Cassani González Raymundo, Engels Elien B, Dubé Bruno, Nadeau Réginald, Vinet Alain, LeBlanc A Robert, Sturmer Marcio, Becker Giuliano, Kus Teresa, Jacquemet Vincent
Hôpital du Sacré-Cœur de Montréal, Centre de Recherche, Montréal, QC, Canada.
J Electrocardiol. 2012 Nov-Dec;45(6):541-5. doi: 10.1016/j.jelectrocard.2012.07.004. Epub 2012 Sep 7.
To quantify the sensitivity of QT heart-rate correction methods for detecting drug-induced QTc changes in thorough QT studies.
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.
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).
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.
在全面的QT研究中，量化QT心率校正方法检测药物诱导的QTc变化的敏感性。
对66名正常受试者在服用安慰剂和莫西沙星（单次口服剂量）期间进行24小时动态心电图分析。提取QT和RR时间序列。使用了三种QTc计算方法：（1）弗里德里西亚公式，（2）具有滞后减少的弗里德里西亚公式，（3）基于传递函数的滞后减少和QT-RR关系的三参数非线性拟合的个体特异性方法。使用受试者操作特征（ROC）曲线在滑动时间窗口中比较安慰剂和莫西沙星给药后的QTc分布。ROC曲线下面积（AUC）作为量化每种方法检测莫西沙星诱导的QTc延长能力的指标。
莫西沙星在峰值效应时使QTc延长10.6±6.6毫秒。在峰值效应时，滞后减少后的AUC显著更大（0.87±0.13对0.82±0.12，p<0.01），表明辨别能力更好。个体特异性校正进一步将AUC提高到0.91±0.11（与具有滞后减少的弗里德里西亚公式相比，p<0.01）。个体特异性方法的性能是个体内QTc标准差显著降低的结果（弗里德里西亚公式为8.8±1.2毫秒，个体特异性方法为5.7±1.1毫秒）。
ROC曲线为在检测药物诱导的QTc延长的背景下对QT心率校正方法进行定量比较提供了一种工具。结果支持更广泛地使用个体特异性QT校正。
