Abstract 15725: Normal Limits of Variability of Spatial QRS-T Angle and Ventricular Gradient: Analysis of 20 Thorough-QT Studies
Introduction: Drug-induced prolongation of the heart-rate corrected QT interval (QTc) is commonly used as a marker of Torsade de Pointes risk of drugs, as evaluated in Thorough-QT (TQT) studies. However, some drugs prolong QTc without an increased risk of Torsade. Identification of complementary ECG biomarkers to differentiate benign from malignant QTc prolongation would be highly desirable. The purpose of this study is to evaluate the reproducibility and consistency of two different biomarkers, the spatial QRS-T angle (previously shown to predict arrhythmic events) and the ventricular gradient ([VG] reflects heterogeneity of action potential morphology) and to establish their normal limits of variability in drug-free conditions (baseline).
Methods: We evaluated 20 TQT studies (avg. 62 subjects/study) with ECGs for multiple baseline days. We derived the vectorcardiogram (VCG) and calculated the spatial QRS-T angle (angle between mean QRS and T vectors) and VG (magnitude of the sum of the VCG during the QT interval). We applied a recently published method developed to assess the reproducibility of QTc measurements to the new biomarkers. For each study, we (1) computed the intra-subject differences in the biomarkers on separate baseline days at each time point throughout the day, (2) calculated the 95% confidence interval (CI) of the differences for each time point and (3) calculated the upper 95% CI of the upper 95% CI in step 2. The upper limit of variability was defined as the mean of step 3 across all studies. Step 3 was repeated with the lower 95% CIs to determine the lower limit of variability.
Results: The mean QRS-T angle was 43.5º and VG was 97.4 mV•ms. The mean intra-subject differences (Methods Step 1) for the 20 studies ranged from -1.33º to 3.52º for the QRS-T angle and -1.47 to 1.93 mV•ms for the VG. The lower and upper limits of variability (Methods Step 3) were -6.46º and 6.11º for the QRS-T angle and -7.16 and 7.59 mV•ms for the VG. As expected, these values were almost symmetrical around 0.
Conclusions: In TQT studies, the normal limits of variability for QRS-T angle are ±7º and VG are ±8 mV•ms. In order to determine if a drug produces a significant change in these biomarkers, we propose that the mean change should surpass these thresholds and the 95% CI exclude 0.
- © 2012 by American Heart Association, Inc.