Atrial Fibrillation, Atrial Flutter
Conditions
Keywords
Mortality, Hospitalization
Brief summary
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.
Detailed description
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.
Interventions
oral administration (tablets)
DRUGplacebo
oral administration (tablets)
Sponsors
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
70 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| First Hospitalization for Cardiovascular Reason or Death From Any Cause | minimum follow-up duration: 1 year ; maximum: 2.5 years | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cardiovascular Death | minimum follow-up duration: 1 year ; maximum: 2.5 years | 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. |
| Death From Any Cause | minimum follow-up duration: 1 year ; maximum: 2.5 years | 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. |
| First Hospitalization for Cardiovascular Reason | minimum follow-up duration: 1 year ; maximum: 2.5 years | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Adjudicated Cardiovascular Death | minimum follow-up duration: 1 year ; maximum: 2.5 years | 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. |
Countries
Argentina, Australia, Austria, Belgium, Canada, Chile, China, Czechia, Finland, Germany, Greece, Hong Kong, Hungary, India, Israel, Italy, Malaysia, Mexico, Morocco, Netherlands, New Zealand, Norway, Philippines, Poland, Portugal, Russia, Singapore, South Africa, South Korea, Spain, Sweden, Taiwan, Thailand, Tunisia, Turkey (Türkiye), United Kingdom, United States
Participant flow
Recruitment details
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.
Participants by arm
| Arm | Count |
|---|---|
| Dronedarone 400mg Bid dronedarone tablets 400mg twice daily | 2,301 |
| Placebo matching placebo tablets | 2,327 |
| Total | 4,628 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 293 | 191 |
| Overall Study | Atrial Fibrillation/Flutter recurrence | 110 | 167 |
| Overall Study | Family request | 6 | 8 |
| Overall Study | Not pre-specified/Not coded | 56 | 70 |
| Overall Study | Other prohibited medication | 5 | 3 |
| Overall Study | Prohibited antiarrhythmic medication | 39 | 88 |
| Overall Study | Protocol Violation | 14 | 14 |
| Overall Study | Withdrawal by Subject | 173 | 175 |
Baseline characteristics
| Characteristic | Total | Placebo | Dronedarone 400mg Bid |
|---|---|---|---|
| Age Continuous | 71.6 years STANDARD_DEVIATION 9 | 71.7 years STANDARD_DEVIATION 9 | 71.6 years STANDARD_DEVIATION 8.9 |
| Age, Customized 18 to < 65 years | 873 participants | 442 participants | 431 participants |
| Age, Customized 65 to < 75 years | 1830 participants | 907 participants | 923 participants |
| Age, Customized >= 75 years | 1925 participants | 978 participants | 947 participants |
| Sex: Female, Male Female | 2169 Participants | 1038 Participants | 1131 Participants |
| Sex: Female, Male Male | 2459 Participants | 1289 Participants | 1170 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1,584 / 2,291 | 1,527 / 2,313 |
| serious Total, serious adverse events | 456 / 2,291 | 489 / 2,313 |
Outcome results
Primary
First Hospitalization for Cardiovascular Reason or Death From Any Cause
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: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dronedarone 400mg Bid | First Hospitalization for Cardiovascular Reason or Death From Any Cause | 734 participants |
| Placebo | First Hospitalization for Cardiovascular Reason or Death From Any Cause | 917 participants |
p-value: <0.000195% CI: [0.69, 0.84]Log Rank
Secondary
Cardiovascular Death
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: All randomized patients population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dronedarone 400mg Bid | Cardiovascular Death | 65 participants |
| Placebo | Cardiovascular Death | 94 participants |
p-value: 0.02595% CI: [0.51, 0.96]Log Rank
Secondary
Death From Any Cause
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: All randomized patients population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dronedarone 400mg Bid | Death From Any Cause | 116 participants |
| Placebo | Death From Any Cause | 139 participants |
p-value: 0.1895% CI: [0.66, 1.08]Log Rank
Secondary
First Hospitalization for Cardiovascular Reason
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: All randomized patients population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dronedarone 400mg Bid | First Hospitalization for Cardiovascular Reason | 675 participants |
| Placebo | First Hospitalization for Cardiovascular Reason | 859 participants |
p-value: <0.000195% CI: [0.67, 0.82]Log Rank
Other Pre-specified
Adjudicated Cardiovascular Death
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: All randomized patients population
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dronedarone 400mg Bid | Adjudicated Cardiovascular Death | 63 participants |
| Placebo | Adjudicated Cardiovascular Death | 90 participants |
p-value: 0.0395% CI: [0.51, 0.98]Log Rank