ADenosine Following Pulmonary Vein Isolation to Target Dormant Conduction Elimination: the ADVICE Trial

Paroxysmal Atrial Fibrillation Clinical Trial

— ADVICE  

Official title:

ADenosine Following Pulmonary Vein Isolation to Target Dormant Conduction Elimination: the ADVICE Trial

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01058980
• Other study ID #: ICM 08-1067
• Status: Completed
• Phase: Phase 4
• First received: January 28, 2010
• Last updated: April 1, 2014
• Start date: December 2009
• Est. completion date: December 2013

Study information

• Verified date: April 2014
• Source: Montreal Heart Institute
• Contact: n/a
• Is FDA regulated: No
• Health authority: Canada: Ethics Review Committee
• Study type: Interventional

Clinical Trial Summary

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.

Description:

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 550
• Est. completion date: December 2013
• Est. primary completion date: September 2013
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Age more than 18 years

• Paroxysmal AF for at least 6 months with at least 3 symptomatic episodes (using patient history) during the previous 6 months

• Patients must be felt to be candidates for AF ablation based on AF that is symptomatic and refractory or intolerant to at least one class 1 or 3 antiarrhythmic agent.

• Documentation of at least one episode of AF on 12 lead ECG, TTM or Holter monitor within 12 months of randomization in the trial

• Patients must be on continuous anticoagulation with warfarin (INR 2-3) or fractionated subcutaneous heparin for >4 weeks prior to the ablation or they have undergone a recent (less than 48 hours before planned ablation) transoesophageal echocardiogram to exclude left atrial thrombus.

• Patients must provide written informed consent to participate in the clinical trial.

Exclusion Criteria:

• Contraindications to oral anticoagulants

• History of any previous ablation or surgical maze for AF

• Intracardiac thrombus

• AF due to reversible cause

• Patients with left atrial size > 55mm or significant mitral valve disease (moderate or severe mitral stenosis or regurgitation)

• Pregnancy

• Asthma, history of bronchospasm or known adverse reaction to adenosine

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Single Blind (Subject), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Atrial Fibrillation
• Dormant Pulmonary Vein Conduction
• Paroxysmal Atrial Fibrillation
• Pulmonary Vein Isolation

Intervention

Procedure:
• Additional ablation until elimination of dormant conduction
Additional RF energy will be delivered at sites of re-conduction on the circular mapping catheter in each PV. Abolition of the dormant conduction will then be assessed by repeated injections of adenosine using the same doses previously used to reveal dormant conduction. Additional ablation as described will be performed until re-injection of adenosine shows no re-conduction in any of the PV.
• No additional ablation
Presence of dormant PV conduction, no additional ablation.
• Registry group
Among those who will be found not to have the presence of dormant conduction, and within each site, three-quarters of the patients will be randomly selected to be included in the registry group.
• Usual medical care
Clinical follow-up will be performed according to the regular follow-up after AF ablation procedures in each of the participating centers. No data will be collected after discharge.One-fourth of the patients will be randomly selected to be included in the usual medical care group.

Locations

Country	Name	City	State
Australia	Royal Perth Hospital	Perth	Western Australia
Austria	KH d. Elisabethinen Linz GmbH	Linz
Belgium	Cliniques universitaires Saint-Luc	Bruxelles
Canada	Foothills Medical Center	Calgary	Alberta
Canada	QE II Health Sciences Center	Halifax	Nova Scotia
Canada	McMaster University and Hamilton Health Sciences	Hamilton	Ontario
Canada	London Health Science Centers	London	Ontario
Canada	Montreal General Hospital	Montreal	Quebec
Canada	Montreal Heart Institute	Montreal	Quebec
Canada	Southlake Regional Health Center	Newmarket	Ontario
Canada	Ottawa Heart Institute	Ottawa	Ontario
Canada	Institut universitaire de cardiologie et de pneumologie de Québec	Quebec
Canada	Centre hospitalier universitaire de Sherbrooke	Sherbrooke	Quebec
Canada	Royal Jubilee Hospital	Vancouver	British Columbia
France	Hôpital Cardiologique du Haut-Lévêque	Bordeaux
Germany	Herz-Zentrum Bad Krozingen	Bad Krozingen
Germany	University Heart Center	Hamburg	Eppendorf
Germany	Deutsches Herzzentrum Muenchen	Munich	Muenchen

Sponsors (4)

Lead Sponsor	Collaborator
Montreal Heart Institute	Canadian Institutes of Health Research (CIHR), Johnson & Johnson, St. Jude Medical

Countries where clinical trial is conducted

Australia,  Austria,  Belgium,  Canada,  France,  Germany, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to first recurrence of electrocardiographically documented, symptomatic AF or atrial flutter/tachycardia between 3 and 12 months post ablation in the absence of antiarrhythmic drug therapy.	The primary outcome is time to first recurrence of symptomatic ECG-documented AF or atrial flutter/tachycardia between days 91 & 365 after ablation, or repeat ablation procedure during the first 90 days. AF or atrial flutter/tachycardia will qualify as an arrhythmia recurrence after ablation if it lasts 30 seconds or longer and is documented by 12-lead ECG, surface ECG rhythm strips, or TTM recordings. Documented episodes will be adjudicated by a blinded committee. Time 0 is defined as day 91 post ablation with FUp's extending 365 days post ablation.	Between 3 and 12 months post ablation	No
Secondary	Time to first recurrence of any electrocardiographically documented AF or atrial flutter/tachycardia (symptomatic or asymptomatic) between days 91 and 365 after ablation.		between 3 and 12 months	No
Secondary	Repeat ablation procedure for documented recurrence of symptomatic AF or atrial flutter/tachycardia.		between 3 and 12 months	No
Secondary	Emergency visits or hospitalizations		between 0 and 12 months	No
Secondary	Antiarrhythmic drug use because of documented recurrence of symptomatic AF or atrial flutter/tachycardia		between 0 and 12 months	Yes
Secondary	Proportion of patients with AF or left atrial flutter/tachycardia occurring during the first 90 days post ablation		between 0 and 3 months	Yes
Secondary	Major peri-procedural complications including stroke, PV stenosis, cardiac perforation, atrio-esophageal fistulae, and death		between 0 and 12 months	Yes
Secondary	Generic and disease specific quality of life (assessed by the Cardiovascular Society Severity in AF (CCS-SAF) scale and SF-36 questionnaire at baseline, and at 3, 6 and 12 months post randomization).		between 0 and 12 months	Yes