Automated Algorithm for J-Tpeak and Tpeak-Tend Assessment of Drug-Induced Proarrhythmia Risk

Abstract

BackgroundProlongation of the heart rate corrected QT (QTc) interval is a sensitive marker of torsade de pointes risk; however it is not specific as QTc prolonging drugs that block inward currents are often not associated with torsade. Recent work demonstrated that separate analysis of the heart rate corrected J-Tpeakc (J-Tpeakc) and Tpeak-Tend intervals can identify QTc prolonging drugs with inward current block and is being proposed as a part of a new cardiac safety paradigm for new drugs (the “CiPA” initiative).MethodsIn this work, we describe an automated measurement methodology for assessment of the J-Tpeakc and Tpeak-Tend intervals using the vector magnitude lead. The automated measurement methodology was developed using data from one clinical trial and was evaluated using independent data from a second clinical trial.ResultsComparison between the automated and the prior semi-automated measurements shows that the automated algorithm reproduces the semi-automated measurements with a mean difference of single-deltas <1 ms and no difference in intra-time point variability (p for all > 0.39). In addition, the time-profile of the baseline and placebo-adjusted changes are within 1 ms for 63% of the time-points (86% within 2 ms). Importantly, the automated results lead to the same conclusions about the electrophysiological mechanisms of the studied drugs.ConclusionsWe have developed an automated algorithm for assessment of J-Tpeakc and Tpeak-Tend intervals that can be applied in clinical drug trials. Under the CiPA initiative this ECG assessment would determine if there are unexpected ion channel effects in humans compared to preclinical studies. The algorithm is being released as open-source software.Trial RegistrationNCT02308748 and NCT01873950

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

“…The differences can be explained by 1) different approaches to detecting the peak of notched T-waves and 2) the influence of U-waves on T offset (end of T-wave) detection. The FDA software consistently used the first peak of the notched T-wave for the Tpeak annotation 8 while the alternative software was designed to use the last significant peak prior to downslope of the T-wave. This resulted in shorter J-T peak c and longer T peak –T end durations (Figure 3a) for FDA measurements.…”

“…This observation brings emphasis to the need to carefully evaluate the influence of algorithm methodological differences on results of ECG biomarkers. The alternative software algorithm consistently selected the last significant peak of the T-wave prior to its downslope for the T-peak annotation, while the FDA algorithm consistently selected the first peak 8 . This resulted in longer J-T peak c values assessed by the alternative algorithm (Table 1 and Figure 2).…”

“…This effect is also complemented with reduction of CI, which should theoretically increase specificity of the biomarker. We hypothesize that using the first peak to measure J-T peak c, as was done by the FDA algorithm 8 , has the potential to bias a drug toward being more safe (false negative) given the hypothesis that a shorter J-T peak c interval may offset the risk associated with QT prolongation 3 . In the absence of a gold standard, however, it is not possible to know which result is more correct without long term follow up in a large cohort of patients.…”

“…The study details and inclusion criteria, were previously reported 3,8 and approved by the US Food and Drug Administration Research Involving Human Subjects Committee and the local institutional review board. All subjects gave written informed consent.…”

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

“…We explored the concordance of JTp intervals when measured by various algorithms. To conduct such an exercise, we invited various stakeholders to an open initiative to apply their JTp measurement technique on a reference set of ECG recordings that was shared through the Telemetric and Holter ECG Warehouse [9,10] This dataset was generated during a study conducted by the FDA to test the hypothesis that hERG potassium channel block prolongs QTc by prolonging both the heart-rate corrected JTp (JTpc) (early repolarization) and Tpeak–Tend (late repolarization) intervals on the ECG, whereas the addition of calcium and/or late sodium current block preferentially shortens JTpc prolongation caused by hERG block [4,5,11]. We report the drug concentration dependency of the JTpc intervals measured by the various technologies, and assess whether JTpc could distinguish between predominantly and strongly hERG-blocking drugs (quinidine and dofetilide) and drugs that have balanced ion channel (hERG and late sodium and/or calcium) blocking properties (ranolazine and verapamil).…”