Lack of correlation between exercise and sibenadet‐induced changes in heart rate corrected measurement of the QT interval

Abstract

What is already known about this subject• When this study was conducted it was already known that the 'standard' methods of correcting the QT interval for hear t rate were not optimal and that bias could result in their use in certain circumstances, in particular when drugs or conditions also induced wide fluctuations in heart rate.• The use of subject specific correction methods had been advocated and whilst these had been shown to apparently correct QT interval over usual physiological heart rates, they had not been tested under conditions where drugs could potentially increase heart rate and 'standard' correction methods gave apparent increases in QT interval. Furthermore, subject specific correction methods had usually been generated over a normal physiological heart rate range and made the assumption that the relationship remained linear outside of this usual range. What this study adds• A subject specific correction factor for QT correction can be calculated from a wide range of heart rates using exercise testing and the relationships between QT and RR are unique for a given individual.• The generation of subject specific correction factors from ECGs collected under resting conditions is not a robust method.• That subject specific correction factors derived from exercise testing are not appropriate to apply to drugs (with no evidence to suggest effects on the QT interval) that induce increases in heart rate and that the relationship between the QT and RR interval during exercise is clearly different to the QT/RR relationship of a drug that increases heart rate. AimsWe sought to investigate subject specific QT interval correction factors (SSCF) determined at rest and after exercise and to determine the validity of these factors after the administration of a probe drug known to increase hear t rate without directly affecting cardiac repolarization. MethodsThirty-two healthy volunteers underwent graded exercise, multiple recordings of electrocardiogram during rest over a day and a treatment phase administering inhaled placebo or sibenadet (a β 2 -adrenoceptor/dopamine D 2 -receptor agonist) at 250, 500 or one of 750 or 1000 µ g. SSCF were determined from linear regression of plots of log RR interval vs. log QT after exercise (QTcX), rest (QTcR), and combined data (QTcC). The SSCFs along with Bazett & Fridericia corrections were applied to the ECGs after inhalation of sibenadet. ResultsSSCFs obtained from the combination of the exercise and resting day (mean QTcC = 0.41) and exercise alone (mean QTcX = 0.40) were similar with a good fit to the data (mean r 2 = 0.92 and 0.93, respectively) while data at rest resulted in a less pronounced slope (mean QTcR = 0.27) and poorer fit (mean r 2 = 0.52). After the administration of sibenadet, none of the SSCFs, Bazett or Fridericia corrections adequately corrected QT for heart rate induced changes. ConclusionsNeither a SSCF from exercise, Bazett's or Fridericia's correction factors, adequately corrected the QT interval after the administration of a sympathomimetic agoni...

The effect of changes in core body temperature on the QT interval in beagle dogs: a previously ignored phenomenon, with a method for correction

“…The formula was tested in the same group of dogs, to mimic clinical situations, such as re‐warming (analogous to procedures for postoperative or cooled patients) and re‐cooling (procedures for heat stroke or fever). Furthermore, we have challenged this formula during exercise tests in conscious telemetered beagle dogs, as exercise also increases body temperature ( Febbraio et al ., 1996 ) and none of the existing formulae correct the QT interval properly during exercise ( Aytemir et al ., 1999 ; Benatar and Decraene, 2001 ; Newbold et al ., 2007 ). The applicability of the formula in dogs and humans under different circumstances was further investigated by a review of published data.…”

Value of non‐clinical cardiac repolarization assays in supporting the discovery and development of safer medicines

“…In 32 human volunteers, Viozan (250-750 mg inhaled) dose-dependently increased heart rate, and consequently shortened uncorrected QT interval (ranging from~10 to 25 beats per min, and~10 to 30 ms placebo subtracted at the low and high dose respectively). When corrected for heart rate, using Bazett, Fridericia or a subject-specific correction formula, QTc was dose-dependently prolonged in all cases (Newbold et al, 2007). Although Fridericia and subjectspecific QTc correction resulted in a much reduced QTc prolongation compared with Bazett-corrected QTc, the magnitude of QTc changes was still >10 ms at the lowest, clinically relevant, dose tested (Newbold et al, 2007).…”

“…In 32 human volunteers, Viozan (250–750 µg inhaled) dose‐dependently increased heart rate, and consequently shortened uncorrected QT interval (ranging from ∼10 to 25 beats per min, and ∼10 to 30 ms placebo subtracted at the low and high dose respectively). When corrected for heart rate, using Bazett, Fridericia or a subject‐specific correction formula, QTc was dose‐dependently prolonged in all cases (Newbold et al. , 2007).…”

“…, 2007). Although Fridericia and subject‐specific QTc correction resulted in a much reduced QTc prolongation compared with Bazett‐corrected QTc, the magnitude of QTc changes was still >10 ms at the lowest, clinically relevant, dose tested (Newbold et al. , 2007).…”

“…Bazett, Fridericia or subject specific. Data extracted from: Valentin and Hammond (2006), Valentin et al. (2006, 2007) and Newbold et al. (2007).…”