Vaibhav Salvi

Update on the evaluation of a new drug for effects on cardiac repolarization in humans: issues in early drug development

Following reports of death from cardiac arrhythmias with drugs like terfenadine and cisapride, the International Conference for Harmonization formulated a guidance (E14) document. This specifies that all new drugs must undergo a ‘thorough QT/QTc’ (TQT) study to detect drug‐induced QT prolongation, a surrogate marker of ventricular tachycardia, especially torsades de pointes (TdPs). With better understanding of data from several completed TQT studies, regulatory requirements have undergone some changes since the E14 guidance was implemented in October 2005. This article reviews the implications of the E14 guidance and the changes in its interpretation including choice of baseline QT, demonstration of assay sensitivity, statistical analysis of the effect of new drug and positive control, and PK‐PD modelling. Some issues like use of automated QT measurements remain unresolved. Pharmaceutical companies too are modifying Phase 1 studies to detect QTc liability early in order to save time and resources. After the E14 guidance, development of several drugs that prolong QTc by >5 ms is being abandoned by sponsors. However, all drugs that prolong the QT interval do not increase risk of TdP. Researchers in regulatory agencies, academia and industry are working to find better biomarkers of drug‐induced TdP which could prevent many useful drugs from being prematurely abandoned. Drug‐induced TdP is a rare occurrence. With fewer drugs that prolong QT interval reaching the licensing stage, knowing which of these drugs are torsadogenic is proving to be elusive. Thus, paradoxically, the effectiveness of the E14 guidance itself has made prospective validation of new biomarkers difficult.

Comparison of 5 methods of QT interval measurements on electrocardiograms from a thorough QT/QTc study: effect on assay sensitivity and categorical outliers

INTRODUCTION We studied moxifloxacin-induced QT prolongation and proportion of categorical QTc outliers when 5 methods of QT measurement were used to analyze electrocardiograms (ECGs) from a thorough QT study. METHODS QT interval was measured by the threshold, tangent, superimposed median beat, automated global median beat, and longest QT methods in a central ECG laboratory in 2730 digital ECGs from 39 subjects during placebo and moxifloxacin treatment. RESULTS All 5 methods were able to demonstrate statistically significant moxifloxacin-induced QTcF prolongation. However, lower bound of 95% 1-sided confidence interval of QTcF prolongation did not exceed 5 milliseconds with the longest QT method. More QTcF outliers were observed with the longest QT and tangent methods, whereas the other 3 methods were comparable. QTcF values greater than 500 milliseconds were observed only with moxifloxacin by the tangent method, and with moxifloxacin and placebo by the longest QT method. CONCLUSION The method of QT measurement must be considered when interpreting individual thorough QT/QTc studies.

Early repolarization and short QT interval in healthy subjects.

BACKGROUND An early repolarization (ER) pattern is common in ECGs from patients with ventricular fibrillation (VF). These patients with ER have shorter QT intervals. Morphological variants of the ER pattern also have been associated with idiopathic VF, but their prevalence in healthy subjects is unclear. OBJECTIVE The purpose of this study was to study the prevalence of ER and its morphological variants, and its association with the QTc interval in healthy subjects. METHODS Digital ECGs from 1886 healthy subjects from Phase I clinical trials were analyzed by a central ECG laboratory. RESULTS ER, defined as J-point elevation ≥0.1 mV in ≥2 contiguous leads, was present in 514 subjects (27.3%), of whom 505 (98.2%) were males. The prevalence of ER declined progressively with increasing age. ER pattern was seen in lateral leads (I, aVL, V(4)-V(6)) in 26.1%, in inferior (II, III, aVF) or inferolateral leads in 8%, and was global in 1.9%. The terminal portion of the QRS complex was notched in 43.1% and slurred in 56.9%. Notching was common in inferior/lateral leads, and slurring was common in anterior leads. A non-ascending ST segment was seen in 71% of ECGs with a notched pattern but in only 12.3% of ECGs with a slurred pattern. The ER group had slower heart rates (9.3 ± 13.3 bpm [mean difference ± SD], P <.001) and shorter QTc intervals (QTcB = 20.2 ± 25.6 ms, QTcF = 11.0 ± 21.9 ms; P <.001). Four subjects in each group had a short QT interval (QTcF <350 ms). CONCLUSION ER and all of its variants are common in healthy young males with slower heart rates and slightly shorter QTc intervals. A short QT interval (QTcF <350 ms) is rare.

Drug-induced QT prolongation when QT interval is measured in each of the 12 ECG leads in men and women in a thorough QT study

Lead II is commonly used to study drug-induced QT prolongation. Whether other ECG leads too show comparable QT prolongation is not known. We studied moxifloxacin-induced QT prolongation in a thorough QT study in healthy subjects (54 males, 43 females). Placebo-subtracted change from baseline in QTc corrected by Fridericias method (ΔΔQTcF) at 1, 1.5, 2 and 4 hours after moxifloxacin was studied in all 12 leads. Unacceptably wide 90% confidence interval (CI) for ΔΔQTcF was seen in three leads; these leads also had maximum ECGs with flat T waves (60% in aVL, 45% in lead III and 42% in V1). After excluding ECGs with flat T waves, 90% lower CI of ΔΔQTcF was ≥ 5 ms in all leads except leads III, aVL and V1 in men. The 90% lower CI exceeded 5 ms in these leads in women despite wide 90% CIs because of greater mean ΔΔQTcF. Leads III, aVL and V1 should be avoided when measuring QT interval in thorough QT studies.

Semiautomated QT interval measurement in electrocardiograms from a thorough QT study: comparison of the grouped and ungrouped superimposed median beat methods

INTRODUCTION We postulated that it may be easier to identify earliest Q onset and latest T offset when the median beats from 12 leads are separated vertically by 5 to 10 mm (ungrouped superimposed median beat [SMB] method) rather than when their baselines closely (but rarely perfectly) overlap (grouped SMB method). METHODS Three readers manually adjudicated annotations placed by an automated algorithm, using grouped (gSMB) and ungrouped (uSMB) methods in 2658 electrocardiograms (ECGs) recorded in 38 subjects in a crossover design thorough QT study at predose and 6 time points postdosing with placebo or moxifloxacin. RESULTS Placebo-subtracted, moxifloxacin-induced QTcF prolongation was comparable with both methods. Maximum QTcF prolongation was seen at 2 hours--10.5 milliseconds (90% confidence interval, 7.9-13.1 milliseconds) with gSMB and 12.9 milliseconds (90% confidence interval, 9.9-15.8 milliseconds) by uSMB. Both methods showed good agreement; mean QT was 4 milliseconds greater by uSMB. Interreader variability of absolute differences in QT measurements was 1 millisecond lower with the uSMB method (6.8 ± 5.7 milliseconds by gSMB and 5.9 ± 4.5 milliseconds by uSMB). CONCLUSION Mean QT was 4 milliseconds longer, and interreader variability, 1 millisecond lower with uSMB. Otherwise, both methods were comparable and detected the moxifloxacin effect.

Comparison of Two Methods of Estimating Reader Variability in QT Interval Measurements in Thorough QT/QTc Studies

Two methods of estimating reader variability (RV) in QT measurements between 12 readers were compared.

Prediction of Mortality Using Measures of Cardiac Autonomic Dysfunction in the Diabetic and Nondiabetic Population: The MONICA/KORA Augsburg Cohort Study Response to Ziegler et al.

A recent article by Ziegler et al. (1) on the value of electrocardiogram (ECG) parameters (corrected QT [QTc] interval and heart rate variability) in identifying diabetic subjects at increased risk of mortality showed that QT interval corrected for heart rate using Bazetts formula (QTcB) >440 ms was associated with higher mortality. While these results are clinically very relevant, the title of the paper suggests that QTc prolongation is caused by cardiac autonomic neuropathy. In fact, other factors may also prolong QTc interval in diabetic subjects (2,3). We analyzed baseline ECGs of 189 diabetic subjects …

Comparison of the spatial QRS-T angle derived from digital ECGs recorded using conventional electrode placement with that derived from Mason-Likar electrode position.

BACKGROUND The spatial QRS-T angle is ideally derived from orthogonal leads. We compared the spatial QRS-T angle derived from orthogonal leads reconstructed from digital 12-lead ECGs and from digital Holter ECGs recorded with the Mason-Likar (M-L) electrode positions. METHODS AND RESULTS Orthogonal leads were constructed by the inverse Dower method and used to calculate spatial QRS-T angle by (1) a vector method and (2) a net amplitude method, in 100 volunteers. Spatial QRS-T angles from standard and M-L ECGs differed significantly (57°±18° vs 48°±20° respectively using net amplitude method and 53°±28° vs 48°±23° respectively by vector method; p<0.001). Difference in amplitudes in leads V4-V6 was also observed between Holter and standard ECGs, probably due to a difference in electrical potential at the central terminal. CONCLUSION Mean spatial QRS-T angles derived from standard and M-L lead systems differed by 5°-9°. Though statistically significant, these differences may not be clinically significant.

Reader variability in QT measurement due to measurement error and variability in leads selection: A simulation study comparing 2-way vs. 3-way interaction ANOVA model

Reader variability (RV) results from measurement differences or variability in lead used for QT measurements; the latter is not reflected in conventional methods for estimating RV. Mean and SD of QT intervals in 12 leads of 100 ECGs measured twice were used to simulate data sets with inter-RV of 5, 10, 15, 20, and 25 ms and intra-RV of 3, 6, 9, 12, and 15 ms. Six hundred twenty-five data sets were simulated such that different leads were used in Read1 and Read2 in 0, 10%, 20%, 30%, 40% of ECGs by 25 readers. RV was estimated using ANOVA interaction models: three-way model using Reader, ECG and lead as factors, and 2-way model using reader and ECG as factors. Estimates from three-way model accurately matched inter- and intra-RV that were introduced during simulation regardless of percent of ECGs with lead selection variability. The two-way model provides identical estimates when both reads are in same leads, but higher, more realistically estimates when measurements are made in different leads.

Limb Lead Interchange in Thorough QT/QTc Studies

The investigators analyzed 85 133 electrocardiograms (ECGs) recorded in 484 subjects from 5 thorough QT/QTc studies (3 using Holter devices, 2 using 12‐lead ECGs) for inadvertent limb lead interchanges using a dedicated quality control process in a central ECG laboratory. Limb lead interchanges were present in 2919 (3.4%) ECGs in 17.9% of subjects and were more frequent with Holter devices (7.5% vs 0.8%, P < .0001), where leads remain connected for prolonged periods, affecting data from several time points. Left arm—left leg interchange was seen in 54% of 12‐lead ECGs and right arm—left arm interchange in 38%. The ECG device itself could identify 21.7% of interchanges, whereas experienced readers blinded to subject and visit identified 79% of interchanges; 21% of interchanges were identified only during the quality control process. If correctly identified, QT measurement could be performed in a precordial lead. If undiagnosed, incorrect QT interval measurements and morphological diagnosis may confound results.