• Marek Malik, Lars Johannesen, Katerina Hnatkova, and Norman Stockbridge.
• National Heart and Lung Institute, Imperial College, Dovehouse Street, London, SW3 6LY, United Kingdom, UK. marek.malik@btinternet.com.
• Drug Saf. 2016 Jun 1; 39 (6): 577-88.

IntroductionClinical pharmacology QT/QTc studies can be smaller if they more efficiently use the data generated.ObjectiveThe aim was to use large sets of electrocardiograms (ECGs) deposited at the US Food and Drug Administration to investigate the implications of heart rate measurement on the accuracy of QTc data.MethodsUsing the data of 80 thorough QT studies, we investigated whether placing study subjects in supine positions during short-term time points stabilizes heart rate (part I, based on 73 studies with 747,912 measured ECGs in 6786 healthy subjects) and whether heart rate measurements different from RR intervals captured simultaneously with QT intervals decrease QTc variability (part II, based on seven studies with 897,570 ECG measurements in 751 healthy subjects).ResultsIn the part I data, when subjects were placed in supine undisturbed positions, heart rate instability (max-min of repeatedly measured heart rates within the same study time point) exceeding 5 beats per minute (bpm) was observed 40 % of the time and exceeded 10 bpm 10 % of the time. In the part II data, even when including QT measurements preceded by variable heart rates, correction of QT durations for RR interval values derived through a simple QT/RR hysteresis model with 95 % adaptation in 120 s led to mean intra-subject standard deviation of QTc (Fridericia formula) of only 7.14 ± 1.98 and 6.38 ± 1.50 ms in women and men, respectively.ConclusionThe QT/RR hysteresis model with 95 % adaptation in 120 s is universally applicable to healthy subjects, providing small QTc variability. Supine positions do not generally stabilize heart rates in healthy subjects. Universally applicable QT/RR hysteresis correction allows clinical QT/QTc studies to include variable heart rate episodes in the time points.

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