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

This study has been completed.
Sponsor:
Collaborators:
Canadian Institutes of Health Research (CIHR)
St. Jude Medical
Johnson & Johnson
Information provided by (Responsible Party):
Laurent Macle, Montreal Heart Institute
ClinicalTrials.gov Identifier:
NCT01058980
First received: January 28, 2010
Last updated: April 1, 2014
Last verified: April 2014
  Purpose

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.


Condition Intervention Phase
Paroxysmal Atrial Fibrillation
Pulmonary Vein Isolation
Dormant Pulmonary Vein Conduction
Procedure: Additional ablation until elimination of dormant conduction
Procedure: No additional ablation
Procedure: Registry group
Procedure: Usual medical care
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment
Official Title: ADenosine Following Pulmonary Vein Isolation to Target Dormant Conduction Elimination: the ADVICE Trial

Resource links provided by NLM:


Further study details as provided by Montreal Heart Institute:

Primary Outcome Measures:
  • 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. [ Time Frame: Between 3 and 12 months post ablation ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • Time to first recurrence of any electrocardiographically documented AF or atrial flutter/tachycardia (symptomatic or asymptomatic) between days 91 and 365 after ablation. [ Time Frame: between 3 and 12 months ] [ Designated as safety issue: No ]
  • Repeat ablation procedure for documented recurrence of symptomatic AF or atrial flutter/tachycardia. [ Time Frame: between 3 and 12 months ] [ Designated as safety issue: No ]
  • Emergency visits or hospitalizations [ Time Frame: between 0 and 12 months ] [ Designated as safety issue: No ]
  • Antiarrhythmic drug use because of documented recurrence of symptomatic AF or atrial flutter/tachycardia [ Time Frame: between 0 and 12 months ] [ Designated as safety issue: Yes ]
  • Proportion of patients with AF or left atrial flutter/tachycardia occurring during the first 90 days post ablation [ Time Frame: between 0 and 3 months ] [ Designated as safety issue: Yes ]
  • Major peri-procedural complications including stroke, PV stenosis, cardiac perforation, atrio-esophageal fistulae, and death [ Time Frame: between 0 and 12 months ] [ Designated as safety issue: Yes ]
  • 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). [ Time Frame: between 0 and 12 months ] [ Designated as safety issue: Yes ]

Enrollment: 550
Study Start Date: December 2009
Study Completion Date: December 2013
Primary Completion Date: September 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Dormant PV conduction

After PVI, dormant conduction will be evaluated using intravenous adenosine. If dormant conduction is present, the patients will be randomized to two parallel groups:

  • Group 1: No additional ablation
  • Group 2: Additional ablation until elimination of dormant conduction.
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.
Procedure: No additional ablation
Presence of dormant PV conduction, no additional ablation.
Active Comparator: No dormant PV conduction
If no dormant conduction is documented, patients will be selected in a random fashion to be included in a registry (follow-up as planned for group 1 and 2 above). The registry group will allow for further assessment of the role of dormant conduction as a predictor of AF recurrence by comparing the success rate after ablation in patients without dormant conduction with those of Group 1 and 2.
Procedure: 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.
Procedure: 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.

Detailed 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

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01058980

Locations
Australia, Western Australia
Royal Perth Hospital
Perth, Western Australia, Australia
Austria
KH d. Elisabethinen Linz GmbH
Linz, Austria, A-4010
Belgium
Cliniques universitaires Saint-Luc
Bruxelles, Belgium
Canada, Alberta
Foothills Medical Center
Calgary, Alberta, Canada, T2N 2T9
Canada, British Columbia
Royal Jubilee Hospital
Vancouver, British Columbia, Canada, V8R 4R2
Canada, Nova Scotia
QE II Health Sciences Center
Halifax, Nova Scotia, Canada, B3H 3A7
Canada, Ontario
McMaster University and Hamilton Health Sciences
Hamilton, Ontario, Canada, L8L 2X2
London Health Science Centers
London, Ontario, Canada, N6A 5W9
Southlake Regional Health Center
Newmarket, Ontario, Canada, L3Y 2P9
Ottawa Heart Institute
Ottawa, Ontario, Canada, K1Y 4W7
Canada, Quebec
Montreal Heart Institute
Montreal, Quebec, Canada, HIT IC8
Montreal General Hospital
Montreal, Quebec, Canada, H3G 1A4
Centre hospitalier universitaire de Sherbrooke
Sherbrooke, Quebec, Canada
Canada
Institut universitaire de cardiologie et de pneumologie de Québec
Quebec, Canada
France
Hôpital Cardiologique du Haut-Lévêque
Bordeaux, France, 33604
Germany
University Heart Center
Hamburg, Eppendorf, Germany
Deutsches Herzzentrum Muenchen
Munich, Muenchen, Germany, D-80636
Herz-Zentrum Bad Krozingen
Bad Krozingen, Germany, 79189
Sponsors and Collaborators
Montreal Heart Institute
Canadian Institutes of Health Research (CIHR)
St. Jude Medical
Johnson & Johnson
Investigators
Principal Investigator: Laurent Macle, MD Montreal Heart Institute
  More Information

No publications provided by Montreal Heart Institute

Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: Laurent Macle, Chair, ADVICE Study, Montreal Heart Institute
ClinicalTrials.gov Identifier: NCT01058980     History of Changes
Other Study ID Numbers: ICM 08-1067
Study First Received: January 28, 2010
Last Updated: April 1, 2014
Health Authority: Canada: Ethics Review Committee

Keywords provided by Montreal Heart Institute:
catheter ablation
atrial fibrillation
adenosine

Additional relevant MeSH terms:
Atrial Fibrillation
Arrhythmias, Cardiac
Heart Diseases
Cardiovascular Diseases
Pathologic Processes
Adenosine
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Central Nervous System Agents
Therapeutic Uses
Anti-Arrhythmia Agents
Cardiovascular Agents
Vasodilator Agents

ClinicalTrials.gov processed this record on August 19, 2014