Dhiraj Narula

Intra- and interreader variability in QT interval measurement by tangent and threshold methods in a central electrocardiogram laboratory

BACKGROUND The QT interval can be measured by tangent (QT(Tan)) and threshold (QT(Thr)) methods; the better method is the one with lower reader variability. METHODS QT(Tan) and QT(Thr) were measured twice in 100 digital electrocardiograms (ECGs) by 8 experienced readers in a central laboratory. For QT(Thr), the end of the T wave was the point where the T wave reached the isoelectric baseline; for QT(Tan), it was the point where a line from the peak of the T wave through the steepest part of the descending limb intercepted the isoelectric baseline. RESULTS The average absolute intrareader variability ranged from 3.4 to 6.9 milliseconds for QT(Tan) and from 3.5 to 5.2 milliseconds for QT(Thr). By analysis of variance, intrareader SD of QT(Tan) was 7.0 and 7.5 milliseconds for QT(Thr); interreader SD was 13.1 milliseconds for QT(Tan) and 11.9 milliseconds for QT(Thr). QT(Tan) was shorter than QT(Thr) in 96 of the 100 ECGs, it exceeded QT(Thr) in 4 ECGs, which had prominent U waves. CONCLUSIONS For trained readers in a central ECG laboratory using sophisticated on-screen tools for QT measurement in high-quality digital ECGs, between- and within-reader variability are comparable for QT(Tan) and QT(Thr). However, QT(Tan) is consistently shorter than QT(Thr) by up to 10 milliseconds.

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.

Effect of Number of Replicate Electrocardiograms Recorded at Each Time Point in a Thorough QT Study on Sample Size and Study Cost

In a “thorough QT/QTc” (TQT) study, several replicate electrocardiograms (ECGs) are recorded at each time point to reduce within‐subject variability. This decreases the sample size but increases the cost of ECG analysis. To determine the most cost‐effective number of ECG replicates, the authors retrospectively analyzed data from the placebo and moxifloxacin arms of a TQT study with crossover design. Six replicate ECGs were recorded at 7 time points on day −1 (baseline day), day 1, and day 3 in 124 normal healthy volunteers who were randomized to receive moxifloxacin or placebo on day 1 and the other treatment on day 3. QT interval was corrected for heart rate by the Fridericia (QTcF) and individual subject‐specific (QTcI) formulas. Within‐subject and between‐subject standard deviations for QTcF obtained by repeated‐measures analysis of covariance were 9.5 and 13.3 milliseconds with 1 replicate; 7.8 and 12.7 milliseconds with 2 replicates; 7.3 and 12.3 milliseconds with 3 replicates; 6.9 and 12.2 milliseconds with 4 replicates; 6.8 and 11.9 milliseconds with 5 replicates; and 6.6 and 11.8 milliseconds with 6 replicates. Within‐ and between‐subject variance with QTcI also declined with increasing replicates. Sample size benefit based on these estimates was negligible beyond 4 replicates. The study cost was least with 3 or 4 replicates, depending on per‐ECG and per‐subject costs.

Z-score for benchmarking reader competence in a central ECG laboratory.

Background: ECGs from thorough QT studies must be read in a central laboratory by trained experts. Standards of expertise are not presently defined. We, therefore, studied the use of Z‐scores to define reader competence.

QTc interval and its variability in patients with schizophrenia and healthy subjects: implications for a thorough QT study

We compared heart rate-corrected QT interval (QTc) and its within- and between-subject variability, in ECGs recorded several days apart for 207 patients with schizophrenia (age range 19-60 yr) with age- and gender-matched healthy controls. Patients had higher heart rates (mean±s.d.) than controls [75±15 beats per minute (bpm) vs. 63±10 bpm; p<0.0001]. QTc by Bazetts formula (QTcB) overestimated QTc interval at high heart rates; consequently QTcB was longer in patients (412±24 ms) than in controls (404±24 ms; p=0.0003). QTc by Fridericias method (QTcF), which was not influenced by heart rate, was comparable (398±22 ms in patients vs. 401±19 ms in controls; p=0.17). Between-subject variability in QTcF was similar in patients (17 ms) and controls (16.2 ms) but within-subject variability was larger (13.1 ms vs. 10 ms, respectively). Thus, a larger sample size is required when thorough QTc studies with a cross-over design are performed in patients with schizophrenia than in healthy subjects; sample size is not increased for studies with a parallel design. Last, QTcF is preferred over QTcB in schizophrenia patients with higher heart rates.

Differences between QT and RR intervals in digital and digitized paper electrocardiograms: contribution of the printer, scanner, and digitization process

BACKGROUND Prints of electrocardiograms (ECGs) are often sent to core laboratories, where they are scanned, converted to a digital format, and read on-screen. These ECGs may differ from the original ECG because of variability introduced by the printer, scanner, or digitization software. METHODS Digital ECGs were recorded in 50 volunteers simultaneously using electrocardiographs from 2 different manufacturers. QT and RR intervals were measured on-screen on the digitized ECGs. To study the contribution of individual steps in the digitization process, differences in RR interval between 2 prints each of 50 digital ECGs, 2 scanned files of 50 prints, 2 digitized files from 50 scanned files, and 2 readings of 50 digitized ECGs (intrareader variability) were analyzed. RESULTS Repeatability coefficient for RR interval measurement was 18.5 milliseconds for machine 1 and 21 milliseconds for machine 2. Contributions of the printer were 6.5 milliseconds for machine 1 and 9.0 milliseconds for machine 2, digitization process was 5.5 milliseconds, and reader variability was 8.0 milliseconds. Variability of the scanner was negligible. CONCLUSIONS The printer and digitization process account for significant differences in interval measurements in digitized ECGs.

Baseline and new-onset morphologic ECG abnormalities in healthy volunteers in phase I studies receiving placebo: changes over a 6-week follow-up period.

Morphological ECG abnormalities occur in 5–12% healthy adults participating in early phase clinical trials. We retrospectively analyzed 16,472 12‐lead ECGs recorded at multiple time points in 420 volunteers (282 males, 138 females; aged 18–76 years) randomized to receive placebo from 19 Phase I studies to see if some baseline ECG abnormalities may disappear or new abnormalities may appear during the study. One hundred forty‐four (34.3%) subjects had abnormal baseline ECGs, of which 66 (44.8%) reverted to normal during follow‐up. Of 276 (65.7%) subjects with normal baseline ECGs, 118 (42.8%) developed ECG abnormalities over the next 6 weeks. Common baseline abnormalities included sinus bradycardia, R wave transition abnormalities, right axis deviation, non‐specific T wave changes and atrial premature complexes. On follow‐up ECGs, prolonged QT interval, first‐degree AV block, sinus bradycardia, short PR interval, and R wave transition abnormalities reverted to normal. Common new‐onset abnormalities in subjects with normal baseline ECGs included sinus bradycardia, prolonged QT interval, non‐specific T wave changes, R wave transition abnormalities, and sinus tachycardia. Thus, transient morphological ECG changes may occur in healthy volunteers possibly due to diurnal variation, effect of food, hormones, or autonomic changes. This should be considered when interpreting “treatment‐emergent” ECG changes in clinical trials.

Sudden Death in Patients With Coronary Heart Disease Without Severe Systolic Dysfunction

Importance The majority of sudden and/or arrhythmic deaths (SAD) in patients with coronary heart disease occur in those without severe systolic dysfunction, for whom strategies for sudden death prevention are lacking. Objective To provide contemporary estimates of SAD vs other competing causes of death in patients with coronary heart disease without severe systolic dysfunction to search for high-risk subgroups that might be targeted in future trials of SAD prevention. Design, Setting, and Participants This prospective observational cohort study included 135 clinical sites in the United States and Canada. A total of 5761 participants with coronary heart disease who did not qualify for primary prevention implantable cardioverter defibrillator therapy based on left ventricular ejection fraction (LVEF) of more than 35% or New York Heart Association (NYHA) heart failure class (LVEF >30%, NYHA I). Exposures Clinical risk factors measured at baseline including age, LVEF, and NYHA heart failure class. Main Outcomes and Measures Primary outcome of SAD, which is a composite of SAD and resuscitated ventricular fibrillation arrest. Results The mean (SD) age of the cohort was 64 (11) years. During a median of 3.9 years, the cumulative incidence of SAD and non-SAD was 2.1% and 7.7%, respectively. Sudden and/or arrhythmic death was the most common mode of cardiovascular death accounting for 114 of 202 cardiac deaths (56%), although noncardiac death was the primary mode of death in this population. The 4-year cumulative incidence of SAD was lowest in those with an LVEF of more than 60% (1.0%) and highest among those with LVEF of 30% to 40% (4.9%) and class III/IV heart failure (5.1%); however, the cumulative incidence of non-SAD was similarly elevated in these latter high-risk subgroups. Patients with a moderately reduced LVEF (40%-49%) were more likely to die of SAD, whereas those with class II heart failure and advancing age were more likely to die of non-SAD. The proportion of deaths due to SAD varied widely, from 14% (18 of 131 deaths) in patients with NYHA II to 49% (37 of 76 deaths) in those younger than 60 years. Conclusions and Relevance In a contemporary population of patients with coronary heart disease without severe systolic dysfunction, SAD accounts for a significant proportion of overall mortality. Moderately reduced LVEF, age, and NYHA class distinguished SAD and non-SAD, whereas other markers were equally associated with both modes of death. Absolute and proportional risk of SAD varied significantly across clinical subgroups, and both will need to be maximized in future risk stratification efforts.

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.

Electrocardiographic markers of myocardial infarction size, transmural extent, and extent of nonviable myocardium - comparison to CMR

Background Myocardial infarction (MI) size is an important determinant of mortality in post-MI patients, but the current gold standard test, cardiovascular magnetic resonance imaging (CMR), is expensive and not widely available. We sought to determine whether information from a readily available standard 12-lead electrocardiogram (ECG) could be utilized to estimate infarct size, extent of transmural infarction, and extent of nonviable myocardium on CMR.