Flecainide-Short Long Study (Flec-SL)

September 10, 2012 updated by: Paulus Kirchhof, Atrial Fibrillation Network

Targeted Pharmacological Reversal of Electrical Remodeling After Cardioversion.

A randomized trial to test the hypothesis that short-term pharmacological reversal of electrical remodeling after cardioversion is equally efficient to prevent recurrent atrial fibrillation as standard long-term antiarrhythmic therapy.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Details of the trial are described in a design paper published in the American Heart Journal (1).

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia with approximately one million affected patients in Germany. Current estimates suggest that the life-time risk for AF is 30% for men and slightly less for women at the age of 40 years. Due to demographic changes in the German population, the incidence and prevalence of AF is expected to double within the next 30 years. AF almost doubles mortality and causes important morbidity, mainly due to thrombo-embolic complications and stroke. In addition, the arrhythmia in itself reduces the chronotropic adaptation of the heart to increased work load and reduces cardiac output, especially in patients with heart failure or other cardiac disease. Restoration of sinus rhythm would reduce this burden of disease.

Acute termination of AF is almost always successful by external electrical cardioversion, especially using recently optimized techniques [biphasic shock wave forms, anterior-posterior electrode position, sintered steel electrode paddles. Maintaining sinus rhythm, however, is a more difficult task. Antiarrhythmic, ion channel-blocking drugs are effective in preventing a part of recurrent episodes of AF. Their long-term use, however, is limited by pro-arrhythmic side effects which are especially apparent during long-term therapy. AF initiates major changes in atrial electrophysiology per se which have been summarized as "electrical remodeling". The main consequence of these changes is a shortening of the atrial refractory period and action potential duration. Electrical remodeling maintains AF and is related to recurrence of AF after successful cardioversion. Electrical remodeling is reversed when sinus rhythm is maintained over approximately 4 weeks after successful cardioversion. Interestingly, the vast majority of AF recurrences occur during these first few weeks after cardioversion.

Conceptually, the initial phase of "reversal" of electrical remodeling can be separated from the long-term treatment aimed at modifying the underlying substrate of AF. Classical sodium- or potassium channel blocking antiarrhythmic drugs prolong the atrial action potential even in the fibrillating atrium and may therefore support or even anticipate reversal of electrical remodeling. Such pharmacological reversal of electrical remodeling may only transiently be required, i.e. until electrical remodeling is in itself reversed by the natural restoration of normal atrial electrophysiology. Atrial action potential prolongation beyond normal values may indeed even be pro-arrhythmic. Therefore, it is tempting to treat the main electrophysiological end point of electrical remodeling, shortening of atrial action potential duration, by a limited short-term use of action potential-prolonging antiarrhythmic drugs.

Hypothesis: Targeted "pharmacological reversal" of atrial remodeling by short-term administration of action potential prolonging antiarrhythmic drugs (4 weeks therapy duration) is equally efficient and potentially safer to prevent recurrent AF after cardioversion when compared to current long-term antiarrhythmic drug therapy.

Trial design: This is a prospective, randomized, controlled, open label, parallel group multi-center investigator-initiated trial. The study medication is prescribed in an open fashion. We chose an open design in order to increase external validity ("relevance for clinical practice") of the results.

After successful cardioversion, patients will be randomized to one of three treatment groups:

Group A: No antiarrhythmic treatment

Group B: 4 weeks antiarrhythmic treatment with flecainide

Group C: Standard long term antiarrhythmic treatment (6 months) with flecainide

Group sizes were calculated to allow demonstration of non-inferiority of the two active treatment arms with a 10% boundary.

Flecainide was chosen for antiarrhythmic treatment in the Flec-SL trial because it is effective in the prevention of recurrent AF after cardioversion in the absence of major structural heart disease, has been safe as an outpatient treatment for recurrent AF, and prolongs the atrial action potential in patients with AF. In addition to its action potential-prolonging effect, flecainide induces post-repolarization refractoriness in the atria, an electrophysiological effect that may assist in the prevention of recurrent AF.

This is an investigator-initiated trial. Sponsor is the AFNET (www.kompetenznetz-vorhofflimmern.de).

Primary end point is the time to persistent AF as assessed by daily telemetric ECG recordings and confirmed by conventional Holter ECG recordings. Secondary end points include burden of AF, time to first symptomatic episode of AF, AF burden (number and duration of AF episodes), number of hospitalizations due to AF, time to termination of trial medication, number of serious adverse events including pro-arrhythmic events, and quality of life. Details of the secondary end points are indicated in the approved trial protocol.

All patients are systematically followed for 6 months by daily telemetric ECG recordings. All recordings are obtained using miniaturized ECG recorders which allow recording of a 60-second ECG and transtelephonic ECG transmission of the ECG via a toll-free number. All ECGs are received at the central analysis unit located at the Institute for Clinical Cardiovascular Research (IKKF) in Munich. Each telemetric ECG is analyzed within 24 hours of receipt at the analysis unit. The study physician is informed in case of any abnormal results within these 24 hours. Suspicion of persistent atrial fibrillation in the Tele-ECG prompts a local visit to record a Holte ECG. The Holter ECGs are centrally analyzed (blinded end point analysis). The systematic telemetric ECG monitoring allows for detection of all episodes of recurrent persistent AF.

Study Type

Interventional

Enrollment (Actual)

760

Phase

  • Not Applicable

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Documented persistent atrial fibrillation
  • Age of 18 years
  • Documented oral anticoagulation (INR ≥ 2) for at least three weeks prior to inclusion, or exclusion of left atrial thrombi by trans-esophageal echocardiography
  • Written informed consent of the patient

Exclusion Criteria:

  • Current therapy with antiarrhythmic agents of class I and class III other than study medication flecainide. Such antiarrhythmic treatment must be stopped five half lives prior to enrollment. Five half lives correspond to 48 hours for almost all antiarrhythmic agents. For details regarding a specific agent, this information can be obtained through the internet at www.rote-liste.de or from the Fachinformation of the specific compound.
  • Long-term therapy with amiodarone within the last 6 months prior to inclusion
  • Symptomatic bradycardia or symptomatic sick sinus syndrome unless treated with a permanent pacemaker
  • Symptomatic higher degree AV nodal block (grade II or III) unless treated with a permanent pacemaker
  • Brugada syndrome
  • Typical angina pectoris symptoms at rest or during exercise
  • Known untreated coronary artery disease with high-degree coronary stenosis (> 80% reduction in luminal diameter)
  • Myocardial infarction within the last 3 months
  • Left ventricular ejection fraction of more than 40%
  • Creatinine clearance < 50 ml/min*1.73 m2 as determined by the Cockroft-Gould formula. The digital data management system will calculate this value for you during the inclusion process. For completeness of documentation, the formula is given below:
  • Men: Creatinine clearance (ml/min) = (140 - age(years)) * body weight (kg) / (72 * serum creatinine level (mg/dl))
  • Women: Value for men * 0,85
  • Manifest hepatic insufficiency
  • Hyperthyroidism or hypothyroidism manifested clinically and in laboratory tests (TSH, T3, T4)
  • Females who are pregnant or breast feeding
  • Females of childbearing potential who are not using a scientifically accepted method of contraception
  • Participation in a clinical trial within the last 30 days. Simultaneous participation in a registry (e.g. project AB1 of the AFNET) is permitted.
  • Drug addiction or chronic alcohol abuse
  • Legal incapacity, or other circumstances which would prevent the patient from understanding the aim, nature or extent of the clinical trial
  • Evidence of an uncooperative attitude
  • Prolongation of the QRS complex by more than 25% during flecainide treatment (measured as the difference in QRS duration between the baseline ECG and the ECG at cardioversion (34))

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
No Intervention: No antiarrhythmic treatment
Control group
Experimental: B-Flecainide treatment
4 weeks treatment with flecainide
Drug: Flecainide
Flecainide 2 - 3 x 100 mg/d The main difference between the two active therapy groups is the duration of treatment.
Other Names:
  • Flecainide in all its approved oral preparations
Experimental: C-Flecainide treatment
6 months flecainide treatment
Drug: Flecainide
Flecainide 2 - 3 x 100 mg/d The main difference between the two active therapy groups is the duration of treatment.
Other Names:
  • Flecainide in all its approved oral preparations

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Time Frame
time to persistent atrial fibrillation as determined by daily telemetric ECG recordings and verified by Holter ECG recording
Time Frame: primary endpoint
primary endpoint

Secondary Outcome Measures

Outcome Measure
Time Frame
time to first symptomatic episode of AF
Time Frame: end of trial
end of trial
AF burden (number and duration of AF episodes)
Time Frame: end of trial
end of trial
number of hospitalizations due to AF
Time Frame: end of trial
end of trial
time to termination of trial medication
Time Frame: end of trial
end of trial
number of serious adverse events including pro-arrhythmic events
Time Frame: end of trial
end of trial
quality of life
Time Frame: end of trial
end of trial

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Atrial Fibrillation Network

Collaborators

German Research Foundation
German Federal Ministry of Education and Research
Meda Pharmaceuticals

Investigators

  • Principal Investigator: P Kirchhof, Prof, AFNET, Kompetenznetz Vorhofflimmern
  • Principal Investigator: G Breithardt, Prof, AFNET, Kompetenznetz Vorhofflimmern

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2005

Primary Completion (Actual)

October 1, 2009

Study Completion (Actual)

March 1, 2011

Study Registration Dates

First Submitted

September 14, 2005

First Submitted That Met QC Criteria

September 14, 2005

First Posted (Estimate)

September 22, 2005

Study Record Updates

Last Update Posted (Estimate)

September 11, 2012

Last Update Submitted That Met QC Criteria

September 10, 2012

Last Verified

September 1, 2012

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • AFNET-B11

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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