title: Universal Correction for QT/RR Hysteresis.
abstract: Clinical pharmacology QT/QTc studies can be smaller if they more efficiently use the data generated.
  
  
  
  The 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.
  
  
  
  Using 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).
  
  
  
  In 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.
  
  
  
  The 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.
authors.affiliation: National Heart and Lung Institute, Imperial College, Dovehouse Street, London, SW3 6LY, United Kingdom, UK. marek.malik@btinternet.com.
authors.forename: Marek
authors.initials: M
authors.lastname: Malik
authors.affiliation: Division of Biomedical Physics, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, MD, USA.|Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Johannesen
authors.affiliation: National Heart and Lung Institute, Imperial College, Dovehouse Street, London, SW3 6LY, United Kingdom, UK.
authors.forename: Katerina
authors.initials: K
authors.lastname: Hnatkova
authors.affiliation: Division of Cardiovascular and Renal Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD, USA.
authors.forename: Norman
authors.initials: N
authors.lastname: Stockbridge
mesh_terms: D016208:Databases, Factual / Q000592:standards; D017277:Drug Approval; D004562:Electrocardiography / Q000592:standards*; D006339:Heart Rate; D006801:Humans; D008955:Models, Cardiovascular; D010600:Pharmacology / Q000592:standards; D015203:Reproducibility of Results; D016683:Supine Position; D014481:United States