Atrial Fibrillation
Conditions
Keywords
Atrial Fibrillation, Paroxysmal, Pulmonary Vein Isolation, Ablation Catheter, Anti-arrhythmic Drug Therapy, First Line Therapy
Brief summary
The purpose of this study is to determine whether catheter-based pulmonary vein isolation is superior to antiarrhythmic drugs as first line therapy in patients with symptomatic paroxysmal recurrent atrial fibrillation not previously treated with therapeutic doses of antiarrhythmic drugs.
Detailed description
Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice and is estimated to affect 2.2 million people in the United States. AF is a major cause of stroke, adversely affects quality of life, and is associated with increased mortality. Despite advances in antiarrhythmic drug therapy, AF continues to be associated with significant morbidity. Although antiarrhythmic drug therapy is currently considered a first-line option, recent data indicate that more than 35% of Patients will have recurrence of AF despite best antiarrhythmic drug (AAD) therapy, and more than 30% of Patients will discontinue the drugs because of adverse reactions. Furthermore, although recent trials have indicated equivalence of rhythm and rate control strategies in some patient populations, 25-35% of Patients with AF who are rate controlled will continue to have activity limiting symptoms. Newer measures to prevent, treat and potentially cure AF are needed. Seminal work by Haissaguerre and replicated by Chen showed that the majority of AF is initiated by ectopic foci found primarily in the pulmonary veins (PV). Experience with the catheter-based Maze technique led to observations that opened the door to effective and practical catheter-based cures for AF. In response to the difficulties of focal ablation, an alternate strategy has been developed that seeks to electrically isolate the Pulmonary Veins from the atrial tissue. Empirical PV isolation targets all of the PV's without regard to the initiation of ectopic beats. The goal is to create entrance block in the PV. Multipolar circular catheters and basket catheters have been developed that facilitate identification of the electrical connections that are present at the junction of the atrium and the PV, and radiofrequency energy is applied in a circumferential fashion until entrance block is achieved. Relative to focal ablation, circumferential PV isolation is simpler to perform, can be completed without inducing AF, has a shorter procedure time, and has a lower incidence of PV stenosis. Comparison: Patients will have ablation to achieve entrance and/or exit block into all pulmonary veins, compared with patients receiving antiarrhythmic drugs given in accordance with ACC/AHA/ESC 2006 Guidelines for the Management of patients with AF.
Interventions
PROCEDUREPulmonary Vein Isolation performed by Catheter Ablation
Ablation will be done to achieve entrance block into all pulmonary veins.
DRUGConventional Antiarrhythmic Drug Therapy
Anti-Arrhythmic Drugs per ACC/AHA 2006 Guidelines for the Management of Patients with AF
Sponsors
Johnson & Johnson
Population Health Research Institute
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Age \> 18 and ≤ 75 years old. 2. Symptomatic, recurrent paroxysmal AF lasting \> 30 seconds (at least 4 episodes within the prior 6 months). At least one episode must be documented by Holter,12-lead ECG, event monitor or rhythm strip.
Exclusion criteria
1. Documented LVEF \<40%. 2. Documented left atrial diameter \>5.5cm. 3. Moderate to severe LVH (LV wall thickness \>1.5cm). 4. Documented valvular disease, coronary heart disease (defined as the presence of \>70% stenosis of coronary arteries or documentation of active myocardial ischemia), post-CABG, postoperative cardiac surgery or peripheral artery disease. 5. Documented AF with electrical cardioversion where full therapeutic antiarrhythmic drug therapy after the cardioversion was prescribed. 6. Untreated hypothyroidism or hyperthyroidism. Patients who are euthyroid on thyroid hormone replacement therapy are acceptable. 7. Contraindication for the use of sotalol, dofetilide and 1C antiarrhythmic drugs(liver enzymes and serum creatinine that are outside the upper normal lab values, e.g. \> 3 times ULN with 2 abnormal lab values). 8. Previous left heart ablation procedure, either by surgery or by percutaneous catheter, for atrial fibrillation. 9. Current enrollment in another investigational drug or device study. 10. Presence of any other condition that the investigator feels would be problematic or would restrict or limit the participation of the Patient for the entire study period. 11. Absolute contra-indication to the use of heparin and or warfarin. 12. Increase risk of bleeding, current peptic ulceration, proliferative diabetic retinopathy, history of severe systemic bleeding, or other history of bleeding diathesis or coagulopathy. 13. Severe pulmonary disease e.g. restrictive pulmonary disease, chronic obstructive disease (COPD). 14. Documented intra-atrial thrombus, tumor, or another abnormality which precludes catheter introduction. 15. Previous use of full therapeutic dose of an antiarrhythmic drug, including amiodarone, propafenone, flecainide, sotalol, quinidine. 16. Pacemaker or Implantable Cardioverter Defibrillator. 17. Women with a positive pregnancy test. 18. Evidence of active cardiac or systemic infection. 19. Medical condition limiting expected survival to less than one year.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Recurrence of Atrial Tachyarrhythmia | Assessed during 21 month follow-up period | Recurrence of electrocardiographically documented atrial fibrillation, atrial flutter or atrial tachycardia lasting \>30 seconds during Follow-up Period. The follow-up period begins 90 days after randomization (the blanking period during which antiarrhythmic drugs are titrated or catheter ablation is performed). |
| Comparison of Proportion of Patients With an Occurrence of Any of a Cluster of Serious Complications in Either Arm | Assessed during entire 24 month study period | Ablation arm cluster: death, cardiac tamponade, severe PV stenosis\>70%, atrioesophageal fistula, thromboembolism, vascular complications (i.e. arterial pseudoaneurysm, arteriovenous fistula and hematoma leading to transfusion), phrenic nerve injury or complete AV block requiring permanent pacemaker implantation. Antiarrhythmic drug arm cluster: Death, torsade de pointes, bradycardia leading to pacemaker insertion, syncope, QRS duration prolongation \> 50% of baseline, 1:1 atrial flutter or any other significant adverse events that leads to drug discontinuation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Episodes of ANY Recurrence of Atrial Tachyarrhythmia | During 21 month follow-up period | Including all episodes of symptomatic or asymptomatic atrial fibrillation, atrial flutter and atrial tachycardia. The follow-up period begins 90 days after randomization (the blanking period during which antiarrhythmic drugs are titrated or catheter ablation is performed). |
| Number of Participants With Recurrence of Atrial Tachyarrhythmia Obtained Clinically | During 21 month follow-up period | Including only events documented by 12 lead ECG, Holter monitoring or rhythm strips but excluding TTM monitoring. The follow-up period begins 90 days after randomization (the blanking period during which antiarrhythmic drugs are titrated or catheter ablation is performed). |
| Number of Participants With Recurrence of Symptomatic Atrial Tachyarrhythmia | 21 months of follow-up | Including only symptomatic episodes of all atrial tachyarrhythmias (atrial fibrillation, atrial flutter and atrial tachycardia). The follow-up period begins 90 days after randomization (the blanking period during which antiarrhythmic drugs are titrated or catheter ablation is performed). |
| Quality of Life EQ-5D Visual Analog Score | Measured At 12 months after randomization | The EQ VAS records the patient's self-rated health on a vertical visual analogue scale. The scale measures how good/bad one's own health is today, in one's own opinion. 0 means the worst imaginable state of health; 100 means the best imaginable state of health. |
| Quality of Life EQ5D Index Score | Measured at 12 months after randomization | The standard EQ-5D questionnaire is completed by study participants. The EQ-5D Index score is a descriptive system comprising five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Self-reported severity for each dimension is given on a 3 level scale: (1) no problems, (2) some problems or (3) major problems. For example a health state: 11223 means: no problems with mobility (1), no problems with self-care (1), some problems with performing usual activity (2), moderate pain/discomfort (2), and major anxiety/depression (3). Thus there are 243 patterns of health state: 11111 to 33333. Scores are converted to a single weighted index score (utility). The index score is derived by applying a formula as developed by Shaw JW, Johnson JA, Coons SJ. US valuation of the EQ-5D health states: development and testing of the D1 valuation model. Med Care 2005; 43(3): 203-220. The final score has a minimum value of 0 and maximum value of 1 (no problems). |
| Number of Participants With Recurrence of Symptomatic Atrial Fibrillation | During 21 month follow-up period | Including only symptomatic episodes of atrial fibrillation in the outcome measure (excluding asymptomatic events and events adjudicated as atrial flutter or atrial tachycardia). The follow-up period begins 90 days after randomization (the blanking period during which antiarrhythmic drugs are titrated or catheter ablation is performed). |
Countries
Canada, Czechia, Germany, Italy, United States
Participant flow
Recruitment details
Eligible consenting patients from 16 sites in Canada and Europe were randomly assigned 1:1 to the Catheter Ablation arm or Antiarrythmic Drug Therapy arm. The randomization schedule was computer generated and stratified by site with variable block size.
Participants by arm
| Arm | Count |
|---|---|
| Catheter Ablation Pulmonary vein isolation performed by catheter ablation for the prevention of recurrence of symptomatic atrial fibrillation | 66 |
| Antiarrhythmic Drug Therapy Conventional antiarrythmic drug therapy for the prevention of recurrence of symptomatic atrial fibrillation | 61 |
| Total | 127 |
Baseline characteristics
| Characteristic | Catheter Ablation | Antiarrhythmic Drug Therapy | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 15 Participants | 13 Participants | 28 Participants |
| Age, Categorical Between 18 and 65 years | 51 Participants | 48 Participants | 99 Participants |
| Age, Continuous | 56.3 years STANDARD_DEVIATION 9.3 | 54.3 years STANDARD_DEVIATION 11.7 | 55.8 years STANDARD_DEVIATION 10.5 |
| Region of Enrollment Canada | 41 participants | 38 participants | 79 participants |
| Region of Enrollment Czech Republic | 2 participants | 2 participants | 4 participants |
| Region of Enrollment Germany | 16 participants | 16 participants | 32 participants |
| Region of Enrollment Italy | 4 participants | 3 participants | 7 participants |
| Region of Enrollment United States | 3 participants | 2 participants | 5 participants |
| Sex: Female, Male Female | 15 Participants | 16 Participants | 31 Participants |
| Sex: Female, Male Male | 51 Participants | 45 Participants | 96 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 65 | 0 / 60 |
| other Total, other adverse events | 21 / 65 | 19 / 60 |
| serious Total, serious adverse events | 6 / 65 | 2 / 60 |
Outcome results
Primary
Comparison of Proportion of Patients With an Occurrence of Any of a Cluster of Serious Complications in Either Arm
Ablation arm cluster: death, cardiac tamponade, severe PV stenosis\>70%, atrioesophageal fistula, thromboembolism, vascular complications (i.e. arterial pseudoaneurysm, arteriovenous fistula and hematoma leading to transfusion), phrenic nerve injury or complete AV block requiring permanent pacemaker implantation. Antiarrhythmic drug arm cluster: Death, torsade de pointes, bradycardia leading to pacemaker insertion, syncope, QRS duration prolongation \> 50% of baseline, 1:1 atrial flutter or any other significant adverse events that leads to drug discontinuation.
Time frame: Assessed during entire 24 month study period
Population: All patients treated
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Catheter Ablation | Comparison of Proportion of Patients With an Occurrence of Any of a Cluster of Serious Complications in Either Arm | 5 Participants |
| Antiarrhythmic Drug Therapy | Comparison of Proportion of Patients With an Occurrence of Any of a Cluster of Serious Complications in Either Arm | 12 Participants |
Primary
Number of Participants With Recurrence of Atrial Tachyarrhythmia
Recurrence of electrocardiographically documented atrial fibrillation, atrial flutter or atrial tachycardia lasting \>30 seconds during Follow-up Period. The follow-up period begins 90 days after randomization (the blanking period during which antiarrhythmic drugs are titrated or catheter ablation is performed).
Time frame: Assessed during 21 month follow-up period
Population: All randomized patients
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Catheter Ablation | Number of Participants With Recurrence of Atrial Tachyarrhythmia | 36 Participants |
| Antiarrhythmic Drug Therapy | Number of Participants With Recurrence of Atrial Tachyarrhythmia | 44 Participants |
Comparison: Event rates were plotted over time using Kaplan-Meier methodology. Only events occurring after the 90-day treatment period were included in the final analysis. Treatment groups were analyzed on an intention-to-treat basis.p-value: 0.001695% CI: [0.35, 0.9]Regression, Cox
Secondary
Episodes of ANY Recurrence of Atrial Tachyarrhythmia
Including all episodes of symptomatic or asymptomatic atrial fibrillation, atrial flutter and atrial tachycardia. The follow-up period begins 90 days after randomization (the blanking period during which antiarrhythmic drugs are titrated or catheter ablation is performed).
Time frame: During 21 month follow-up period
Population: All patients randomized
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Catheter Ablation | Episodes of ANY Recurrence of Atrial Tachyarrhythmia | 213 Episodes |
| Antiarrhythmic Drug Therapy | Episodes of ANY Recurrence of Atrial Tachyarrhythmia | 502 Episodes |
p-value: <0.000195% CI: [0.28, 0.4]Regression, Cox
Secondary
Number of Participants With Recurrence of Atrial Tachyarrhythmia Obtained Clinically
Including only events documented by 12 lead ECG, Holter monitoring or rhythm strips but excluding TTM monitoring. The follow-up period begins 90 days after randomization (the blanking period during which antiarrhythmic drugs are titrated or catheter ablation is performed).
Time frame: During 21 month follow-up period
Population: All patients randomized
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Catheter Ablation | Number of Participants With Recurrence of Atrial Tachyarrhythmia Obtained Clinically | 16 participants |
| Antiarrhythmic Drug Therapy | Number of Participants With Recurrence of Atrial Tachyarrhythmia Obtained Clinically | 19 participants |
p-value: 0.6695% CI: [0.42, 1.72]Regression, Cox
Secondary
Number of Participants With Recurrence of Symptomatic Atrial Fibrillation
Including only symptomatic episodes of atrial fibrillation in the outcome measure (excluding asymptomatic events and events adjudicated as atrial flutter or atrial tachycardia). The follow-up period begins 90 days after randomization (the blanking period during which antiarrhythmic drugs are titrated or catheter ablation is performed).
Time frame: During 21 month follow-up period
Population: All patients randomized
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Catheter Ablation | Number of Participants With Recurrence of Symptomatic Atrial Fibrillation | 27 participants |
| Antiarrhythmic Drug Therapy | Number of Participants With Recurrence of Symptomatic Atrial Fibrillation | 35 participants |
p-value: 0.01795% CI: [0.3, 0.89]Regression, Cox
Secondary
Number of Participants With Recurrence of Symptomatic Atrial Tachyarrhythmia
Including only symptomatic episodes of all atrial tachyarrhythmias (atrial fibrillation, atrial flutter and atrial tachycardia). The follow-up period begins 90 days after randomization (the blanking period during which antiarrhythmic drugs are titrated or catheter ablation is performed).
Time frame: 21 months of follow-up
Population: All patients randomized
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Catheter Ablation | Number of Participants With Recurrence of Symptomatic Atrial Tachyarrhythmia | 31 participants |
| Antiarrhythmic Drug Therapy | Number of Participants With Recurrence of Symptomatic Atrial Tachyarrhythmia | 36 participants |
p-value: 0.0395% CI: [0.33, 0.95]Regression, Cox
Secondary
Quality of Life EQ5D Index Score
The standard EQ-5D questionnaire is completed by study participants. The EQ-5D Index score is a descriptive system comprising five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Self-reported severity for each dimension is given on a 3 level scale: (1) no problems, (2) some problems or (3) major problems. For example a health state: 11223 means: no problems with mobility (1), no problems with self-care (1), some problems with performing usual activity (2), moderate pain/discomfort (2), and major anxiety/depression (3). Thus there are 243 patterns of health state: 11111 to 33333. Scores are converted to a single weighted index score (utility). The index score is derived by applying a formula as developed by Shaw JW, Johnson JA, Coons SJ. US valuation of the EQ-5D health states: development and testing of the D1 valuation model. Med Care 2005; 43(3): 203-220. The final score has a minimum value of 0 and maximum value of 1 (no problems).
Time frame: Measured at 12 months after randomization
Population: EQ-5D completed at 12 months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Catheter Ablation | Quality of Life EQ5D Index Score | 1 Index score |
| Antiarrhythmic Drug Therapy | Quality of Life EQ5D Index Score | 1 Index score |
Secondary
Quality of Life EQ-5D Visual Analog Score
The EQ VAS records the patient's self-rated health on a vertical visual analogue scale. The scale measures how good/bad one's own health is today, in one's own opinion. 0 means the worst imaginable state of health; 100 means the best imaginable state of health.
Time frame: Measured At 12 months after randomization
Population: Participants with EQ5D VAS completed at 12 months after randomization.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Catheter Ablation | Quality of Life EQ-5D Visual Analog Score | 85 score on a scale |
| Antiarrhythmic Drug Therapy | Quality of Life EQ-5D Visual Analog Score | 80 score on a scale |