Clinical trial NCT02509754: Atrial Fibrillation Ablation Compared to Rate Control Strategy in Patients With Impaired Left Ventricular Function
Official title: Atrial Fibrillation Ablation Compared to Rate Control Strategy in Patients With Recently Diagnosed Impaired Left Ventricular Function: a Multicenter, Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Persistent Atrial Fibrillation
Congestive Heart Failure Due to Left Ventricular Systolic Dysfunction
Keywords: atrial fibrillation
congestive heart failure
catheter ablation
rate control
left ventricular function
Lead sponsor: University of Turin, Italy
Sponsor class: OTHER
Collaborators: name: Centro Cardiologico Monzino
name: Humanitas Research Hospital IRCCS, Rozzano-Milan
name: University of Padova
name: Policlinico Casilino ASL RMB
First posted: 2015-07-28
Enrollment: 180
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: Atrial fibrillation (AF) and congestive heart failure (CHF) are two epidemics that share several physiopathological links. CHF patients present a significantly increased risk of developing AF and the related detrimental hemodynamic effects are even more relevant than in patients without CHF.

Within CHF patients rate control is the most widely used strategy to manage AF, having proved non-inferior to rhythm control strategies. However, by this strategy, the hemodynamic effects of AF persist, not contrasting the natural evolution towards progressive left ventricular (LV) function, cardiac output , and symptoms worsening. Rhythm control strategy, instead, has shown, in the general population, advantages over rate control concerning survival, quality of life and thromboembolic events. The main limitation is that antiarrhythmic therapy used to achieve this goal has several side effects, and that transcatheter AF ablation has been assessed only in modest sample size studies.

Available literature focusing on a direct comparison between two specific management strategies in patients with CHF and AF is limited to a small randomized study comparing pulmonary veins isolation to AV node ablation and biventricular PM implantation (PABA-CHF study). Additional indirect evidences may derive from meta-analyses of observational studies.

The investigators therefore designed this multicenter, randomized controlled trial aiming to assess if, in recently diagnosed (less than 6 months) and optimally treated CHF patients with impaired LV function, AF catheter ablation is effective in improving LV function and clinical functional class, potentially driving to a reduction of device implantations (ICD/CRTs).

Detailed description: Atrial fibrillation (AF) is the most common arrhythmia among the general population. Its prevalence increases with advanced age but also with the presence of structural heart disease. In particular patients suffering from congestive heart failure (CHF) with low left ventricular (LV) ejection fraction present a significantly increased risk of developing AF and its detrimental hemodynamic effects, due to the loss of atrial contraction, and fast and irregular beats, are an even more relevant compared to patients without CHF.

In CHF patients rate control is the most widely used strategy to manage AF; in fact, it has proved non-inferior to rhythm control strategies concerning survival rates . However, adequate ventricular rate is difficult to achieve; moreover, by rate control strategy, the detrimental hemodynamic effects of AF persist, leading to a further impair in LV function, cardiac output, and symptoms. This frequently leads to the fact that, despite optimal medical therapy (OMT) for at least 3 months, the patients require implantable cardioverter defibrillator (ICD), and, in case of poor rate control AV node ablation with resynchronization therapy (CRT). The latter, however, infer pacemaker (PM)-dependence, and relate to a not negligible risk of cardiac rhythm device peri-implantation and long-term complications (infections, leads failure).

On the other side rhythm control may represent an option. In the general population, in fact, recent evidences suggest an advantage over rate control concerning survival, quality of life and thromboembolic events. The main limitation, however, stands in how to achieve rhythm control: antiarrhythmic therapy has several side effects (amiodarone, in fact the only recommended drug, is thrived by frequent adverse events) and transcatheter AF ablation has been assessed only in modest sample size studies.

Available literature focusing on a comparison between different management strategies in patients with CHF and AF is limited. A small randomized study compared pulmonary veins (PVs) isolation to AV node ablation and biventricular PM implantation, showing improved 6-month outcome, defined by a composite end point of LV ejection fraction, 6-minutes walking distance and Minnesota Living with Heart Failure (MLWHF) questionnaire, in patients treated by PVs isolation. However, only 81 patients were enrolled in this short-term study, and no hard end point tested. More recently, and actually ongoing, the AATAC-AF study, is comparing amiodarone and catheter ablation in patients with chronic AF and an implantable device (biventricular PM or ICD). Also in this case, the preliminary results support an improved 24 month outcome, in terms of sinus rhythm (SR) achievement, quality of life and LV function, in patients undergoing AF ablation .

In addition to these direct comparisons, other indirect evidences support catheter ablation rhythm control . In a recent meta-analysis, PVs isolation, linear lesions and ablation of fragmented potentials in left atrium, although with a relatively high need for repeated procedures, have proven not only to be safe but also effective in improving symptoms (related to both CHF and AF), LV function and maintaining SR. In fact, in this analysis, 60% of the patients with a left ventricular function below 35% at baseline improved to a value above this limit following AF ablation.

We therefore designed this multicenter, randomized controlled trial aiming to assess if, in recently diagnosed (less than 6 months) and optimally treated CHF patients with impaired LV function, AF catheter ablation is effective in improving LV function and clinical functional class, potentially driving to a reduction of device implantations (ICD/CRTs).

The aim of the present study is to assess within patients with concomitant CHF and persistent AF whether AF ablation, compared to optimal rate control strategy, is superior in terms of LV function and clinical functional class. In addition, long-term outcome and complications will be recorded and compared.

This study is a prospective, multicenter, randomized, two-arms parallel-group trial. Randomization is performed through a 24-hour, centralized, computer system. Enrollment will occur at 5 centers in Italy. The study protocol will receive approval by the ethics review board at each institution before study enrollment, and patients will be randomized to undergo either arm of the study in an open fashion, due to the nature of the alternative procedures.

Written informed consent, including description of the procedure and risk of complications, is obtained from each patient before study inclusion.

At 3, 6 and 12 months from the index procedure a complete follow-up visit is performed for all patients in both study arms. Clinical assessment will include signs and symptoms of heart failure, NYHA functional class evaluation, quality of life assessment by MLWHF questionnaire and a 12-lead ECG. Additionally, all patients will undergo a complete transthoracic echocardiographic evaluation, including LV ejection fraction, end-diastolic and end-systolic volumes, LV diastolic function, LA volume, mitral regurgitation or stenosis grade, right ventricular diameter and systolic function (TAPSE). A 6-minute walking test will be performed aiming to reproducibly quantify the functional class of the patients at each scheduled evaluation. A 24-hour ECG Holter will be performed in all patients, to detect AF recurrences in the AF ablation arm, mean heart rate (both for patients in AF and SR) and ventricular arrhythmias burden. For patients implanted with a device, AF burden, ICD interventions and percentage of biventricular pacing will be recorded. Finally, the incidence of heart failure hospitalizations, ischemic or hemorrhagic strokes and all-cause mortality will be assessed in both groups. Additional clinical assessment will be performed in case of heart failure acute worsening.

No external source of funding will contribute to this study, and no conflict of interest has been to be declared. All data are independently collected, managed, and analyzed with a restricted-access database. The steering committee, is responsible for the design and conduct of the study and for the drafting and editing of the results. The steering committee will have full access to the final study data and statistical analysis.

Eligibility criteria: Inclusion Criteria:

* Recent (no longer than 6 months) diagnosis of congestive heart failure, defined as left ventricular ejection fraction lower or equal than 35% along with the presence of symptoms of heart failure, with a NYHA class II, III or ambulatory IV;
* Optimal medical therapy from at least 3 months (including a beta-blocker, an angiotensin-converting-enzyme (ACE) inhibitor or angiotensin-receptor blocker (ARB) and, in NYHA III and IV patients, spironolactone);
* Persistent atrial fibrillation (at least 3 months or, alternatively, a minimum of two previous episodes lasting longer than 7 days);
* Refractory to at least one, or intolerant to, antiarrhythmic drug/s;
* Must be able to provide written informed consent.

Exclusion Criteria:

* Reversible causes of atrial fibrillation or congestive heart failure;
* Permanent or long-standing persistent atrial fibrillation (lasting more than 1 year);
* Previous surgical or transcatheter AF ablation;
* Previously implanted CRT with or without concomitant AV node ablation;
* QRS duration above 150 msec or above 120 msec in the presence of complete left bundle branch block (class IIa indication for CRT implantation);
* Life expectancy of one year or less;
* High likelihood of undergoing cardiac transplantation within the next year;
* Contraindication to anticoagulant therapy;
* Documented intraatrial thrombus, tumor, or other abnormality that precludes catheter introduction and manipulation;
* Inability to perform a 6-minute walking test;
* Absence of optimal medical therapy as previously described;
* Cardiac surgery, myocardial infarction or percutaneous coronary intervention within the previous 3 months.

Primary outcomes:
measure: composite of the improvement of left ventricular ejection fraction above 35% and concomitant NYHA class lower than II, measured as number of patients reporting both conditions at follow-up
timeFrame: 6 months
Secondary outcomes:
measure: 6-minute walking test distance, meaused in metres
timeFrame: 3, 6 and 12 months
measure: quality of life, assessed with Minnesota Living With Heart Failure questionnaire score
timeFrame: 3, 6 and 12 months
measure: number of heart failure hospitalizations
timeFrame: 3, 6 and 12 months
measure: number of ICD interventions
timeFrame: 3, 6 and 12 months
measure: number of patients suffering ischemic or hemorrhagic stroke
timeFrame: 3, 6 and 12 months
measure: all-cause mortality
timeFrame: 3, 6 and 12 months
measure: periprocedural major complications
timeFrame: 3 months
Other outcomes:
Locations:
Study officials:
References:
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