Validation of electrocardiographic criteria for identifying left ventricular dysfunction in patients with previous myocardial infarction.

BACKGROUND: Eleven criteria correlating electrocardiogram (ECG) findings with reduced left ventricular ejection fraction (LVEF) have been previously published. These have not been compared head-to-head in a single study. We studied their value as a screening test to identify patients with reduced LVEF estimated by cardiac magnetic resonance (CMR) imaging. METHODS: ECGs and CMR from 548 patients (age 61 + 11 years, 79% male) with previous myocardial infarction (MI), from the DETERMINE and PRE-DETERMINE studies, were analyzed. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of each criterion for identifying patients with LVEF ≤ 30% and ≤ 40% were studied. A useful screening test should have high sensitivity and NPV. RESULTS: Mean LVEF was 40% (SD = 11%); 264 patients (48.2%) had LVEF ≤ 40%, and 96 patients (17.5%) had LVEF ≤ 30%. Six of 11 criteria were associated with a significant lower LVEF, but had poor sensitivity to identify LVEF ≤ 30% (range 2.1%-55.2%) or LVEF ≤ 40% (1.1%-51.1%); NPVs were good for LVEF ≤ 30% (range 82.8%-85.9%) but not for LVEF ≤ 40% (range 52.1%-60.6%). Goldberger's third criterion (RV4/SV4 < 1) and combinations of maximal QRS duration > 124 ms + either Goldberger's third criterion or Goldberger's first criterion (SV1 or SV2 + RV5 or RV6 ≥ 3.5 mV) had high specificity (95.4%-100%) for LVEF ≤ 40%, although seen in only 48 (8.8%) patients; predictive values were similar on subgroup analysis. CONCLUSIONS: None of the ECG criteria qualified as a good screening test. Three criteria had high specificity for LVEF ≤ 40%, although seen in < 9% of patients. Whether other ECG criteria can better identify LV dysfunction remains to be determined.

Reference values of ECG parameters derived from 906 echocardiographically confirmed healthy Indian children: A population-based study from Gujarat.

INTRODUCTION: There are few published studies on reference ranges of ECG parameters in children; some ethnic differences have been described. METHODS: We studied digital 12­lead ECGs (1000 samples/s) from 906 healthy rural Indian children (467 boys: 439 girls) aged 5-15 years. PR, QRS, and QT were measured using superimposed median beat. Age-wise normal limits (median, 2nd and 98th percentile) were defined. RESULTS: Heart rate decreased while PR interval and QRS duration increased with age. QTcB interval remained unchanged from 5 to 12 years and decreased thereafter due to QTcB shortening in boys but not in girls. "Juvenile T wave pattern" was seen in 95% of children aged 5-8 years in lead V1 and 55-60% in V2, V3; it decreased with age. RV dominance (R/S > 1) in lead V1 was seen in 13% at 5 years, 1% at 10 years and none at 14 years. CONCLUSION: Reference ranges in Indian children are similar to those in other ethnic groups.

For neonatal ECG screening there is no reason to relinquish old Bazett's correction.

Aims: There is an almost endless controversy regarding the choice of the QT correction formula to be used in electrocardiograms (ECG) in neonates for screening for long QT syndrome (LQTS). We compared the performance of four commonly used formulae and a new formula derived from neonates. Methods and results: From a cohort of 44 596 healthy neonates prospectively studied in Italy between 2001 and 2006, 5000 ECGs including 17 with LQTS-causing mutation identified by genotyping were studied using four QT correction formulae [Bazett's (QTcB), Fridericia's (QTcF), Framingham (QTcL), and Hodges (QTcH)]. A neonate-specific exponential correction (QTcNeo) was derived using 2500 randomly selected ECGs and validated for accuracy in the remaining 2500 ECGs. Digital ECGs were recorded between the 15th and 25th day of life; QT interval was measured manually in leads II, V5, and V6. To assess the ability to provide heart rate (HR) independent QT correction, regression analysis of the QTc-HR plots for all 5000 ECGs with each correction formula was done. QTcB provided the most HR independent correction with a slope closest to zero (slope +0.086 ms/b.p.m.) followed by QTcF (slope -0.308 ms/b.p.m.), QTcL (slope -0.364 ms/b.p.m.), and QTcH (slope +0.962 ms/b.p.m.). The QTc-HR slope of QTcNeo (QT/RR0.467) was similar to QTcB. The ability to correctly identify neonates with LQTS was best with QTcB, QTcF, and QTcNeo (comparable areas under the receiver operating characteristic curves) with positive predictive value of 39-40% and sensitivity of 100%. Cut-off values were 460 ms for QTcB, 394 ms for QTcF, and 446 ms for QTcNeo. Conclusions: The Bazett's correction provides an effective HR independent QT correction and also accurately identifies the neonates affected by LQTS. It can be used with confidence in neonates, although other methods could also be used with appropriate cut-offs.

Individual-Specific QT Interval Correction for Drugs With Substantial Heart Rate Effect Using Holter ECGs Extracted Over a Wide Range of Heart Rates.

Although fixed QT correction methods are typically used to adjust for the effect of heart rate on the QT interval in thorough QT/QTc studies, individual-specific QT correction (QTcI = QT/RRI ) is advisable for drugs that increase the heart rate by >5 to 10 beats/minute (bpm). QTcI is traditionally derived using resting drug-free electrocardiograms (ECGs) collected at prespecified times. However, the resting heart rate range in healthy individuals is narrow, and extrapolation of inferences from these data to higher heart rates could be inappropriate. Accordingly, the QTcI derived from triplicate ECGs extracted at prespecified times (the traditional [T] method, yielding QTcIT) was compared with QTcIs obtained using ECGs with a wider heart rate range (alternative Holter [H] method, yielding QTcIH) from 24-hour Holter recordings from 40 healthy individuals selected from a central ECG laboratory database. For QTcIH, 10-second ECGs were extracted at stable heart rates in the ranges of 51-60, 61-70, 71-80, and 81-90 bpm (9 ECGs in each bin = 36 ECGs). An independent set of 40 ECGs with heart rates from 51 to 90 bpm was extracted from each individual to validate the accuracy of QTcI by the 2 methods. For the validation set, the QTcIH was a better QT correction method (slope of QTc vs heart rate closer to zero) than QTcIT. The mean difference between QTcIT and QTcIH increased from 3.1 milliseconds at 65 bpm to 10.0 milliseconds at 90 bpm (P < 0.01). The QTcIT exceeded QTcIH at heart rates > 60 bpm. Employment of the QTcIH may be more appropriate for studies involving drugs that increase heart rate.

Recent developments in the science of proarrhythmic cardiac safety of new drugs.

Following marketing withdrawals of several drugs due to proarrhythmic safety concerns, the ICH Guidelines S7B and E14 were released in 2005 and have guided pre-approval cardiac safety assessments in multiple regulatory jurisdictions. While this S7B-E14 paradigm has successfully prevented drugs with unanticipated potential for inducing Torsades de Pointes entering the market, it has unintentionally resulted in the termination of development programs for potentially important compounds that could have exhibited a favourable benefit-risk balance. The Comprehensive In vitro Proarrhythmia Assay paradigm is currently attracting considerable attention as a solution to this problem. While much evaluative work in this new paradigm will be conducted in the non-clinical domain, human electrocardiographic assessments will remain an important component of the overall investigational strategy, possibly being conducted in Phase I trials employing exposure-response modelling. This article reviews recent developments in proarrhythmic cardiac safety assessments of new drugs, their rationales, and current limitations.

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.

Detecting moxifloxacin-induced QTc prolongation in thorough QT and early clinical phase studies using a highly automated ECG analysis approach.

BACKGROUND AND PURPOSE: Exposure-response (ER) modelling (concentration-QTc analysis) is gaining as much acceptance as the traditional by-time analysis of the placebo-adjusted change from baseline in the QTc interval (ΔΔQTcF). It has been postulated that intensive ECG analysis and ER modelling during early-phase drug development could be a cost-effective approach of estimating QT liability of a new drug, in a small number of subjects. EXPERIMENTAL APPROACH: We used a highly automated analysis of ECGs from 46 subjects from a crossover thorough QT/QTc study to detect ΔΔQTcF with moxifloxacin. Using these data, we also simulated (bootstrapped) 1000 datasets of a parallel study with eight subjects receiving moxifloxacin and eight others receiving placebo. KEY RESULTS: The slope from the concentration-QTc analysis for moxifloxacin in 46 subjects was 4.12 ms of ΔΔQTcF per µg(-1) mL(-1) ; at mean Cmax of 2.95 µg·mL(-1) , estimated ΔΔQTcF was 13.4 ms (90% confidence interval 11.3, 15.4 ms). In the 1000 simulated datasets, in 996 datasets, ER modelling showed that the upper bound of the 90% confidence interval for ΔΔQTcF at geometric mean Cmax exceeded 10 ms. In 895 of these 996 datasets, the slope of the ER relationship was statistically significantly positive. Thus, with a small sample size (eight subjects on active drug and eight on placebo), moxifloxacin-induced QTc prolongation was demonstrated using ER analysis with statistical power of >80%. CONCLUSIONS AND IMPLICATIONS: Our study adds to the growing body of data supporting intensive ECG collection and analysis in early-phase studies to estimate QT liability.

Arrhythmias Seen in Baseline 24-Hour Holter ECG Recordings in Healthy Normal Volunteers During Phase 1 Clinical Trials.

Regulatory agencies encourage sponsors to submit 24-hour ambulatory ECG data for assessing cardiac safety of new drugs, and some arrhythmias, hitherto considered rare, have been observed in some early-phase studies. Interpretation of these observations is difficult given the dearth of published data on the prevalence of cardiac arrhythmias seen during 24-hour continuous ECG monitoring in healthy volunteers (HV) from clinical trials. We analyzed drug-free ambulatory ECG recordings from 1273 HV (1000 males, 273 females; age 18-65 years) from 22 phase 1 studies that were analyzed in a core ECG laboratory; all subjects had normal screening ECGs. Supraventricular arrhythmias such as supraventricular premature complexes were observed in 60.8% of healthy volunteers, supraventricular tachycardia in 2.2%, and atrial fibrillation in 0.1%. Ventricular arrhythmias included premature ventricular complexes (PVCs) in 43.4%, >200 PVCs per 24 hours in 3.3%, multifocal PVCs in 5.3%, nonsustained ventricular tachycardia in 0.7%, and accelerated idioventricular rhythm in 0.3%. Bradyarrhythmias included sinus pause >3 seconds in 0.3%, and second-degree AV block in 2.4%. Complete heart block and torsades de pointes were not seen in any subject. Based on the observed incidence, we estimated the maximum number of healthy subjects in whom these arrhythmias may be seen as a matter of chance in studies with smaller sample sizes if the study drug has no arrhythmogenic effect. Our results and these estimates could help interpret whether cardiac arrhythmias observed in early-phase studies are due to chance or possibly are a drug effect.

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.

Comparison of two methods of estimating reader variability in QT interval measurements in thorough QT/QTc studies.

BACKGROUND: Two methods of estimating reader variability (RV) in QT measurements between 12 readers were compared. METHODS: Using data from 500 electrocardiograms (ECGs) analyzed twice by 12 readers, we bootstrapped 1000 datasets each for both methods. In grouped analysis design (GAD), the same 40 ECGs were read twice by all readers. In pairwise analysis design (PAD), 40 ECGs analyzed by each reader in a clinical trial were reanalyzed by the same reader (intra-RV) and also by another reader (inter-RV); thus, variability between each pair of readers was estimated using different ECGs. RESULTS: Inter-RV (mean [95% CI]) between pairs of readers by GAD and PAD was 3.9 ms (2.1-5.5 ms) and 4.1 ms (2.6-5.4 ms), respectively, using ANOVA, 0 ms (-0.0 to 0.4 ms), and 0 ms (-0.7 to 0.6 ms), respectively, by actual difference between readers and 7.7 ms (6.2-9.8 ms) and 7.7 ms (6.6-9.1 ms), respectively, by absolute difference between readers. Intra-RV too was comparable. CONCLUSIONS: RV estimates by the grouped- and pairwise analysis designs are comparable.

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 Fridericia's 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.

Cardiovascular safety monitoring during oncology drug development and therapy.

Assessments of cardiac and cardiovascular toxicity are prominent components of drug safety endeavors during drug development and clinical practice. Oncologic drugs bring several challenges to both domains. First, during drug development, it is necessary to adapt the ICH E14 "Thorough QT/QTc Study" because the cytotoxic nature of many oncologics precludes their being administered to healthy individuals. Second, appropriate benefit-risk assessments must be made by regulators: given the benefit these drugs provide in life-threatening illnesses, a greater degree of risk may be acceptable when granting marketing authorization than for drugs for less severe indications. Third, considerable clinical consideration is needed for patients who are receiving and have finished receiving pharmacotherapy. Paradoxically, although such therapy has proved very successful in many cases, with disease states going into remission and patients living for many years after cessation of treatment, cardiotoxicities can manifest themselves relatively soon or up to a decade later. Oncologic drugs have been associated with various off-target cardiovascular responses, including cardiomyopathy leading to heart failure, cardiac dysrhythmias, thromboembolic events, and hypertension. Follow-up attention and care are, therefore, critical. This article reviews the process of benefit-risk estimation, provides an overview of nonclinical and preapproval clinical assessment of cardiovascular safety of oncology drugs, and discusses strategies for monitoring and management of patients receiving drugs with known cardiotoxicity risk. These measures include cardiac function monitoring, limitation of chemotherapy dose, use of anthracycline analogs and cardioprotectants, and early detection of myocardial cell injury using biomarkers.

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.

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTc modelling in a phase 1 study with oral rac-sotalol.

AIM: To study the differences in QTc interval on ECG in response to a single oral dose of rac-sotalol in men and women. METHODS: Continuous 12-lead ECGs were recorded in 28 men and 11 women on a separate baseline day and following a single oral dose of 160 mg rac-sotalol on the following day. ECGs were extracted at prespecified time points and upsampled to 1000 Hz and analyzed manually in a central ECG laboratory on the superimposed median beat. Concentration-QTc analyses were performed using a linear mixed effects model. RESULTS: Rac-sotalol produced a significant reduction in heart rate in men and in women. An individual correction method (QTc I) most effectively removed the heart rate dependency of the QTc interval. Mean QTc I was 10 to 15 ms longer in women at all time points on the baseline day. Rac-sotalol significantly prolonged QTc I in both genders. The largest mean change in QTc I (ΔQTc I) was greater in females (68 ms (95% confidence interval (CI) 59, 76 ms) vs. 27 ms (95% CI 22, 32 ms) in males). Peak rac-sotalol plasma concentration was higher in women than in men (mean Cmax 1.8 µg ml(-1) (range 1.1-2.8) vs. 1.4 µg ml(-1) (range 0.9-1.9), P = 0.0009). The slope of the concentration-ΔQTc I relationship was steeper in women (30 ms per µg ml(-1) vs. 23 ms per µg ml(-1) in men; P = 0.0135). CONCLUSIONS: The study provides evidence for a greater intrinsic sensitivity to rac-sotalol in women than in men for drug-induced delay in cardiac repolarization.

Choice of an alternative lead for QT interval measurement in serial ECGs when Lead II is not suitable for analysis.

INTRODUCTION: Conventionally, QT interval is measured in lead II. There are no data to select an alternative lead for QT measurement when it cannot be measured in Lead II for any reason. METHODS AND RESULTS: We retrospectively analyzed ECGs from 1906 healthy volunteers from 41 phase I studies. QT interval was measured on the median beat in all 12 leads. The mean difference in QT interval between lead aVR and in Lead II was the least, followed by aVF, V5, V6 and V4; lead aVL had maximum difference. The T wave was flat (<0.1 mV) in Lead II in 6.9% of ECGs; it was also flat in 20% of these ECGs (1.4% of all ECGs) in Leads aVR, aVF and V5. CONCLUSIONS: When QT interval cannot be measured in Lead II, the best alternative leads are aVR, aVF, V5, V6 and V4 in that sequence. It differs maximally from that in Lead II in Lead aVL.

Cardiovascular risk of oral antidiabetic drugs: current evidence and regulatory requirements for new drugs.

BACKGROUND: Better control of diabetes mellitus reduces microvascular complications, but has limited effect on macrovascular complications including cardiovascular mortality. A spate of controversial reports has shown that some new oral antidiabetic drugs may paradoxically increase cardiovascular events and mortality. We review here published data on cardiac safety of currently available oral antidiabetic drugs. METHODS: Literature search was performed for "cardiovascular risk" and "antidiabetic drugs" or individual oral antidiabetic drugs. RESULTS: Some sulfonylureas increase cardiovascular risk presumably by preventing protective ischemic cardiac preconditioning. Rosiglitazone increases risk of myocardial infarction and death possibly by increasing serum triglycerides and LDL-cholesterol levels. Muraglitazar increased risk of cardiovascular death, myocardial infarction, or stroke due to as yet unidentified reasons. Only insulin sensitizing drugs like metformin and pioglitazone have been consistently shown to reduce cardiovascular risk. Beneficial effects of tight glucose control with insulin or insulin secretagogues on macrovascular complications are inconsistent; their benefits may be negated by increased risk of hypoglycemia which in turn increases adverse cardiovascular events. Increased cardiovascular risk of some antidiabetic drugs was missed during drug development and detected only on meta-analysis of clinical trial data. Regulatory agencies in North America and Europe have therefore proposed stringent guidelines for study design, data analysis and quantification of cardiovascular risk of new antidiabetic drugs. CONCLUSIONS: Physicians should weigh the cardiovascular risk against potential benefits when prescribing antidiabetic medications. The proposed regulatory measures will ensure approval of safer drugs, but may also lengthen the drug development cycle or even deter development of potentially useful drugs.

Morphological abnormalities in baseline ECGs in healthy normal volunteers participating in phase I studies.

BACKGROUND & OBJECTIVES: Morphological abnormalities in 12-lead electrocardiograms (ECGs) are seen in subgroups of healthy individuals like athletes and air-force personnel. As these populations may not truly represent healthy individuals, we assessed morphological abnormalities in ECG in healthy volunteers participating in phase I studies, who are screened to exclude associated conditions. METHODS: ECGs from 62 phase I studies analyzed in a central ECG laboratory were pooled. A single drug-free baseline ECG from each subject was reviewed by experienced cardiologists. ECG intervals were measured on five consecutive beats and morphological abnormalities identified using standard guidelines. RESULTS: Morphological abnormalities were detected in 25.5 per cent of 3978 healthy volunteers (2495 males, 1483 females; aged 18-76 yr); the presence was higher in males (29.3% vs. 19.2% in females; P<0.001). Rhythm abnormalities were the commonest (11.5%) followed by conduction abnormalities (5.9%), axis deviation (4%), ST-T wave changes (3.1%) and chamber enlargement (1.4%). Incomplete right bundle branch block (RBBB), short PR interval and right ventricular hypertrophy were common in young subjects (<20 yr) while atrial fibrillation, first degree atrioventricular block, complete RBBB and left anterior fascicular block were more prevalent in elderly subjects (>65 yr). Prolonged PR interval, RBBB and intraventricular conduction defects were more common in males while sinus tachycardia, short PR interval and non-specific T wave changes were more frequent in females. INTERPRETATION & CONCLUSIONS: Morphological abnormalities in ECG are commonly seen in healthy volunteers participating in phase I studies; and vary with age and gender. Further studies are required to determine whether these abnormalities persist or if some of these disappear on follow up.