First-line Cryoablation for Early Treatment of Persistent Atrial Fibrillation

Study Overview
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Brief Summary
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The goal of this multicentre, prospective, randomized, open, blinded for evaluation of end point (PROBE) controlled parallel-group superiority trial, is to compare the efficacy of antiarrhythmic drug (AAD) therapy and cryoballoon pulmonary vein isolation (PVI) regarding freedom from atrial fibrillation (%) assessed by an implantable cardiac monitor (ICM), ECG tracing or Holter at 12 months in patients with persistent AF. The main question[s] it aims to answer are: Will first-line cryoballoon ablation for PVI compared to AAD, result in 25 % higher freedom from atrial tachyarrhythmias lasting > 6 minutes at 12 months (primary outcome) excluding three months initial blanking period, in patients with symptomatic and recurrent persistent AF? Will first-line cryoablation for PVI, compared to AAD result in a superior improvement in health related Quality of Life (HRQoL), AF/AT burden, AF/AT progression and reversion, more reverse atrial remodeling, cognitive function, healthcare utilization with associated costs, better safety, at 12-24-36 months as compared with drug use? Participants will be randomized 1:1 to first-line PVI using the cryoballoon or to first-line antiarrhythmic drug therapy and during 3 years follow-up undergo regular; Continuous ECG monitoring for assessment of first AF recurrence and AF burden using an implantable cardiac monitor, Regular echocardiographic exams for reverse atrial remodelling assessment, HRQoL questionnaires Assessment of cognitive function Atrial fibrillation evaluation regarding structured characterisation and AF progression/regression Assessment of Health care use and costs Safety

Detailed Description
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The primary goal is to evaluate if early pulmonary vein isolation (PVI) performed with the Arctic Front cryoballoon as first-line therapy is superior to antiarrhythmic drugs (AAD) in preventing atrial arrhythmia recurrences in patients with persistent atrial fibrillation (AF). The main secondary goal is to evaluate the impact of early invasive intervention on health related quality of life (HRQOL) and symptoms, and on safety in comparison to primary AAD therapy, using generic and disease-specific HRQOL questionnaires and also assess Quality Adjusted Life Years (QALYs) score and EHRA classification of symptoms. The third goal is to assess the impact of an early intervention on cardiovascular health care use and its relation to AF/AT burden and to assess treatment burden and cost-effectiveness compared to AAD. Study Design: Multicentre, prospective 1:1 randomized open blinded for evaluation of end point (PROBE) controlled parallel-group superiority trial comparing first-line pulmonary vein isolation (PVI) using the cryoballoon (Arctic Front AdvanceR, Medtronic) and first-line antiarrhythmic drug (AAD) therapy. Patients will be randomized 1:1 to first-line PVI using the cryoballoon or to first-line AAD therapy. A 1:1 block randomization immediately after implantation of an implantable cardiac monitor (ICM ) before run-in. After fulfilling inclusion criteria and no exclusion criteria, an ICM (Reveal Linq™, Medtronic, Inc., Minneapolis, MN) will be injected subcutaneously for continuous rhythm monitoring during a 2 months run-in period prior initiation of allocated treatment, and then during 3 years of follow up. A 6 minutes detection cut-off for AF will be used. Patients and physicians will be blinded to the ICM result. Three month blanking period after treatment will not be included in the analysis. SAEs detected via ICM will be managed independently from the blinding of AF. If the ICM has to be explanted the patient should continue in the study with alternative monitoring tool as defined. The trial will be performed at 4-5 university centres in Sweden, at 1-2 centres in United Kingdom (UK) and at 4-5 centres in Europe, all with experience in Cryoballoon AF ablation. Each centre will register at least 20 -30 patients for a total of 220 patients. AAD therapy prescribed by the local investigators and collected by the subjects at a pharmacy as in normal clinical practice. They should be initiated with either dronedarone or flecainide as first options. Dronedarone:- 400 mg twice daily or Flecainide:- (50-)100 (-200) mg twice daily or slow release (100-)200 mg once daily. The 3-month blanking period will allow for drug titration and optimization. A change to the other of the two first option AADs guided by lack of efficacy defined by AF related symptoms or intolerable side effects. Thereafter, other AADs may be tested in order; propafenone and sotalol as long as the medication changes is within the 3 months blanking period: Propafenone:- 150 mg three times daily increasing to 300 mg twice daily, if necessary max 300 mg three times daily. Sotalol:- 80 mg twice daily up to 160 mg twice daily. Once the blanking period has ended, a change in medication will be defined as clinical endpoint, i.e. treatment failure. Surveillance of proarrhythmia risk by analysing ECG for prolonged corrected QT interval (QTc), widened QRS-complex, and prolonged PR interval at each follow-up. ECG monitoring on days 1-3 in patients prescribed flecainide, propafenone, or sotalol is recommended. Cardioversion should be performed as soon as possible with adequate protection against thromboembolism if at risk. Physicians advised to keep patients in the same treatment arm during follow-up. If symptoms worsen despite AAD therapy due to limited efficacy at adequate dosages, the patient may, if requested, undergo AF ablation with PVI following preferably a minimum of 12 months AAD therapy. Catheter ablation with PVI should follow clinical routine. PVI alone will be performed using a 28 mm cryoballoon with an Achieve circular mapping (ACM) catheter for recording of pulmonary vein potentials. Cryoballoon application for 4 minutes in each vein guided by disappearance of PV potentials or by reduction of temperature to at least minus 40 C degrees within the first 120 seconds if no PV potentials can be visualized. After ablation of all pulmonary veins, entrance block during sinus rhythm should be assessed with PV entrance block documented from each PV using a circular mapping catheter. Biomarkers s100b, troponin-T (TnT) and NT-pro-BNP (brain natriuretic peptide) will be obtained from peripheral venous blood in the lab on the day of the procedure (baseline) before placing the catheters in the heart and again after all ablation applications after the transseptal catheter has been withdrawn. All three markers are thereafter sampled a third time from peripheral blood after 6-18 hours, and NT-pro-BNP at 3, 12, 24, 36 months follow up. Follow-up Re-ablations may be performed at earliest 3 months after the prior AF ablation procedure if symptoms persists or recurs provided an AF/AT is ECG documented. PVI alone will be performed using a cryoballoon with a circular mapping catheter for assessing entrance conduction block. Patients may be offered a 3rd AF ablation. If patient declines a repeat intervention despite symptomatic recurrence of AF, the patient may be offered AAD, and will be defined as failed ablation unless a beta-blocking agent alone is prescribed. If all PVs are isolated at a repeat ablation procedure, other lesions may be performed except for posterior wall isolation unless pulsed field ablation is used, but treatment will be defined as failed PVI. The study duration is 3 years with 18 months' enrolment period. Patients will be followed at three, six, nine, 12, 18, 24, 30 and 36 months after the ablation procedure or start of AAD therapy. A nurse telephone visit will be scheduled at 6, 9, 18 and 30 months for recording of clinical events, medication and adverse events. All endpoints will be evaluated at last visit before cross-over. A clinical event is any event related to a cardiovascular disease or AF/AT; such as acquisition of a new comorbidity, new risk factor that results in increased bleeding risk, new cardiovascular intervention such as cardioversion, angiography, bypass surgery etc but which is not defined as an AE. All Serious Adverse Events (SAE) will be documented on the Adverse events Form AND Serious adverse events Form and reported to an independent Clinical Events Committee. All deaths events will be documented on Death report forms.All-cause death will be classified as either Non-cardiovascular (including unknown, excluding sudden death or Cardiovascular death (Cardiac (sudden (including arrhythmic, myocardial infarction) vs non-sudden) or Vascular) Statistical analysis Safety - All randomized patients will be included in the safety analysis. Only observed observations are used in the safety analysis. Modified Intention to treat (mITT) - All randomized patients who receive treatment. The main analysis will be performed on the mITT-population. Per protocol (PP) - All randomized patients completing the study treatment period of 12 months without any major protocol violation (for example ineligibility, early withdrawals, poor compliance). The PP population will be defined at clean file. Missing Data; The Primary variable will be imputed using a worst case imputation for the Logistic Regression if the magnitude of the missing data is small, say, approximately 5%. The Statistical Analysis Plan will include an outline for the multiple imputation strategy to be used for the situation with a larger amount of missing primary endpoints. The hypothesis generating analyses of Secondary Variables will use a simplistic Last Observation approach in case the amount of missing data is limited, say, less than 5%. The Statistical analysis Plan (SAP) will include an outline for the multiple imputation strategy to be used for the situation with a larger amount of missing secondary endpoints. Subgroups and explorative analyses; Explorative analyses may be performed to investigate relationships between treatments and endpoints, and for predictive factors for AF recurrences. Statistical methods; The Primary variable, freedom from atrial tachyarrhythmia at least 12 months with 90-day initial blanking period, will be analyzed using a Logistic Regression adjusted for the following additional covariates (baseline values): Coronary artery disease, Hypertension and left atrial volume index. Graphical methods such as Kaplan-Meier plots will be used to visualize the treatment effect in the full study population: Freedom of tachyarrhythmia up to 12 months with 90-day blanking period. The main analysis population will be a modified Intention to Treat population: all treated patients as randomized. The number of randomized subjects who are not treated are assumed to be at most a handful. The Per Protocol population will be defined at the Clean File Meeting and will be used for sensitivity analysis for the analysis of the primary variable using the same methods as for the main analysis. The set of secondary variables will not be adjusted for multiplicity. All findings among secondary variables in main population viewed as exploratory and hypothesis generating. The statistical Methods for each of the Secondary Endpoints will be described in detail in the Statistical Analysis Plan. All continuous variables will be presented per treatment group using descriptive statistics by mean, standard deviation (SD), max and min values, in addition medians, 25th and 75th percentiles will be presented when suitable. The mean difference between treatment groups will be presented with 95% Confidence Intervals (CIs). Sample Calculation: Study randomized 1:1: Proportion of freedom from atrial tachy-arrhythmia before 12 months with 90-day blanking period estimated to reach 55% in Ablation group based on previous cryoballoon AF ablation study of persistent AF patients monitored by ICM versus 30% in Drug arm, based on 25% difference in freedom from AF between treatment groups in a first line treatment study of paroxysmal AF patients. The 40% freedom from AF postablation in persist AF patients judged too pessimistic for a first line trial. Three prior AAD trials evaluating drug efficacy in persistent AF patients post cardioversion, using intermittent recordings, reported freedom from AF ranging between 30 and 42 %. Recognising that ICM would detect more AF episodes, the freedom from AF post cardioversion on AAD at 12 months is therefore estimated to be in the lower range, i.e. 30 %, in this trial. A 2 minutes AF detection cut-off has a lower positive predictive value versus a 6 min cut-off episode duration, which will decrease number of total episode count and false positive detection without neglecting relevant clinical information, keeping AF-burden unaffected. It therefore seems rational to use 6 minutes as AF episode cut-off, which is anticipated to at most increase the freedom from AF by 5% in both treatment groups but without affecting the relative treatment differences in the 2 groups. To have a 90% chance (i.e. power=90%) at the 5% significance level of detecting an improvement in the primary outcome from 30% in the control group to 55% in the ablation group, a total of 156 patients are needed. Adjusting for an assumed cross over rate of approximately 10% in the drug arm and 5% in the Ablation arm the total sample size will be 220. Treatment allocation sequence generated in Statistical Analysis Software (SAS) or R by the Biostatistics section at Uppsala Clinical Research Centre (UCR) by using permuted blocks and 1:1 allocation, stratification by center and type of persistent AF. Patients randomized using the Interactive Web Response System (IWRS) function in Viedoc.

Official Title
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First-line Cryoablation for Early Treatment of Persistent Atrial Fibrillation - a Randomized Study Comparing Early Trigger Isolation Using the Cryoballoon Versus Antiarrhythmic Medication

Conditions
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Atrial Fibrillation, Persistent

Intervention / Treatment
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* Device: Pulmonary vein isolation
* Drug: dronedarone - Multaq™ OR flecainide - Tambocor™ OR propafenone - Rytmonorm™ OR sotalol - Sotacor™


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Non-longstanding persistent symptomatic AF with at least 2 episodes within last 24 months, the latest episode within the previous 6 months and one documented on a 12 lead ECG or Holter monitor, that is classified as either Classical persistent AF (continuously sustained beyond 7 days and <12 months in duration) as defined by ESC guidelines14 OR Persistent AF which has progressed from paroxysmal AF (patients who have been cardioverted within 7 days of onset provided a history of spontaneous conversion to sinus rhythm is lacking during the past 24 months). Candidate for rhythm control therapy; AF ablation or AAD based on symptomatic AF. Exclusion Criteria: Regular daily use of AAD class I or III at adequate therapeutic dosages (pill-in-the-pocket permitted, beta-blockers permitted). Previous AF ablation or surgery. Severe heart failure (NYHA III-IV). Reduced left ventricular ejection fraction (LVEF ≤40 % during sinus rhythm). Hypertrophic cardiomyopathy (septal or posterior wall thickness >1.5 cm) Severely enlarged LA with left atrial volume indexed to body surface area (LAVI, ml/m2) > 48. Significant valvular disease requiring treatment or valve prothesis. Severe Chronic Obstructive Pulmonary Disease (COPD) stage III or chronic kidney disease (eGFR< 30 umol/l)). Planned cardiac intervention within the next 12 months or cardiac surgery last 6 months. Myocardial infarction, revascularisation previous 6 months. Stroke or Transient Ischemic Attack (TIA) within previous 6 months. Tachycardiomyopathy. Dependent on VVI (ventricular single chamber inhibited) pacing. Conventional contraindications for AF ablation including AF due to reversible causes and contraindications for both class IC and class III antiarrhythmic drugs. Expected survival less than 3 years, alcohol or drug abuse. Participation in another trial or absence of consent.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicentre, prospective 1:1 randomized open blinded for evaluation of end point (PROBE) controlled parallel-group superiority trial comparing first-line pulmonary vein isolation (PVI) using the cryoballoon (Arctic Front AdvanceR, Medtronic) and first-line antiarrhythmic drug (AAD) therapy.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cryoballoon pulmonary vein isolation<br>Cryoballoon (Arctic Front AdvanceR, Medtronic) for pulmonary vein isolation | Device: Pulmonary vein isolation<br>* Arctic Front™ Cryoballoon Advance, Medtronic, for pulmonary vein isolation<br>|
| Active Comparator: Antiarrhythmic drug<br>Tablet Dronedarone:- 400 mg twice daily or Tablet Flecainide:- (50-)100 (-200) mg twice daily or slow release (100-)200 mg once daily. If these drugs fail or give side effects: Tablet Propafenone:- 150 mg 3 times daily increasing to 300 mg twice daily, if necessary max 300 mg three times daily. Dose reduction for patients <70 kg bodyweight. Tablet Sotalol:- 80 mg twice daily up to 160 mg twice daily. Dose reduction to half dosage if a creatinine clearance is 30-60 ml/min. | Drug: dronedarone - Multaq™ OR flecainide - Tambocor™ OR propafenone - Rytmonorm™ OR sotalol - Sotacor™<br>* Antiarrhythmic drugs<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients free from first atrial tachyarrhythmia recurrence lasting 6 minutes or longer | In the absence of antiarrhythmic drugs in ablation group as documented by an implantable cardiac monitor from initiation of treatment. | 12 months after initiation of allocated treatment excluding the first 3 months blanking period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total atrial arrhythmia burden (percentage of time in AF/AT) | Measured from the continuous implantable cardiac monitor with a 6 minutes AF episode detection cut-off limit. | baseline,12, 24, 36 months after initiation of treatment excluding the 3 months blanking period | 
| AF progression and reversion | Progression to longstanding persistent or permanent AF/AT and regression going in opposite direction from persistent to paroxysmal AF or to sinus rhythm. Measured as combination of reduced number of progressions or increased number of AF/AT regression . | baseline,12, 24, 36 months follow-up excluding 3 months blanking period | 
| Generic Health Related Quality of life (HRQoL) | Generic Medical Outcomes Study Short Form-36 (SF-36) quality of life questionnaire using 8 subscales: physical functioning, role physical, bodily pain, general health, vitality, social functioning, role emotional, and mental health. Scores from 0 to 100; lower scores poorer QoL. | baseline, 12, 24, 36 months follow-up | 
| Symptoms | European Heart Rhythm Association (EHRA) Symptom Classification assessing the severity of AF related symptoms | baseline, 12, 24, 36 months after initiation of treatment | 
| AF specific Health Related Quality of Life | Assessed by University of Toronto Atrial Fibrillation Severity Scale (AFSS); 19-item AF-specific scale; ratings AF including 4 categories; AF burden (calculated from modified sum of frequency, duration and severity of episodes); Total AF Burden=AF frequency + AF duration + AF severity. Each of 3 measures contributes equally to Total AF Burden score, and varies from 1-10 to yield Total AF Burden scores ranging from 3-30 where higher scores indicate greater AF burden. Global Well Being (visual analogue scale 1-10; worst - best possible life); AF Symptom Score (sum of 7 items on specified symptoms); For each of 7 questions (answers vary from 0=I have not had this symptom in past 4 weeks to 5=A great deal), values determined and summed together to form a total score (0-35). This score assumes linearity of severity. Health Care Utilization (number of cardioversions, ablations, emergency room visits, hospitalizations due to arrhythmia, and specialist appointments). | baseline, 12, 24, 36 months after initiation of treatment excluding the 3 months blanking period | 
| Cognitive function | Trail Making Test (TMT) parts A and B. Patient is asked to draw lines from figures in consecutive orders n 1-2-3 etc (TMT A) and from figures to letters 1-A-2-B etc.(TMT B) Examiner starts timing both part A and B and counts errors made. The Time in seconds and Number of errors are counted for both A and B test. The rhythm and pulse at the time of the evaluation will be recorded but is not used as a measure other than a binary value for correlation with cognitive function. | baseline,12, 24, 36 months after initiation of treatment | 
| Rate of Healthcare utilizations for cardiovascular reasons | Number of cardioversions, ablations, drug initiations, cardiovascular hospitalizations, emergency department visits and unplanned outpatient visits and its relation to AF/AT burden. Cardiovascular means related to AF including any treatment or diagnostic procedure for AF/AT, i.e. cardioversions, medication, further AF ablations after AF/AT recurrence, or any adverse events related to AF/AT or its treatment (acute stroke), heart failure, myocardial ischemic events; adverse events (eg. pacemaker implantation). | baseline,12, 24, 36 months after initiation of treatment excluding the 3 months blanking period | 
| Cost-effectiveness analysis by EuroQol-5 Dimensions (EQ-5D) | Quality-adjusted life years (QALYs) using EQ-5D; QALYs will then be incorporated with medical costs; cost/QALY to compare the treatments. i) EQ-5D descriptive system with five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression, each with 5 levels. Digits combined into a 5-digit number for patient's health state. ii) Visual analogue vertical line scale (EQ-VAS) with endpoints labelled 'The best and worst health you can imagine' as a quantitative measure of health outcome reflecting patient's own judgement. Cost-effectiveness analysis of the treatments examining costs and health outcomes of the two interventions. It compares the interventions by estimating how much it costs to gain a unit of a health outcome. | 36 months | 
| Proportion of patients with Reverse atrial remodeling | Proportion of patients with Reverse atrial remodeling as defined by at least 15% decrease of Left atrial maximal volume index (ml/m2) or increase of left atrial strain during reservoir phase (percentage) or left atrial strain during contraction phase (percentage) versus baseline. | baseline, 12, 24 and 36 months | 
| Proportion of patients free from ECG documented atrial tachyarrhythmia recurrence lasting 6 minutes or longer after the 1st and last ablation procedure respectively | Defined as single and multiple procedure success | 36 months | 
| Adverse events | Type and frequency of adverse events and serious adverse events related or not to treatment. | 12, 24, 36 months | 
| Numbers of withdrawals / 'cross-overs' | Frequency of withdrawals / 'cross-overs' in each treatment group | 12, 24, 36 months | 
| Covariate adjusted primary endpoint freedom from first atrial tachyarrhythmia recurrence lasting 6 minutes or longer | Analysis using following covariates at baseline: coronary artery disease, hypertension, left atrial volume index. | 12 and 36 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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atrial fibrillation, ablation, first-line, antiarrhythmics, burden, symptoms