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Concept: Antiarrhythmic agent

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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

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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

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BACKGROUND: -Supraventricular tachycardia (SVT) is one of the most common conditions requiring emergent cardiac care in children yet its management has never been subjected to a randomized controlled clinical trial. The purpose of this study was to compare the efficacy and safety of the 2 most commonly used medications for antiarrhythmic prophylaxis of SVT in infants: digoxin and propranolol. METHODS AND RESULTS: -This was a randomized, double-blind, multi-center study of infants <4 months with SVT (AVRT or AVNRT), excluding Wolff-Parkinson-White, comparing digoxin to propranolol. The primary end-point was recurrence of SVT requiring medical intervention. Time to recurrence and adverse events were secondary outcomes. Sixty-one patients completed the study, 27 randomized to digoxin and 34 to propranolol. SVT recurred in 19% of patients on digoxin and 31% of patients on propranolol. (P=0.25). No recurrence occurred after 110 days of treatment. The 6-month recurrence-free status was 79% for patients on digoxin and 67% for patients on propranolol (P=0.34, and there were no first recurrences in either group between 6 and 12 months. There were no deaths and no serious adverse events related to study medication. CONCLUSIONS: -There was no difference in SVT recurrence in infants treated with digoxin versus propranolol. The current standard practice may be treating infants longer than required and indicates the need for a placebo-controlled trial. Clinical Trial Registration Information-http://clinicaltrials.gov; NCT-00390546.

Concepts: Pharmacology, Clinical trial, Randomized controlled trial, Pharmaceutical industry, Clinical research, Supraventricular tachycardia, Antiarrhythmic agent, Tachycardia

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Ventricular arrhythmias may be benign, requiring only evaluation for associated risks and then reassurance, or associated with a risk of sudden death or significant morbidity. Therapies for these arrhythmias have evolved considerably over the past twenty years. For some, a definitive, curative therapy is available in the form of catheter ablation. Others are best managed with an implantable defibrillator that provides effective arrhythmia termination and protection from sudden death, with antiarrhythmic drugs or ablation to control recurrent arrhythmias. Although progress has been substantial, many challenges remain.

Concepts: Medicine, Risk, Implantable cardioverter-defibrillator, Therapy, Cardiac electrophysiology, Antiarrhythmic agent, Therapy?, Cardiac dysrhythmia

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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

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Background Recurrent ventricular tachycardia among survivors of myocardial infarction with an implantable cardioverter-defibrillator (ICD) is frequent despite antiarrhythmic drug therapy. The most effective approach to management of this problem is uncertain. Methods We conducted a multicenter, randomized, controlled trial involving patients with ischemic cardiomyopathy and an ICD who had ventricular tachycardia despite the use of antiarrhythmic drugs. Patients were randomly assigned to receive either catheter ablation (ablation group) with continuation of baseline antiarrhythmic medications or escalated antiarrhythmic drug therapy (escalated-therapy group). In the escalated-therapy group, amiodarone was initiated if another agent had been used previously. The dose of amiodarone was increased if it had been less than 300 mg per day or mexiletine was added if the dose was already at least 300 mg per day. The primary outcome was a composite of death, three or more documented episodes of ventricular tachycardia within 24 hours (ventricular tachycardia storm), or appropriate ICD shock. Results Of the 259 patients who were enrolled, 132 were assigned to the ablation group and 127 to the escalated-therapy group. During a mean (±SD) of 27.9±17.1 months of follow-up, the primary outcome occurred in 59.1% of patients in the ablation group and 68.5% of those in the escalated-therapy group (hazard ratio in the ablation group, 0.72; 95% confidence interval, 0.53 to 0.98; P=0.04). There was no significant between-group difference in mortality. There were two cardiac perforations and three cases of major bleeding in the ablation group and two deaths from pulmonary toxic effects and one from hepatic dysfunction in the escalated-therapy group. Conclusions In patients with ischemic cardiomyopathy and an ICD who had ventricular tachycardia despite antiarrhythmic drug therapy, there was a significantly lower rate of the composite primary outcome of death, ventricular tachycardia storm, or appropriate ICD shock among patients undergoing catheter ablation than among those receiving an escalation in antiarrhythmic drug therapy. (Funded by the Canadian Institutes of Health Research and others; VANISH ClinicalTrials.gov number, NCT00905853 .).

Concepts: Pharmacology, Myocardial infarction, Cardiology, Ventricular tachycardia, Supraventricular tachycardia, Antiarrhythmic agent, Amiodarone, Ventricular fibrillation

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Catheter ablation is increasingly offered to patients who suffer from symptoms due to atrial fibrillation (AF), based on a growing body of evidence illustrating its efficacy compared with antiarrhythmic drug therapy. Approximately one-third of AF ablation procedures are currently performed in patients with persistent or long-standing persistent AF. Here, we review the available information to guide catheter ablation in these more chronic forms of AF. We identify the following principles: Our clinical ability to discriminate paroxysmal and persistent AF is limited. Pulmonary vein isolation is a reasonable and effective first approach for catheter ablation of persistent AF. Other ablation strategies are being developed and need to be properly evaluated in controlled, multicentre trials. Treatment of concomitant conditions promoting recurrent AF by life style interventions and medical therapy should be a routine adjunct to catheter ablation of persistent AF. Early rhythm control therapy has a biological rationale and trials evaluating its value are underway. There is a clear need to generate more evidence for the best approach to ablation of persistent AF beyond pulmonary vein isolation in the form of adequately powered controlled multi-centre trials.

Concepts: Medicine, Heart, Atrial fibrillation, Therapy, Antiarrhythmic agent

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This article is one of ten reviews selected from the Annual Update in Intensive Care and Emergency medicine 2017. Other selected articles can be found online at http://ccforum.com/series/annualupdate2017 . Further information about the Annual Update in Intensive Care and Emergency Medicine is available from http://www.springer.com/series/8901 .

Concepts: Myocardial infarction, Cardiology, Cardiac arrest, Asystole, Cardiac electrophysiology, Antiarrhythmic agent, Amiodarone, Ventricular fibrillation

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Background -Out-of-hospital cardiac arrest (OHCA) commonly presents with non-shockable rhythms (asystole and pulseless electrical activity (PEA)). Whether antiarrhythmic drugs are safe and effective when these evolve to shockable rhythms (ventricular fibrillation/pulseless ventricular tachycardia (VF/VT)) during resuscitation is not known. Methods -Adults with non-traumatic OHCA, vascular access and VF/VT anytime after ≥1 shock(s) were prospectively randomized, double-blind, to receive amiodarone, lidocaine or placebo by paramedics. Patients presenting with initial shock-refractory VF/VT were previously reported. The current study was a pre-specified analysis in a separate cohort who initially presented with non-shockable OHCA and were randomized upon subsequently developing shock-refractory VF/VT. The primary outcome was survival to hospital discharge; secondary outcomes included discharge functional status and adverse drug-related effects. Results -Of 37,889 patients with OHCA, 3,026 with initial VF/VT and 1,063 with initial non-shockable-turned-shockable rhythms were treatment-eligible, randomized and received their assigned drug. Baseline characteristics among non-shockable-turned-shockable patients were balanced across treatment arms except that placebo recipients included fewer men and were less likely to receive bystander-CPR. Active-drug recipients in this cohort required fewer shocks, supplemental doses of their assigned drug and ancillary antiarrhythmic drugs than placebo-recipients (p<0.05). In all, 16 (4.1%) amiodarone, 11 (3.1%) lidocaine and 6 (1.9%) placebo-treated patients survived to hospital discharge (p=0.24). There was no significant interaction of treatment assignment and discharge survival with the initiating OHCA rhythm (asystole, PEA, or VF/VT); survival in each of these categories was consistently higher with active-drugs, though the trends were not statistically significant. Adjusted absolute differences (95% confidence interval) in survival from non-shockable-turned-shockable arrhythmias with amiodarone vs placebo were 2.3% (-0.3, 4.8), p=0.08 and for lidocaine vs placebo 1.2% (-1.1, 3.6), p=0.30. Over one-half of these survivors were functionally independent or required minimal assistance. Drug-related adverse effects were infrequent. Conclusions -Outcome from non-shockable-turned-shockable OHCA is poor, but not invariably fatal. Though not statistically significant, point estimates for survival were greater after amiodarone or lidocaine than placebo, without increased risk of adverse effects or disability, and consistent with previously observed favorable trends from treatment of initial shock-refractory VF/VT with these drugs. Together the findings may signal a clinical benefit that invites further investigation. Clinical Trial Registration -URL: ClinicalTrials.gov Unique Identifier: NCT01401647.

Concepts: Pharmacology, Clinical trial, Myocardial infarction, Cardiac arrest, Supraventricular tachycardia, Antiarrhythmic agent, Amiodarone, Ventricular fibrillation