title: Automated Algorithm for J-Tpeak and Tpeak-Tend Assessment of Drug-Induced Proarrhythmia Risk.
abstract: BACKGROUND
  Prolongation 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).
  
  
  METHODS
  In 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.
  
  
  RESULTS
  Comparison 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.
  
  
  CONCLUSIONS
  We 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.
  
  
  BACKGROUND
  NCT02308748 and NCT01873950.
authors.affiliation: Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, United States of America.
authors.forename: Lars
authors.initials: L
authors.lastname: Johannesen
authors.affiliation: Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, United States of America.|BSICoS Group, Aragón Institute for Engineering Research (I3A), IIS Aragón, University of Zaragoza, Zaragoza, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Vicente
authors.affiliation: Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, United States of America.
authors.forename: Meisam
authors.initials: M
authors.lastname: Hosseini
authors.affiliation: Office of Clinical Pharmacology, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, United States of America.
authors.forename: David G
authors.initials: DG
authors.lastname: Strauss
mesh_terms: D000465:Algorithms; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000503:physiopathology*; D001331:Automation / Q000379:methods; D064420:Drug-Related Side Effects and Adverse Reactions / Q000503:physiopathology*; D004562:Electrocardiography / Q000379:methods; D006329:Heart Conduction System / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced / Q000503:physiopathology; D004364:Pharmaceutical Preparations / Q000008:administration & dosage*; D012306:Risk; D016171:Torsades de Pointes / Q000139:chemically induced / Q000503:physiopathology
chemical_list: D004364:Pharmaceutical Preparations