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.

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.

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.

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.

The effect of oral magnesium, alone or as an adjuvant to sotalol, after cardioversion in patients with persistent atrial fibrillation.

AIMS: To determine whether magnesium given orally decreases the recurrence rate of atrial fibrillation after elective direct current cardioversion of persistent atrial fibrillation. METHODS AND RESULTS: Consecutive outpatients were randomized to treatment with oral magnesium (10.3 mmol) or placebo twice daily in a double-blind fashion. Two groups were studied; magnesium study: 170 patients with atrial fibrillation persistent for >1 month, scheduled for their first direct current cardioversion. No concomitant antiarrhythmic drugs of class I or III were allowed. Sotalol and magnesium study: 131 patients with recurrence of persistent atrial fibrillation after previous direct current cardioversion, or a history of paroxysmal atrial fibrillation, treated with sotalol. Patients were followed until recurrence of atrial fibrillation or for at least 6 months. Magnesium study: at cardioversion 67 of 85 (79%) in the placebo group and 64 of 85 (75%) in the magnesium group had converted to sinus rhythm. At the end of the study, with a follow-up of 6 to 42 months, 15% of patients in the placebo group and 19% of patients in the magnesium group remained in sinus rhythm (Log rank test: P=0.37). Sotalol and magnesium study: pharmacological conversion to sinus rhythm, after oral treatment, was achieved in 34 of 131 (26%) patients. Sinus rhythm, with or without cardioversion, was restored in 89% and 85% of the patients in the placebo and magnesium groups, respectively. At the end of the study, with a follow-up of 6 to 42 months, 37% of patients in the placebo group and 30% of patients in the magnesium group remained in sinus rhythm (Log rank test: P=0.64). CONCLUSION: In patients with persistent atrial fibrillation, oral treatment with magnesium alone or as an adjuvant to sotalol, does not influence the recurrence rate of atrial fibrillation after elective cardioversion.

Comparison of QT dispersion during atrial fibrillation and sinus rhythm in the same patients, at normal and prolonged ventricular repolarization.

AIMS: Drug-induced increase in QT dispersion has been associated with increased risk of ventricular proarrhythmia. The aim of the present study was to compare QT dispersion during atrial fibrillation and sinus rhythm in the same patients at normal and prolonged ventricular repolarization. METHODS AND RESULTS: Sixty-one patients who had had chronic atrial fibrillation for 8 +/- 14 months received a 6 h infusion of the Ikr-blocker almokalant, the first 90 min of which are used for this analysis. The following day, after conversion to sinus rhythm, by almokalant (n = 19) or direct current cardioversion (n=42), an identical 90 min infusion was administered. Prior to infusion, there was no difference in precordial QT dispersion between atrial fibrillation and sinus rhythm (29 +/- 12 vs 36 +/- 17 ms, P=ns). During infusion, at prolonged repolarization, the increase in QT dispersion was greater during sinus rhythm than during atrial fibrillation (58 +/- 49 vs 30 +/- 15 ms, P=0.0011, after 30 min infusion). No correlation was found between QT dispersion and the QT or RR interval. CONCLUSION: QT dispersion during atrial fibrillation does not differ from QT dispersion during sinus rhythm during normal repolarization. while measurement of QT dispersion during prolonged repolarization, induced by an Ikr-blocker, yielded larger values during sinus rhythm than during atrial fibrillation.

Effects of the Ikr-blocker almokalant and predictors of conversion of chronic atrial tachyarrhythmias to sinus rhythm. A prospective study.

PURPOSE: To assess the efficacy of the Ikr-blocker almokalant attempting to convert chronic atrial tachyarrhythmias, and to find predictors of conversion, to sinus rhythm. METHODS: The electrophysiological effects of a 6-hour infusion of almokalant, to a total dose of 25 +/- 4 mg, were assessed by ECG and transesophageal atrial electrograms (TAE) in 100 consecutive patients with atrial fibrillation/flutter (n = 95/5) of 8 +/- 12 months' duration (range 1 to 99 months). RESULTS: The conversion rate was 32%. The time to conversion was 3.5 +/- 2.2 hours. During infusion increases in QTtop (292 +/- 35 to 335 +/- 44 ms, p < 0.001, after 30 minutes), QT (387 +/- 40 to 446 +/- 60 ms, p < 0.001), corrected QT (425 +/- 30 to 487 +/- 44 ms, p < 0.001), and QT dispersion (21 +/- 12 to 29 +/- 31 ms, p = 0.02), were paralleled by decreases in T wave amplitude (0.31 +/- 0.19 to 0.23 +/- 0.16 mV, p < 0.001), and atrial rate (425 +/- 78 to 284 +/- 44 beats per minute (bpm) on ECG, and 396 +/- 72 to 309 +/- 44 bpm on TAE), with no differences between converters to sinus rhythm and non-converters. Patients with aberrantly conducted beats, and T wave variation, also increased. Calcium antagonists were more common among converters. A decreasing T wave amplitude predicted conversion. Four patients developed torsades de pointes. CONCLUSIONS: This study demonstrates class III action of almokalant, with a conversion rate of 32% of long-standing, chronic atrial tachyarrhytmias. An early decrease in T wave amplitude was associated with conversion to sinus rhythm.

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%.

Assessment of accessory pathway and atrial refractoriness by transoesophageal and intracardiac atrial stimulation: an analysis of methodological agreement.

AIMS: Measurement of the refractory properties of asymptomatic overt accessory pathways is performed to assess the risk for significant arrhythmias. We hypothesized that a transoesophageal atrial stimulation (TAS) protocol would accurately predict simultaneously measured invasive intra cardiac stimulation (ICS) of the anterograde effective refractory period of the accessory pathway (AP-ERP) METHODS AND RESULTS: Fourteen single pathway Wolff-Parkinson-White (WPW) syndrome patients underwent TAS during ICS and 24 h prior to it. The AP-ERP was measured using incremental atrial extra stimuli from TAS, the right atrium (RA) and the coronary sinus (CS) using drive trains of 500 and 600 ms. Stimulus latency was measured from intracardiac electrocardiograms. For methodological comparison, Altman-Bland analysis was used to create the limits of agreement (within-patient mean of differences +/- two standard deviations). There were no or small differences in the AP-ERP, as assessed by TAS, compared to RA and CS. Methodological disagreement between the three sites were common, however, and the limits of agreement ranged from +/- 30 to +/- 76 ms. The concordance between TAS and RA, with regards to the AP-ERP value of 270 ms, was 63% when measured as S1S2 and was 67% when measured as A1A2. The stimulation site delay was significantly shorter for TAS compared to RA and CS sites. The two TAS procedures performed a day apart, revealed a coefficient of variation of 9% and a coefficient of reproducibility of 63 ms. CONCLUSIONS: Despite adequate reproducibility, TAS fails to predict the AP-ERP by ICS. Differences in stimulus latency is responsible, in part, for the disagreement. Invasive ICS cannot be replaced by TAS for risk stratifying WPW patients.

Electrocardiographic and clinical predictors of torsades de pointes induced by almokalant infusion in patients with chronic atrial fibrillation or flutter: a prospective study.

The aim of this study was to identify predictors of torsades de pointes (TdP) in patients with atrial fibrillation (AF) or flutter exposed to the Class III antiarrhythmic drug almokalant. TdP can be caused by drugs that prolong myocardial repolarization. One hundred patients received almokalant infusion during AF (infusion 1) and 62 of the patients during sinus rhythm (SR) on the following day (infusion 2). Thirty-two patients converted to SR. Six patients developed TdP. During AF, T wave alternans was more common prior to infusion (baseline) in patients developing TdP (50% vs 4%, P < 0.01). After 30 minutes of infusion 1, the TdP patients exhibited a longer QT interval (493 +/- 114 vs 443 +/- 54 ms [mean +/- SD], P < 0.01), a larger precordial QT dispersion (50 +/- 74 vs 27 +/- 26 ms, P < 0.05), and a lower T wave amplitude (0.12 +/- 0.21 vs 0.24 +/- 0.16 mV, P < 0.01). After 30 minutes of infusion 2, they exhibited a longer QT interval (672 +/- 26 vs 489 +/- 74 ms, P < 0.001), a larger QT dispersion in precordial (82 +/- 7 vs 54 +/- 52 ms, P < 0.01) and extremity leads (163 +/- 0 vs 40 +/- 34 ms, P < 0.001), and T wave alternans was more common (100% vs 0%, P < 0.001). Risk factors for development of TdP were at baseline: female gender, ventricular extrasystoles, and treatment with diuretics; and, after 30 minutes of infusion: sequential bilateral bundle branch block, ventricular extrasystoles in bigeminy, and a biphasic T wave. Patients developing TdP exhibited early during almokalant infusion a pronounced QT prolongation, increased QT dispersion, and marked morphological T wave changes.

Modification of atrioventricular conduction as adjunct therapy for pacemaker-treated patients with hypertrophic obstructive cardiomyopathy.

AIMS: Atrioventricular synchronous pacing offers symptomatic relief for patients with drug-refractory hypertrophic obstructive cardiomyopathy. Successful treatment requires complete right ventricular apical pre-excitation. Enhanced atrioventricular conduction renders this difficult in some patients. The aim of this study was to evaluate whether selective prolongation of atrioventricular conduction is a useful tool for optimization of treatment in patients with hypertrophic obstructive cardiomyopathy primarily refractory to cardiac pacing. METHODS: Six patients refractory to pacemaker treatment for 3-19 months underwent radiofrequency modification of atrioventricular conduction. Patients were followed with echo-Doppler, exercise testing and clinical evaluation for 6-12 months after modification. RESULTS: Intrinsic PQ time was significantly prolonged from 175 +/- 18 ms to 253 +/- 22 ms; however, one patient exhibited complete block at one month follow-up. Left ventricular outflow tract obstruction decreased from 74 +/- 17 mmHg to 28 +/- 27 mmHg at the 6-month follow-up. Symptomatic improvement of at least one functional class was recorded in all patients; exercise tolerance remained unchanged, however, less angina and dyspnoea were reported in everyday life. CONCLUSION: Radiofrequency modification of atrioventricular conduction, with persistent prolongation of the PQ interval, enhances the effects of pacing in patients with hypertrophic obstructive cardiomyopathy. This treatment enhances left ventricular outflow tract gradient reduction and improves symptoms.

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).

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.

Assessment of frequency dependency of the class III effects of almokalant: a study using programmed stimulation and recording of monophasic action potentials and ventricular paced QT intervals.

The aim of the present study was to assess the frequency dependency of the effects of almokalant, a selective class III antiarrhythmic drug, on ventricular repolarization using recordings of monophasic action potentials and measurements of ventricular paced QT intervals. Twenty male volunteers were studied during almokalant infusion aiming at plasma concentrations (Cpl) of 20, 50, 100, and 150 nmol/l. The duration of monophasic action potential at 90% repolarization (MAPD) was measured during incremental and premature ventricular extrastimulation. The ventricular paced QT interval was measured during incremental stimulation from the apical region (RV APEX) and the outflow tract (RVOT) of the right ventricle, and the frequency dependence was analyzed using a linear regression model. At an almokalant dose of Cpl > or = 50, there was a significant prolongation of the MAPD of 10-15%. The prolongation was of equal magnitude at all paced cycle lengths (CL). The MAPD of ventricular extrasystole increased in parallel over the range of coupling intervals studied and was significantly prolonged at Cpl 100 and 150. The ratio between the MAPD of the extrasystoles and preceding beats was unaltered after almokalant infusion. The ventricular paced QT intervals increased during almokalant infusion in a similar manner as that of the MAPD. During RV APEX stimulation, the prolongation was more pronounced at low heart rates, an effect that was not seen during RV OT stimulation. Almokalant significantly prolonged the MAPD at dose levels Cpl > or = 50. There was no evidence of a frequency dependence of this effect. The ventricular paced QT intervals were prolonged in a similar manner as that of the MAPD, and this effect exhibited a small reverse frequency dependence during RV APEX stimulation.

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.