Methodologies to characterize the QT/corrected QT interval in the presence of drug-induced heart rate changes or other autonomic effects

Garnett, Christine; Zhu, Hao; Malík, Marek; Fossa, Anthony A.; Zhang, Joanne; Badilini, Fabio; Li, Jianguo; Darpö, Börje; Sager, Philip T.; Rodríguez, I.

doi:10.1016/j.ahj.2012.02.023

Cited by 105 publications

(165 citation statements)

References 78 publications

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“…A limitation of the study is the methodology used for heart rate correction of the QT interval. For drugs with a pronounced effect on the heart rate such as rac-sotalol, standard correction methods may not completely remove the heart rate dependence of the derived QTc interval [36], as demonstrated by the slope of the QTc/RR regression lines (Figure 3). Even so, our findings were essentially the same for a population-derived method, QTcF, a study-specific method, QTcN and for a method based on each subject's QT/RR pairs, QTcI.…”

Section: Study Limitationsmentioning

confidence: 99%

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QT_cmodelling in a phase 1 study with oral rac-sotalol

Darpö

Karnad

Badilini³

et al. 2014

Br J Clin Pharmacol

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AIMTo study the differences in QTc interval on ECG in response to a single oral dose of rac-sotalol in men and women. METHODSContinuous 12-lead ECGs were recorded in 28 men and 11 women on a separate baseline day and following a single oral dose of 160 mg rac-sotalol on the following day. ECGs were extracted at prespecified time points and upsampled to 1000 Hz and analyzed manually in a central ECG laboratory on the superimposed median beat. Concentration-QTc analyses were performed using a linear mixed effects model. RESULTSRac-sotalol produced a significant reduction in heart rate in men and in women. An individual correction method (QTcI) most effectively removed the heart rate dependency of the QTc interval. Mean QTcI was 10 to 15 ms longer in women at all time points on the baseline day. Rac-sotalol significantly prolonged QTcI in both genders. The largest mean change in QTcI (ΔQTcI) was greater in females (68 ms (95% confidence interval (CI) 59, 76 ms) vs. 27 ms (95% CI 22, 32 ms) in males). Peak rac-sotalol plasma concentration was higher in women than in men (mean Cmax 1.8 μg ml −1 (range 1.1-2.8) vs. 1.4 μg ml −1 (range 0.9-1.9), P = 0.0009). The slope of the concentration-ΔQTcI relationship was steeper in women (30 ms per μg ml −1 vs. 23 ms per μg ml −1 in men; P = 0.0135). CONCLUSIONSThe study provides evidence for a greater intrinsic sensitivity to rac-sotalol in women than in men for drug-induced delay in cardiac repolarization. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Women have a longer QTc interval and an increased risk for pro-arrhythmias caused by drug-induced delayed cardiac repolarization.• This increased risk cannot be explained by gender differences in plasma concentration of the drug.• This study evaluated the QTc-plasma concentration relationship after dosing of rac-sotalol in men and women. WHAT THIS STUDY ADDS• When given a therapeutic dose of rac-sotalol, the slope of the relationship between rac-sotalol concentration and change in QTc interval was steeper in women.• This indicates a greater sensitivity in women as compared with men for rac-sotalol-induced QT prolongation, which may contribute to the greater pro-arrhythmic risk in women.

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Section: Study Limitationsmentioning

confidence: 99%

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QT_cmodelling in a phase 1 study with oral rac-sotalol

Darpö

Karnad

Badilini³

et al. 2014

Br J Clin Pharmacol

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“…The majority of these studies investigated the relationship by means of linear regression between simultaneously measured QT and RR intervals; only infrequently was the linear regression applied to logarithmically transformed QT and RR data. However, the pattern of the QT/RR relationship is not necessarily linear (9) and is known to be frequently steeper at faster heart rates compared with slower heart rates. In studies using a linear QT/RR relationship, this possibly creates a systematic bias when the target clinical populations differ or can be expected to differ in heart rate (4,6), making the observations of the differences between linear QT/RR slopes potentially erroneous.…”

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confidence: 99%

“…Since the design of accurate individual QT rate corrections depends on accurate mathematical description of baseline QT/RR relationship (9), it has been proposed to fit different nonlinear models to the data of different individuals, which, in essence, means to classify the curvatures of the QT/RR patterns into several distinct categories (10,12). While this technology has been used successfully in studies of electrocardiographic drug effects (24,25), it does not deal with the problem of the QT/RR curvature fully (26).…”

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confidence: 99%

QT/RR curvatures in healthy subjects: sex differences and covariates

Malik

Hnatkova²,

Kowalski

et al. 2013

American Journal of Physiology-Heart and Circulatory Physiology

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Data of a large clinical study were used to investigate how much are the QT/RR patterns in healthy subjects curved and whether these curvatures differ between women and men. Daytime drug-free 12-lead Holter recordings were repeated 4 times in each of 176 female healthy subjects and 176 male healthy subjects aged 32.7 Ϯ 9.1 yr. In each of the subjects, up to 1,440 carefully verified QT interval measurements were obtained with QT/RR hysteresis-corrected RR intervals. Individual subject data were used to fit the following regression equation: QT ϭ ϩ (␦/␥)(1 Ϫ RR ␥ ) ϩ ε, where QT and RR are QT and RR measurements (in s), is regression intercept, ␦ is the QT/RR slope, ␥ is the QT/RR curvature and provides the lowest regression residual, and ε represents normally distributed zero-centered errors. The bootstrap technique showed the intrasubject reproducibility of QT/RR slopes and curvatures. In women and men, QT/RR curvatures were 0.544 Ϯ 0.661 and 0.797 Ϯ 0.706, respectively (P ϭ 0.0006). The corresponding QT/RR slopes were 0.158 Ϯ 0.030 and 0.139 Ϯ 0.023, respectively (P Ͻ 0.0001). QT/RR curvatures were related to QT/RR slopes but not to individually corrected mean QTc intervals or individual QT/RR hysteresis profiles. The individual heart rate correction formula derived from the curvilinear regression provided a significantly lower intrasubject variability of QTc interval than individual optimisation of linear or log-linear QT/RR heart rate corrections. The QT/RR curvature can be reliable measured and expressed numerically. The corresponding heart rate correction formula provides more compact data than the previously proposed approaches. There are substantial sex differences in QT/RR patterns. Women have a QT/RR pattern that is not only steeper than men but also more curved.QT/RR curvature profile; intrasubject stability; intersubject differences; QT heart rate correction THE DEPENDENCY of the duration of ventricular repolarization on the underlying heart rate is well known. It is also known that it is related to a similar dependency of action potential durations (7) that shows regional differences within the ventricular myocardium (23). Similarly, delayed adaptation of action potential durations after abrupt changes in stimulation rates are well known (8). The intracellular mechanism underlying the repolarization dependency and thus the pattern of the QT/RR relationship are not completely understood and have been subject of both animal and modeling experiments of ionic currents (11,19,22). Why the QT/RR relationship and adaptation exhibits substantial intersubject differences with intrasubject stability (3, 27) is not known. Further studies of the phenomenon require appropriate tools for the description of the relationship.A number of studies (5, 6, 10, 16) assessed the slope of the QT/RR relationship in long-term Holter recordings and investigated its meaning as a clinical characteristic. The majority of these studies investigated the relationship by means of linear regression between simultaneously measured QT a...

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“…However, if investigating QTc changes associated with systematic heart rate acceleration or deceleration, the technology of individualised heart rate correction needs to be applied to avoid correction errors. 5 Following the mathematical implementation used when the technique of individualised heart rate correction was introduced, 6 has been used [7][8][9] (where the RR interval measured in seconds represents the heart rate underlying the QT interval measurement). The first of these equations assumes linear relationship between QT and RR intervals; the other assumes linear relationship between the logarithms of QT and RR values.…”

Section: Introductionmentioning

confidence: 99%

Importance of subject-specific QT/RR curvatures in the design of individual heart rate corrections of the QT interval

Malik

Hnatkova

Kowalski

et al. 2012

Journal of Electrocardiology

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Methodologies to characterize the QT/corrected QT interval in the presence of drug-induced heart rate changes or other autonomic effects

Cited by 105 publications

References 78 publications

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QT_cmodelling in a phase 1 study with oral rac-sotalol

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QT_cmodelling in a phase 1 study with oral rac-sotalol

QT/RR curvatures in healthy subjects: sex differences and covariates

Importance of subject-specific QT/RR curvatures in the design of individual heart rate corrections of the QT interval

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Methodologies to characterize the QT/corrected QT interval in the presence of drug-induced heart rate changes or other autonomic effects

Cited by 105 publications

References 78 publications

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTcmodelling in a phase 1 study with oral rac-sotalol

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTcmodelling in a phase 1 study with oral rac-sotalol

QT/RR curvatures in healthy subjects: sex differences and covariates

Importance of subject-specific QT/RR curvatures in the design of individual heart rate corrections of the QT interval

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Are women more susceptible than men to drug-induced QT prolongation? Concentration-QT_cmodelling in a phase 1 study with oral rac-sotalol

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QT_cmodelling in a phase 1 study with oral rac-sotalol