Effect of Amiodarone on the Procedure Outcome in Long-standing Persistent Atrial Fibrillation Undergoing Pulmonary Vein Antral Isolation (SPECULATE)

This prospective randomized study aims to investigate the effect of continuous versus interrupted use of Amiodarone on the procedure outcome in long-standing persistent (LSP) atrial fibrillation patients undergoing pulmonary vein antral isolation (PVAI).

Study Overview

• Status: Completed
• Conditions: Atrial Fibrillation
• Intervention / Treatment: Drug: Amiodarone; Drug: Amiodarone

Detailed Description

Background: Atrial Fibrillation (AF) is the most prevalent sustained clinical arrhythmia encountered in clinical practice. Its prevalence is 0.4-1% in the general population and greater than 8% in individuals >80 years of age. An estimated 2.5million individual in North America and 4.5 million in Europe are affected by AF (1). There are two fundamental principles in the management of AF; 1) anticoagulation to reduce the risk of thromboembolism, 2) ablation therapy or drugs or both to control the arrhythmia (2).

Amiodarone, a potent antiarrhythmic drug, is recommended for both atrial and ventricular arrhythmia. It has a combination of Beta-blockade, calcium-, sodium- and potassium-channel blockade effect. Most importantly, the potassium-channel blockade slows repolarization, causing an increase in the action-potential duration and in the refractoriness of the cardiac musculature (3). As the myocardium remains unresponsive, the premature depolarizations which were previously causing AF are prevented from propagation.

During the ablation procedure, mapping electrograms using circular mapping catheter and provocative maneuvers such as administration of isoproterenol in incremental doses are commonly used to aid in identification of pulmonary vein (PV) and non-PV triggers. In addition, areas with complex fractionated atrial electrograms (CFAE) are identified and eliminated by ablation. In patients with LSP, inclusion of PV and non-PV triggers as ablation targets, improves the procedure outcome.

As Amiodarone increases the refractoriness of the myocardium, it is possible that under the effect of Amiodarone some of the focal triggers could be masked or remain unidentified during mapping or isoproterenol-provocation. These unrecognized triggers could cause recurrence of AF during the post-ablation period. In other words, discontinuation of Amiodarone at least 5-months before ablation could result in unmasking of all the focal triggers that would have otherwise stayed unrecognized and eliminating those triggers would significantly improve the success rate of the procedure.

Our study aims to investigate the role of Amiodarone in influencing the procedure outcome in LSP-AF patients undergoing catheter ablation.

Hypothesis: Withdrawal of Amiodarone 4 months before procedure results in unmasking of additional focal triggers, ablation of which leads to an improved procedure outcome in LSP_AF patients.

Inclusion Criteria:

1. History of LSP AF
2. Age > 18 years
3. Willing and ability to understand and sign an informed consent
4. Patients on chronic Amiodarone therapy (≥ 3 months)

Exclusion Criteria:

1. Unstable angina
2. Concomitant treatment with other class I or III antiarrhythmic drugs
3. Myocardial infarction within past 3 months)
4. Presence of any disease that is likely to shorten life expectancy to < 1 year
5. Symptomatic heart failure, NYHA III or IV
6. Contraindications for Amiodarone
7. Chronic liver diseases
8. Pregnant or breast-feeding mothers

Primary Outcome Measure:

Recurrence of AF, atrial flutter or atrial tachycardia

Secondary Outcome Measures:

Difference in the occurrence of relapse between the control and the study groups

Study design:

This is a multi-center, prospective study in which consecutively enrolled patients treated with Amiodarone for long standing persistent AF will be randomized to either the study or the control group.

Study group: Amiodarone therapy will be stopped at least 4-months before ablation procedure and ablation will be performed off Amiodarone. Patients will not take Amiodarone during the blanking period (8 weeks post-ablation).

Control group: Patient will continue taking Amiodarone before, during and after ablation (8 weeks post-ablation).

After the blanking period, everybody would be off Amiodarone unless they have recurrence. Anti-arrhythmic drugs other than Amiodarone would be tried if patient develops recurrence and repeat ablation would be considered.

Follow-Up:

Patients will be followed up for 3 years post-ablation. An ECG and telemetry transmission monitor report will be obtained in all patients at each follow-up examination.

Patients will be supplied with an Event Recorder for trans-telephonic rhythm transmission (telemetry) for 5 months after ablation, and will be asked to transmit their rhythm data every time they had symptoms compatible with arrhythmias; and at least once a week, even if they were asymptomatic. Holter monitoring will be performed at 6-month post-ablation. The arrhythmic episodes will be documented based on ECG, Holter data, Event Recorder data and/or implanted device data (when available).

In case of recurrence, if patients undergo repeat ablations, all procedures will happen off amiodarone. After redo, patients will be followed up for 1 year for recurrence in the same way as described above.

• Study Type: Interventional
• Enrollment (Anticipated): 176
• Phase: Phase 3

Contacts and Locations

Study Locations

• United States
  • Texas
    • Austin, Texas, United States, 78705
      • St.David's Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. History of LSP AF
2. Age > 18 years
3. Willing and ability to understand and sign an informed consent
4. Patients on chronic Amiodarone therapy (≥ 3 months)

Exclusion Criteria:

1. Unstable angina
2. Concomitant treatment with other class I or III antiarrhythmic drugs
3. Myocardial infarction within past 3 months)
4. Presence of any disease that is likely to shorten life expectancy to < 1 year
5. Symptomatic heart failure, NYHA III or IV
6. Contraindications for Amiodarone
7. Chronic liver diseases
8. Pregnant or breast-feeding mothers

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Control; Patient will continue taking Amiodarone before, during and after catheter ablation (8 weeks post-ablation).	Drug: Amiodarone; Patient will continue taking Amiodarone before, during and after ablation (8 weeks post-ablation).; Drug: Amiodarone; Amiodarone therapy will be stopped at least 5-months before ablation procedure and ablation will be performed off Amiodarone. Patients will not take Amiodarone during the blanking period (8 weeks post-ablation).
Active Comparator: Study; Amiodarone therapy will be stopped at least 5-months before ablation procedure and ablation will be performed off Amiodarone. Patients will not take Amiodarone during the blanking period (8 weeks post-ablation).	Drug: Amiodarone; Patient will continue taking Amiodarone before, during and after ablation (8 weeks post-ablation).; Drug: Amiodarone; Amiodarone therapy will be stopped at least 5-months before ablation procedure and ablation will be performed off Amiodarone. Patients will not take Amiodarone during the blanking period (8 weeks post-ablation).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Recurrence of atrial arrhythmia	Recurrence of AF, atrial flutter or atrial tachycardia	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Relapse of AF	Difference in the occurrence of relapse between the control and the study groups	1 yeay

Collaborators and Investigators

• Sponsor: Texas Cardiac Arrhythmia Research Foundation
• Collaborators: Stanford University; Case Western Reserve University; University of Kansas; California Pacific Medical Center; Southlake Regional Health Centre; Catholic University, Italy
• Investigators: Principal Investigator: Andrea Natale, MD, TCAI, St.David's Medical Center

Publications and helpful links

General Publications

• Mohanty S, Di Biase L, Mohanty P, Trivedi C, Santangeli P, Bai R, Burkhardt JD, Gallinghouse JG, Horton R, Sanchez JE, Hranitzky PM, Zagrodzky J, Al-Ahmad A, Pelargonio G, Lakkireddy D, Reddy M, Forleo G, Rossillo A, Themistoclakis S, Hongo R, Beheiry S, Casella M, Dello Russo A, Tondo C, Natale A. Effect of periprocedural amiodarone on procedure outcome in patients with longstanding persistent atrial fibrillation undergoing extended pulmonary vein antrum isolation: results from a randomized study (SPECULATE). Heart Rhythm. 2015 Mar;12(3):477-483. doi: 10.1016/j.hrthm.2014.11.016. Epub 2014 Nov 18. Erratum In: Heart Rhythm. 2015 May;12(5):1100.

Study record dates

Study Major Dates

• Study Start: October 1, 2010
• Primary Completion (Actual): May 1, 2014
• Study Completion (Actual): July 1, 2014

Study Registration Dates

• First Submitted: July 29, 2010
• First Submitted That Met QC Criteria: July 29, 2010
• First Posted (Estimate): August 2, 2010

Study Record Updates

• Last Update Posted (Estimate): August 21, 2014
• Last Update Submitted That Met QC Criteria: August 20, 2014
• Last Verified: August 1, 2014

More Information

Terms related to this study

• Keywords: Catheter Ablation; AF; Amiodarone; Recurrence of AF
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Arrhythmias, Cardiac; Atrial Fibrillation; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Vasodilator Agents; Enzyme Inhibitors; Membrane Transport Modulators; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; Sodium Channel Blockers; Cytochrome P-450 CYP2D6 Inhibitors; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP2C9 Inhibitors; Potassium Channel Blockers; Amiodarone
• Other Study ID Numbers: TCAI-SPECULATE