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

Abstract

FDA investigators recently demonstrated in a crossover study that early (J-Tpeakc) 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 findings by 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 (AIC) values.

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

“…The differences observed in QT measurements shown in Figure may be explained by different methodologies as well as inclusion of a larger set of beats with BTB5 protocol. Further, the Fridericia correction has limited ability to compensate for HR differences that exceed 10 bpm …”

“…All ECGs were obtained from the E‐OTH‐12‐0109‐020 (FDA‐1) and EOTH‐12‐0109‐021 (FDA‐2) databases archived in the Telemetric and Holter ECG Warehouse at the University of Rochester Medical Center, Rochester, NY. The downloaded signals were processed using a previously validated, fully automated software system Rhythm Express (VivaQuant, St. Paul, MN) to generate the vector magnitude ECG of the vectorcardiogram and automatically measure cardiac intervals, as previously reported . JTp was corrected for heart rate using the published formula (JTpc = JTp/RR 0.58 with RR in seconds), and QT was corrected with Fridericia's correction (QTcF = QT/RR 1/3 with RR in seconds).…”

“…The downloaded signals were processed using a previously validated, fully automated software system 8,9 Rhythm Express (VivaQuant, St. Paul, MN) to generate the vector magnitude ECG of the vectorcardiogram 10 and automatically measure cardiac intervals, as previously reported. 11 JTp was corrected for heart rate using the published formula 3 (JTpc = JTp/RR 0.58 with RR in seconds), and QT was corrected with Fridericia's correction (QTcF = QT/RR 1/3 with RR in seconds). R-R interval is the interval between peaks of sequential QRS complexes on ECG.…”

“…The differences between mean maximum drug effects for each method were compared using a two-sample t-test. These differences may be attributed to the choice of T-peak between the two measurement algorithms, intermittent inclusion of the U-waves in the FDA algorithm for dofetilide and quinidine, 11 and inclusion of cardiac cycles with a wider range of heart rates in protocols with longer averaging periods. Further, a progressive reduction in average 95% confidence intervals was observed when measurements were derived from btb intervals vs. TSAT: 25% lower for BTBT, 35% lower for BTB5, and 43% lower for BTB30.…”

“…Often, the HR distribution within each 10-second segment tends to cluster around lower HR with occasional beats of higher HR that are typically excluded in order to satisfy TSAT beat-selection protocol. The differences observed in QT measurements shown in Figure 5 may be explained by different methodologies 11 as well as inclusion of a larger set of beats with BTB5 protocol.…”