title: ICH E14-compatible holter bin method and its equivalence to individual heart rate correction in the assessment of drug-induced QT changes.
abstract: BACKGROUND
  The Holter bin method evaluates QT interval changes in the presence of heart rate changes without correcting the QT interval. However, the method does not allow time-matched comparisons, thus contradicting available guidance and good practice. We report a modification of the methods that allows time-matched comparisons without any heart rate correction.
  
  
  RESULTS
  The modified Holter bin method (a) finds matching baseline heart rates for each QT reading on treatment and (b) calculates ΔQT values from the QT intervals on baseline and on treatment that match in heart rates. The difference between ΔQT values on active treatment and placebo provides the ΔΔQT value. The method was compared with the individual correction method in the data of the mirabegron thorough QT study in which supratherapeutic doses of this β3-adrenoceptor agonist led to substantial heart rate changes. The modified Holter bin method reproduced closely the results obtained with the individual heart rate correction. At all time points of the mirabegron study, the differences between the mean ΔΔQT values by the Holter bin method and the individual correction method were below 1 millisecond. Compared to the individual correction, the Holter bin method led to slight increases in the standard deviations of ΔΔQT values, but these were on average below 0.25 millisecond.
  
  
  CONCLUSIONS
  The Holter bin methodology can be modified to make it compatible with the available guidance and with good practice of clinical investigations. The results obtained with the modified Holter bin method are practically the same as with individualized heart rate corrected QT intervals. The close correspondence between the 2 methods demonstrates that the present possibilities of comparing QT interval duration in the presence of experiment-induced heart rate differences are not influenced by methodological artifacts.
authors.affiliation: St. Paul's Cardiac Electrophysiology, University of London, and Imperial College, London, UK.
authors.forename: Marek
authors.initials: M
authors.lastname: Malik
authors.forename: Katerina
authors.initials: K
authors.lastname: Hnatkova
authors.forename: Donna
authors.initials: D
authors.lastname: Kowalski
authors.forename: James J
authors.initials: JJ
authors.lastname: Keirns
authors.forename: E Marcel
authors.initials: EM
authors.lastname: Van Gelderen
mesh_terms: D000083:Acetanilides / Q000009:adverse effects; D058667:Adrenergic beta-3 Receptor Agonists / Q000009:adverse effects; D000328:Adult; D018592:Cross-Over Studies; D004311:Double-Blind Method; D015716:Electrocardiography, Ambulatory / Q000295:instrumentation / Q000379:methods*; D005260:Female; D006339:Heart Rate / Q000502:physiology*; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000175:diagnosis / Q000503:physiopathology*; D008297:Male; D013844:Thiazoles / Q000009:adverse effects
chemical_list: D000083:Acetanilides; D058667:Adrenergic beta-3 Receptor Agonists; D013844:Thiazoles; C520025:mirabegron
keywords: Holter monitor; QT heart rate correction; RR bin method; mirabegron; time-matched comparisons