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Concept: Flecainide

157

We sought to describe the management of patients with atrial fibrillation (AF) in Europe after the release of the 2010 AF Guidelines of the European Society of Cardiology.METHODS AND RESULTS: The PREFER in AF registry enrolled consecutive patients with AF from January 2012 to January 2013 in 461 centres in seven European countries. Seven thousand two hundred and forty-three evaluable patients were enrolled, aged 71.5 ± 11 years, 60.1% male, CHA2DS2VASc score 3.4 ± 1.8 (mean ± standard deviation). Thirty per cent patients had paroxysmal, 24.0% had persistent, 7.2% had long-standing persistent, and 38.8% had permanent AF. Oral anticoagulation was used in the majority of patients: 4799 patients (66.3%) received a vitamin K antagonist (VKA) as mono-therapy, 720 patients a combination of VKA and antiplatelet agents (9.9%), 442 patients (6.1%) a new oral anticoagulant drugs (NOAC). Antiplatelet agents alone were given to 808 patients (11.2%), no antithrombotic therapy to 474 patients (6.5%). Of 7034 evaluable patients, 5530 (78.6%) patients were adequately rate controlled (mean heart rate 60-100 bpm). Half of the patients (50.7%) received rhythm control therapy by electrical cardioversion (18.1%), pharmacological cardioversion (19.5%), antiarrhythmic drugs (amiodarone 24.1%, flecainide or propafenone 13.5%, sotalol 5.5%, dronedarone 4.0%), and catheter ablation (5.0%).CONCLUSION: The management of AF patients in 2012 has adapted to recent evidence and guideline recommendations. Oral anticoagulant therapy with VKA (majority) or NOACs is given to over 80% of eligible patients, including those at risk for bleeding. Rate is often adequately controlled, and rhythm control therapy is widely used.

Concepts: Atrial fibrillation, Warfarin, Standard deviation, Anticoagulant, Amiodarone, Cardioversion, Vitamin K, Flecainide

28

The present studies explored the intrinsic vasorelaxant and inotropic effects of the mixed potassium and sodium channel blocker atrial antiarrhythmic vernakalant and the Class IC antiarrhythmic agent flecainide in human isolated subcutaneous resistance artery and ventricular trabecular muscle preparations. At test concentrations encompassing free plasma concentrations associated with clinical efficacy for conversion of atrial fibrillation, vernakalant (1-10 μM) displayed no significant direct effects on human resistance artery tone or ventricular contractility. In contrast, tested at equimolar concentrations, flecainide significantly reduced peak isometric contractile force (10 μM) and maximal rates of force development and decline (3 and 10 μM) in the human ventricular muscle preparation while displaying no significant effect on human resistance artery tone. The lack of effects of vernakalant on human resistance artery tone and ventricular muscle contractile function suggest that direct vasorelaxant and inotropic effects do not underlie the rare hypotensive events observed clinically with vernakalant, raising the possibility that secondary (e.g. reflex) effects may mediate these events. The demonstration of negative inotropic effects with flecainide in the human ventricular muscle preparations in the absence of an effect on resistance artery tone suggests that the hemodynamic effects of flecainide observed clinically result primarily from direct negative inotropic effects.

Concepts: Heart, Atrial fibrillation, Antiarrhythmic agent, Amiodarone, Antiarrhythmic agents, Flecainide

28

Objectives. Recent-onset (duration ≤ 1 week) atrial fibrillation (AF) has a high rate of spontaneous conversion to sinus rhythm (SR); still anti-arrhythmic drugs (AAD) are given for conversion purposes. We assessed the effect of AADs by reviewing the literature regarding conversion rates of available drugs in a systematic manner. Design. PubMed searches were performed using the terms “drug name”, “atrial fibrillation”, and “clinical study/RCT”, and a list of 1302 titles was generated. These titles, including abstracts or complete papers when needed, were reviewed for recent-onset of AF, the use of a control group, and the endpoint of SR within 24 hours. Postoperative and intensive care settings were excluded. Results. Five AADs were demonstrated to have an effect, and these were Amiodarone, Ibutilide (only one study and risk of torsade de pointes), Flecainide and Propafenone (only to be used in patients without structural heart disease) and Vernakalant. The time taken for conversion differed markedly; Vernakalant converted after 10 minutes, while Amiodarone converted only after 24 hours; Propafenone and Flecainide had conversion times in-between. Conclusions. For a rapid response in a broad group of patients, Vernakalant appears to be a reasonable first choice, while Flecainide and Propafenone can be used in patients without structural heart disease.

Concepts: Pharmacology, Heart, Atrial fibrillation, Ventricular tachycardia, Antiarrhythmic agent, Amiodarone, Antiarrhythmic agents, Flecainide

25

-Atrial fibrillation (AF) requires arrhythmogenic changes in atrial ion channels/receptors and usually altered atrial structure. AF is commonly treated with antiarrhythmic drugs (AADs); the most effective block many ion channels/receptors. Modest efficacy, intolerance, and safety concerns limit current AADs. We hypothesized that combining agents with multiple anti-AF mechanisms at reduced individual drug doses might produce synergistic efficacy plus better tolerance/safety.

Concepts: Atrial fibrillation, Cardiac electrophysiology, Atrial flutter, Amiodarone, Digoxin, Flecainide, Procainamide, Dronedarone

24

Suppressing perioperative inflammation and post-operative atrial fibrillation requires effective drug delivery platforms (DDP). Localized anti-inflammatory and anti-arrhythmic agent release may be more effective than intravenous treatment to improve patient outcomes. This study utilized a dexamethasone (DEX) and amiodarone (AMIO)-loaded Parylene-C (PPX) nano-structured film to inhibit inflammation and atrial fibrillation. The PPX film was tested in an established pericardial adhesion rabbit model. Following sternotomy, the anterior pericardium was resected and the epicardium was abraded. Rabbits were randomly assigned to five treatment groups: control, oxidized PPX (PPX-Oxd), PPX-Oxd infused with DEX (PPX-Oxd[DEX]), native PPX (PPX), and PPX infused with DEX and AMIO (PPX[AMIO, DEX]). 4 weeks post-sternotomy, pericardial adhesions were evaluated for gross adhesions using a 4-point grading system and histological evaluation for epicardial neotissue fibrosis (NTF). Atrial fibrillation duration and time per induction were measured. The PPX[AMIO, DEX] group had a significant reduction in mean adhesion score compared with the control group (control 2.75 ± 0.42 vs. PPX[AMIO, DEX] 0.25 ± 0.42, P < 0.001). The PPX[AMIO, DEX] group was similar to native PPX (PPX 0.38 ± 0.48 vs. PPX[AMIO, DEX] 0.25 ± 0.42, P[double bond, length as m-dash]NS). PPX-Oxd group adhesions were indistinguishable from controls (PPX-Oxd 2.83 ± 0.41 vs. control 2.75 ± 0.42, P[double bond, length as m-dash]NS). NTF was reduced in the PPX[AMIO, DEX] group (0.80 ± 0.10 mm) compared to control (1.78 ± 0.13 mm, P < 0.001). Total duration of atrial fibrillation was decreased in rabbits with PPX[AMIO, DEX] films compared to control (9.5 ± 6.8 s vs. 187.6 ± 174.7 s, p = 0.003). Time of atrial fibrillation per successful induction decreased among PPX[AMIO, DEX] films compared to control (2.8 ± 1.2 s vs. 103.2 ± 178 s, p = 0.004). DEX/AMIO-loaded PPX films are associated with reduced perioperative inflammation and a diminished atrial fibrillation duration. Epicardial application of AMIO, DEX films is a promising strategy to prevent post-operative cardiac complications.

Concepts: Heart, Redox, Atrial fibrillation, Antiarrhythmic agent, Pericardium, Amiodarone, Digoxin, Flecainide

3

Catecholaminergic 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.

Concepts: Clinical trial, Cardiology, Ventricular tachycardia, Amiodarone, Flecainide, Catecholaminergic polymorphic ventricular tachycardia

2

BACKGROUND: Standard radiofrequency ablation is effective in eliminating atrial fibrillation (AF), but requires multiple lesion delivery at the risk of significant complications. OBJECTIVES: The STOP AF Pivotal Trial was intended to assess the safety and effectiveness of a novel cryoballoon ablation technology designed to achieve single-delivery pulmonary vein (PV) isolation. METHODS: Patients with documented symptomatic paroxysmal AF and previously failed therapy with ≥ 1 membrane active anti-arrhythmic drug underwent 2:1 randomization to either cryoballoon ablation (n=163) or drug therapy (n=82). A 90-day blanking period allowed for optimization of anti-arrhythmic drug therapy and re-ablation if necessary. Effectiveness of the cryoablation procedure, versus drug therapy was determined at 12 months. RESULTS: Patients had highly symptomatic AF (78% paroxysmal, 22% early persistent) and had failed at least 1 antiarrhythmic drug. Cryoablation produced acute isolation of ≥ 3 PVs in 98.2% and all 4 PVs in 97.6% of patients; PVs isolation was achieved with the balloon catheter alone in 83%. At 12 months, treatment success was 69.9% (114/163) of cryoablation patients compared to 7.3% of anti-arrhythmic drug patients, [absolute difference: 62.6% (p < 0.001)]. Sixty-five (79%) of drug-treated patients crossed over to cryoablation during 12 months of study follow-up due to recurrent, symptomatic AF constituting drug treatment failure.There were 7 of the resulting 228 cryoablated patients (3.1%) with a ≥ 75% reduction in PV area during 12 months of follow-up. Twenty nine of 259 procedures (11.2%) were associated with phrenic nerve palsy as determined by X-ray screening; 25 of these had resolved by 12 months. Cryoablation patients had significantly improved symptoms at 12 months. CONCLUSION: The STOP-AF Trial demonstrated that cryoballoon ablation is a safe and effective alternative to anti-arrhythmic medication for the treatment of patients with symptomatic paroxysmal AF, who have failed at least one anti-arrhythmic drug, with risks within accepted standards for ablation therapy.

Concepts: Heart, Atrial fibrillation, Cardiac electrophysiology, Antiarrhythmic agent, Amiodarone, Digoxin, Flecainide, Procainamide

1

Atrial fibrillation (AF) is an extremely prevalent arrhythmia that presents a wide range of therapeutic challenges. AF usually begins in a self-terminating paroxysmal form (pAF). With time, the AF pattern often evolves to become persistent (nonterminating within 7 days). Important differences exist between pAF and persistent AF in terms of clinical features, in particular the responsiveness to antiarrhythmic drugs and ablation therapy. AF mechanisms have been extensively reviewed, but few or no Reviews focus specifically on the pathophysiology of pAF. Accordingly, in this Review, we examine the available data on the electrophysiological basis for pAF occurrence and maintenance, as well as the molecular mechanisms forming the underlying substrate. We first consider the mechanistic insights that have been obtained from clinical studies in the electrophysiology laboratory, noninvasive observations, and genetic studies. We then discuss the information about underlying molecular mechanisms that has been obtained from experimental studies on animal models and patient samples. Finally, we discuss the data available from animal models with spontaneous AF presentation, their relationship to clinical findings, and their relevance to understanding the mechanisms underlying pAF. Our analysis then turns to potential factors governing cases of progression from pAF to persistent AF and the clinical implications of the basic mechanisms we review. We conclude by identifying and discussing questions that we consider particularly important to address through future research in this area.

Concepts: Atrial fibrillation, Cardiac electrophysiology, Atrial flutter, Metaphysics, Amiodarone, Digoxin, Flecainide, Procainamide

1

Amiodarone (AMD) is a potent antiarrhythmic drug with high efficacy for treating atrial fibrillation and tachycardia. The pharmacologic profile of AMD is complex. AMD possesses biophysical characteristics of all of class I, II, III, and IV agents. Despite its adverse side effects, AMD remains the most commonly prescribed antiarrhythmic drug. AMD was described to prolong the QT interval and can lead to torsades de pointes. Our goal was to study the effects of AMD on peak and late sodium currents (INa,P and INa,L) and determine whether these effects change as AMD is metabolized into N-desethylamiodarone (DES). We hypothesized that AMD and DES block both INa,P and INa,L with similar profiles due to structural similarities. Given the inherent small amounts of INa,L in NaV1.5, we screened AMD and DES against the Long QT-3-causing mutation, ΔKPQ, to better detect any drug-mediated effect on INa,L. Our results show that AMD and DES do not affect WT or ΔKPQ activation; however, both drugs altered the apparent valence of steady-state fast-inactivation. In addition, AMD and DES preferentially block ΔKPQ peak conductance compared to WT. Both compounds significantly increase INa,L and window currents. We conclude that both compounds have pro-arrhythmic effects on NaV1.5, especially ΔKPQ; however, DES seems to have a greater pro-arrhythmic effect than AMD.

Concepts: Atrial fibrillation, Cardiac electrophysiology, Ventricular tachycardia, Antiarrhythmic agent, Adverse drug reaction, Amiodarone, Digoxin, Flecainide

1

Concerns have been expressed about the reliability of clinical practice guidelines. We analyzed 3 guidelines from medical specialty societies about dronedarone hydrochloride, an antiarrhythmic drug related to amiodarone hydrochloride, for treatment of patients with atrial fibrillation. We compared the recommendations in these guidelines with the conclusions about dronedarone that we reached by applying the Grading of Recommendations Assessment, Development and Evaluation (GRADE) Method to the same evidence base. In our analysis, as a rate control drug, dronedarone was better than placebo only for a surrogate outcome (heart rate). As a rhythm control drug, dronedarone was associated with 13 (95% CI, -15 to 61) excess deaths per 1000 patients treated as compared with placebo. Compared with amiodarone, dronedarone was less effective (214 [95% CI, 130 to 294] more recurrences of atrial fibrillation per 1000 patients treated) and similarly tolerated (-28 [95% CI, -69 to 33] more serious adverse events requiring drug suspension per 1000 patients treated). Despite the limits of the evidence, all 3 guidelines recommended dronedarone for prevention of recurrences of atrial fibrillation; 2 of the guidelines recommended it as a rate control agent. Our findings raise questions about the reliability of these clinical practice guidelines, as well as the financial associations between many of the panel members and the manufacturer of dronedarone.

Concepts: Clinical trial, Atrial fibrillation, Antiarrhythmic agent, Amiodarone, Digoxin, Antiarrhythmic agents, Flecainide, Dronedarone