Clinical trial NCT05631730: Effect and Safety of Flecainide and Metoprolol Versus Metoprolol Alone to Suppress Ventricular Arrhythmias in Arrhythmic Mitral Valve Prolapse
Official title: 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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Mitral Valve Prolapse
Ventricular Arrhythmias and Cardiac Arrest
Keywords: arrhythmic mitral valve prolapse
mitral annular disjunction
ventricular arrhythmia
Lead sponsor: Oslo University Hospital
Sponsor class: OTHER
Collaborators: name: The Research Council of Norway
name: University of Oslo
First posted: 2022-11-30
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Intervention model description: Crossover prospective randomized open-label blinded-endpoint (PROBE) trial.
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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/inducers, (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.

Primary outcomes:
measure: Number of ventricular tachyarrhythmias
timeFrame: 12 months
Secondary outcomes:
measure: Burden of premature ventricular complexes
timeFrame: 12 months
measure: Change in health-related quality of life
timeFrame: 12 months
measure: Number of severe ventricular tachycardias
timeFrame: 12 months
measure: Safety composite
timeFrame: 12 months
Other outcomes:
measure: Number of ventricular tachycardias
timeFrame: 12 months
measure: Number of ventricular fibrillations
timeFrame: 12 months
measure: Burden of premature ventricular complexes
timeFrame: 12 months
measure: Health-related quality of life
timeFrame: 12 months
measure: Number of severe ventricular arrhythmias
timeFrame: 12 months
measure: Cardiac function
timeFrame: 12 months
measure: N-terminal pro-B-type natriuretic peptide
timeFrame: 12 months
measure: Change in New York Heart Association (NYHA) class
timeFrame: 12 months
measure: Change in T-wave inversions
timeFrame: 12 months
measure: Change in degree of mitral regurgitation
timeFrame: 12 months
measure: Change in health-related quality of life - Hospital Anxiety and Depression Scale questionnaire
timeFrame: 12 months
measure: Primary endpoint sensitivity analysis
timeFrame: 12 months
measure: Secondary safety endpoint sensitivity analysis
timeFrame: 12 months
Locations:
city: Oslo
country: Norway
facility: Oslo University Hospital Rikshospitalet
Study officials:
affiliation: Department of Cardiology, Oslo University Hospital Rikshospitalet, Oslo, Norway
name: Eivind W Aabel, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: