Atrial Fibrillation
Conditions
Keywords
atrial fibrillation
Brief summary
The purpose of this trial is to evaluate the safety and efficacy of the Medtronic Cardiac Ablation System compared to medical therapy in the persistent and long-standing persistent atrial fibrillation population.
Interventions
PROCEDUREMedtronic Cardiac Ablation System
Arm 1 (Ablation Management): Ablation procedures using investigational catheters in left atrium. Cardioversion could be used to restore sinus rhythm if needed.
DRUGClass I or III Antiarrhythmic Medications
Arm 2 (Medical Management): Class I or III antiarrhythmic drugs. Changes in dosing, antiarrhythmic drugs or combinations of antiarrhythmic drugs were allowed. Direct current cardioversions were also allowed at the discretion of the investigator.
Sponsors
Medtronic Cardiac Rhythm and Heart Failure
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
Inclusion criteria
* History of symptomatic, continuous atrial fibrillation defined as: Continuous atrial fibrillation lasting greater than 1 year but less than 4 years or nonself-terminating atrial fibrillation, lasting greater than 7 days but no more than 1 year, with at least one failed direct current cardioversion. A failed cardioversion was defined as an unsuccessful cardioversion or one in which normal sinus rhythm was established but not maintained beyond 7 days. * Atrial fibrillation symptoms included the following: palpitations, fatigue,exertional dyspnea, exercise intolerance * Age between 18 and 70 years * Failure of at least one Class I or III rhythm control drug * Willingness, ability and commitment to participate in baseline and follow-up evaluations for the full length of the study.
Exclusion criteria
* Structural heart disease of clinical significance including: * Previous cardiac surgery (excluding coronary artery bypass graft and mitral valve repair) * Symptoms of congestive heart failure including, but not limited to, New York Heart Association (NYHA) Class III or IV congestive heart failure and/or documented ejection fraction \<40% measured by acceptable cardiac testing * Left atrial diameter \>55 mm * Moderate to severe mitral or aortic valvular heart disease * Stable/unstable angina or ongoing myocardial ischemia * Myocardial infarction (MI) within 3 months of enrollment * Congenital heart disease (not including atrial septal defect or patent foramen ovale without a right to left shunt) where the underlying abnormality increases the risk of an ablative procedure * Prior atrial septal defect of patent foramen ovale closure with a device using a percutaneous approach * Hypertrophic cardiomyopathy (left ventricular septal wall thickness \>1.5 cm) * Pulmonary hypertension (mean or systolic pulmonary artery pressure \>50 mm Hg on Doppler echo) * Any prior ablation for atrial fibrillation * Enrollment in any other ongoing arrhythmia study * Any ventricular tachyarrhythmia currently being treated where the arrhythmia or the management may interfere with this study * Active infection or sepsis * Any history of cerebral vascular disease including stroke or transient ischemic attacks * Pregnancy or lactation * Left atrial thrombus at the time of ablation * Untreatable allergy to contrast media * Any diagnosis of atrial fibrillation secondary to electrolyte imbalance, thyroid disease, or any other reversible or non-cardiovascular causes * History of blood clotting (bleeding or thrombotic) abnormalities * Known sensitivities to heparin or warfarin * Severe chronic obstructive pulmonary disease (defined as forced expiratory volume 1 (FEV1) \<1) * Severe co-morbidity or poor general physical/mental health that, in the opinion of the investigator, will not allow the subject to be a good study candidate
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Chronic Effectiveness | 6 months | The chronic efficacy endpoint was a treatment success/failure measure for each subject computed at 6 months. Treatment success included: 1. A 90% reduction in clinically significant atrial fibrillation from baseline to the 6 month time point based on a Holter recording. Clinically significant atrial fibrillation was defined as sustained atrial fibrillation lasting more than 10 minutes. 2. The subject was off all antiarrhythmic drugs at 6 months (Ablation Management arm only) 3. The Investigator judged all procedures to be acutely successful (Ablation Management arm only). |
| Acute Safety | 7 days | The primary endpoint for acute safety was a success/failure variable calculated for each subject in Ablation Management at the 7 day post-procedure time point. Any subject with at least one adverse event adjudicated by the Data Safety Monitoring Board as both serious and either probably or definitely procedure and/or device-related occurring within 7 days of the ablation procedure was considered an acute safety failure, regardless of whether the event occurred following the index or retreatment ablation procedure. |
| Chronic Safety | 6 months | The primary endpoint for chronic safety was a success/failure variable calculated for each subject at 6 months. Any subject that had at least one adverse event that met designated seriousness and relatedness criteria for the particular treatment group as adjudicated by the Data Safety Monitoring Board was considered a chronic safety failure. Adverse events in Ablation Management that were acute (≤7 days) were not included in the chronic safety primary endpoint. Given the disparity in the length of time at risk between treatment arms,the Chronic Safety endpoint was not statistically powered. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Improvement in Atrial Fibrillation (AF) Symptom Severity Scores Over 6 Months Compared to Baseline. | 6 months | The severity of subject's atrial fibrillation related symptoms on a scale from 1 (no symptoms) to 5 (most severe). The symptoms included palpitations, fatigue, shortness of breath, lightheadedness or dizziness, and lack of energy during exertion or exercise. The scores were tabulated at the 1, 3 and 6 month follow-up visits. Scores could range from 5 to 25, indicating a spectrum of subject status from asymptomatic to severely symptomatic. |
| Acute Efficacy | Procedure conclusion | A treatment success/failure up to the conclusion of the procedure for each subject in Ablation Management. A subject was considered successfully treated if the following were true: * Medtronic ablation catheters were used to achieve procedure success. * All accessible pulmonary veins were isolated. * At least 50% reduction of complex fractionated atrial electrograms mapped and ablated with Medtronic ablation catheters. * Sinus rhythm was achieved upon leaving the electrophysiology lab (±cardioversion). |
| Improved Quality of Life Over 6 Months Compared to Baseline. | 6 months | The SF-36 questionnaire was administered to subjects at baseline, 1, 3 and 6 month visits. The SF-36 is a multi-purpose, short-form health survey with only 36 questions. It yields an 8-scale profile of functional health and well-being scores as well as psychometrically-based Physical Component Score and Mental Component Score. The possible range for Physical Component Score and Mental Component Score is 0 to 100. The higher score, the better quality of life. |
| Improvement of Left Atrial Size at 6 Months Compared to Baseline. | 6 months | Left atrial diameter (LAD), as measured by transthoracic echocardiogram (TTE) looking at the longitudinal long axis at baseline and at the 6 month follow-up visit in both the Ablation and Medical Management arms. |
| Improvement of Left Ventricular Ejection Fraction at 6 Months Compared to Baseline. | 6 months | Left ventricular ejection fraction (LVEF), as measured by transthoracic echocardiogram at baseline and 6 months in both the Ablation and Medical Management arms. |
Countries
Netherlands, United States
Participant flow
Recruitment details
The first subject was enrolled on November 28, 2007. The very last ablation procedure was a retreatment ablation procedure for a Medical Management Crossover subject that occurred on May 7, 2010 with the final follow-up on November 1, 2010.
Pre-assignment details
32 subjects signed Informed Consent forms but withdrew from the study prior to randomization. * 24 failed to meet inclusion/exclusion criteria * 6 elected to withdraw * 1 subject was withdrawn by the Sponsor after being consented. * 1 subject was withdrawn as screening was incomplete prior to closing enrollment for the study
Participants by arm
| Arm | Count |
|---|---|
| Ablation Management Pre- and post- procedure anticoagulation was managed according to the preference of the investigator. Left atrial access was obtained by a single transseptal puncture. No ablations were to occur until the activated clotting time reached 300 seconds, which was to be maintained for the duration of the ablation. During the index ablation procedure, investigators were required to use all 3 investigational catheters. Cardioversion could be used to restore sinus rhythm if needed. If there was a recurrence of atrial fibrillation, a repeat ablation procedure could be performed any time during the follow-up period. With a retreatment, the follow-up clock was restarted. Subjects were seen pre-discharge and at in-clinic follow-up visits at 1, 3, and 6 months. | 138 |
| Medical Management Medical Management subjects were prescribed Class I or III antiarrhythmic drugs. Changes in dosing, antiarrhythmic drugs or combinations of antiarrhythmic drugs were allowed. Direct current (DC) cardioversions were also allowed at the discretion of the investigator. Anticoagulation was to be maintained at an International Normalized Ratio greater than 2. Subjects were seen at in-clinic follow-up visits at 1, 3, and 6 months. Subjects who demonstrated chronic treatment failure while under drug therapy could cross over, and receive an ablation as early as 4 months post randomization. | 72 |
| Total | 210 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Withdrawal by Subject | 13 | 5 |
Baseline characteristics
| Characteristic | Ablation Management | Medical Management | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 45 Participants | 29 Participants | 74 Participants |
| Age, Categorical Between 18 and 65 years | 93 Participants | 43 Participants | 136 Participants |
| Age, Continuous | 59.6 years STANDARD_DEVIATION 8.3 | 60.7 years STANDARD_DEVIATION 8.9 | 60.0 years STANDARD_DEVIATION 8.5 |
| Left Atrial Diameter | 4.5 centimeters STANDARD_DEVIATION 0.5 | 4.6 centimeters STANDARD_DEVIATION 0.5 | 4.6 centimeters STANDARD_DEVIATION 0.5 |
| Left Ventricular Ejection Fraction | 54.7 percent STANDARD_DEVIATION 7.1 | 54.9 percent STANDARD_DEVIATION 6.7 | 54.7 percent STANDARD_DEVIATION 7 |
| Number of DC cardioversions in past 4 years | 2.0 cardioversions STANDARD_DEVIATION 1.1 | 2.4 cardioversions STANDARD_DEVIATION 3.5 | 2.1 cardioversions STANDARD_DEVIATION 2.2 |
| Number of previously failed AADs per subject | 1.4 antiarrhythmic drugs STANDARD_DEVIATION 0.6 | 1.1 antiarrhythmic drugs STANDARD_DEVIATION 0.4 | 1.3 antiarrhythmic drugs STANDARD_DEVIATION 0.6 |
| Region of Enrollment Netherlands | 12 participants | 7 participants | 19 participants |
| Region of Enrollment United States | 126 participants | 65 participants | 191 participants |
| Sex: Female, Male Female | 23 Participants | 12 Participants | 35 Participants |
| Sex: Female, Male Male | 115 Participants | 60 Participants | 175 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 25 / 138 | 3 / 72 |
| serious Total, serious adverse events | 41 / 138 | 3 / 72 |
Outcome results
Primary
Acute Safety
The primary endpoint for acute safety was a success/failure variable calculated for each subject in Ablation Management at the 7 day post-procedure time point. Any subject with at least one adverse event adjudicated by the Data Safety Monitoring Board as both serious and either probably or definitely procedure and/or device-related occurring within 7 days of the ablation procedure was considered an acute safety failure, regardless of whether the event occurred following the index or retreatment ablation procedure.
Time frame: 7 days
Population: An Intention to Treat (ITT) analysis was performed in which all data was analyzed according to the subject's assigned randomization group.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ablation Management | Acute Safety | 12.3 percentage of participants |
Comparison: H0: Pa ≥ 0.16 Ha: Pa \< 0.16~where Pa is the proportion of acute safety failures in the ablation management arm.p-value: 0.1427Fisher Exact
Primary
Chronic Effectiveness
The chronic efficacy endpoint was a treatment success/failure measure for each subject computed at 6 months. Treatment success included: 1. A 90% reduction in clinically significant atrial fibrillation from baseline to the 6 month time point based on a Holter recording. Clinically significant atrial fibrillation was defined as sustained atrial fibrillation lasting more than 10 minutes. 2. The subject was off all antiarrhythmic drugs at 6 months (Ablation Management arm only) 3. The Investigator judged all procedures to be acutely successful (Ablation Management arm only).
Time frame: 6 months
Population: An Intention to Treat (ITT) analysis was performed in which all data was analyzed according to the subject's assigned randomization group. The primary missing value imputation technique for all primary endpoint analyses was the passive method of imputation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ablation Management | Chronic Effectiveness | 56 percentage of participants with success |
| Medical Management | Chronic Effectiveness | 26 percentage of participants with success |
Comparison: H0: Pa ≤ Pm Ha: Pa \> Pm~where Pa is the proportion of successfully treated subjects in the ablation management arm and Pm is the proportion of successfully treated subjects in the optimal medical management/drug therapy arm.p-value: <0.0001Chi-squared
Primary
Chronic Safety
The primary endpoint for chronic safety was a success/failure variable calculated for each subject at 6 months. Any subject that had at least one adverse event that met designated seriousness and relatedness criteria for the particular treatment group as adjudicated by the Data Safety Monitoring Board was considered a chronic safety failure. Adverse events in Ablation Management that were acute (≤7 days) were not included in the chronic safety primary endpoint. Given the disparity in the length of time at risk between treatment arms,the Chronic Safety endpoint was not statistically powered.
Time frame: 6 months
Population: An Intention to Treat (ITT) analysis was performed in which all data was analyzed according to the subject's assigned randomization group. The primary missing value imputation technique for all primary endpoint analyses was the passive method of imputation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ablation Management | Chronic Safety | 9 participants |
| Medical Management | Chronic Safety | 3 participants |
Comparison: H0: Pa ≥ Pm + 0.06 Ha: Pa \< Pm + 0.06~where Pa is the proportion of failed subjects in the ablation management arm and Pm is the proportion of failed subjects in the optimal medical management/drug therapy arm.p-value: 0.0033t-test, 1 sided
Secondary
Acute Efficacy
A treatment success/failure up to the conclusion of the procedure for each subject in Ablation Management. A subject was considered successfully treated if the following were true: * Medtronic ablation catheters were used to achieve procedure success. * All accessible pulmonary veins were isolated. * At least 50% reduction of complex fractionated atrial electrograms mapped and ablated with Medtronic ablation catheters. * Sinus rhythm was achieved upon leaving the electrophysiology lab (±cardioversion).
Time frame: Procedure conclusion
Population: An Intention to Treat (ITT) analysis was performed in which all data was analyzed according to the subject's assigned randomization group. The primary missing value imputation technique for all primary endpoint analyses was the passive method of imputation.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Ablation Management | Acute Efficacy | 92.8 percentage of participants |
Secondary
Improved Quality of Life Over 6 Months Compared to Baseline.
The SF-36 questionnaire was administered to subjects at baseline, 1, 3 and 6 month visits. The SF-36 is a multi-purpose, short-form health survey with only 36 questions. It yields an 8-scale profile of functional health and well-being scores as well as psychometrically-based Physical Component Score and Mental Component Score. The possible range for Physical Component Score and Mental Component Score is 0 to 100. The higher score, the better quality of life.
Time frame: 6 months
Population: An Intention to Treat (ITT) analysis was performed in which all data was analyzed according to the subject's assigned randomization group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ablation Management | Improved Quality of Life Over 6 Months Compared to Baseline. | Physical Component Score at Baseline | 42.54 Scores on a scale | Standard Deviation 10.45 |
| Ablation Management | Improved Quality of Life Over 6 Months Compared to Baseline. | Physical Component Score at 1 Month | 45.61 Scores on a scale | Standard Deviation 9.98 |
| Ablation Management | Improved Quality of Life Over 6 Months Compared to Baseline. | Physical Component Score at 3 Months | 48.30 Scores on a scale | Standard Deviation 9.76 |
| Ablation Management | Improved Quality of Life Over 6 Months Compared to Baseline. | Physical Component Score at 6 Months | 49.12 Scores on a scale | Standard Deviation 9.56 |
| Ablation Management | Improved Quality of Life Over 6 Months Compared to Baseline. | Mental Component Score at Baseline | 47.19 Scores on a scale | Standard Deviation 11.02 |
| Ablation Management | Improved Quality of Life Over 6 Months Compared to Baseline. | Mental Component Score at 1 Month | 51.53 Scores on a scale | Standard Deviation 10.34 |
| Ablation Management | Improved Quality of Life Over 6 Months Compared to Baseline. | Mental Component Score at 3 Months | 53.42 Scores on a scale | Standard Deviation 9.27 |
| Ablation Management | Improved Quality of Life Over 6 Months Compared to Baseline. | Mental Component Score at 6 Months | 53.45 Scores on a scale | Standard Deviation 9.07 |
| Medical Management | Improved Quality of Life Over 6 Months Compared to Baseline. | Mental Component Score at 6 Months | 50.06 Scores on a scale | Standard Deviation 11.26 |
| Medical Management | Improved Quality of Life Over 6 Months Compared to Baseline. | Physical Component Score at Baseline | 42.26 Scores on a scale | Standard Deviation 9.85 |
| Medical Management | Improved Quality of Life Over 6 Months Compared to Baseline. | Mental Component Score at Baseline | 47.99 Scores on a scale | Standard Deviation 12.13 |
| Medical Management | Improved Quality of Life Over 6 Months Compared to Baseline. | Physical Component Score at 1 Month | 43.05 Scores on a scale | Standard Deviation 10.46 |
| Medical Management | Improved Quality of Life Over 6 Months Compared to Baseline. | Mental Component Score at 3 Months | 48.97 Scores on a scale | Standard Deviation 10.52 |
| Medical Management | Improved Quality of Life Over 6 Months Compared to Baseline. | Physical Component Score at 3 Months | 43.99 Scores on a scale | Standard Deviation 9.97 |
| Medical Management | Improved Quality of Life Over 6 Months Compared to Baseline. | Mental Component Score at 1 Month | 48.96 Scores on a scale | Standard Deviation 11.54 |
| Medical Management | Improved Quality of Life Over 6 Months Compared to Baseline. | Physical Component Score at 6 Months | 44.98 Scores on a scale | Standard Deviation 9.59 |
p-value: <0.025Mixed Models Analysis
Secondary
Improvement in Atrial Fibrillation (AF) Symptom Severity Scores Over 6 Months Compared to Baseline.
The severity of subject's atrial fibrillation related symptoms on a scale from 1 (no symptoms) to 5 (most severe). The symptoms included palpitations, fatigue, shortness of breath, lightheadedness or dizziness, and lack of energy during exertion or exercise. The scores were tabulated at the 1, 3 and 6 month follow-up visits. Scores could range from 5 to 25, indicating a spectrum of subject status from asymptomatic to severely symptomatic.
Time frame: 6 months
Population: An Intention to Treat (ITT) analysis was performed in which all data was analyzed according to the subject's assigned randomization group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ablation Management | Improvement in Atrial Fibrillation (AF) Symptom Severity Scores Over 6 Months Compared to Baseline. | Measurement at Baseline | 12.38 AF Symptom Severity Score | Standard Deviation 4.21 |
| Ablation Management | Improvement in Atrial Fibrillation (AF) Symptom Severity Scores Over 6 Months Compared to Baseline. | Measurement at 1 Month | 8.95 AF Symptom Severity Score | Standard Deviation 3.58 |
| Ablation Management | Improvement in Atrial Fibrillation (AF) Symptom Severity Scores Over 6 Months Compared to Baseline. | Measurement at 3 Months | 7.56 AF Symptom Severity Score | Standard Deviation 2.97 |
| Ablation Management | Improvement in Atrial Fibrillation (AF) Symptom Severity Scores Over 6 Months Compared to Baseline. | Measurement at 6 Months | 7.58 AF Symptom Severity Score | Standard Deviation 3.53 |
| Medical Management | Improvement in Atrial Fibrillation (AF) Symptom Severity Scores Over 6 Months Compared to Baseline. | Measurement at 6 Months | 9.84 AF Symptom Severity Score | Standard Deviation 4.34 |
| Medical Management | Improvement in Atrial Fibrillation (AF) Symptom Severity Scores Over 6 Months Compared to Baseline. | Measurement at Baseline | 12.72 AF Symptom Severity Score | Standard Deviation 4.47 |
| Medical Management | Improvement in Atrial Fibrillation (AF) Symptom Severity Scores Over 6 Months Compared to Baseline. | Measurement at 3 Months | 10.03 AF Symptom Severity Score | Standard Deviation 3.89 |
| Medical Management | Improvement in Atrial Fibrillation (AF) Symptom Severity Scores Over 6 Months Compared to Baseline. | Measurement at 1 Month | 9.90 AF Symptom Severity Score | Standard Deviation 3.85 |
p-value: <0.0001Mixed Models Analysis
Secondary
Improvement of Left Atrial Size at 6 Months Compared to Baseline.
Left atrial diameter (LAD), as measured by transthoracic echocardiogram (TTE) looking at the longitudinal long axis at baseline and at the 6 month follow-up visit in both the Ablation and Medical Management arms.
Time frame: 6 months
Population: An Intention to Treat (ITT) analysis was performed in which all data was analyzed according to the subject's assigned randomization group. The primary missing value imputation technique for all primary endpoint analyses was the passive method of imputation.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ablation Management | Improvement of Left Atrial Size at 6 Months Compared to Baseline. | Measurement at Baseline | 4.5 centimeters | Standard Deviation 0.53 |
| Ablation Management | Improvement of Left Atrial Size at 6 Months Compared to Baseline. | Measurement at 6 Months | 4.4 centimeters | Standard Deviation 0.67 |
| Medical Management | Improvement of Left Atrial Size at 6 Months Compared to Baseline. | Measurement at Baseline | 4.6 centimeters | Standard Deviation 0.49 |
| Medical Management | Improvement of Left Atrial Size at 6 Months Compared to Baseline. | Measurement at 6 Months | 4.6 centimeters | Standard Deviation 0.56 |
Comparison: H0: μa = μm Ha: μa ≠ μm~where μa is the change of LAD from baseline to 6 month in Ablation Management arm, and μm is the change of LAD from baseline to 6 month in Medical Management arm.p-value: 0.35ANOVA
Secondary
Improvement of Left Ventricular Ejection Fraction at 6 Months Compared to Baseline.
Left ventricular ejection fraction (LVEF), as measured by transthoracic echocardiogram at baseline and 6 months in both the Ablation and Medical Management arms.
Time frame: 6 months
Population: An Intention to Treat (ITT) analysis was performed in which all data was analyzed according to the subject's assigned randomization group.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Ablation Management | Improvement of Left Ventricular Ejection Fraction at 6 Months Compared to Baseline. | Measurement at Baseline | 54.7 percent | Standard Deviation 7.09 |
| Ablation Management | Improvement of Left Ventricular Ejection Fraction at 6 Months Compared to Baseline. | Measurement at 6 Months | 58.3 percent | Standard Deviation 6.73 |
| Medical Management | Improvement of Left Ventricular Ejection Fraction at 6 Months Compared to Baseline. | Measurement at Baseline | 54.9 percent | Standard Deviation 6.73 |
| Medical Management | Improvement of Left Ventricular Ejection Fraction at 6 Months Compared to Baseline. | Measurement at 6 Months | 57.0 percent | Standard Deviation 6.06 |
Comparison: H0: μa = μm Ha: μa ≠ μm~where μa is the change of LVEF from baseline to 6 month in Ablation Management arm, and μm is the change of LVEF from baseline to 6 month in Medical Management arm.p-value: 0.06ANOVA