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

Raymundo Cassani González, Elien B Engels, Bruno Dubé, Réginald Nadeau, Alain Vinet, A Robert LeBlanc, Marcio Sturmer, Giuliano Becker, Teresa Kus, Vincent Jacquemet

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)541-545
Number of pages5
JournalJournal of Electrocardiology
Volume45
Issue number6
DOIs
Publication statusPublished - 11 Sep 2012
Externally publishedYes

Keywords

  • Algorithms
  • Aza Compounds
  • Diagnosis, Computer-Assisted
  • Electrocardiography, Ambulatory
  • Female
  • Fluoroquinolones
  • Heart Rate
  • Humans
  • Male
  • Quinolines
  • ROC Curve
  • Reproducibility of Results
  • Sensitivity and Specificity
  • Young Adult
  • Clinical Trial
  • Journal Article
  • Research Support, Non-U.S. Gov't

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