Barbey Jean T, Connolly Margaret, Beaty Brenda, Krantz Mori J
Social & Scientific Systems, Inc, Silver Spring, MD.
PAREXEL International Corp, Waltham, MA.
Ann Noninvasive Electrocardiol. 2016 Jan;21(1):82-90. doi: 10.1111/anec.12277. Epub 2015 May 4.
Electrocardiographic (ECG) safety evaluation is a required element of drug development. Performance characteristics of ECG measurement methodologies have rarely been studied prospectively.
We conducted a randomized, placebo-controlled, crossover study in 24 subjects to evaluate effects of moxifloxacin on the Fridericia rate-corrected QT (QTcF) interval. Five ECG replicates were obtained at 30 time points. Change from baseline QTcF (ΔQTcF) was fit by mixed-model analysis of variance to evaluate residual standard deviation. Precision was defined as intrasubject QTcF variance. Two core lab approaches were compared: QTinno, fully automated, 5 replicates and HeartSignals, computer-assisted manual, 3 replicates. Core lab values were then compared to an automated commercial algorithm (VERITAS).
Twenty-three subjects provided 3450 ECGs potentially available for analysis. QTinno QTcF values were based upon 3419 ECGs, HeartSignals data on 2028 ECGs. Variance was similar between the QTinno and HeartSignals approaches (41.5 and 44 ms(2)). After excluding VERITAS QTcF measurements that deviated by >40 ms on visual review, variance in a set of 1907 common ECGs was lowest for HeartSignal, followed by QTinno and VERITAS (43.8, 52.6, 89.4 ms(2)) P = 0.02 HeartSignals versus QTinno, P < 0.0001 for both HeartSignals and QTinno versus VERITAS.
A fully automated core lab approach using 5 replicates and a computer-assisted manual approach using 3 replicates were equally precise. When an identical number of ECGs were compared, the computer-assisted manual method was most precise, while the commercial algorithm was relatively imprecise. Although suitable for clinical assessment the standard commercial algorithm cannot be recommended for regulated safety research.
心电图（ECG）安全性评估是药物研发的必要环节。ECG测量方法的性能特征鲜有前瞻性研究。
我们对24名受试者进行了一项随机、安慰剂对照、交叉研究，以评估莫西沙星对弗里德里西亚心率校正QT（QTcF）间期的影响。在30个时间点获取了5份ECG复制品。通过混合模型方差分析拟合基线QTcF（ΔQTcF）的变化，以评估残余标准差。精密度定义为受试者内QTcF方差。比较了两种核心实验室方法：完全自动化的QTinno方法（5份复制品）和计算机辅助人工方法HeartSignals（3份复制品）。然后将核心实验室值与一种自动化商业算法（VERITAS）进行比较。
23名受试者提供了3450份可能可供分析的ECG。QTinno的QTcF值基于3419份ECG，HeartSignals的数据基于2028份ECG。QTinno和HeartSignals方法之间的方差相似（分别为41.5和44 ms²）。在视觉检查中排除偏差>40 ms的VERITAS QTcF测量值后，1907份常见ECG的一组中方差最低的是HeartSignal，其次是QTinno和VERITAS（分别为43.8、52.6、89.4 ms²），HeartSignals与QTinno相比P = 0.02，HeartSignals和QTinno与VERITAS相比P均<0.0001。
使用5份复制品的完全自动化核心实验室方法和使用3份复制品的计算机辅助人工方法同样精确。当比较相同数量的ECG时，计算机辅助人工方法最精确，而商业算法相对不精确。虽然适用于临床评估，但不推荐将标准商业算法用于规范的安全性研究。
