First-line catheter ablation for early treatment of Persistent (ongoing unless cardioverted) Atrial Fibrillation (AF) – a randomized study comparing isolation of pulmonary veins triggering AF using a Cryoballoon versus antiarrhythmic medication.

INTERVENTION: Product Code: SCP209245,Pharmaceutical Form: ,Other descriptive name: ,Product Code: SCP175137,Pharmaceutical Form: ,Other descriptive name: ,Product Code: SCP208166,Pharmaceutical Form: ,Other descriptive name: ,Product Code: SCP15543769,Pharmaceutical Form: ,Other descriptive name: CONDITION: MedDRA version: 22.0Level: LLTClassification code: 10081865Term: Cardiac catheter ablationSystem Organ Class: 10042613 Persistent symptomatic atrial fibrillation ; MedDRA version: 22.0Level: LLTClassification code: 10081865Term: Cardiac catheter ablationSystem Organ Class: 10042613 Therapeutic area: Diseases [C] ‐ Cardiovascular Diseases [C14] PRIMARY OUTCOME: Main Objective:The main focus is to evaluate the impact of early interventional management of persistent AF.; ; The primary goal is to evaluate if early pulmonary vein isolation performed with the Arctic Front cryoballoon as first‐line therapy is superior to antiarrhythmic drugs (AAD) in preventing atrial arrhythmia recurrences. ; ; We hypothesized that first‐line PVI using the cryoballon, at an early stage of the AF disease, will result in a 25 % reduction in any atrial tachyarrhythmia recurrence at 12 months compared to the AAD group. Primary end point(s):The primary endpoint is freedom from atrial tachyarrhythmia recurrence lasting = 6 minutes (in the absence of AAD in ablation group) as documented by 12‐lead ECG, ECG rhythm strip, Holter, or an ICM, from initiation of treatment excluding the first 3 months (blanking period) to 12 months post after initiation of allocated treatment. Secondary Objective:The 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 (hospitalisations and other health care utilization) and its relation to AF burden and to assess treatment burden and cost‐effectiveness compared to AAD. INCLUSION CRITERIA: Non‐longstanding persistent symptomatic AF with at least 2 episodes within last 24 months (both shorter than 12 months in duration), the latest episode within the previous 6 months and, one should be documented on a 12 lead ECG or Holter monitor. a) Classical persistent AF as defined by ESC guidelines, b) Persistent AF which has progressed from paroxysmal AF (patients who have been cardioverted within 7 days of onset provided a history of spontaneous conversion of episodes to sinus rhythm is lacking in near time),Age 18 – 75 years,Candidate for rhythm control therapy; AF ablation or AAD based on symptomatic AF. As an example, BMI >35 would not according to clinical praxis be a candidate for AF ablation and thereby not suitable for participation in the study. SECONDARY OUTCOME: Secondary end point(s):Compare the effect of the two first‐line treatment strategies with respect to AF progression and reversion as measured by combination of reduced number of AF progressions or increased number of AF reversions after 3 months blanking. Progression or transition to more severe AF forms such as longstanding persistent or permanent AF and AF regression as going in the opposite direction from persistent to paroxysmal to sinus rhythm at 12, 24 and 36 months. Secondary end point(s):Compare the effect of the two first‐line treatment strategies with respect to blood pressure, systolic and diastolic (mmHg) after 10 minutes rest at baseline compared to each of months 12, 24, and 36 months. The rhythm and pulse at the time of the evaluation will be recorded. Secondary end point(s):Compare the effect of the two first‐line treatment strategies with respect to cognitive function as measured by Trail Making Test A and B from baseline to each of months 12, 24, and 36 months. The rhythm and pulse at the time of the evaluation will be recorded. Secondary end point(s):Compare the effect of the two first‐line treatment strategies with respect to covariate adjusted primary endpoint (analysis using following covariates at baseline: coronary artery disease, hypertension, LAVI). Secondary end point(s):Compare the effect of the two first‐line treatment strategies with respect to EHRA Symptom Classification, assessed as change from baseline to each of months 12, 24, and 36 months. Secondary end point(s):Compare the effect of the two first‐line treatment strategies with respect to frequency and type of adverse events, recorded continuously and classified whether related to treatment, and whether serious. Secondary end point(s):Compare the effect of the two first‐line treatment strategies with respect to frequency of withdrawals / 'cross‐overs' over time. Secondary end point(s):Compare the effect of the two first‐line treatment strategies with respect to health care costs at 36 months. Secondary end point(s):Compare the effect of the two first‐line treatment strategies with respect to healthcare utilization for cardiovascular reasons (number of cardioversions, ablations, AAD initiations, cardiovascular hospitalizations, emergency department visits and unplanned outpatient visits after 3 months blanking) and its relation to AF burden. Secondary end point(s):Compare the effect of the two first‐line treatment strategies with respect to Quality of Life measured by SF‐36, EQ‐5D and AFSS as change from baseline to each of months 12, 24, and 36 months. The rhythm and pulse at the time of the evaluation will be recorded. Secondary end point(s):Compare the effect of the two first‐line treatment strategies with respect to reverse atrial remodeling assessed by P wave variables from ECG (P‐wave duration), biomarkers (NT pro‐BNP, IL6, D‐dimer), and left atrial size and function (LAVI, ejection fraction, atrial strain) by echocardiography, corrected for BSA, at 12, 24 and 36 months. Secondary end point(s):Compare the effect of the two first‐line treatment strategies with respect to single and multiple procedure success (freedom from ECG documented atrial tachyarrhythmia after the 1st and last ablation procedure respectively) at 12, 24, and 36 months. Secondary end point(s):Compare the effect of the two first‐line treatment strategies with respect to total atrial arrhythmia burden (% time in AF/AT) at 12, 24, and 36 months.