Effect and Safety of Flecainide and Metoprolol Versus Metoprolol Alone to Suppress Ventricular Arrhythmias in Arrhythmic Mitral Valve Prolapse (FLECAPRO)

Effect and Safety of Flecainide and Metoprolol Versus Metoprolol Alone to Suppress Ventricular Arrhythmias in Arrhythmic Mitral Valve Prolapse

An Investigator-Initiated Prospective Randomized Open-Label Blinded-Endpoint Crossover Trial Comparing the Effect and Safety of Flecainide and Metoprolol Versus Metoprolol Alone to Suppress Ventricular Arrhythmias in Arrhythmic Mitral Valve Prolapse

FLECAPRO is a randomized controlled crossover trial assessing the effect and safety of adding flecainide to standard beta-blocker therapy to reduce the burden of ventricular arrhythmias in patients with arrhythmic mitral valve prolapse. The primary endpoint of will be assessed using an implantable loop recorder with blinded endpoint adjudication.

Mitral valve prolapse (MVP) is a common condition characterized by bulging one or both mitral leaflets into the left atrium. Although mainly a benign cardiac condition, a subgroup of patients develop severe ventricular arrhythmias that are a significant cause of sudden cardiac death in young adults. Arrhythmic MVP is defined as the presence of mitral valve prolapse with or without mitral annulus disjunction (MAD) combined with frequent ventricular ectopy, complex ectopy or sustained ventricular arrhythmia in the absence of another well-defined arrhythmic substrate. In these patients, ventricular arrhythmias most commonly originate from the mitral annulus, papillary muscles and outflow tracts. Several risk markers have been proposed, but clinical risk stratification remains challenging. Ventricular arrhythmias in patients with arrhythmic mitral valve prolapse are associated with excess long-term mortality. There is no established medical therapy to suppress ventricular arrhythmias and relieve arrhythmic symptoms in these patients, and conventional beta-blocker therapy is often unsuccessful for both. Invasive catheter ablation can suppress ventricular arrhythmias, and thus relieve symptoms, in a subset of patients. However, many patients have multifocal ventricular ectopy, often originating from deep in the myocardium or papillary muscles and not easily accessible for catheter ablation. Furthermore, recurrence of ventricular arrhythmias is common despite initial successful catheter ablation procedures. The only strategy to prevent sudden cardiac death for high-risk patients is to implant an implantable cardioverter defibrillator (ICD), but this approach does not provide any symptomatic relief. Thus, most patients with arrhythmic mitral valve prolapse lack effective treatment options with proven efficacy in clinical trials. Flecainide is a class 1c antiarrhythmic drug with a potent sodium channel-blocking effect frequently used in atrial tachyarrhythmias. Flecainide was developed as a treatment for ventricular arrhythmias, but its use subsided due to safety concerns when used in patients with acute myocardial infarction. However, this knowledge stems from a patient population before modern revascularization strategies after myocardial infarction and is extrapolated to patients with other structural heart diseases. Lately, flecainide has been shown to be safe in patients with stable coronary artery disease. Furthermore, flecainide reduces ventricular arrhythmias in patients with premature ventricular complex (PVC)-mediated cardiomyopathy, arrhythmogenic cardiomyopathy and catecholaminergic polymorphic ventricular tachycardia without short-term adverse effects. However, flecainide has not been studied in arrhythmic mitral valve prolapse patients. The main goal of FLECAPRO is to evaluate the effect and safety of adding flecainide to standard beta-blocker therapy to reduce the burden of ventricular arrhythmias in patients with arrhythmic mitral valve prolapse. We hypothesize that a flecainide-based strategy is superior to a beta blocker-based strategy to suppress ventricular arrhythmias in patients with arrhythmic mitral valve prolapse.

Separate endpoint adjudication committee blinded to randomized allocation of patients to treatment groups

Participants will receive flecainide 50 mg twice daily (BID), with a dosage target of 100 mg BID. The maximum daily dose of flecainide will not exceed 300 mg. The first dose of flecainide will be initiated in-hospital with a 12-lead electrocardiogram (ECG) taken after 3 hours. If the ECG is considered normal after flecainide treatment, the participant will continue with 50 mg BID from the next day. Participants will receive a dosage of Metoprolol taking into consideration prior beta-blocker use and concomitant medications. The maximum daily dose of metoprolol will not exceed 200 mg. Within the run-in period, the dosage of both Flecainide and Metoprolol will be increased to the maximum tolerable dose. The Study Team can change the immediate-release formulation of Flecainide to controlled release at the same daily dose of flecainide. Whether metoprolol sustained release will be dosed once daily (QD) or BID, will be up to the investigator and patient preference.

Participants will receive a dosage of Metoprolol taking into consideration prior beta-blocker use and concomitant medications. Within the run-in period, the dosage will be increased to the maximum tolerable dose. Whether metoprolol sustained release will be dosed QD or BID, will be up to the investigator and patient preference. The maximum daily dose of metoprolol will not exceed 200 mg.

Flecainide is mainly used for pharmacological conversion in patients with atrial tachyarrhythmias and to suppress ventricular arrhythmias in patients with structurally normal hearts.

Metoprolol is a beta-blocker and class II antiarrhythmic drug considered standard care in most cardiac diseases predisposing to ventricular arrhythmias, including arrhythmic mitral valve prolapse.

Sum of ventricular fibrillation and ventricular tachycardia (broad complex tachycardia with heart rate >140/min) on implantable loop recorder during 12 months. Intention-to-treat, superiority.

First hierarchical key secondary outcome. Assessed by 24-hour Holter monitoring. Intention-to-treat, superiority

Second hierarchical key secondary outcome. Number of patients with ≥5-point increase in Short Form 36 overall summary score. Intention-to-treat, superiority

Third hierarchical key secondary outcome. Sum of (i) non-sustained ventricular tachycardia with syncope, (ii) sustained ventricular tachycardia and (iii) ventricular fibrillation. Intention-to-treat, superiority

Sum of (i) number of adverse events, (ii) number of serious adverse events, and (iii) higher degree atrioventricular (AV)-block (Mobitz type 2 or 3rd-degree AV-block). Safety population.

Exploratory outcome of the individual component of the primary endpoint. Ventricular tachycardia (broad complex tachycardia with heart rate >140/min) on implantable loop recorder during 12 months.

Exploratory outcome of the individual component of the primary endpoint. Ventricular fibrillations on implantable loop recorder during 12 months.

Exploratory outcome of the individual component of key secondary endpoints. Assessed by 24-hour Holter monitoring

Exploratory outcome of the individual component of key secondary endpoints. Number of patients with ≥5-point increase in Short Form 36 overall summary score.

Exploratory outcome of the individual component of key secondary endpoints. Sum of (i) non-sustained ventricular tachycardia with syncope, (ii) sustained ventricular tachycardia and (iii) ventricular fibrillation.

Exploratory outcome. Assessed by change in the Hospital Anxiety and Depression Scale (HADS) questionnaire (0-21 with higher scores indicating greater anxiety or depression).

Exploratory outcome. Sum of ventricular fibrillation and ventricular tachycardia (broad complex tachycardia with heart rate >140/min) on implantable loop recorder during 12 months. Per-protocol sensitivity analysis.

Exploratory outcome. Sum of (i) number of adverse events, (ii) number of serious adverse events, and (iii) higher degree AV-block (Mobitz type 2 or 3rd-degree AV-block). Intention-to-treat.

Inclusion Criteria: Participants must be 18 years of age or older at the time of signing the informed consent. Participants must have mitral valve prolapse evident by echocardiography or cardiac magnetic resonance imaging, defined as more than or equal to 2 mm atrial displacement of any part of the mitral leaflets. Participants must have ventricular arrhythmias, defined as at least one of the following (i) premature ventricular complex burden ≥3% per 24 hours by Holter monitoring, (ii) premature ventricular complex burden ≥1% per 24 hours if multifocal or occurring in bi-/trigemini and/or couplets by Holter monitoring, (iii) sustained or non-sustained ventricular tachycardia, (iv) aborted cardiac arrest. Participants must have a clinical indication for antiarrhythmic treatment due to ventricular arrhythmias. Participants must be capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF). Participants (only women of childbearing) must accede to mandatory use of a contraceptive method for the duration of the trial and until 3 days after discontinuation of study medication. Exclusion Criteria: Strict contraindications to flecainide or metoprolol use Heart failure (signs or symptoms, elevated N-terminal proBNP) Abnormal liver or kidney function (Aspartate aminotransferase (AST)/Alanine aminotransferase (ALT) three times upper normal, estimated glomerular filtration (eGRF) <60) Prior myocardial infarction or ischemic heart disease Ion channelopathy, including Brugada syndrome and long QT syndrome Genetic cardiomyopathy (hypertrophic cardiomyopathy, arrhythmogenic cardiomyopathy, dilated cardiomyopathy, including genotype positive phenotype negative individuals) Atrial flutter or permanent atrial fibrillation Sinus node dysfunction Ongoing electrolyte disorders More than moderate valvular disease according to international guidelines Pre-excitation Any degree of AV-block, except due to enhanced vagal tone (e.g. Wenckebach-block at night in young athletes or 1st-degree AV block that disappears during exercise) Bundle branch block (QRS duration >120 ms) or intraventricular conduction defect with QRS >120 ms. Prior flecainide therapy. Concomitant use of the following medications (i) CYP2D6 inhibitors/mediators, (ii) class I, III or IV antiarrhythmic drugs, (iii) clozapine, quinidine, cimetidine, bupropion, or (iii) monoamineoxidase (MAO) inhibitors Pregnancy Not willing to use a mandatory contraceptive method for the duration of the trial.

We will share anonymized data sets with the medical community via the medical journal upon submitting the manuscript.

Will be made available with the publication of the primary analysis and remain available for 1 year. Thereafter, it can be made available upon request.

Researchers and clinicians with valid medical questions to be addressed. The data will not be available for commercial use.

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