Thoracoscopic surgical versus catheter ablation approaches for primary treatment of persistent atrial fibrillation

Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia *in the
European Union, its prevalence is 1.5-2% in the total population, and this
number is expected to increase in the coming decades. AF is classified as
paroxysmal or persistent AF, based on the duration and persistency of the
arrhythmia. Persistent AF refers to episodes of AF that last longer than 7
days, and/or require electrical or chemical cardioversion for the restoration
of sinus rhythm. Despite state-of-the-art pharmacological therapies targeting
the ventricular rate or aiming to restore sinus rhythm (SR), many patients with
AF stay symptomatic. Ablation strategies to isolate pulmonary veins (PV) have
been deployed to treat AF in these patients.
Catheter ablation targeting endocardial pulmonary vein isolation (PVI) has
become the common treatment for AF in patients with an indication for invasive
treatment. Although reasonably efficacious in patients with paroxysmal AF (that
is spontaneaously terminating) and normally sized left atria, the results of
catheter ablation in persistent AF are more modest, with 20% of patients being
free of AF after a single procedure, increasing to 45% after multiple
procedures. Other, using phased RF ablation, report a 12 month success rate of
36% is described. Repeated procedures are frequently required patients with
persistent AF. The limited effectiveness is argued to be caused by limitations
of the current catheter technology to perform reliable transmural linear
ablation around the PVs, but also to a more progressed substrate.
Alternatively, the arrhythmic substrate can be altered epicardially via a
thoracoscopic approach, namely thoracoscopic surgical ablation for PVI. The
Heart Rhythm Society guideline recommends surgical ablation as reasonable in
highly symptomatic patients, since surgical PVI is highly promising with a
single procedure success rate of 67% without AAD at one year follow-up.
Recently, a meta-analysis by Kim et al. indeed showed that surgical PVI has a
higher success rate compared to catheter PVI in patients with persistent AF
However, the results are limited by the non-standardized follow-up methods for
AF detection. Also, several studies report more procedure related complications
associated with thoracoscopic surgery.
Apart from the ablation platform used, adjuvant ablations of AF substrates in
the atrium is being employed increasingly in patients with persistent AF. A
variety of techniques, such as ablation of complex fractioned atrial
electrograms (CFAE), extended lesion sets and ganglion plexus GP ablation, are
being used. Although all these approaches initially seemed promising, recently
adjuvant ablations techniques were assessed by two randomized trials. The STAR
AF II trial randomized patients to catheter PVI alone, plus ablation of CFAEs
or plus linear ablation across the left atrial roof and mitral valve isthmus.
They found no difference in reduction of recurrence rate of AF in patients with
persistent AF. Furthermore, the AFACT trial evaluated epicardial ablation of
ganglion plexus and Marshall*s ligament in patients with persistent AF by
randomization. The results showed no reduction of AF recurrence in persistent
AF, at the cost of more procedure related complications in the ganglion plexus
ablation arm compared to control. No studies have been conducted comparing
surgical ablation with catheter ablation in patients with persistent AF as a
primary invasive procedure after failing treatment with anti-arrhythmic
medication.
Consequently, this current study aims to assess a patient specific therapy plan
for patients with persistent AF by randomizing catheter versus thoracoscopic
surgical ablation for AF, confined to PVI, without adjuvant substrate ablation
in those patients. The inherent risk of applying more ablation lesions is the
creation of a new arrhythmogenic substrate, causing atrial tachycardia, which
is generally harder to treat. Indeed, the AFACT trial demonstrated a
significantly higher percentage of atrial tachycardias in patients with
recurrent AF, although the number of recurrences was equivalent between the
groups with and without GP ablation. The protocol foresees in crossing-over to
the other treatment arm in case of AF recurrence, and thus selects patients who
benefit from a single procedure, as well as offers optimal care, consisting of
both strategies combined to those who need that.

This current study aims to assess a patient specific therapy plan for patients
with persistent AF by randomizing catheter versus thoracoscopic ablation for PV
isolation without adjuvant substrate ablation in those patients. Subjects will
be randomized (1:1) to one of the two study-arms (catheter or thoracoscopic PV
ablation). Follow-up will be 5 years, with heart rhythm monitoring every three
months (this is standard of care for thoracoscopic surgical ablation) during
the first year. After the first year, yearly heart rhythm monitoring will
continue up to 5 years, with a hospital visit at 3 and 5 years. In case
symptomatic AF recurs after a three month blanking period and before 1 year
post-primary treatment, the subject will cross-over to the other treatment arm
unless further invasive treatment is not desired. Primary end point is freedom
of any atrial tachyarrhythmia lasting more than 30 seconds without the use of
antiarrhythmic drugs at 12 months, with the exclusion of a blanking period of
the first three months after the procedure. Secondary endpoints include:
freedom of arrhythmia with AAD after a single procedure, freedom of arrhythmia
after 12 months without AAD after a second procedure, long-term freedom of
arrhythmia (up to 5 years), quality of life (QoL) and cost-effectiveness
analysis.

This is a prospective, non-blinded randomized multicenter study with an event
driven design (primary endpoint after 72 recurrences of atrial tachyarrhythmia)
in subjects with an indication for non-pharmacological treatment of persistent
AF. Subjects will be randomized (1:1) to one of the two study-arms
(thoracoscopic or catheter PVI). Both thoracoscopic and catheter PVI are
already part of daily practice. Follow-up will be 5 years, with 24 hour holter
monitoring every three months during the first year and yearly holter
monitoring thereafter. A blanking period of 3 months post-procedure will be
applied. During this period, recurrence of AF is not considered a failure of
the procedure.
In case of symptomatic AF recurrence within 1 year after primary treatment, the
subject will cross-over to the other treatment arm. The anticipated inclusion
duration is one year. The inclusion is expected to be feasible, since all
participating centers are high volume and experienced centers for the treatment
of persistent AF.

Pumonary vein isolation by means of catheter ablation or thoracoscopic surgical
ablation

Since two standard treatments for AF are compared, the added risk of this study
is neglegible.
For this study, extra blood samples are collected at 2 moments in time. These
blood draws are combined with clinical blood draws, so the burden and risks for
the patients are neglegible. Also, two questionnaires regarding the quality of
life are filled out by the patient at these two moments. Apart from this, the
follow up for the study is the same as the regular follow-up for patients after
an ablation procedure. Thereafter there are 3 extra yearly holter
registrations, ECG's and a visit with the researcher. This includes anamnesis,
physical examination and assessment of (S)AE's. The added risk of the holter
monitoring is neglegible. In case silent AF is detected by these rhythm
monitoring treatment can be adjusted accordingly, potentially preventing
complications.