Paroxysmal Atrial Fibrillation
Conditions
Keywords
Atrial Fibrillation
Brief summary
This study (STOP AF) is a prospective, randomized, controlled, multicenter, pivotal clinical investigation conducted at 26 investigational sites in the United States and Canada. Subjects with paroxysmal atrial fibrillation (PAF) referred for ablative intervention after efficacy failure of one or more Study Atrial Fibrillation (AF) Drugs (flecainide, propafenone or sotalol) were randomized 2:1 to cryoablation intervention (Experimental Subjects, ES) or to a Study AF Drug (Control Subjects, CS). Subjects were followed for 12 months with scheduled and symptom-driven assessments to detect recurrent atrial fibrillation by means of periodic electrocardiograms, weekly scheduled trans-telephonic monitoring, patient-initiated trans-telephonic monitoring, and 24-hour Holter monitoring at 6 and 12 months. The first 90 days after study therapy was initiated was considered a blanked period for all subjects.
Detailed description
STOP AF (PS-023) is a randomized, controlled study of subjects 18 to 75 years old who had been referred for ablative intervention after failing one or two (but not all three) anti-arrhythmic drugs used in the treatment of AF (flecainide, propafenone and sotalol). Study subjects were randomized into two arms: the cryoablation (treatment) arm and the membrane-active antiarrhythmic drug (control) arm. A 90- day blanked follow-up period, including reablation and medication adjustments was applied in both arms to optimize therapies. All subjects underwent follow-up assessments at 1, 3, 6, 9 and 12 months, weekly transtelephonic monitoring, 24-hour Holter monitoring and CT/MRI of the pulmonary veins(at 6 and 12 months) during the trial period. Control subjects who were confirmed to be chronic treatment failures were permitted to crossover to cryoablation in this trial. Acute procedural success was defined for subjects that underwent cryoablation and demonstrated electrical isolation in ≥ 3 Pulmonary Veins (PVs) at the conclusion of the first protocol-defined cryoablation procedure using the Arctic Front® Cardiac CryoAblation Catheter System. The primary effectiveness endpoint was defined as having acute procedural success and freedom from chronic treatment failure (CTF) for experimental subjects, and freedom from CTF for control subjects. Freedom from (CTF) was defined for both groups as the occurrence of detectable AF during a non-blanked follow-up period, or an AF Intervention, or the use of a non-study AF drug at any time. The co-primary safety outcome measures were Cryoablation Procedure Events (CPEs) in cryoablated subjects and Major Atrial Fibrillation Events (MAFEs) in both groups. CPEs were device- or procedure-related serious adverse events. Other safety assessments were made during the course of the STOP AF trial specific to pulmonary vein stenosis (PVS) and phrenic nerve injury.
Interventions
DEVICEArctic Front® Cryoablation Catheter
Experimental Subjects received cryoablation intended to isolate the pulmonary veins and ablate arrhythmia foci with the cryoablation catheter system.
DRUGFlecainide or Sotalol or Propafenone
Flecainide 200 mg / day Propafenone 450 mg / day Propafenone-SR 650 mg / day Sotalol 240 mg / day
Sponsors
Medtronic
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 75 Years
Healthy volunteers
No
Inclusion criteria
* Documented Paroxysmal Atrial Fibrillation (PAF): PAF diagnosis, 2 episodes of PAF within the last 2 months, at least 1 episode of PAF must be documented * Age 18-75 * Documented Effectiveness Failure of one (1) AF drug * Willing to be randomized to either group and do full 12 month follow-up * Able to follow standardized AF drug protocol
Exclusion criteria
* Any cardioversion within 3 months or more than 2 within 2 years * Amiodarone within 6 months * LA size \> 5.0cm * Previous LA ablation/surgery, structural heart disease, heart failure class III or IV * Hypertrophic cardiomyopathy, Mitral prosthesis * Unstable angina, uncontrolled hyperthyroidism * Stroke or TIA within 6 months, MI within 2 months, cardiac surgery within 3 months * Thrombocytosis, thrombocytopenia * Any condition contraindicating chronic anticoagulation * EF \<40% * Pregnancy * Life expectancy \<1year
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Acute Procedural Success (APS) | 371.4 Minutes (Average) | Acute Procedural Success was defined as a demonstration of electrical isolation in ≥ 3 Pulmonary Veins (PVs) at the conclusion of the first protocol-defined cryoablation procedure. APS was decided at the end of the procedure the mean time was calculated for the time frame. |
| Freedom From Chronic Treatment Failure (CTF) | 12 month follow up period | Subjects that did not have or were free of CTF. CTF was defined as the occurence of an Atrial Fibrillation (AF) intervention, use of non-study AF drug therapy, or the occurence of detectable AF which is is defined as an episode of AF, documented in a tracing, and lasting more than 30 seconds, occurring during a Non Blanked Follow-up Period. |
| Treatment Success | 12 months | Treatment Success was defined as Acute Procedure Success (APS) and freedom from Chronic Treatment Failure (CTF) for Experimental Subjects, and freedom from CTF for Control Subjects. Under this pre-specified definition of Treatment Success, Experimental Subjects must have had APS and remained free of CTF during the 12-month follow-up duration, while Control Subjects must have remained free of CTF during the 12-month follow-up duration. |
| Freedom From Major Atrial Fibrillation Events (MAFEs) | 12 Months | Subjects that did not have or were free of MAFEs. MAFEs were serious adverse events categorized as cardiovascular death, myocardial infarction, stroke, or hospitalization for AF recurrence/ablation, flutter ablation, embolic events, heart failure, hemorrhage or anti-arrhythmic drug treatment. |
| Cryoablation Procedure Events (CPEs) | To end of ablation procedure | Subjects that had CPEs. CPEs were device- or procedure-related serious adverse events (SAE) categorized as access site complications, cardiac damage, pulmonary vein (PV) stenosis, embolic complications, arrhythmias, unresolved phrenic nerve palsy and death. |
Countries
Canada, United States
Participant flow
Recruitment details
Investigators at 26 sites in the United States and Canada, enrolled and randomized a total of 245 study subjects, during the 21 months trial period, between 10 October 2006 and 30 June 2008.
Participants by arm
| Arm | Count |
|---|---|
| Cryoablation an experimental group receiving cryoablation and, optionally, a previously failed Atrial Fibrillation Drug.3 Subjects withdrew consent 5 subjects were a screen failure. Therefore N=163 for Experimental group. | 163 |
| Standard Treatment With Drugs Only a control group receiving only an Atrial Fibrillation Drug. 4 Subject withdrew consent and 1 subject was a screen failure. Therefore- Control Treatment group N= 82. | 82 |
| Total | 245 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 1 | 0 |
| Overall Study | Screen Failures | 5 | 1 |
| Overall Study | Withdrawal by Subject | 3 | 7 |
Baseline characteristics
| Characteristic | Cryoablation | Standard Treatment With Drugs Only | Total |
|---|---|---|---|
| Age, Continuous | 56.7 years STANDARD_DEVIATION 0.73 | 56.4 years STANDARD_DEVIATION 1.04 | 56.6 years STANDARD_DEVIATION 0.6 |
| Region of Enrollment Canada | 40 participants | 19 participants | 59 participants |
| Region of Enrollment United States | 123 participants | 63 participants | 186 participants |
| Sex: Female, Male Female | 38 Participants | 18 Participants | 56 Participants |
| Sex: Female, Male Male | 125 Participants | 64 Participants | 189 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 19 / 163 | 16 / 65 |
| serious Total, serious adverse events | 20 / 163 | 12 / 82 |
Outcome results
Primary
Acute Procedural Success (APS)
Acute Procedural Success was defined as a demonstration of electrical isolation in ≥ 3 Pulmonary Veins (PVs) at the conclusion of the first protocol-defined cryoablation procedure. APS was decided at the end of the procedure the mean time was calculated for the time frame.
Time frame: 371.4 Minutes (Average)
Population: Subjects evaluated were from the modified Intent to Treat subset (mITT)or subjects that were enrolled, randomized and received treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cryoablation | Acute Procedural Success (APS) | 160 participants |
Primary
Cryoablation Procedure Events (CPEs)
Subjects that had CPEs. CPEs were device- or procedure-related serious adverse events (SAE) categorized as access site complications, cardiac damage, pulmonary vein (PV) stenosis, embolic complications, arrhythmias, unresolved phrenic nerve palsy and death.
Time frame: To end of ablation procedure
Population: Data for subjects who were randomized to the Experimental group and received cryoablation therapy were included in this analysis. All CPEs reported in the Experimental group were included in the analysis regardless of their association with the first or a repeat cryoablation.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cryoablation | Cryoablation Procedure Events (CPEs) | 5 participants |
Comparison: The test hypothesis is UCBExperimental\_CPE ≥ 14.8% vs UCBExperimental\_CPE \< 14.8%.The performance goal 14.8% was chosen based on a review of SSEDs for similar types of ablation trials.The expected rate for CPEs in a well-monitored trial of left atrial RF ablation for AF was estimated to be 10% (corresponding to a CPE-free rate of 90%).In a trial with 160 subject, the resulting one-sided 95% upper confidence bound would be 14.8%.p-value: <0.001Fisher Exact
Primary
Freedom From Chronic Treatment Failure (CTF)
Subjects that did not have or were free of CTF. CTF was defined as the occurence of an Atrial Fibrillation (AF) intervention, use of non-study AF drug therapy, or the occurence of detectable AF which is is defined as an episode of AF, documented in a tracing, and lasting more than 30 seconds, occurring during a Non Blanked Follow-up Period.
Time frame: 12 month follow up period
Population: This section includes data for subjects who were randomized, received treatment and were followed through 12-Months post randomized treatment regardless of AF Drug usage. Subjects who experienced Acute Procedural Failure in the Experimental group were not included in this analysis of post-procedural failure causes.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cryoablation | Freedom From Chronic Treatment Failure (CTF) | 117 participants |
| Standard Treatment With Drugs Only | Freedom From Chronic Treatment Failure (CTF) | 6 participants |
Primary
Freedom From Major Atrial Fibrillation Events (MAFEs)
Subjects that did not have or were free of MAFEs. MAFEs were serious adverse events categorized as cardiovascular death, myocardial infarction, stroke, or hospitalization for AF recurrence/ablation, flutter ablation, embolic events, heart failure, hemorrhage or anti-arrhythmic drug treatment.
Time frame: 12 Months
Population: mITT set included all subjects (82 CS, 163 ES) who were enrolled, randomized, and received treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cryoablation | Freedom From Major Atrial Fibrillation Events (MAFEs) | 158 participants |
| Standard Treatment With Drugs Only | Freedom From Major Atrial Fibrillation Events (MAFEs) | 75 participants |
Comparison: The null hypothesis is the proportion of subjects free from MAFE in the experimental group is inferior to that in the control group using 10% non-inferiority margin.A sample size of 160 evaluable cryoablation and 80 control subjects (one-sided α = 0.05, 2:1 randomization) was required to provide 80% power assuming the rate of free from MAFE at 12 months 80.5 and 77% in experimental and control groups respectively .p-value: <0.001t-test, 1 sided
Primary
Treatment Success
Treatment Success was defined as Acute Procedure Success (APS) and freedom from Chronic Treatment Failure (CTF) for Experimental Subjects, and freedom from CTF for Control Subjects. Under this pre-specified definition of Treatment Success, Experimental Subjects must have had APS and remained free of CTF during the 12-month follow-up duration, while Control Subjects must have remained free of CTF during the 12-month follow-up duration.
Time frame: 12 months
Population: The mITT population consisted of all subjects, who were enrolled, randomized and received treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cryoablation | Treatment Success | 114 participants |
| Standard Treatment With Drugs Only | Treatment Success | 6 participants |
Comparison: The null hypothesis is the success rate in experimental group is less than and equal to the one in control group. This comparison of the rates was performed using a 2-sided Fisher's Exact. A sample size of 240(160 experimental and 80 control) is required to provide 80% power to detect the treatment difference using a 2-sided (alpha = 0.05)Fisher's Exact Test of binomial proportions assuming the success rate was 40% for control and 60% for treatment.p-value: <0.0001Fisher Exact