Moving towards better predictors of drug-induced torsades de pointes.

Drug-induced torsades de pointes (TdP) remains a significant public health concern that has challenged scientists who have the responsibility of advancing new medicines through development to the patient, while assuring public safety. As a result, from the point of discovering a new molecule to the time of its registration, significant efforts are made to recognize potential liabilities, including the potential for TdP. With this background, the ILSI (HESI) Proarrhythmia Models Project Committee recognized that there was little practical understanding of the relationship between drug effects on cardiac ventricular repolarization and the rare clinical event of TdP. A workshop was therefore convened at which four topics were considered including: Molecular and Cellular Biology Underlying TdP, Dynamics of Periodicity, Models of TdP Proarrhythmia and Key Considerations for Demonstrating Utility of Pre-Clinical Models. The series of publications in this special edition has established the background, areas of debate and those that deserve scientific pursuit. This is intented to encourage the research community to contribute to these important areas of investigation in advancing the science and our understanding of drug-induced proarrhythmia.

International Life Sciences Institute (Health and Environmental Sciences Institute, HESI) initiative on moving towards better predictors of drug-induced torsades de pointes.

Knowledge of the cardiac safety of emerging new drugs is an important aspect of assuring the expeditious advancement of the best candidates targeted at unmet medical needs while also assuring the safety of clinical trial subjects or patients. Present methodologies for assessing drug-induced torsades de pointes (TdP) are woefully inadequate in terms of their specificity to select pharmaceutical agents, which are human arrhythmia toxicants. Thus, the critical challenge in the pharmaceutical industry today is to identify experimental models, composite strategies, or biomarkers of cardiac risk that can distinguish a drug, which prolongs cardiac ventricular repolarization, but is not proarrhythmic, from one that prolongs the QT interval and leads to TdP. To that end, the HESI Proarrhythmia Models Project Committee recognized that there was little practical understanding of the relationship between drug effects on cardiac ventricular repolarization and the rare clinical event of TdP. It was on that basis that a workshop was convened in Virginia, USA at which four topics were introduced by invited subject matter experts in the following fields: Molecular and Cellular Biology Underlying TdP, Dynamics of Periodicity, Models of TdP Proarrhythmia, and Key Considerations for Demonstrating Utility of Pre-Clinical Models. Contained in this special issue of the British Journal of Pharmacology are reports from each of the presenters that set out the background and key areas of discussion in each of these topic areas. Based on this information, the scientific community is encouraged to consider the ideas advanced in this workshop and to contribute to these important areas of investigations over the next several years.

Results from the IQ-CSRC prospective study support replacement of the thorough QT study by QT assessment in the early clinical phase.

The QT effects of five "QT-positive" and one negative drug were tested to evaluate whether exposure-response analysis can detect QT effects in a small study with healthy subjects. Each drug was given to nine subjects (six for placebo) in two dose levels; positive drugs were chosen to cause 10 to 12 ms and 15 to 20 ms QTcF prolongation. The slope of the concentration/ΔQTc effect was significantly positive for ondansetron, quinine, dolasetron, moxifloxacin, and dofetilide. For the lower dose, an effect above 10 ms could not be excluded, i.e., the upper bound of the confidence interval for the predicted mean ΔΔQTcF effect was above 10 ms. For the negative drug, levocetirizine, a ΔΔQTcF effect above 10 ms was excluded at 6-fold the therapeutic dose. The study provides evidence that robust QT assessment in early-phase clinical studies can replace the thorough QT study.

Incidence of sudden death after radiofrequency ablation of the atrioventricular junction for atrial fibrillation.

This study assesses the incidence of sudden death and classifies the causes of death following radiofrequency ablation of the atrioventricular (AV) junction. We studied 220 patients with paroxysmal (n = 105) or chronic (n = 115) atrial fibrillation (AF) and a mean age of 64 +/- 12 years. These patients were followed 31 +/- 15 months after radiofrequency ablation of the AV junction and pacemaker implantation. In 86 patients, structural heart disease was identified before the procedure. All patients were traced via the Swedish National Civic Registry and Cause of Death Registry. The cause-of-death was classified according to data from death certificates, autopsy protocols, and medical records. Thirty-one patients (mean age 69 +/- 11 years, 16 men) died 15 +/- 15 months (range 0.2 to 60) after the procedure. There were 6 sudden unexplained deaths, 14 cardiovascular deaths, and 11 deaths from noncardiovascular causes. Eleven patients, all with structural heart disease, died suddenly out of hospital 16 +/- 16 months (range 0.2 to 42) after the procedure. In 6 of these there was no obvious cause of death. Three of these 6 patients underwent autopsy, which showed extensive coronary artery disease (n = 1), severe heart failure (n = 1) and cardiac hypertrophy and dilation (n = 1). The remaining 3 all had depressed left ventricular systolic function and a history of congestive heart failure. Five of the patients who died suddenly from cardiovascular causes had autopsies that revealed acute myocardial infarction (n = 4) and massive pulmonary embolism (n = 1).

Frequency and long term follow up of valvar insufficiency caused by retrograde aortic radiofrequency catheter ablation procedures.

OBJECTIVE: To assess the frequency of valvar complications caused by left sided radiofrequency catheter ablation using the retrograde aortic technique. METHODS: 179 patients (118 male) with a mean (SD) age of 43 (17) years underwent 216 procedures at one centre. The target of the ablation was an accessory atrioventricular pathway in 144 patients, the atrioventricular junction in 29 patients, and a ventricular tachycardia in six patients. In 25 patients structural heart disease was identified before the procedure (ischaemic heart disease 10, cardiomyopathy nine, valvar three, other three). Echo/Doppler examinations were performed the day before the procedure and within 24 hours postablation; the investigations were all reviewed by the same investigator. Patients with identified valvar injury caused by the procedure were followed for 42 (7) months. RESULTS: Valvar injury caused by the ablation procedure was identified in four young (age 30 (8) years), otherwise healthy patients with left lateral atrioventricular accessory pathways. Mild mitral insufficiency with a central regurgitation jet was detected in two patients and remained unchanged at follow up. Mild aortic insufficiency was detected in another two patients. In one of these the regurgitation jet was central and remained unchanged at follow up. In one patient the regurgitation jet was located between the non-coronary and left cusps in relation to a loosely attached structure. Both the structure and the valvar regurgitation disappeared during follow up. No clinical complications occurred in any of the patients during follow up. CONCLUSION: In this study, the frequency of valvar complications after left sided radiofrequency catheter ablation using the retrograde aortic technique was 1.9%.

Torsades de pointes induced by transesophageal atrial stimulation after administration of almokalant.

This case-report describes a patient who developed a torsades de pointes tachycardia after infusion of almokalant, a selective class III antiarrhythmic agent. The patient was studied with transesophageal atrial stimulation because of Wolff-Parkinson-White syndrome. After a base-line procedure during which an orthodromic tachycardia was induced and pace-terminated, almokalant was given intravenously. The corrected QT interval was markedly prolonged despite similar plasma concentration compared to the rest of the studied patients. During the continued pacing protocol several episodes of non-sustained ventricular tachycardia was observed after pacing induced pauses. A sustained orthodromic tachycardia with left bundle branch morphology was induced, and another almokalant infusion was given. At a plasma concentration of approximately 252 nmol/l the corrected QT interval was further prolonged to 680 ms and the patient developed a torsades de pointes tachycardia after a pacing induced pause. The tachycardia degenerated into ventricular fibrillation that required immediate defibrillation. One week later the patient underwent ablation of the accessory pathway. The QT interval was in the absence of preexcitation normal, and programmed electrical stimulation did not reveal any ventricular arrhythmias. Further studies will have to be performed to clarify whether an early and marked QT interval prolongation, such as observed in this patient, will be useful in identifying patients prone for proarrhythmias in relation to therapy with selective class III drugs.

The use of beat-to-beat electrocardiogram analysis to distinguish QT/QTc interval changes caused by moxifloxacin from those caused by vardenafil.

QT correction factors (QTc) can cause errors in the interpretation of drug effects on cardiac repolarization because they do not adequately differentiate changes when heart rate or autonomic state deviates from the baseline QT/RR interval relationship. The purpose of our study was to determine whether the new method of QT interval dynamic beat-to-beat (QTbtb) analysis could better discriminate between impaired repolarization caused by moxifloxacin and normal autonomic changes induced by subtle reflex tachycardia after vardenafil. Moxifloxacin produced maximum mean increases of 13-14 ms in QTbtb, QTcF, and QTcI after 4 h. After vardenafil administration, a 10-ms effect could be excluded at all time points with QTbtb but not with QTcF or QTcI. Subset analysis of the vardenafil upper pharmacokinetic quartile showed that the upper bound of QTcF and QTcI was >10 ms, whereas that of QTbtb was <8 ms. This study demonstrated that newer methods of electrocardiogram (ECG) analysis can differentiate changes in the QT interval to improve identification of proarrhythmia risk.

Comparison of manual and automated measurements of the QT interval in healthy volunteers: an analysis of five thorough QT studies.

We analyzed five crossover, thorough QT (TQT) studies to compare automated, manual, and computer-assisted (CA) measurement methods. All the methods detected moxifloxacin-induced, baseline-adjusted, placebo-subtracted mean changes in Fridericia-corrected QT interval (QTcF), with peak effect ranging from 10 to 21 ms. The variability associated with manual and CA measurements was generally 5-28% greater than that associated with automated methods. The performances of automated, manual, and CA measurements were comparable for the purpose of demonstrating assay sensitivity in TQT studies with healthy volunteers.

Effect of almokalant, a selective potassium channel blocker, on the termination and inducibility of paroxysmal supraventricular tachycardias: a study in patients with Wolff-Parkinson-White syndrome and atrioventricular nodal reentrant tachycardia. Almokalant PSVT Study Group.

Almokalant is a newly developed selective blocker of the delayed outward K+ current and exhibits the electrophysiological properties of a class III antiarrhythmic agent. In a Scandinavian multicenter, placebo-controlled trial, the antiarrhythmic efficacy of almokalant was investigated in patients with paroxysmal supraventricular tachycardia: 87 patients with mean age of 50 +/- 14 years (range 21-71 years), with reciprocating tachycardia due to either Wolff-Parkinson-White (WPW) syndrome (n = 58) or atrioventricular nodal reentry tachycardia (AVNRT) (n = 29) were studied with transesophageal atrial stimulation. After a baseline procedure, during which sustained tachycardia was induced and overdrive terminated, tachycardia was reinduced and an intravenous (i.v.) infusion of either placebo or almokalant (aiming at a pseudoequilibrium plasma level of 20, 50, 100, or 150 nM) (Cpl 20-Cpl 150), was administered. Each patient was studied at two Cpl. Thirty-nine patients were randomly assigned in a double-blind fashion to either placebo+almokalant at Cpl 20 or Cpl 20 + Cpl 50; 26 patients were studied openly at Cpl 50 + Cpl 100, and 22 were studied openly at Cpl 100 + Cpl 150 almokalant. The antiarrhythmic efficacy was assessed as the ability to terminate induced tachycardia and to suppress inducibility: The proportion of patients in which the tachycardia was terminated was placebo 3 of 20 (15%); Cpl 20, 7 of 36 (19%): Cpl 50, 10 of 36 (28%); Cpl 100, 14 of 35 (40%); and Cpl 150, 5 of 9 (56%).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of almokalant, a class III antiarrhythmic agent, on supraventricular, reentrant tachycardias. Almokalant Paroxysmal Supraventricular Tachycardia Study Group.

The aim of the present study was to investigate the effects of almokalant on sustained reentrant supraventricular tachycardias. Reentrant tachycardias were induced, using transesophageal atrial stimulation, in 82 patients with atrioventricular reentrant tachycardia (n = 54) or AV nodal reentrant tachycardia (n = 28). After a baseline procedure during which the tachycardia was induced and overdrive terminated, the tachycardia was reinduced and studied during 12 minutes of infusion of either placebo or almokalant, aiming at plasma concentrations of 20, 50, 100, and 150 nmol/l. Each patient was studied at two dose levels during the same procedure. There was an increase in the RR interval during tachycardia of 6% at 100 nmol/l (p = 0.001 vs. baseline tachycardia). The QT interval during tachycardia increased by 5% (p = 0.001) at 50 nmol/l and by 10% (p = 0.001) at 100 nmol/l. Bundle branch block during tachycardia developed in 13% during almokalant infusion, aiming at 20 nmol/l, in 25% at 50 nmol/l, in 50% at 100 nmol/l, and in 33% at 150 nmol/l. Rapid baseline tachycardia, increasing almokalant dose, and an increasing number of induced tachycardias correlated with the appearance of bundle branch block. In six patients with AV nodal reentrant tachycardia, 2:1 AV block occurred, in all cases preceded by bundle branch block. The QT prolongation during sustained tachycardia was larger in patients who were noninducible at the same plasma concentration level than in the inducible patients. Almokalant caused bundle branch block and 2:1 AV block during sustained supraventricular tachycardia. These findings emphasize the importance of studying drug effects at rates in the range of clinical tachycardias that expose the conduction system to the limits of its refractoriness.