AtRial fibrillation ablation to prevent disease progression of AF-induced atrial Cardiomyopathy in womEn and men

It is hypothesised that the stage of atrial cardiomyopathy (ACMP) and the
timing of ablation for atrial fibrillation (AF) may have an impact on the
occurrence of ACMP-associated adverse outcomes in patients with AF, including
AF recurrences, ischemic stroke, and heart failure (HF) with preserved, mildly
reduced and reduced left-ventricular ejection fraction. ACMP results into an
atrial substrate being less responsive to rhythm control (including AF
ablation) and leading to higher AF recurrence rates and AF progression. Since
AF begets AF by advancing the ACMP, early intervention with rhythm control
therapies, particularly AF ablation, has shown promise in interrupting ACMP
advancement and AF progression. However, existing studies do not specifically
explore ACMP's role and the potential of AF ablation in slowing down ACMP
progression and ACMP associated outcomes. The RACE X trial aims to fill this
gap by randomizing ACMP patients with AF to AF ablation or pharmacological
rhythm management (rate and/or rhythm control), providing evidence on ACMP's
importance in treatment and prognosis, and reduce hospitalizations/urgent
visits for cardiovascular (CV) reasons and CV mortality of patients with AF.

The primary objective is to study whether AF ablation, as opposed to
pharmacological rhythm management (rate and/or rhythm control according to ESC
guidelines), can reduce the incidence of the composite primary endpoint of CV
death and CV hospitalisation/urgent visits in patients diagnosed with ACMP and
AF. The secondary objectives are ACMP progression as measured by LAVI increase,
ACMP associated outcomes (hospitalisations/urgent visits for AF, HF, ischemic
stroke, and cardiovascular death), all-cause mortality, repeated
hospitalisations/urgent visits for ACMP related outcomes, AF symptoms, quality
of life (QoL) and healthcare costs. The exploratory objectives include ACMP
progression as measured by additional transthoracic echocardiogram (TTE)
measurements, extended ECG (extECG), MRI (subset), CT (subset), circulating
biomarkers (Cardiolines subset), and electrophysiological mapping (subset).

The RACE X trial is a prospective, multicentre, randomized, open-label,
blinded-endpoint, superiority, parallel arm, phase IIIb trial. Patients with
ACMP and AF are randomized to either receive rhythm control through AF ablation
or pharmacological rhythm management in addition to anticoagulation (if
indicated) and treatment of comorbidities. Follow-up assessments will be
conducted using questionnaires and data from routine clinical care. The trial
will take place in 15 participating hospitals in the Netherlands. Patients that
are not eligible because of not fulfilling the ACMP inclusion criterion (left
atrial volume index (LAVI) >34 ml/m2), but do undergo AF ablation, will be
enrolled in a parallel observational RACE X registry and information on
occurrence of CV death and CV hospitalization/urgent visits is collected, in
collaboration with the Netherlands Heart Registration (NHR). In the RACE X
registry, management of AF is led to the discretion of the treating physician.

Patients will then be randomly assigned in a 1:1 ratio, stratified by sex and
type of AF (paroxysmal or persistent), to either AF ablation or pharmacological
rhythm management (being rate or rhythm control).

AF ablation is a well-established and safe technique, known for its efficiency
and minimal patient burden. Follow-up assessments will be conducted remotely
using mHealth applications, reducing the need for frequent site visits and
minimizing patient effort. Additional study procedures, such as blood sampling,
extended electrocardiography, transthoracic echocardiography, and will be
integrated into routine clinical care. Consequently, the number of additional
procedures (blood sampling at randomisation and end of study for those
participating in Cardiolines biobank substudy, extended ECG (5-minute duration)
at randomisation and end of study, transthoracic echocardiogram at end of
study, mHealth follow up and questionnaires and visits specifically for the
study purposes is negligible, ensuring a streamlined and efficient study
process.