of patients with the event at the end of the study period.
Time Frame minimum follow-up duration: 1 year ; maximum: 2.5 years  

Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
«All randomized patients» population

Reporting Groups
  Description
Dronedarone 400mg Bid dronedarone tablets 400mg twice daily
Placebo matching placebo tablets

Measured Values
   Dronedarone 400mg Bid   Placebo 
Participants Analyzed 
[Units: Participants]
 2301   2327 
Adjudicated Cardiovascular Death 
[Units: Participants]
 63   90 


Statistical Analysis 1 for Adjudicated Cardiovascular Death
Groups [1] All groups
Statistical Test Type [2] Superiority or Other
Statistical Method [3] Log Rank
P Value [4] 0.03
Hazard Ratio (HR) [5] 0.71
95% Confidence Interval 0.51 to 0.98
[1] Additional details about the analysis, such as null hypothesis and power calculation:
  No text entered.
[2] Details of power calculation, definition of non-inferiority margin, and other key parameters:
  No text entered.
[3] Other relevant method information, such as adjustments or degrees of freedom:
  No text entered.
[4] Additional information, such as whether or not the p-value is adjusted for multiple comparisons and the a priori threshold for statistical significance:
  Cumulative incidences calculated in each group using non-parametric Kaplan-Meier estimates. Median time-to-event was not reached in any group. The comparison was performed at the 5% level using a 2-sided Log rank
[5] Other relevant estimation information:
  The hazard ratio was estimated by a Cox's proportional hazard model with treatment arm factor. It represents the relative hazard of adjudicated cardiovascular death for the dronedarone group compared with the placebo group.




  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
  Hide Limitations and Caveats

Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
No text entered.


  More Information