Flecainide-Short Long Study (Flec-SL)
Information source: German Atrial Fibrillation Network
Information obtained from ClinicalTrials.gov on December 08, 2011
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Atrial Fibrillation
Intervention: Flecainid (Drug)
Sponsored by: German Atrial Fibrillation Network
Official(s) and/or principal investigator(s):
Paulus - Kirchhof, PD, Dr., Principal Investigator, Affiliation: AFNET, Kompetenznetz Vorhofflimmern
Günter - Breithardt, Prof., Dr., Principal Investigator, Affiliation: AFNET, Kompetenznetz Vorhofflimmern
Paulus - Kirchhof, PD, Dr.med., Phone: ++49(0) 251-83 45160, Ext: -, Email: firstname.lastname@example.org
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.
Official title: Targeted Pharmacological Reversal of Electrical Remodeling After Cardioversion.
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: time to persistent atrial fibrillation as determined by daily telemetric ECG recordings and verified by Holte ECg recording
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
quality of life
Details of the trial are described in a design paper that will appear soon 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
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
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.
Minimum age: 18 Years.
Maximum age: N/A.
- 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
- 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
- Symptomatic higher degree AV nodal block (grade II or III) unless treated with a
- 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 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,
- Females who are pregnant or breast feeding
- Females of childbearing potential who are not using a scientifically accepted method
- 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
Locations and Contacts
Paulus - Kirchhof, PD, Dr.med., Phone: ++49(0) 251-83 45160, Ext: -, Email: email@example.com
University Hospital of Muenster, Muenster, Nordrhein-Westfalen 48129, Germany; Recruiting
Paulus - Kirchhof, PD, Dr., Phone: ++49-(0)251 83 45160, Email: firstname.lastname@example.org
Sabine - Juergensmeyer, Dr., Phone: ++49-(0)251 83 47624, Email: email@example.com
Paulus - Kirchhof, PD, Dr., Principal Investigator
Günter - Breithardt, Prof., Dr., Principal Investigator
Stefan - Orwat, Dr., Sub-Investigator
Sabine - Juergensmeyer, Dr., Sub-Investigator
Kompetenznetz Vorhofflimmern (AFNET)
Starting date: March 2005
Last updated: December 9, 2005