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Trial registered on ANZCTR


Registration number
ACTRN12614001231639
Ethics application status
Approved
Date submitted
21/10/2014
Date registered
25/11/2014
Date last updated
25/11/2014
Type of registration
Retrospectively registered

Titles & IDs
Public title
Paroxysmal Atrial Fibrillation Ablation: complex fractionated atrial electrograms ablation in addition to pulmonary vein isolation versus pulmonary vein isolation
Scientific title
Patients with paroxysmal Atrial Fibrillation Ablation: complex fractionated atrial electrograms ablation in addition to pulmonary vein isolation versus pulmonary vein isolation alone on maintenance of sinus rhythm. (PAFA-SP)
Secondary ID [1] 285531 0
none
Universal Trial Number (UTN)
Trial acronym
PAFA-SP
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Paroxysmal atrial fibrillation 293348 0
Condition category
Condition code
Cardiovascular 293618 293618 0 0
Other cardiovascular diseases
Surgery 293671 293671 0 0
Surgical techniques

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Pulmonary vein isolation (PVI) during paroxysmal Atrial Fibrillation (75 patients): During the procedure, 4 catheters were introduced via the right femoral vein under lidocaine local anesthesia. A decapolar catheter (InquiryTM St. Jude Medical Inc., St.Paul, MN, USA) was positioned inside the coronary sinus (CS) and a tetrapolar catheter (SupremeTM CRD-2, St. Jude Medical Inc., St.Paul, MN, USA) on the His bundle. Left atrium access was obtained by a single interatrial septal puncture with a BRK needle (St. Jude Medical Inc., St.Paul, MN, USA). Subsequently a circumferential decapolar catheter for pulmonary vein mapping (AFocusIITM 10 pole with a 20 mm diameter; St. Jude Medical Inc., St.Paul, MN, USA) , and the ablation catheter as were positioned into the left atrium.
The ablation was performed with open irrigated ablation catheter Therapy Cool Path DuoTM (St. Jude Medical Inc., St.Paul, MN, USA). 3-D electroanatomic mapping was performed using EnSite NavXTM-software version 8.0 (St. Jude Medical Inc., St.Paul, MN, USA). The time of the procedure never exceeded four hours.
The first objective was to systematically isolate all segmental ostial pulmonary veins. Pulmonary vein isolation was confirmed by entrance block.
Repeated electrophysiological procedures were carried out for recurrent atrial arrhythmias (after the blanking period or 3 months). The first objective was to assess pulmonary vein reconduction, followed by electrical re-isolation.
Intervention code [1] 290473 0
Treatment: Surgery
Comparator / control treatment
Complex fractionated atrial electrograms ablation in addition to pulmonary vein isolation (75 patients): During the procedure, 4 catheters were introduced via the right femoral vein under lidocaine local anesthesia. A decapolar catheter (InquiryTM St. Jude Medical Inc., St.Paul, MN, USA) was positioned inside the coronary sinus (CS) and a tetrapolar catheter (SupremeTM CRD-2, St. Jude Medical Inc., St.Paul, MN, USA) on the His bundle. Left atrium access was obtained by a single interatrial septal puncture with a BRK needle (St. Jude Medical Inc., St.Paul, MN, USA). Subsequently a circumferential decapolar catheter for pulmonary vein mapping (AFocusIITM 10 pole with a 20 mm diameter; St. Jude Medical Inc., St.Paul, MN, USA) , and the ablation catheter as were positioned into the left atrium.
The ablation was performed with open irrigated ablation catheter Therapy Cool Path DuoTM (St. Jude Medical Inc., St.Paul, MN, USA). 3-D electroanatomic mapping was performed using EnSite NavXTM-software version 8.0 (St. Jude Medical Inc., St.Paul, MN, USA).
The first objective was to systematically isolate all segmental ostial pulmonary veins. Pulmonary vein isolation was confirmed by entrance block. If atrial fibrillation (AF) persisted after pulmonary vein isolation, the procedure was continued using electrogram-guided ablation for complex fractionated atrial electrograms. Complex fractionated atrial electrograms were defined as atrial electrograms with a cycle length (CL) =120 milliseconds or atrial electrograms with fractionation composed of =2 defections and/or with continuous baseline activity. After the creation of left atrial lesions, radiofrequency application was continued inside the coronary sinus and in the right atrium if the right appendage cycle length was shorter than the left, especially at the cavotricuspid isthmus, superior vena cava, crista terminalis and right atrial septum. The tachycardia cycle length was monitored in both the right and the left atrial appendage to assist in determining the optimal site of ablation. If AF converted into atrial tachycardia (AT), activation mapping and catheter ablation of these tachycardias were performed until restoration of SR. ATs were ablated if a patient had =1 stable AT. Atrial tachycardia was defined as organized atrial rhythm with a stable CL, a consistent endocardial activation sequence in both atria and a monomorphic P wave. The endpoint for complex fractionated electrogram (CFE) ablation was (i) the elimination of all CFE sites in the left atrium (LA), CS, and right atrium (RA), and termination of AF with (ii) non-inducibility of AF post-ablation. If AF did not terminate after eliminating all the CFE sites, sinus rhythm was restored by electrical cardioversion. After the restoration of sinus rhythm, the induction of atrial fibrillation was again attempted; if the arrhythmia was not inducible, the procedure was stopped and if AF was still inducible, the ablation continued until the its noninducibility. Atrial fibrillation was considered inducible if it lasted more than 1 min.The time of the procedure never exceeded four hours.
Repeated electrophysiological procedures were carried out for recurrent atrial arrhythmias (after the blanking period or 3 months). The first objective was to assess pulmonary vein reconduction, followed by electrical re-isolation. The aim of electrogram-guided ablation was the restoration of sinus rhythm , or all complex fractionated atrial electrograms (CFAEs) abolished or reduced in amplitude (>80%).
Control group
Active

Outcomes
Primary outcome [1] 293423 0
Outcome of atrial fibrillation ablation after pulmonary vein isolation or a stepwise approach.

"Procedure success" is defined as freedom from atrial arrhythmia (atrial fibrillation, atrial flutter, atrial tachycardia) off antiarrhythmic drug during follow-up after first and second ablation.
"Procedure failure" is defined as atrial arrhythmia recurrence during follow-up .

The primary outcome of the study was freedom from AF recurrency 3 and 12 months after ablation (excluding the pre-specified blanking period from months 0 to 3). Evaluation included assessment of arrhythmia-related symptoms, adverse events, treatment adherence and any additional therapy since the previous follow-up visit and a 12-lead electrocardiogram. A 48-hour Holter monitoring was also performed every month, and in addition to clinical examinations (the questionnaire was designed for this study), a structured questionnaire was administered to record arrhythmia recurrence and any other symptom.
Timepoint [1] 293423 0
Time Frame: After first and second catheter ablation, all patients were followed up in our outpatient clinic at 1week, 2 weeks, 1 month, 2,3,6 and 12 months
Secondary outcome [1] 311004 0
In patients who experience "procedure failure" (defined above), a re-do ablation may be performed. Then the patients will be followed-up again for atrial arrhythmia (atrial fibrillation, atrial flutter, atrial tachycardia) recurrence.Evaluation included assessment of arrhythmia-related symptoms, adverse events, treatment adherence and any additional therapy since the previous follow-up visit and a 12-lead electrocardiogram. A 48-hour Holter monitoring was also performed every month, and in addition to clinical examinations (the questionnaire was designed for this study), a structured questionnaire was administered to record arrhythmia recurrence and any other symptom.
Timepoint [1] 311004 0
After first and second catheter ablation, all patients were followed up in our outpatient clinic at 1week, 2 weeks, 1 month, 2,3,6 and 12 months

Eligibility
Key inclusion criteria
The inclusion criteria is paroxysmal atrial fibrillation was defined accordingly to the Task Force for the Management of Atrial Fibrillation of ESC/ECATS 2007
Minimum age
18 Years
Maximum age
80 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Persistent atrial fibrillation, permanent atrial fibrillation.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Randomization was carried out by the statistical unit using a computer-generated random-table.The code was revealed to the researchers once recruitment, data collection and all analyses were completed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
The differences in AF/AT recurrence rate according to type of ablation and other recorded variables were initially examined using chi-squared test for categorical variables and t-test for continuous variables. Cox proportional hazards analysis was then used to compute the adjusted relative hazards of AT and/or AF recurrence by each variable, after both the first and the second ablation procedures. The dependent variable was recurrence of either AF or AT in both models. We recorded the following variables, all of which were a priori considered for inclusion in multivariate analysis: age, gender, BMI, current cigarette smoking, hypertension, diabetes, dyslipidemia, ischemic heart disease, left ventricular hypertrophy, valvular heart disease, idiopathic dilated cardiomiopathy, AF duration, number of AF episodes per month, left atrial size and volume, left ventricle ejection fraction, antiarrhythmics, amiodarone, beta-blockers and calcium channel blockers use, procedural, radiofrequency and fluoroscopy time, Complex Fractionated Atrial Electrograms (CFAEs) and ablation complications. Covariates were selected for inclusion in final models using a stepwise forward process with the following inclusion criteria: p-value less than 0.15 at univariate analysis and equal to20% change in the hazard ratio of significant predictors. Age and procedure complications were forced to entry. A minimum events-to-variable ratio of 10 was maintained in multivariate modeling to avoid overfitting, and Schoenfeld’s test was carried out to check the validity of proportional hazards assumption. There were no missing values. A p-value of less than 0.05 was considered significant for all analyses.
The sample size estimation was based on the following conservative assumptions: Alpha equal to 0.05; mean SD maintance of sinus rhythmin both the pulmonary vein isolation and the stepwise ablation groups. Using the above parameters, minimum 100 patients were needed to achieve 90% power with 10% expected withdrawals/dropouts.
Statistical significance was defined as a two-sided p-value less than 0.05; all analyses were carried out using STATA statistical software, version 13.1 (Stata Corporation, College Station, Texas, USA, 2013).

Recruitment
Recruitment status
Active, not recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment outside Australia
Country [1] 6428 0
Italy
State/province [1] 6428 0

Funding & Sponsors
Funding source category [1] 290133 0
Self funded/Unfunded
Name [1] 290133 0
Address [1] 290133 0
Country [1] 290133 0
Primary sponsor type
Individual
Name
Massimiliano Faustino
Address
Electrophysiology Operating Unit, Cardiovascular Department, “Spirito Santo” Via Fonte Romana no. 8 Hospital, ASL Pescara, 65124 Pescara, Italy
Country
Italy
Secondary sponsor category [1] 288844 0
None
Name [1] 288844 0
Address [1] 288844 0
Country [1] 288844 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 291839 0
Azienda USL Pescara
Ethics committee address [1] 291839 0
Via Fonte Romana no.8 Hospital, ASL Pescara, 65124 Pescara, Italy
Ethics committee country [1] 291839 0
Italy
Date submitted for ethics approval [1] 291839 0
Approval date [1] 291839 0
17/10/2006
Ethics approval number [1] 291839 0

Summary
Brief summary
Paroxysmal atrial fibrillation (PAF), arrhythmogenic activity usually originates in the muscle sleeves of the pulmonary veins (PVs) and may trigger and perpetuate the arrythmias. Randomized trials have shown that catheter ablation is superior to antiarrhythmic drug therapy in maintaining sinus rhythm (SR). Circumferential isolation of the PVs has become the cornerstone strategy for PAF catheter ablation with a success rate ranging from 38 - 70% after a single procedure to 65 - 90% after repeated procedures.
Once initiated from a trigger, PAF will not be maintained if the appropriate substrates are not present. The atria of patients with PAF can present very different patterns during electroanatomic mapping due to atrial myocardial fibrosis which is significantly increased in patients with PAF as compared with those in sinus rhythm. There are multiple potential etiological causes for this relationship. Aging and co-existing cardiovascular diseases (e.g. hypertension) are thought to play an important role in the development of myocardial fibrosis and, consequently, in maintaining PAF. In patients with PAF and structural atrial disease, PVs ablation may fail and cause progressive atrial remodeling which explain the recurrences and the development of ‘new’ arrhythmias. Thus alternative approaches aimed at modifying atrial substrates in order to prevent maintaining PAF has been proposed. There is no consensus about the best catheter ablation strategy. The purpose of this prospective study was to determine whether ablation of both CFAEs and PVs is associated with a higher probability of maintaining sinus rhythm as compared to PV isolation alone in patients with PAF refractory to anti-arrhythmic therapy. One hundred fifty patients with paroxysmal AF refractory to at least one anti-arrhythmic drug, were consecutively enrolled for a first-time catheter ablation at Electrophysiology laboratory of Clinica Pierangeli Pescara and Electrophysiology Unit, Cardiovascular Department, “Spirito Santo” Hospital, Pescara between January 2007 and July 2012.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 52242 0
Dr Massimiliano Faustino
Address 52242 0
“Spirito Santo” Hospital Via Fonte Romana no. 8 Hospital, ASL Pescara, 65124 Pescara, Italy
Country 52242 0
Italy
Phone 52242 0
+393473578209
Fax 52242 0
Email 52242 0
massimilian.faustin@libero.it
Contact person for public queries
Name 52243 0
Dr Massimiliano Faustino
Address 52243 0
“Spirito Santo” Hospital Via Fonte Romana no. 8 Hospital, ASL Pescara, 65124 Pescara, Italy
Country 52243 0
Italy
Phone 52243 0
+393473578209
Fax 52243 0
Email 52243 0
massimilian.faustin@libero.it
Contact person for scientific queries
Name 52244 0
Dr Massimiliano Faustino
Address 52244 0
“Spirito Santo” Hospital Via Fonte Romana no. 8 Hospital, ASL Pescara, 65124 Pescara, Italy
Country 52244 0
Italy
Phone 52244 0
+393473578209
Fax 52244 0
Email 52244 0
massimilian.faustin@libero.it

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary