An evaluation of multiple algorithms for the measurement of the heart rate corrected JTpeak interval

Abstract

Interest in the effects of drugs on the heart rate-corrected JTpeak (JTpc) interval from the body-surface ECG has spawned an increasing number of scientific investigations in the field of regulatory sciences, and more specifically in the context of the Comprehensive in vitro Proarrhythmia Assay (CiPA) initiative. We conducted a novel initiative to evaluate the role of automatic JTpc measurement technologies by comparing their ability to distinguish multi- from single-channel blocking drugs. A set of 5,232 ECGs was shared by the FDA (through the Telemetric and Holter ECG Warehouse) with 3 ECG device companies (AMPS, Mortara, and Philips). We evaluated the differences in drug-concentration effects on these measurements between the commercial and the FDA technologies. We provide a description of the drug-induced placebo-corrected changes from baseline for dofetilide, quinidine, ranolazine, and verapamil, and discuss the various differences across all technologies. The results revealed only small differences between measurement technologies confirming that the JTpc interval distinguishes between multi- and single-channel (hERG) blocking drugs when evaluating the effects of dofetilide, quinidine, ranolazine, and verapamil. In the case of quinidine and dofetilide, we noticed a poor consistency across technologies because of the lack of standard definitions for the location of the peak of the T-wave (T-apex) when the T-wave morphology is abnormal.

QT Assessment in Early Drug Development: The Long and the Short of It

“…Pursuant to these observations, at a recent presentation by Vicente [81], updated commentary was provided about the utility of measuring the early phase (J-T peak c) and late phase (J-T peak c-Tend) of the J-T interval as biomarkers that may modulate proarrhythmic concerns in the setting of a moderately positive QT signal and reduce the need for intensive ECG monitoring in late stage trials. To this end, open source code was released by the FDA using a vector magnitude function and software vendors including AMPS [82], Mortara and Philips have developed technology which offers measurement of these intervals based upon different mathematical models [83]. Although a meaningful disparity between the different vendors’ algorithms has not been evidenced, a number of critical elements in this approach have yet to be standardized which may affect the accuracy and utility of this biomarker.…”

Mechanistic Model‐Informed Proarrhythmic Risk Assessment of Drugs: Review of the “CiPA” Initiative and Design of a Prospective Clinical Validation Study

“…In addition, the J‐Tpeak interval can be corrected for heart rate and has sufficient power to differentiate changes with exposure–response analysis in the small sample sizes (Section 2 in the statistical analysis plan in the Online Supplement) typical of phase I studies. The J‐Tpeakc analysis algorithm has been released as an open‐source code to facilitate widespread testing (https://github.com/FDA/ecglib), which has been performed by multiple independent groups as a part of an “ECG challenge” associated with the 2017 International Society of Computerized Electrocardiology annual conference …”

The Potential Role of the J‐Tpeak Interval in Proarrhythmic Cardiac Safety: Current State of the Science From the American College of Clinical Pharmacology and the Cardiac Safety Research Consortium

“…Analyses using concentration‐response models as well as an analysis based on the area under the receiver operating characteristic curve showed that the J‐T peak c was the best biomarker to differentiate balanced ion channel block from predominant hERG block . In addition, analyses using different J‐T peak c ECG methods by other research groups showed similar results . These findings suggest that J‐T peak c might be used to differentiate QTc‐prolonging drugs with predominant hERG block versus balanced ion channel block.…”

“…5,19 In addition, analyses using different J-T peak c ECG methods by other research groups showed similar results. 20,21 These findings suggest that J-T peak c might be used to differentiate QTc-prolonging drugs with predominant hERG block versus balanced ion channel block.…”