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

详细信息    查看全文

• 作者：Raymundo Cassani Gonzá ; lez ; BSc^a ; Elien B. Engels ; BSc^a ; Bruno Dubé ; MSc^a ; Ré ; ginald Nadeau ; MD^a ; Alain Vinet ; PhD^a ; ^b ; A. Robert LeBlanc ; PhD^a ; ^b ; Marcio Sturmer ; MD^a ; Giuliano Becker ; MD^a ; Teresa Kus ; MD ; PhD^a ; ^c ; Vincent Jacquemet ; PhD^a ; ^b ; ^{vincent.jacquemet@umontreal.ca}
• 关键词：Thorough QT study ; Corrected QT ; Drug-induced QT prolongation ; Subject-specific correction
• 刊名：Journal of Electrocardiology
• 出版年：2012
• 出版时间：November-December, 2012
• 年：2012
• 卷：45
• 期：6
• 页码：541-545
• 全文大小：511 K

文摘

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 ¡À 6.6 ms at peak effect. The AUC was significantly larger after hysteresis reduction (0.87 ¡À 0.13 vs. 0.82 ¡À 0.12, p < 0.01) at peak effect, indicating a better discriminating capability. Subject-specific correction further increased the AUC to 0.91 ¡À 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 ¡À 1.1 ms vs. 8.8 ¡À 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.