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J Electrocardiol. 2012 Nov-Dec;45(6):541-5. doi: 10.1016/j.jelectrocard.2012.07.004. Epub 2012 Sep 7.

Assessment of the sensitivity of detecting drug-induced QTc changes using subject-specific rate correction.

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1
Hôpital du Sacré-Cœur de Montréal, Centre de Recherche, Montréal, QC, Canada.

Abstract

AIMS:

To quantify the sensitivity of QT heart-rate correction methods for detecting drug-induced QTc changes in thorough QT studies.

METHODS:

Twenty-four-hour Holter ECGs were analyzed in 66 normal subjects during placebo and moxifloxacin delivery (single oral dose). QT and RR time series were extracted. Three QTc computation methods were used: (1) Fridericia's formula, (2) Fridericia's formula with hysteresis reduction, and (3) a subject-specific approach with transfer function-based hysteresis reduction and three-parameter non-linear fitting of the QT-RR relation. QTc distributions after placebo and moxifloxacin delivery were compared in sliding time windows using receiver operating characteristic (ROC) curves. The area under the ROC curve (AUC) served as a measure to quantify the ability of each method to detect moxifloxacin-induced QTc prolongation.

RESULTS:

Moxifloxacin prolonged the QTc by 10.6 ± 6.6 ms at peak effect. The AUC was significantly larger after hysteresis reduction (0.87 ± 0.13 vs. 0.82 ± 0.12, p<0.01) at peak effect, indicating a better discriminating capability. Subject-specific correction further increased the AUC to 0.91 ± 0.11 (p<0.01 vs. Fridericia with hysteresis reduction). The performance of the subject-specific approach was the consequence of a substantially lower intra-subject QTc standard deviation (5.7 ± 1.1 ms vs. 8.8 ± 1.2 ms for Fridericia).

CONCLUSION:

The ROC curve provides a tool for quantitative comparison of QT heart rate correction methods in the context of detecting drug-induced QTc prolongation. Results support a broader use of subject-specific QT correction.

[Indexed for MEDLINE]

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