Errors and misconceptions in ECG measurement used for the detection of drug induced QT interval prolongation.
Drug-induced changes in cardiac repolarisation receive substantial attention by regulatory agencies. Since there are presently no established accurate possibilities of testing the propensity to torsade induction during clinical drug development, the regulators require drug-related QT interval changes to be thoroughly investigated with almost all new pharmacological agents. Small QT interval changes are easy to miss and the regulators therefore expect the relevant studies to be very precise. Such a precision is not easy to achieve and different strategies have been proposed. The purpose of this article is to review the most frequent misconceptions and errors in the electrocardiogram handling and measurements related to the detection to drug-induced QT interval changes. Specifically, the article discusses (a) the possibilities of automatic measurement by standard electrocardiographic equipment, (b) the danger of casual measurement by central laboratories handling the electrocardiograms, (c) the selection of recording leads for QT interval measurement, and (d) the problem of the so-called heart rate hysteresis of the QT interval adaptation. Suggestions are made for drug developers of what study design and quality control aspects are needed to avoid the most frequent imprecisions.
Malik
Marek
M
Department of Cardiac and Vascular Sciences, St George's Hospital Medical School, London, England, UK. m.malik@sghms.ac.uk
D000222:Adaptation, Physiological / Q000187:drug effects; D003951:Diagnostic Errors; D004341:Drug Evaluation; D064420:Drug-Related Side Effects and Adverse Reactions; D004562:Electrocardiography / Q000187:drug effects / Q000295:instrumentation / Q000379:methods*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D009200:Myocardial Contraction / Q000187:drug effects*; D016171:Torsades de Pointes / Q000139:chemically induced