Errors of fixed QT heart rate corrections used in the assessment of drug-induced QTc changes
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Author(s)
Type
Journal Article
Abstract
The accuracy of studies of drug-induced QTc changes depends, among others, on the accuracy of heart rate correction of QT interval. It has been recognised that when a drug leads to substantial heart rate changes, fixed universal corrections cannot be used and that alternative methods such as subject-specific corrections established for each study participant need to be considered. Nevertheless, the maximum heart rate change that permits use of fixed correction with reasonable accuracy has not been systematically investigated. We have therefore used full QT/heart-rate profiles of 751 healthy subjects (mean age 34.2±9.6 years, 335 females) and compared their subject-specific corrections with 6 fixed corrections, namely Bazett, Fridericia, Framingham, Hodges, Rautaharju, and Sarma formulae. The comparison was based on statistical modelling experiments which simulated clinical studies of N=10 or N=50 female or male subjects. The experiments compared errors of ΔQTc intervals calculated as differences between QTc intervals at an initial heart rate (40 to 120 beats per minute, bpm) and after a heart rate change (-20 to +20 bpm). The experiments also investigated errors due to spontaneous heart rate fluctuation and due to omission of correction for QT/RR hysteresis. In each experiment, the absolute value of the single-sided 90th percentile most remote from zero was used as the error estimate. Each experiment was repeated 10,000 times with random selection of modelled study group. From these repetitions, median and upper 80th percentile was derived and graphically displayed for all different combinations of initial heart rate and heart rate change. The results showed that Fridericia formula might be reasonable (with estimated errors of ΔQTc below 8 ms) in large studies if the heart rate does not change more than ±10 bpm and that the errors by fixed corrections and the errors due to omission of QR/RR hysteresis are additive. Additionally, the results suggest that the variability introduced into QTc data by not correcting for the underlying heart rate accurately might have a greater impact in smaller studies. The errors by Framingham formula were practically the same as with the Fridericia formula. Other investigated fixed heart rate corrections led to larger ΔQTc errors.
Date Issued
2019-06-18
Date Acceptance
2019-05-06
Citation
Frontiers in Physiology, 2019, 10
ISSN
1664-042X
Publisher
Frontiers Media
Journal / Book Title
Frontiers in Physiology
Volume
10
Copyright Statement
© 2019 Hnatkova, Vicente, Johannesen, Garnett, Stockbridge and Malik.
This is an open-access article distributed under the terms of the Creative Commons
Attribution License (CC BY). The use, distribution or reproduction in other forums
is permitted, provided the original author(s) and the copyright owner(s) are credited
and that the original publication in this journal is cited, in accordance with accepted
academic practice. No use, distribution or reproduction is permitted which does not
comply with these terms.
This is an open-access article distributed under the terms of the Creative Commons
Attribution License (CC BY). The use, distribution or reproduction in other forums
is permitted, provided the original author(s) and the copyright owner(s) are credited
and that the original publication in this journal is cited, in accordance with accepted
academic practice. No use, distribution or reproduction is permitted which does not
comply with these terms.
Sponsor
British Heart Foundation
Grant Number
NH/16/2/32499
Subjects
Science & Technology
Life Sciences & Biomedicine
Physiology
drug safety
drug-induced QTc changes
heart rate correction of QT interval
Fridericia QTc formula
Framingham QTc formula
subject-specific QTc corrections
PROARRHYTHMIC RISK-ASSESSMENT
HEALTHY-SUBJECTS
CARDIAC SAFETY
QT/RR HYSTERESIS
THOROUGH QT/QTC
INTERVAL
DEPENDENCE
DESIGN
Framingham QTc formula
Fridericia QTc formula
drug safety
drug-induced QTc changes
heart rate correction of QT interval
subject-specific QTc corrections
Publication Status
Published
Article Number
635
Date Publish Online
2019-06-18