Validation of electrocardiographic criteria for identifying left ventricular dysfunction in patients with previous myocardial infarction.

Background: Eleven criteria correlating electrocardiogram (ECG) findings with reduced left ventricular ejection fraction (LVEF) have been previously published. These have not been compared head-to-head in a single study. We studied their value as a screening test to identify patients with reduced LVEF estimated by cardiac magnetic resonance (CMR) imaging.

Reference values of ECG parameters derived from 906 echocardiographically confirmed healthy Indian children: A population-based study from Gujarat.

Introduction: There are few published studies on reference ranges of ECG parameters in children; some ethnic differences have been described.

Methods: We studied digital 12‑lead ECGs (1000 samples/s) from 906 healthy rural Indian children (467 boys: 439 girls) aged 5-15 years. PR, QRS, and QT were measured using superimposed median beat.

For neonatal ECG screening there is no reason to relinquish old Bazett's correction.

Aims: There is an almost endless controversy regarding the choice of the QT correction formula to be used in electrocardiograms (ECG) in neonates for screening for long QT syndrome (LQTS). We compared the performance of four commonly used formulae and a new formula derived from neonates.

Methods And Results: From a cohort of 44 596 healthy neonates prospectively studied in Italy between 2001 and 2006, 5000 ECGs including 17 with LQTS-causing mutation identified by genotyping were studied using four QT correction formulae [Bazett's (QTcB), Fridericia's (QTcF), Framingham (QTcL), and Hodges (QTcH)].

Individual-Specific QT Interval Correction for Drugs With Substantial Heart Rate Effect Using Holter ECGs Extracted Over a Wide Range of Heart Rates.

Although fixed QT correction methods are typically used to adjust for the effect of heart rate on the QT interval in thorough QT/QTc studies, individual-specific QT correction (QTcI = QT/RR ) is advisable for drugs that increase the heart rate by >5 to 10 beats/minute (bpm). QTcI is traditionally derived using resting drug-free electrocardiograms (ECGs) collected at prespecified times. However, the resting heart rate range in healthy individuals is narrow, and extrapolation of inferences from these data to higher heart rates could be inappropriate.

Recent developments in the science of proarrhythmic cardiac safety of new drugs.

Following marketing withdrawals of several drugs due to proarrhythmic safety concerns, the ICH Guidelines S7B and E14 were released in 2005 and have guided pre-approval cardiac safety assessments in multiple regulatory jurisdictions. While this S7B-E14 paradigm has successfully prevented drugs with unanticipated potential for inducing Torsades de Pointes entering the market, it has unintentionally resulted in the termination of development programs for potentially important compounds that could have exhibited a favourable benefit-risk balance. The Comprehensive In vitro Proarrhythmia Assay paradigm is currently attracting considerable attention as a solution to this problem.

Comparison of the spatial QRS-T angle derived from digital ECGs recorded using conventional electrode placement with that derived from Mason-Likar electrode position.

Background: The spatial QRS-T angle is ideally derived from orthogonal leads. We compared the spatial QRS-T angle derived from orthogonal leads reconstructed from digital 12-lead ECGs and from digital Holter ECGs recorded with the Mason-Likar (M-L) electrode positions.

Methods And Results: Orthogonal leads were constructed by the inverse Dower method and used to calculate spatial QRS-T angle by (1) a vector method and (2) a net amplitude method, in 100 volunteers.

Detecting moxifloxacin-induced QTc prolongation in thorough QT and early clinical phase studies using a highly automated ECG analysis approach.

Background And Purpose: Exposure-response (ER) modelling (concentration-QTc analysis) is gaining as much acceptance as the traditional by-time analysis of the placebo-adjusted change from baseline in the QTc interval (ΔΔQTcF). It has been postulated that intensive ECG analysis and ER modelling during early-phase drug development could be a cost-effective approach of estimating QT liability of a new drug, in a small number of subjects.

Experimental Approach: We used a highly automated analysis of ECGs from 46 subjects from a crossover thorough QT/QTc study to detect ΔΔQTcF with moxifloxacin.

Arrhythmias Seen in Baseline 24-Hour Holter ECG Recordings in Healthy Normal Volunteers During Phase 1 Clinical Trials.

Regulatory agencies encourage sponsors to submit 24-hour ambulatory ECG data for assessing cardiac safety of new drugs, and some arrhythmias, hitherto considered rare, have been observed in some early-phase studies. Interpretation of these observations is difficult given the dearth of published data on the prevalence of cardiac arrhythmias seen during 24-hour continuous ECG monitoring in healthy volunteers (HV) from clinical trials. We analyzed drug-free ambulatory ECG recordings from 1273 HV (1000 males, 273 females; age 18-65 years) from 22 phase 1 studies that were analyzed in a core ECG laboratory; all subjects had normal screening ECGs.

Baseline and new-onset morphologic ECG abnormalities in healthy volunteers in phase I studies receiving placebo: changes over a 6-week follow-up period.

Morphological ECG abnormalities occur in 5-12% healthy adults participating in early phase clinical trials. We retrospectively analyzed 16,472 12-lead ECGs recorded at multiple time points in 420 volunteers (282 males, 138 females; aged 18-76 years) randomized to receive placebo from 19 Phase I studies to see if some baseline ECG abnormalities may disappear or new abnormalities may appear during the study. One hundred forty-four (34.

Comparison of two methods of estimating reader variability in QT interval measurements in thorough QT/QTc studies.

Background: Two methods of estimating reader variability (RV) in QT measurements between 12 readers were compared.

Methods: Using data from 500 electrocardiograms (ECGs) analyzed twice by 12 readers, we bootstrapped 1000 datasets each for both methods. In grouped analysis design (GAD), the same 40 ECGs were read twice by all readers.

Cardiovascular safety monitoring during oncology drug development and therapy.

Assessments of cardiac and cardiovascular toxicity are prominent components of drug safety endeavors during drug development and clinical practice. Oncologic drugs bring several challenges to both domains. First, during drug development, it is necessary to adapt the ICH E14 "Thorough QT/QTc Study" because the cytotoxic nature of many oncologics precludes their being administered to healthy individuals.

Drug-induced QT prolongation when QT interval is measured in each of the 12 ECG leads in men and women in a thorough QT study.

Lead II is commonly used to study drug-induced QT prolongation. Whether other ECG leads too show comparable QT prolongation is not known. We studied moxifloxacin-induced QT prolongation in a thorough QT study in healthy subjects (54 males, 43 females).

Reader variability in QT measurement due to measurement error and variability in leads selection: a simulation study comparing 2-way vs. 3-way interaction ANOVA model.

Reader variability (RV) results from measurement differences or variability in lead used for QT measurements; the latter is not reflected in conventional methods for estimating RV. Mean and SD of QT intervals in 12 leads of 100 ECGs measured twice were used to simulate data sets with inter-RV of 5, 10, 15, 20, and 25 ms and intra-RV of 3, 6, 9, 12, and 15 ms. Six hundred twenty-five data sets were simulated such that different leads were used in Read1 and Read2 in 0, 10%, 20%, 30%, 40% of ECGs by 25 readers.

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTc modelling in a phase 1 study with oral rac-sotalol.

Aim: To study the differences in QTc interval on ECG in response to a single oral dose of rac-sotalol in men and women.

Methods: Continuous 12-lead ECGs were recorded in 28 men and 11 women on a separate baseline day and following a single oral dose of 160 mg rac-sotalol on the following day. ECGs were extracted at prespecified time points and upsampled to 1000 Hz and analyzed manually in a central ECG laboratory on the superimposed median beat.

Choice of an alternative lead for QT interval measurement in serial ECGs when Lead II is not suitable for analysis.

Introduction: Conventionally, QT interval is measured in lead II. There are no data to select an alternative lead for QT measurement when it cannot be measured in Lead II for any reason.

Methods And Results: We retrospectively analyzed ECGs from 1906 healthy volunteers from 41 phase I studies.

Cardiovascular risk of oral antidiabetic drugs: current evidence and regulatory requirements for new drugs.

Background: Better control of diabetes mellitus reduces microvascular complications, but has limited effect on macrovascular complications including cardiovascular mortality. A spate of controversial reports has shown that some new oral antidiabetic drugs may paradoxically increase cardiovascular events and mortality. We review here published data on cardiac safety of currently available oral antidiabetic drugs.

Morphological abnormalities in baseline ECGs in healthy normal volunteers participating in phase I studies.

Background & Objectives: Morphological abnormalities in 12-lead electrocardiograms (ECGs) are seen in subgroups of healthy individuals like athletes and air-force personnel. As these populations may not truly represent healthy individuals, we assessed morphological abnormalities in ECG in healthy volunteers participating in phase I studies, who are screened to exclude associated conditions.

Methods: ECGs from 62 phase I studies analyzed in a central ECG laboratory were pooled.

Early repolarization and short QT interval in healthy subjects.

Background: An early repolarization (ER) pattern is common in ECGs from patients with ventricular fibrillation (VF). These patients with ER have shorter QT intervals. Morphological variants of the ER pattern also have been associated with idiopathic VF, but their prevalence in healthy subjects is unclear.

Semiautomated QT interval measurement in electrocardiograms from a thorough QT study: comparison of the grouped and ungrouped superimposed median beat methods.

Introduction: We postulated that it may be easier to identify earliest Q onset and latest T offset when the median beats from 12 leads are separated vertically by 5 to 10 mm (ungrouped superimposed median beat [SMB] method) rather than when their baselines closely (but rarely perfectly) overlap (grouped SMB method).

Methods: Three readers manually adjudicated annotations placed by an automated algorithm, using grouped (gSMB) and ungrouped (uSMB) methods in 2658 electrocardiograms (ECGs) recorded in 38 subjects in a crossover design thorough QT study at predose and 6 time points postdosing with placebo or moxifloxacin.

Results: Placebo-subtracted, moxifloxacin-induced QTcF prolongation was comparable with both methods.

QTc interval and its variability in patients with schizophrenia and healthy subjects: implications for a thorough QT study.

We compared heart rate-corrected QT interval (QTc) and its within- and between-subject variability, in ECGs recorded several days apart for 207 patients with schizophrenia (age range 19-60 yr) with age- and gender-matched healthy controls. Patients had higher heart rates (mean±s.d.

Comparison of 5 methods of QT interval measurements on electrocardiograms from a thorough QT/QTc study: effect on assay sensitivity and categorical outliers.

Introduction: We studied moxifloxacin-induced QT prolongation and proportion of categorical QTc outliers when 5 methods of QT measurement were used to analyze electrocardiograms (ECGs) from a thorough QT study.

Methods: QT interval was measured by the threshold, tangent, superimposed median beat, automated global median beat, and longest QT methods in a central ECG laboratory in 2730 digital ECGs from 39 subjects during placebo and moxifloxacin treatment.

Results: All 5 methods were able to demonstrate statistically significant moxifloxacin-induced QTcF prolongation.

Limb lead interchange in thorough QT/QTc studies.

The investigators analyzed 85,133 electrocardiograms (ECGs) recorded in 484 subjects from 5 thorough QT/QTc studies (3 using Holter devices, 2 using 12-lead ECGs) for inadvertent limb lead interchanges using a dedicated quality control process in a central ECG laboratory. Limb lead interchanges were present in 2919 (3.4%) ECGs in 17.