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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.
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Diagnóstico por Computador/normas , Electrocardiografía Ambulatoria/instrumentación , Electrocardiografía Ambulatoria/métodos , Electrodos , Procesamiento de Señales Asistido por Computador/instrumentación , Diagnóstico por Computador/instrumentación , Diseño de Equipo , Análisis de Falla de Equipo , Humanos , Valores de Referencia , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
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.
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Electrocardiografía/métodos , Electrocardiografía/estadística & datos numéricos , Frecuencia Cardíaca/fisiología , Variaciones Dependientes del Observador , Proyectos de Investigación , Análisis de Varianza , HumanosRESUMEN
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.
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Antibacterianos/efectos adversos , Electrocardiografía/métodos , Fluoroquinolonas/efectos adversos , Síndrome de QT Prolongado/inducido químicamente , Síndrome de QT Prolongado/diagnóstico , Adulto , Femenino , Voluntarios Sanos , Humanos , Masculino , Persona de Mediana Edad , Moxifloxacino , Placebos , Sensibilidad y EspecificidadRESUMEN
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.
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Arritmias Cardíacas/inducido químicamente , Arritmias Cardíacas/diagnóstico , Electrocardiografía/instrumentación , Modelos Estadísticos , Análisis de Varianza , Simulación por Computador , Humanos , Variaciones Dependientes del ObservadorRESUMEN
INTRODUCTION: Real-world evidence on insulin glargine 100 U/ml (Gla-100) initiation in Indian type 2 diabetes mellitus (T2DM) individuals is limited. The present study aimed to evaluate the effectiveness of Gla-100 in insulin-naïve T2DM participants from India. METHODS: This post hoc analysis includes real-world data of insulin-naïve Indian participants with T2DM who started Gla-100 treatment in two Asian registries: FINE ASIA and GOAL. Changes in glycated hemoglobin (HbA1c), fasting plasma glucose (FPG), body weight, insulin dose, and incidence of hypoglycemia from baseline to 6 months were assessed. RESULTS: A total of 955 participants with T2DM were identified and analyzed. The mean [standard deviation (SD)] age and duration of diabetes were 54.7 (9.8) years and 9.8 (6.3) years, respectively. Mean HbA1c and FPG were significantly reduced after 6 months of Gla-100 treatment [- 2.07 (1.4) %; - 94.4 (65.2) mg/dl, respectively]. HbA1c targets of < 7.0% and < 7.5% were achieved by 292 (30.6%) and 589 (61.7%) study participants, respectively. The overall incidence of hypoglycemia was low (n = 52; 5.4%); only two participants (0.2%) reported severe hypoglycemia. Insulin was titrated with a mean (SD) increment of 2.5 (5.6) U/day after 6 months, leading to a mean Gla-100 dose of 18.2 (8.9) U/day. Mean body weight remained unchanged from baseline to 6 months (- 0.1 kg). CONCLUSION: In routine clinical practice, Gla-100 significantly improved glycemic parameters after 6 months of treatment with a low risk of hypoglycemia and no weight change in participants with T2DM.
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INTRODUCTION: There are limited data on the real-world management of diabetes in the Indian population. In this 2-year analysis of the LANDMARC study, the management of type 2 diabetes mellitus (T2DM) and related complications were assessed. METHOD: This multicenter, observational, prospective study included adults aged ≥25 to ≤60 years diagnosed with T2DM (duration ≥2 years at enrollment) and controlled/uncontrolled on ≥2 anti-diabetic agents. This interim analysis at 2 years reports the status of glycaemic control, diabetic complications, cardiovascular (CV) risks and therapy, pan-India including metropolitan and non-metropolitan cities. RESULTS: Of the 6234 evaluable patients, 5318 patients completed 2 years in the study. Microvascular complications were observed in 17.6% of patients (1096/6234); macrovascular complications were observed in 3.1% of patients (195/6234). Higher number of microvascular complications were noted in patients from non-metropolitan than in metropolitan cities (p < .0001). In 2 years, an improvement of 0.6% from baseline (8.1%) in mean glycated haemoglobin (HbA1c) was noted; 20.8% of patients met optimum glycaemic control (HbA1c < 7%). Hypertension (2679/3438, 77.9%) and dyslipidaemia (1776/3438, 51.7%) were the predominant CV risk factors in 2 years. The number of patients taking oral anti-diabetic drugs in combination with insulin increased in 2 years (baseline: 1498/6234 [24.0%] vs. 2 years: 1917/5763 [33.3%]). While biguanides and sulfonylureas were the most commonly prescribed, there was an evident increase in the use of dipeptidyl peptidase-IV inhibitors (baseline: 3049/6234, 48.9% vs. 2 years: 3526/5763, 61.2%). CONCLUSION: This longitudinal study represents the control of T2DM, its management and development of complications in Indian population. CLINICAL TRIAL REGISTRATION NUMBER: CTRI/2017/05/008452.
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Diabetes Mellitus Tipo 2 , Adulto , Humanos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Estudios Prospectivos , Hemoglobina Glucada , Estudios Longitudinales , Hipoglucemiantes/uso terapéuticoRESUMEN
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.
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Algoritmos , Diagnóstico por Computador/métodos , Electrocardiografía/métodos , Frecuencia Cardíaca , Síndrome de QT Prolongado/diagnóstico , Síndrome de QT Prolongado/fisiopatología , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Variaciones Dependientes del Observador , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
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.
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Electrocardiografía/métodos , Sistema de Conducción Cardíaco/fisiología , Femenino , Frecuencia Cardíaca/fisiología , Humanos , Síndrome de QT Prolongado/fisiopatología , Masculino , Valores de Referencia , Estudios RetrospectivosRESUMEN
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.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Angiopatías Diabéticas/prevención & control , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Administración Oral , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/prevención & control , Ensayos Clínicos como Asunto , Diabetes Mellitus Tipo 2/complicaciones , Aprobación de Drogas , Humanos , Preparaciones Farmacéuticas , Factores de Riesgo , Resultado del TratamientoRESUMEN
INTRODUCTION: Longitudinal data on management and progression of type 2 diabetes mellitus (T2DM) in India are scarce. LANDMARC (CTRI/2017/05/008452), first-of-its-kind, pan-India, prospective, observational study aimed to evaluate real-world patterns and management of T2DM over 3 years. METHODS: Adults (≥25 to ≤60 years old at T2DM diagnosis; diabetes duration ≥2 years at enrolment; controlled/uncontrolled on ≥2 anti-diabetic agents) were enrolled. The first-year trends for glycaemic control, therapy and diabetic complications, including those from metropolitan and non-metropolitan cities are reported here. RESULTS: Of 6236 enrolled participants, 5654 completed 1 year in the study. Although the overall mean glycated haemoglobin (HbA1c) improved by 0.5% (baseline: 8.1%) at 1 year, only 20% of the participants achieved HbA1c <7%. Participants from metropolitan and non- metropolitan cities showed similar decrease in glycaemic levels (mean change in HbA1c: -0.5% vs. -0.5%; p = .8613). Among diabetic complications, neuropathy was the predominant complication (815/6236, 13.1% participants). Microvascular complications (neuropathy, nephropathy and retinopathy) were significantly (p < .0001) higher in non-metropolitan than metropolitan cities. Hypertension (2623/6236, 78.2%) and dyslipidaemia (1696/6236, 50.6%) continued to be the most commonly reported cardiovascular risks at 1 year. After 1 year, majority of the participants were taking only oral anti-diabetic drugs (OADs) (baseline: 4642/6236 [74.4%]; 1 year: 4045/6013 [67.3%]), while the proportion of those taking insulin along with OADs increased (baseline: 1498/6236 [24.0%] vs. 1 year: 1844/6013 [30.7%]). Biguanides and sulfonylureas were the most used OADs. The highest increase in use was seen for dipeptidyl peptidase-IV inhibitors (baseline: 3047/6236 [48.9%]; 1 year: 3529/6013 [58.7%]). Improvement in all glycaemic parameters was significantly (p < .0001) higher in the insulin vs. the insulin-naïve subgroups; in the insulin-naïve subgroup, no statistical difference was noted in those who received >3 vs. ≤3 OADs. CONCLUSIONS: First-year trends of the LANDMARC study offer insights into real-world disease progression, suggesting the need for controlling risk factors and timely treatment intensification in people with T2DM.
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Diabetes Mellitus Tipo 2 , Adulto , Diabetes Mellitus Tipo 2/complicaciones , Hemoglobina Glucada , Humanos , Hipoglucemiantes/uso terapéutico , Estudios Longitudinales , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
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.
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Algoritmos , Artefactos , Diagnóstico por Computador/métodos , Electrocardiografía/métodos , Síndrome de QT Prolongado/diagnóstico , Animales , Frecuencia Cardíaca , Variaciones Dependientes del Observador , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
INTRODUCTION: Longitudinal data on progression, complications, and management of type 2 diabetes mellitus (T2DM) across India are scarce. LANDMARC (CTRI/2017/05/008452), the first pan-India, longitudinal, prospective, observational study, aims to understand the management and real-world outcomes of T2DM over 3 years. METHODS: Adults (≥25 to ≤60 years old at T2DM diagnosis; diabetes duration ≥2 years at enrollment; controlled/uncontrolled on ≥2 anti-diabetic agents) were enrolled. Baseline characteristics were analyzed using descriptive statistics. RESULTS: Of the 6279 recruited participants, 6236 were eligible for baseline assessment (56.6% [n/N = 3528/6236] men; mean ± SD age: 52.1 ± 9.2 years, diabetes duration: 8.6 ± 5.6 years). mean ± SD HbA1c, fasting plasma glucose, and postprandial glucose values were 64 ± 17 mmol/mol (8.1 ± 1.6%), 142.8 ± 50.4 mg/dl, and 205.7 ± 72.3 mg/dl, respectively. Only 25.1% (n/N = 1122/6236) participants had controlled glycemia (HbA1c < 53 mmol/mol, <7%). Macrovascular and microvascular complications were prevalent in 2.3% (n/N = 145/6236) and 14.5% (n/N = 902/6236) participants, respectively. Among those with complications, non-fatal myocardial infarction (n/N = 74/145, 51.0%) and neuropathy (n/N = 737/902, 81.7%) were the most reported macrovascular and microvascular complication, respectively. Hypertension (n/N = 2566/3281, 78.2%) and dyslipidemia (n/N = 1635/3281, 49.8%) were the most reported cardiovascular risks. Majority (74.5%; n/N = 4643/6236) were taking oral anti-diabetic drugs (OADs) only, while 24.4% (n/N = 1522/6236) participants were taking OADs+insulin. Biguanides (n/N = 5796/6236, 92.9%) and sulfonylureas (n/N = 4757/6236, 76.3%) were the most reported OADs. Basal (n/N = 837/6236, 13.4%) and premix (n/N = 684/6236, 11.0%) insulins were the most reported insulins. CONCLUSIONS: Baseline data from LANDMARC help understand the clinical/medical profile of study participants and underscore the extent of suboptimal glycemic control and prevalence of associated complications in a vast majority of Indians with T2DM.
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Diabetes Mellitus Tipo 2 , Adulto , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/epidemiología , Hemoglobina Glucada , Humanos , Hipoglucemiantes/efectos adversos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Estudios ProspectivosRESUMEN
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.
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Electrocardiografía , Sistema de Conducción Cardíaco/fisiopatología , Fibrilación Ventricular/fisiopatología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
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.
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Electrocardiografía/instrumentación , Sistema de Conducción Cardíaco/fisiología , Electrodos , HumanosRESUMEN
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.