Dataset Information

Safety and efficacy of flecainide for patients with catecholaminergic polymorphic ventricular tachycardia: A systematic review and meta-analysis.

ABSTRACT:

Background

Owing to reports of recurrent cardiac events in some catecholaminergic polymorphic ventricular tachycardia (CPVT) patients using ?-blockers, safer alternatives are being investigated. Flecainide is an alternative adjunctive anti-arrhythmic agent known to provide incomplete protection to CPVT patients.

Methods

To investigate the efficacy and tolerability of flecainide, we searched 4 databases for retrospective cohort studies (RCs) and randomized controlled trials (RCTs) investigating the efficacy and safety of flecainide for CPVT patients. Data were extracted and analyzed (risk ratio [RR] or mean difference [MD]) using RevMan software. Seven RCs and 1 RCT (333 CPVT patients; 152 patients treated with flecainide) were identified.

Results

Flecainide monotherapy was superior to standard therapy in alleviating the risk of arrhythmic events (RR?=?0.46, confidence interval [CI]?=?[0.38, 0.56], P?ConclusionsFlecainide is an effective and safe anti-arrhythmic agent, and its use as a monotherapy might be a good alternative for CPVT patients with ?-blocker intolerance. Combination therapy was superior to ?-blocker monotherapy. More randomized clinical trials are required to explore the long-term efficacy and safety of flecainide in these patients.

SUBMITTER: Wang G

PROVIDER: S-EPMC6716729 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Publications

Safety and efficacy of flecainide for patients with catecholaminergic polymorphic ventricular tachycardia: A systematic review and meta-analysis.

Wang Guangqiang G Zhao Na N Zhong Shu S Wang Yingrong Y Li Jianping J

Medicine 20190801 34

<h4>Background</h4>Owing to reports of recurrent cardiac events in some catecholaminergic polymorphic ventricular tachycardia (CPVT) patients using β-blockers, safer alternatives are being investigated. Flecainide is an alternative adjunctive anti-arrhythmic agent known to provide incomplete protection to CPVT patients.<h4>Methods</h4>To investigate the efficacy and tolerability of flecainide, we searched 4 databases for retrospective cohort studies (RCs) and randomized controlled trials (RCTs) ...[more]

PMID: 31441899

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Project description:ImportanceCatecholaminergic polymorphic ventricular tachycardia (CPVT) is a potentially lethal genetic arrhythmia syndrome characterized by polymorphic ventricular tachycardia with physical or emotional stress, for which current therapy with β-blockers is incompletely effective. Flecainide acetate directly suppresses sarcoplasmic reticulum calcium release-the cellular mechanism responsible for triggering ventricular arrhythmias in CPVT-but has never been assessed prospectively.ObjectiveTo determine whether flecainide dosed to therapeutic levels and added to β-blocker therapy is superior to β-blocker therapy alone for the prevention of exercise-induced arrhythmias in CPVT.Design, setting, and participantsThis investigator-initiated, multicenter, single-blind, placebo-controlled crossover clinical trial was conducted from December 19, 2011, through December 29, 2015, with a midtrial protocol change at 10 US sites. Patients with a clinical diagnosis of CPVT and an implantable cardioverter-defibrillator underwent a baseline exercise test while receiving maximally tolerated β-blocker therapy that was continued throughout the trial. Patients were then randomized to treatment A (flecainide or placebo) for 3 months, followed by exercise testing. After a 1-week washout period, patients crossed over to treatment B (placebo or flecainide) for 3 months, followed by exercise testing.InterventionsPatients received oral flecainide or placebo twice daily, with the dosage guided by trough serum levels.Main outcomes and measuresThe primary end point of ventricular arrhythmias during exercise was compared between the flecainide and placebo arms. Exercise tests were scored on an ordinal scale of worst ventricular arrhythmia observed (0 indicates no ectopy; 1, isolated premature ventricular beats; 2, bigeminy; 3, couplets; and 4, nonsustained ventricular tachycardia).ResultsOf 14 patients (7 males and 7 females; median age, 16 years [interquartile range, 15.0-22.5 years]) randomized, 13 completed the study. The median baseline exercise test score was 3.0 (range, 0-4), with no difference noted between the baseline and placebo (median, 2.5; range, 0-4) exercise scores. The median ventricular arrhythmia score during exercise was significantly reduced by flecainide (0 [range, 0-2] vs 2.5 [range, 0-4] for placebo; P < .01), with complete suppression observed in 11 of 13 patients (85%). Overall and serious adverse events did not differ between the flecainide and placebo arms.Conclusions and relevanceIn this randomized clinical trial of patients with CPVT, flecainide plus β-blocker significantly reduced ventricular ectopy during exercise compared with placebo plus β-blocker and β-blocker alone.Trial registrationclinicaltrials.gov Identifier: NCT01117454.

Project description:RationaleAutosomal-dominant mutations in ryanodine receptor type 2 ( RYR2) are responsible for ≈60% of all catecholaminergic polymorphic ventricular tachycardia. Dysfunctional RyR2 subunits trigger inappropriate calcium leak from the tetrameric channel resulting in potentially lethal ventricular tachycardia. In vivo CRISPR/Cas9-mediated gene editing is a promising strategy that could be used to eliminate the disease-causing Ryr2 allele and hence rescue catecholaminergic polymorphic ventricular tachycardia.ObjectiveTo determine if somatic in vivo genome editing using the CRISPR/Cas9 system delivered by adeno-associated viral (AAV) vectors could correct catecholaminergic polymorphic ventricular tachycardia arrhythmias in mice heterozygous for RyR2 mutation R176Q (R176Q/+).Methods and resultsGuide RNAs were designed to specifically disrupt the R176Q allele in the R176Q/+ mice using the SaCas9 ( Staphylococcus aureus Cas9) genome editing system. AAV serotype 9 was used to deliver Cas9 and guide RNA to neonatal mice by single subcutaneous injection at postnatal day 10. Strikingly, none of the R176Q/+ mice treated with AAV-CRISPR developed arrhythmias, compared with 71% of R176Q/+ mice receiving control AAV serotype 9. Total Ryr2 mRNA and protein levels were significantly reduced in R176Q/+ mice, but not in wild-type littermates. Targeted deep sequencing confirmed successful and highly specific editing of the disease-causing R176Q allele. No detectable off-target mutagenesis was observed in the wild-type Ryr2 allele or the predicted putative off-target site, confirming high specificity for SaCas9 in vivo. In addition, confocal imaging revealed that gene editing normalized the enhanced Ca2+ spark frequency observed in untreated R176Q/+ mice without affecting systolic Ca2+ transients.ConclusionsAAV serotype 9-based delivery of the SaCas9 system can efficiently disrupt a disease-causing allele in cardiomyocytes in vivo. This work highlights the potential of somatic genome editing approaches for the treatment of lethal autosomal-dominant inherited cardiac disorders, such as catecholaminergic polymorphic ventricular tachycardia.

Dataset Information

Safety and efficacy of flecainide for patients with catecholaminergic polymorphic ventricular tachycardia: A systematic review and meta-analysis.

Background

Methods

Results

Publications

Safety and efficacy of flecainide for patients with catecholaminergic polymorphic ventricular tachycardia: A systematic review and meta-analysis.

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