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Etripamil is a fast-acting, intranasally administered calcium-channel blocker in development for on-demand therapy outside a health-care setting for paroxysmal supraventricular tachycardia. We aimed to evaluate the efficacy and safety of etripamil 70 mg nasal spray using a symptom-prompted, repeat-dose regimen for acute conversion of atrioventricular-nodal-dependent paroxysmal supraventricular tachycardia to sinus rhythm within 30 min.

Background: Diagnosing obstructive coronary artery disease (CAD) in at-risk patients can be challenging and typically requires both noninvasive imaging methods and coronary angiography, the gold standard. Previous studies have suggested that peripheral blood gene expression can indicate the presence of CAD. Objective: To validate a previously developed 23-gene, expression-based classification test for diagnosis of obstructive CAD in non-diabetic patients. Design: Multicenter prospective trial with blood samples obtained before coronary angiography. (ClinicalTrials.gov registration number: NCT00500617) Setting: 39 centers in the United States. Patients: An independent validation cohort of 526 nondiabetic patients with a clinical indication for coronary angiography. Measurements: Receiver-operating characteristic (ROC) analysis of classifier score measured by real-time polymerase chain reaction, additivity to clinical factors, and reclassification of patient disease likelihood versus disease status defined by quantitative coronary angiography. Obstructive CAD was defined as 50% or greater stenosis in 1 or more major coronary arteries by quantitative coronary angiography. Results: The area under the ROC curve (AUC) was 0.70 [+ or -] 0.02 (P < 0.001); the test added to clinical variables (Diamond--Forrester method) (AUC, 0.72 with the test vs. 0.66 without; P = 0.003) and added somewhat to an expanded clinical model (AUC, 0.745 with the test vs. 0.732 without; P = 0.089). The test improved net reclassification over both the Diamond--Forrester method and the expanded clinical model (P < 0.001). At a score threshold that corresponded to a 20% likelihood of obstructive CAD (14.75), the sensitivity and specificity were 85% and 43% (yielding a negative predictive value of 83% and a positive predictive value of 46%), with 33% of patient scores below this threshold. Limitation: Patients with chronic inflammatory disorders, elevated levels of leukocytes or cardiac protein markers, or diabetes were excluded. Conclusion: A noninvasive whole-blood test based on gene expression and demographic characteristics may be useful for assessing obstructive CAD in nondiabetic patients without known CAD. Primary Funding Source: CardioDx.

Cenobamate is an antiseizure medication for uncontrolled focal seizures. This thorough QT study assessed the effects of therapeutic and supratherapeutic cenobamate doses (maximum recommended dose, 400 mg/day) on correct QT interval (QTc) in healthy adults (N = 108) randomly assigned to 1 of 3 treatments: (A) cenobamate (days 1‐63) up‐titrated by 50‐mg increments weekly to a 200 mg/day therapeutic dose (day 35) and then by 100 mg weekly to a 500 mg/day supratherapeutic dose (day 63), with placebo‐moxifloxacin (days −1 and 64); (B) moxifloxacin 400 mg (day −1; positive control), placebo‐cenobamate (days 1‐63), and placebo‐moxifloxacin (day 64); and (C) placebo‐moxifloxacin (day −1), placebo‐cenobamate (days 1‐64), and moxifloxacin 400 mg (day 64). The primary end point was baseline‐adjusted, placebo‐corrected QTc (ΔΔQTcF; corrected for heart rate [HR] by Fridericia's method) with cenobamate 200 and 500 mg/day. Baseline electrocardiographic parameters were balanced across groups. Mean ΔΔQTcF was negative throughout for cenobamate doses (largest: day 35, −10.8 milliseconds; day 63, −18.4 milliseconds). Based on concentration‐QTc analysis, ∆∆QTcF effect was predicted as −9.85 and −17.14 milliseconds at mean peak plasma levels of therapeutic (200 mg/day; 23.06 μg/mL) and supratherapeutic (500 mg/day; 63.96 μg/mL) doses. Cenobamate had no clinically relevant prolonging effect on electrocardiographic parameters (eg, PR, QRS); HR effects were similar to placebo. Cenobamate showed slight dose‐related shortening of QTc, but to a degree not known to be clinically relevant (no reductions ≤340 milliseconds). Cenobamate had no clinically relevant effects on HR or electrocardiographic parameters and no QTc‐prolonging effect at therapeutic/supratherapeutic doses. Cenobamate is contraindicated in patients with short‐QT syndrome and caution should be used when coadministering with drugs that shorten QT interval.

A Cardiac Safety Research Consortium / Health and Environmental Sciences Institute / FDA-sponsored Think Tank Meeting was convened in Washington, DC, on May 21, 2018, to bring together scientists, clinicians, and regulators from multiple geographic regions to evaluate progress to date in the Comprehensive In Vitro Proarrhythmia Assay (CiPA) Initiative, a new paradigm to evaluate proarrhythmic risk. Study reports from the 4 different components of the CiPA paradigm (ionic current studies, in silico modeling to generate a Torsade Metric Score, human induced pluripotent stem cell–derived ventricular cardiomyocytes, and clinical ECG assessments including J-Tpeakc) were presented and discussed. This paper provides a high-level summary of the CiPA data presented at the meeting.

Increases in heart rate were seen during the clinical program for fixed-dose combination phentermine (PHEN) and topiramate (TPM), an oral medication indicated for weight management; however, the effect on cardiovascular (CV) outcomes is uncertain.

Long QT syndrome (LQTS) stems from pathogenic variants in KCNQ1(LQT1), KCNH2(LQT2), or SCN5A(LQT3) and is characterized by action potential duration (APD) prolongation. Inhibition of serum and glucocorticoid regulated kinase-1 (SGK1) is proposed as a novel therapeutic for LQTS.

Background:Drug-induced QT prolongation (DI-QTP) is a clinical entity in which administration of a HERG/IKrblocker such as dofetilide prolongs the cardiac action potential duration (APD) at the cellular level and the QT interval clinically, and increases the risk for a potentially lethal, QT-triggered ventricular arrhythmia. There may be a role for inhibition of INaLto counter DI-QTP. Recently, we have shown that inhibition of serum and glucocorticoid regulated kinase-1 (SGK1) reduces the APD90 in induced pluripotent stem cell derived cardiomyocytes (iPSC-CM) from patients with LQT3 and ameliorates increases in INaL.Objective:To test the efficacy of novel SGK1 inhibitors (SGK-I) in re-engineered cardiomyocyte models of dofetilide-induced APD prolongation.Methods:Normal iPSC-CMs were treated with dofetilide [5 nM] to produce a DI-QTP iPSC-CM model. The SGK1-I’s therapeutic efficacy for shortening the dofetilide-induced APD90 prolongation was compared to mexiletine. The APD90 values were recorded 4 hours after treatment using FluoVolt, a voltage-sensitive fluorescent dye.Results:The APD90 was significantly prolonged in normal iPSC-CMs treated with dofetilide (673 ± 8 ms with dofetilide vs 436 ± 4 ms with DMSO, p<0.0001). While 10 μM mexiletine shortened the average APD90 of dofetilide-treated normal iPSC-CMs from 673 ± 4 ms to 563 ± 8 ms (46% attenuation, p<0.0001), 30 nM of SGK-I shortened the APD90 from 673 ± 4 ms to 478 ± 10 ms (82% attenuation, p<0.0001).Conclusions:Therapeutically inhibiting SGK1 effectively shortens the cardiomyocyte APD in a human heart cell model of DI-QTP. The novel SGK1 inhibitor normalized the pathological APD prolongation almost fully (> 80%) in the iPSC-CM model treated with dofetilide. This pre-clinical data supports further development of this therapeutic strategy to counter and neutralize the threat of DI-QTP.

The early and efficient assessment of cardiac safety liabilities is essential to confidently advance novel drug candidates. This article discusses evolving mechanistically based preclinical strategies for detecting drug-induced electrophysiological and structural cardiotoxicity using in vitro human ion channel assays, human-based in silico reconstructions and human stem cell-derived cardiomyocytes. These strategies represent a paradigm shift from current approaches, which rely on simplistic in vitro assays that measure blockade of the Kv11.1 current (also known as the hERG current or IKr) and on the use of non-human cells or tissues. These new strategies have the potential to improve sensitivity and specificity in the early detection of genuine cardiotoxicity risks, thereby reducing the likelihood of mistakenly discarding viable drug candidates and speeding the progression of worthy drugs into clinical trials.

In December 2008, the US Food and Drug Administration (FDA) issued a guidance for industry requiring sponsors to demonstrate that a new antidiabetic therapy being developed to treat type 2 diabetes does not increase cardiovascular (CV) risk to an unacceptable extent. CV events reported during phase 2 and phase 3 trials should be prospectively and independently adjudicated. Before submission of a new drug application or biologics license application, sponsors should compare the incidence of major CV events occurring with the investigational agent versus the control group to show that the upper bound of the 2-sided 95% confidence interval (CI) for the estimated risk ratio is less than 1.8. If the CI includes 1.3, a postmarketing trial will be necessary to definitively show that the upper bound of the 95% CI for the estimated risk ratio is then less than 1.3. In 2012, the European Medicines Agency (EMA) issued an updated guideline on the clinical investigation of medicinal products in the treatment or prevention of diabetes mellitus that detailed its CV safety assessment requirements. Although similar to the FDA guidance, the EMA guideline does not prospectively define any pre- or postapproval risk margins. This expert perspective, prepared by members of the Cardiac Safety Research Consortium, discusses clinical development strategies, operational issues, and statistical methodological issues to satisfy the FDA’s CV safety requirements, and, where appropriate, the EMA guideline. Actual case examples, where applicable, are presented.

Introduction:Etripamil (E) is a rapidly and short acting, nasally administered calcium channel blocker being developed to terminate AV nodal-dependent PSVT. The NODE-301 first in class, multicenter study, evaluated self-administration of E nasal spray 70 mg outside a healthcare environment for acute termination of PSVT. This post-hoc analysis addresses the effect of E on heart rate (HR) during PSVT prior to conversion to sinus rhythm (SR).Methods:In NODE-301, 156 subjects experienced a vagal-maneuver refractory, symptomatic episode of confirmed PSVT, 107 subjects self-administered E and 49 placebo (P) (2:1 randomization) during PSVT. Each PSVT was documented by an ambulatory cardiac monitoring system that was placed on the chest after symptoms began. Baseline (average of four values before drug administration), and every minute of HR data were captured from baseline until one minute before the PSVT was converted to SR. Adequate HR data were available for 150 subjects, 102 on E and 48 on P. Six subjects were not included in this analysis, 4 converted before one minute (3 E and 1 P) and 2 E subjects experienced an early defect of recording.Results:Baseline mean (±SE) HR were 179 (±2.8) and 174 (±4.0) bpm for E and P respectively. Mean change in HR from baseline was greater in the E group than P group (p<0.0001). This decrease appeared within the first minute (-5 bpm ±0.9), 3 min (-10 bpm ±1.2), 10 min (-16 bpm ±2.1), 30 min (-14 bpm ±3.4) and 40 min (-13 bpm ±2.9) after E administration. The notable decrease in the E group was sustained through the 60minute observation period. A statistically significant difference in HR was reached between E and P notably at 3 (p<0.03), 10 (p<0.0001), 30 (p<0.0002), and 40 min (p<0.004).Conclusion:Etripamil significantly decreases the HR in PSVT prior to conversion to SR and is sustained over the 60 min observation. This finding may provide clinical benefits to patients for self-management of PSVT.

Proarrhythmias due to drug‐induced QT prolongation are the second most common cause for drug withdrawal and have caused increasing concern. Two new International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guidelines were recently endorsed in which nonclinical (S7B) and clinical (E14) methodologies are discussed and guidance is given to the industry. This commentary describes the key components of the E14 document, the impact of nonclinical testing on the clinical program, the thorough QT study, and the impact of its result on late‐stage development. The studies described in S7B and E14 will contribute to a better understanding of the link between nonclinical assays and QT prolongation in humans. Differences in interpretation among individual regulators in the major regions with respect to measures proposed in the E14 guideline might impact regional regulatory decisions. These differences include the value of nonclinical assays for the subsequent clinical testing and how predictive a negative thorough QT study result is for proarrhythmic risk in patients.

In the past 2 years, significant advances have been made in class III antiarrhythmic drug therapy. In patients with ventricular arrhythmias and implantable cardioverter defibrillators (ICDs), antiarrhythmic agents are increasingly being used as adjunct therapy to decrease the frequency of ICD discharges. Sotalol was recently shown to be effective in reducing tachyarrhythmias in patients with ICDs. Intravenous amiodarone is being used for the acute treatment of unstable ventricular arrhythmia and is being investigated for the treatment of acute out-of-hospital cardiac arrest. Class III agents are increasingly being used for prophylaxis in patients who have atrial fibrillation or atrial flutter, and data point to an important role for these agents in reducing supraventricular tachyarrhythmias after cardiac surgery. Future studies will need to directly compare these agents with pure anti-adrenergic maneuvers in postoperative patients. In addition to terminating atrial fibrillation and atrial flutter, ibutilide significantly reduces human atrial defibrillation thresholds and increases the percentage of patients who can be cardioverted from atrial fibrillation to sinus rhythm. The US Food and Drug Administration is expected to approve dofetilide for clinical use soon, and it is currently reviewing azimilide (which seems to be devoid of frequency-dependent effects on repolarization) for prophylaxis against atrial fibrillation and atrial flutter. Dronedarone, tedisamal, and trecetilide are now under active study intended to determine their usefulness in patients with cardiac arrhythmias. Experimental studies are ongoing to identify pharmacologic agents that will selectively prolong repolarization in the atria without exerting electrophysiologic effects in the ventricles.

Sustained ventricular arrhythmias commonly occur in post-myocardial infarction patients. Electrophysiology studies have greatly contributed to understanding the mechanisms of these arrhythmias and in guiding therapy. In addition to pharmacologic therapy, new treatment modalities-which include arrhythmia surgery, device therapy, and percutaneous catheter ablation-have resulted in a significantly improved outcome in patients with malignant ventricular arrhythmias

Narrow complex tachycardias are a common clinical problem and can be divided into those in which the arrythmic circuit is located exclusively in the atrium and those that involve the atrioventricular (AV) node or and accessory pathway. There have been recent advances in the nonpharmacologic treatments of supraventricular tachycardias, most notably in surgery and radiofrequency percutaneous catheter ablation for AV nodal reentry, AV reciprocating tachycardia, atrial flutter, and atrial tachycardias.

Ventricular tachycardia is the most common cause of wide complex tachycardia, although the differential diagnosis also includes supraventricular tachycardia with aberration and pre-excited tachycardias. This article discusses the various types and settings in which ventricular tachycardia occurs, along with criteria for the clinical and electrocardiographic differentiation of wide complex tachycardias. Acute and chronic treatments are discussed, concentrating on the recent advances in pharmacologic treatment of ventricular tachycardia.

To assess the effects of early thrombolytic therapy on the incidence of clinical and induced ventricular arrhythmias in high risk postmyocardial infarction patients, 32 patients with a transmural anterior myocardial infarction complicated by left ventricular aneurysm formation were prospectively evaluated. Sixteen patients (Group A) received routine care because of contraindication to thrombolytic therapy or other factors and 16 (Group B) received either tissue plasminogen activator or streptokinase within 6 h of the onset of chest pain. The two groups were similar in left ventricular ejection fraction (mean ± SD, 28 ± 9% [Group A] versus 30 ± 8% [Group B]) and occurrence of spontaneous nonsustained ventricular tachycardia, new bundle branch block and congestive heart failure. Group B patients had higher peak creatine kinase MB levels (446 ± 336 versus 205 ± 120 IU; p = 0.017) and earlier time to peak creatine kinase values (13.4 ± 6.6 versus 19.1 ± 6.1 h; p = 0.006).

The clinical significance of rapid self-terminating ventricular tachycardia induced during electrophysiologic study was prospectively evaluated in three patient groups with clinical ventricular arrhythmias. Group A (11 patients) had inducible rapid self-terminating ventricular tachycardia only (mean cycle length ≤250 ms and ≥10 beats in duration). In Group B (22 patients) induction of this arrhythmia was followed by the induction of sustained ventricular tachycardia. In Group C (82 patients) sustained ventricular tachycardia was induced without preceding rapid self-terminating ventricular tachycardia.

Ventricular tachycardia late after myocardial infarction is usually due to reentry in the infarct region. These reentry circuits can be large, complex and difficult to define, impeding study in the electrophysiology laboratory and making catheter ablation difficult. Pacing through the electrodes of the mapping catheter provides a new approach to mapping. When pacing stimuli capture the effects on the tachycardia depend on the location of the pacing site relative to the reentry circuit. The effects observed allow identification of various portions of the reentry circuit, without the need for locating the entire circuit. Isthmuses where relatively small lesions produced by radiofrequency catheter ablation can interrupt reentry can often be identified. A classification that divides reentry circuits into one or more functional components helps to conceptualize the reentry circuit and predicts the likelihood that heating with radiofrequency current will terminate tachycardia. These methods are helping to define human reentry circuits.

Objectives. This study sought to determine the relation of the paced QRS configuration and conduction delay during pace mapping to reentry circuit sites in patients with ventricular tachycardia late after myocardial infarction.

Objectives. Currently available antiarrhythmic drugs have limited efficacy for short-term, rapid termination of atrial fibrillation and atrial flutter.

The purpose of this study was to examine the efficacy and safety of amiodarone to maintain sinus rhythm in patients with refractory atrial fibrillation or flutter. One hundred ten patients with atrial fibrillation or flutter, refractory to ≥1 class I antiarrhythmk agents (mean±SD 2.5±1.5, median 2), were given low-dose amiodarone (mean maintenance dose 268±100mg/day) to determine Hs efficacy to maintain normal sinus rhythm after chemical or electrical carcKoversion. Fifty-three patients had chronic and 57 patients had paroxysmal atrial fibrillation or flutter. Mean age of the study population was 60±13 years, and me mean follow-up was 36±38 months (range 31 days to 137 months). Actuarial rates for maintenance of sinus rhythm were 0.87, 0.70, and 0.55 at 1,3, and 5 years, respectively. Twenty-one patients (19%) with arrhythmia recurrence had an increase in amiodarone dose, and after a mean additional follow-up of 2.5 years, 86% remained in normal sinus rhythm. The only observed predictor of atrial fibrillation or flutter recurrence was paroxysmal arrhythmia (40% recurrence vs 9% in patients with chronic atrial fibrillation or flutter; p<0.001). Actuarial rates for withdrawal because of adverse effects were 0.08, 0.22, and 0.30 at 1, 3, and 5 years, respectively. The most frequent adverse effects necessitating withdrawal were skin discoloration (4.5%), pulmonary nbrosis (3.6%; none fatal), and thyroid toxkity (2.7%). No deaths occurred during the study period. In conclusion, amiodarone has a high degree of efficacy for maintaining normal sinus rhythm in patients with atrial fibrillation or flutter, with a relatively low incidence of adverse effects necessitating withdrawal.

During the past 10 years there has been a major shift in antiarrhythmic drug development from class I to class III antiarrhythmic agents. The first two class III antiarrhythmic drugs that became available, sotalol and amiodarone, also have potent antiadrenergic actions. Newer antiarrhythmic drugs either block a specific ionic current (eg,dofetilide-induced blockade of the rapidly activating component of the delayed rectifier potassium current) or block multiple ionic channels (eg,ibutilide and azimilide) in order to prolong atrial and ventricular action potentials without other specific pharmacologic effects. Recent data suggest that these new class III antiarrhythmic drugs are highly effective for treating patients with rhythm disorders with an acceptable degree of proarrhythmia. This manuscript reviews the newer class III agents’ effectiveness in treating atrial and ventricular arrhythmias and the recent studies examining drug-induced prolongation of atrial repolarization to prevent or terminate postoperative atrial fibrillation.