Comparison of Electrocardiographic Biomarkers for Differentiating Drug-Induced Single vs. Multiple Cardiac Ion Channel Block.

Since introduction of the International Conference on Harmonization proarrhythmia guidelines in 2005, no new marketed drugs have been associated with unacceptable risk of Torsade de Pointes. Although cardiac safety improved, these guidelines had the unintended consequence of eliminating potentially beneficial drugs from pipelines early in development. More recently, it has been shown that a corrected QT (QTc) prolonging drug may be safe if it impacts multiple ion channels vs. only human ether-a-go-go related gene (hERG) and that this effect can be discriminated using QT subintervals. We compared the predictive power of four electrocardiogram (ECG) repolarization metrics to discriminate single vs. multichannel block: (i) traditional 10-second signal averaged triplicates, and (ii) three metrics that used increasing density of automatically measured beat-to-beat (btb) intervals. Predictive power was evaluated using logistic regression and quantified with receiver operating characteristic (ROC) area under the curve (AUC). Compared with the traditional 10-second signal averaged triplicates, the reduction in classification error ranged from 2-6 with increasing density of btb measurements.

Comparison of one- and three-lead ECG to measure cardiac intervals and differentiate drug-induced multi-channel block.

INTRODUCTION: FDA has established initiatives to characterize clinical and non-clinical biomarkers to enable more precise prediction of proarrhythmia risk based upon knowledge of drug effect on multiple cardiac ion channels (Colatsky et al., 2016). The FDA has recently demonstrated superiority of early ventricular repolarization interval (JTp) in differentiating pure hERG block from multi-channel block in human subjects. Preclinical studies often acquire a single lead ECG, whereas FDA measurements of JTp were derived ​from a spatial vectorcardiogram computed using multiple leads. This study compares QT subintervals derived from single lead vs. spatial magnitude (SM) ECG and contrasts information obtained from multilead and single lead ECGs in the canine model. METHODS: Four beagle dogs were instrumented with 3-lead Holter monitors to acquire continuous surface ECG recordings for three consecutive days. A 24-h baseline recording was obtained on day 1 followed by administration of dofetilide on day 2 and atropine and dofetilide on day 3. Lead II and SM ECGs were automatically analyzed using the AE-1010 Rhythm Express™ (RE) software (VivaQuant, St. Paul, MN USA) without manual intervention or editing of the results (auto). Five-minute averages of beat-to-beat intervals measured on each lead were compared for agreement assessed by Bland-Altman (BA) statistics and consistency measured as the repeatability standard deviation (SD) from 5-min intervals. The fully automated results were screened by an operator (semi-automated) and compared to automated results. RESULTS: JTp and TpTe measured using SM lead are less sensitive to changes in posture and respiration related changes in T-wave morphology. The 24-h repeatability SD of 5-min subintervals for JTp and TpTe over the three days was improved by 15.4% and 15.5% respectively with the highest improvements of 23.3% for JTp on day 2 and 25.3% for TpTe on day 3. Drug induced changes in QTcV, QRS, RR, and PR intervals were qualitatively similar between the SM lead and Lead II and in close agreement based on BA statistics. Semi-automated and automated measurements from SM Lead were in close agreement based on BA statistics. DISCUSSION: Single lead ECG is adequate for PR, RR, QRS, and QT, but produces different and more variable results when assessing QT subintervals relative to the SM lead. Close agreement between automated and semi-automated measurements demonstrates Rhythm Express accuracy and the potential to streamline interval analysis.

Comparison of Two Highly Automated ECG Algorithms for Detection of Drug-Induced Cardiac Ion Channel Block.

US Food and Drug Administration (FDA) investigators recently demonstrated in a crossover study that early (J-Tpeak c) and late (Tpeak -Tend ) repolarization duration can differentiate selective potassium block with a high arrhythmia risk from multichannel block with lower risk in subjects receiving dofetilide, verapamil, quinidine, or ranolazine. The purpose of this study was to determine if the findings by the FDA using their published software algorithm could be corroborated using an alternative software algorithm for the same metrics and to determine if methodological differences resulted in clinically meaningful differences in interpretation. Exposure-response relationships computed with linear mixed effects models and mean maximal effects on ECG intervals measured by the two algorithms were similar, corroborating the FDA findings, but with some differences in the modeled slopes and magnitude of changes. The alternative software resulted in an average 25% reduction in the 95% confidence intervals of the mixed effects models with generally lower Akaike Information Criterion values.

Evaluation of an algorithm for highly automated measurements of QT interval.

INTRODUCTION: Noise, artifact, and labile morphology of ECGs collected from freely moving animals in safety pharmacology studies render accurate measurements of QT interval challenging. Consequently, a high percentage of beats are uninterpretable and results provided by currently available analysis algorithms often require extensive manual review to correct errors. Performance of a novel algorithm, Multi-Domain Signal Processing™ (MDSP), is evaluated as a means of removing noise (denoising) without distorting morphology and for obtaining accurate beat-to-beat QT measurements. METHODS: Performance was evaluated using controlled experiments and an observational evaluation as follows: a) a clean ECG strip was intentionally corrupted with varying levels of noise to provide recordings of known signal-to-noise ratio (SNR). SNR and fidelity were compared pre- and post-MDSP denoising, b) beat-to-beat QT of a noisy ECG was measured manually pre- and post-MDSP denoising and automatically by MDSP, c) beat-to-beat QT of a clean ECG was measured manually and automatically using MDSP, and d) beat-to-beat QT was computed for 3 freely moving non-human primates (NHP) pre- and post-torsadogen administration and the impact of averaging on QTSD, QT/RR dynamics and relationship was evaluated. RESULTS: MDSP reduced noise amplitude by up to 85% while preserving signal morphology. Mean QTs for manual and automatic measurements on a noisy ECG were within 2±15ms. MDSP-denoising prior to manual QT measurements resulted in a 22% decrease in QTSD compared to measurements obtained without denoising. Average QT standard deviation of the mean (QTSD) for automatic MDSP-derived measurements for 3 freely moving subjects was 7ms with 2.5% of beats automatically excluded due to noise. DISCUSSION: This work demonstrates that the MDSP algorithm shows promise as a tool for providing accurate automatic beat-to-beat measurements of QT interval from NHP in safety pharmacology studies. A methodology is presented for characterizing the impact of noise on algorithm performance.