Paroxysmal Atrial Fibrillation Clinical Trial
Official title:
ADenosine Following Pulmonary Vein Isolation to Target Dormant Conduction Elimination: the ADVICE Trial
Atrial fibrillation (AF) is the most common heart rhythm disorder, impairs quality of life and increases stroke risk and mortality. Despite advances in medical treatment, AF remains uncontrolled in many patients. In many patients, AF is initiated by abnormal electrical impulses from the pulmonary veins. A catheter ablation procedure called pulmonary vein isolation (PVI) has therefore been developed, using heat to isolate the PV foci from the heart. PVI is very effective, but must be repeated in up to 50% of cases because the foci isolation is not permanent after initial PVI. The intravenous administration of a drug called adenosine during the PVI procedure can unmask residual conduction that would otherwise remain unnoticed, so-called "dormant conduction". In our experience, additional ablation guided by adenosine reduces AF recurrence and the need for a repeat PVI procedure. However, the adenosine-guided approach has not yet been proven as standard therapy. The present study, to be conducted at 15 clinical centres in Canada, Europe and Australia is therefore intended to evaluate the efficacy of adenosine-guided ablation to prevent AF recurrence. Five hundred twenty-six patients will be included in the study, which should be completed within 2 years. In all patients, the presence of dormant conduction will be tested with adenosine during PVI. If dormant conduction is observed, additional ablation will be performed in half of these patients selected randomly. If there is no dormant conduction, randomly selected patients will be followed in a registry. If the adenosine-guided approach is demonstrated to improve the success rate of PVI procedures, it should become the standard approach for a "permanent cure" of AF, and therefore benefit patients by reducing arrhythmia recurrence, hospitalizations and the need for repeat interventions.
Atrial fibrillation (AF), the most frequently treated cardiac arrhythmia, impairs quality of
life and increases stroke risk and mortality. Despite advances in antiarrhythmic drug
therapy, AF remains uncontrolled in many patients. More effective measures to prevent, treat
and potentially cure AF are needed. Ectopic foci originating from pulmonary veins (PVs)
initiate AF in many patients. PV isolation (PVI), in which PV conduction is eliminated by
catheter ablation, has emerged as an effective treatment in selected patients. However AF
recurs in up to 50%, due to recovery of PV conduction. Dormant PV conduction (PV conduction
suppressed at time of PVI with subsequent recovery) has been proposed to explain
recurrences. We demonstrated that adenosine can restore conduction in viable PVs after
attempted PVI by activating outward K+-currents, leading to selective hyperpolarization of
PV cardiomyocytes and removal of voltage-dependent Na+-channel inactivation. Thus, adenosine
can be used to differentiate permanent PV-atrial block from dormant PV conduction and to
identify the need for additional ablation. We recently performed a pilot study in 47
patients, in whom adenosine was used to guide additional ablation. Results were compared to
47 historical controls. Dormant conduction was observed in 55% of patients undergoing PVI
and additional adenosine-guided ablation decreased the AF recurrence rate from 49% to 21%.
An adequately-powered prospective randomized controlled clinical trial is required to
confirm these findings.
The primary objective of the proposed ADVICE trial is to evaluate the impact of
adenosine-guided PVI in preventing AF recurrences among patients with paroxysmal AF. We
hypothesize that a PVI ablation strategy that incorporates elimination of dormant conduction
unmasked by intravenous adenosine will decrease symptomatic AF recurrence compared to
standard PVI, without incurring significant additional risk. This prospective randomized
study will be conducted at 15 clinical centers in Canada, Europe and Australia. Patients
with paroxysmal AF referred for PVI will be recruited. Standard PVI will be performed in all
patients until elimination of PV conduction. All patients will subsequently receive
intravenous adenosine in an attempt to unmask dormant conduction. If dormant conduction is
elicited, patients will be randomized to no further ablation (Group 1; control) or
additional adenosine-guided ablation until dormant conduction is abolished (Group 2;
adenosine-guided PVI). If no dormant conduction is revealed, randomly selected patients will
be followed in a registry to further assess the role of dormant conduction as a predictor of
AF recurrence. Portable electrocardiographic monitors will be provided to all patients. The
primary outcome will be the time to first documented symptomatic AF episode post-PVI based
on an intention-to-treat analysis. Since symptomatic AF recurrence is anticipated in 45% of
controls, 210 patients with dormant conduction are required in order to be able to detect a
difference of 20%, with a power of at least 85%. Assuming the presence of dormant conduction
in a minimum of 40% of patients after standard PVI, 526 patients will be enrolled in the
study. Enrolment is expected to be completed within 12 months, with all patients followed
for 12 months.
Demonstrated superiority of an adenosine-guided PVI ablation strategy would represent a
major advancement in refining the interventional approach for AF. The ADVICE trial carries
the potential, therefore, to alter the standard of care and benefit patients with AF by
reducing arrhythmia recurrence, hospitalizations and the need for repeat interventions
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment
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