Drug-induced QT Interval Prolongation Research Articles

A real-world pharmacovigilance study of drug-induced QT interval prolongation: analysis of spontaneous reports submitted to FAERS.

To identify the most commonly reported drugs associated with QT interval prolongation in the FDA Adverse Event Reporting System (FAERS) and evaluate their risk for QT interval prolongation. We employed the preferred term (PT) "electrocardiogram QT prolonged" from the Medical Dictionary for Regulatory Activities (MedDRA) 26.0 to identify adverse drug events (ADEs) of QT interval prolongation in the FAERS database from the period 2004-2022. Reporting odds ratio (ROR) was performed to quantify the signals of ADEs. We listed the top 40 drugs that caused QT interval prolongation. Among them, the 3 drugs with the highest number of cases were quetiapine (1,151 cases, ROR = 7.62), olanzapine (754 cases, ROR = 7.92), and citalopram (720 cases, ROR = 13.63). The two most frequently reported first-level Anatomical Therapeutic Chemical (ATC) groups were the drugs for the nervous system (n = 19, 47.50%) and antiinfectives for systemic use (n = 7, 17.50%). Patients with missing gender (n = 3,482, 23.68%) aside, there were more females (7,536, 51.24%) than males (5,158, 35.07%) were involved. 3,720 patients (25.29%) suffered serious clinical outcomes resulting in deaths or life-threatening conditions. Overall, most drugs that caused QT interval prolongation had early failure types according to the assessment of the Weibull's shape parameter (WSP) analysis. Our study offered a list of drugs that frequently caused QT interval prolongation based on the FAERS system, along with a description of some risk profiles for QT interval prolongation brought on by these drugs. When prescribing these drugs in clinical practice, we should closely monitor the occurrence of ADE for QT interval prolongation.

Advancing Adverse Drug Reaction Prediction with Deep Chemical Language Model for Drug Safety Evaluation.

The accurate prediction of adverse drug reactions (ADRs) is essential for comprehensive drug safety evaluation. Pre-trained deep chemical language models have emerged as powerful tools capable of automatically learning molecular structural features from large-scale datasets, showing promising capabilities for the downstream prediction of molecular properties. However, the performance of pre-trained chemical language models in predicting ADRs, especially idiosyncratic ADRs induced by marketed drugs, remains largely unexplored. In this study, we propose MoLFormer-XL, a pre-trained model for encoding molecular features from canonical SMILES, in conjunction with a CNN-based model to predict drug-induced QT interval prolongation (DIQT), drug-induced teratogenicity (DIT), and drug-induced rhabdomyolysis (DIR). Our results demonstrate that the proposed model outperforms conventional models applied in previous studies for predicting DIQT, DIT, and DIR. Notably, an analysis of the learned linear attention maps highlights amines, alcohol, ethers, and aromatic halogen compounds as strongly associated with the three types of ADRs. These findings hold promise for enhancing drug discovery pipelines and reducing the drug attrition rate due to safety concerns.

Abstract 16962: A Polygenic Predictor of Baseline QT is Associated With Sotalol-Induced QT Prolongation

Background: Drug-induced QT interval prolongation raises the risk of fatal arrhythmia and is a central issue in safety pharmacology. Yet individual QT drug response is highly variable, and risk stratification remains a challenge. We hypothesized that genetic factors underlying the baseline QT influence this variation in QT drug response. Methods: A cohort of 990 healthy subjects was prospectively challenged with a single 80 mg oral sotalol dose. Exclusion criteria included abnormal ECG, cardiac disease, and QT-prolonging drug use. ECGs were obtained at baseline and 3 hours post-dose. QT response was defined as absolute change in Fridericia heart-rate corrected QT (ΔQTc). Plasma sotalol was measured 3 hours post-dose. Subjects were genotyped on the MEGA array. Principal component analysis of genotypes was used to define genetic ancestry. A polygenic score (PGS) for the baseline QTc comprised of 465,399 common variants was calculated from assayed and imputed genotypes. The difference in PGS between subjects with high QT response (ΔQTc≥60 ms) and those with ΔQTc<60ms was assessed by Mann Whitney test. A multivariable regression model was used to assess the association between PGS and ΔQTc after covariate adjustment. Results: Of the 990 subjects, 952 (96%) passed genomic quality control and were included in analysis. 62% were female (n=590), with median age 23 (interquartile range (IQR) 21-32). Self-reported ancestry was 89% European (n=850) and 11% North African (n=102). The median ΔQTc 3 hours post-sotalol was 21 ms (IQR 12-30). Ten subjects (1%) had ΔQTc≥60 ms, and their PGS was significantly higher compared to those with ΔQTc<60 ms ( P =0.0097, Figure 1A). In the regression model, PGS was positively associated with ΔQTc ( P =0.0007, Figure 1B). Conclusion: Common genetic variants associated with the baseline QT also capture part of the repolarization response to sotalol. This adds to the emerging concept that the genetic architecture of a trait can predict drug response.

The risk of treatment-induced QT interval prolongation

ObjectiveQT interval prolongation can increase patients’ hospital stay and mortality rate. This study aims to determine the incidence of drug-induced QT interval prolongation and establish which QT interval measurement method is the most appropriate for electrocardiographic monitoring. MethodA retrospective observational study was conducted of patients admitted to the Clínica Bíblica Hospital during 2018. The electronic medical records of patients hospitalized for longer than 48 hours and whose drug regimen included at least one drug potentially able to prolong the QT interval were reviewed. Manually-measured QT intervals were corrected using Fridericia's and Rautaharju's formulae, while automatically-measured QT intervals were corrected with Bazett's formula. Risk was assessed using the RISQ-PATH scale. ResultsOf the 141 patients analyzed, 23 had arrhythmia as per their clinical history and 14 suffered a complication during their stay in hospital. A total of 113 (80%) had a high RISQ-PATH score and only 64 were subjected to an electrocardiogram on admission. Patients received a mean of three potentially QT interval prolonging drugs. Most of the QT intervals measured automatically were shorter than those obtained manually. Of all corrections, the longest QTc interval values were obtained with Bazett's formula, and the shortest with Rautaharju's formula. None of the patients developed TdP or complex ventricular tachycardia. ConclusionsEvery effort should be made to implement strategies conducive to more effective monitoring of the QT interval to prevent QT interval prolongation related complications in hospitalized patients.

Multifactorial model for prediction of the development of polymorphic ventricular tachycardia in patients with drug-induced QT interval prolongation induced by class III antiarrhythmic drugs

Aim. To develop a multifactorial model for predicting the development of polymorphic ventricular tachycardia (VT) in patients with drug-induced long QT syndrome (LQTS) induced by class III antiarrhythmic drugs (AADs) by identifying electrocardiographic, laboratory and molecular genetic predictors.Methods. The study included 64 patients (37 (57.9%) women and 27 (42.1%) men, mean age 57.2±9.4 years) with ischemic heart disease and/or arterial hypertension. and cardiac arrhythmias, in which drug-induced prolongation of the QTc interval (Bazett) (over 450 ms in men and over 470 ms in women) was noted with the use of class III AADs (amiodarone or sotalol) in a cardiac hospital. Depending on the presence or absence of non-sustained polymorphic VT according to 24-hour ECG Holter monitoring, patients were further divided into two groups: 17 patients with episodes of non-sustained polymorphic VT and 47 patients without such episodes. All patients underwent clinical and laboratory, instrumental and molecular genetic studies, which included taking an anamnesis, recording ECG in 12 leads, biochemical blood test, determining the levels of neuronal NO-synthase (NOS1) and the adapter protein of neuronal NO-synthase (NOS1AP) in blood serum by enzyme immunoassay, determination of nitric oxide synthase gene polymorphisms by polymerase chain reaction. To assess the relationship of the studied parameters with the achievement of the end point, the method of logistic regression with a binary response and the logit function of the connection was used.Results. To assess the risk of developing non-sustained polymorphic VT in patients with drug-induced LQTS while taking class III AADs, a complex binary logistic regression model was developed, including the following indicators: patient gender (p=0.019), relative variance of the QT interval (p=0.002), duration of the Tpeak-Tend interval, (p=0.034), serum magnesium (p=0.004) and NOS1 (p=0.004) levels, as well as the AA genotype of the G84A polymorphism of the NOS1 gene (p=0.049). With the calculated value of the threshold probability p≥0.48, the developed model makes it possible to identify patients at high risk of developing polymorphic VT in patients with drug-induced LQTS with a sensitivity of 94.12%, a specificity of 89.36%, and an area under the ROC curve of 0.977 (0.95-1.0, p<0.001).Conclusion. The developed complex model will allow predicting the risk of proarrhythmic effects in patients with drug-induced LQTS, which will lead to a decrease in the number of cardiovascular events in this category of patients.

Analysis of clinical characteristics and automatic monitoring of drug-induced arrhythmias in 167,546 inpatients.

The purpose of this study was to analyze the occurrence characteristics, clinical manifestations, medication distribution, and incidence of drug-induced arrhythmias in a real-world inpatient population. According to the inclusion and exclusion criteria as well as the ADR evaluation criteria, we retrospectively evaluated hospitalized patients in 2019 using the arrhythmia module of the Adverse Drug Event Active Surveillance and Assessment System-II (ADE-ASAS-II). A detailed analysis was performed on the demographic data, ADR manifestations, and medication distribution of 2097 patients with drug-induced arrhythmias and QT interval prolongation. Of the 167,546 hospitalized patients, there were 1809 cases of drug-induced arrhythmias, with an incidence of 1.08%. The ADRs in 45.35% of positive patients occurred within 3days after medication administration, and 46.73% of the patients were 65years old or older. The predominant ADRs identified in this study were extrasystole, tachycardia, and QT interval prolongation, of which the incidence was 0.20%. Levofloxacin was the most involved drug, and levofloxacin-associated rates of incidence of arrhythmia and QT interval prolongation were 1.24% and 0.44%, respectively. The risk factors for drug-induced arrhythmias were male sex, advanced age, emaciation, obesity, and underlying illnesses such as cardiovascular diseases, diabetes mellitus, cerebrovascular diseases, and hepatic and renal inadequacy (P < 0.05). The incidence of drug-induced arrhythmias was in the range of common, while QTc interval prolongation was occasional. It is necessary to pay attention to patients with risk factors.

Risk stratification of drug-induced long QT syndrome caused by class III antiarrhythmic drugs

Aim. To develop a personalized risk assessment score for the development of drug-induced QT interval prolongation while taking class III antiarrhythmic drugs (AAD).Methods. We studied data from 110 patients with coronary artery disease and/or hypertension, who had heart arrhythmias and were taking class III AAD (amiodarone or sotalol) in a cardiology department. All patients underwent clinical, laboratory and instrumental studies, including history taking, 12-lead electricardiography recording, biochemical blood test, determination of the levels of neuronal NO-synthase (NOS1) and adapter protein of neuronal NO-synthase (NOS1AP) in blood plasma by ELISA, as well as the determination of polymorphisms G84A of the NOS1 gene using polymerase chain reaction. In order to stratify the risk of drug-induced QT interval prolongation, the method of linear discriminant analysis with stepwise inclusion was applied. The training sample consisted of 70 patients (63.6%), the test sample of 40 patients (36.4%). The score was developed on a training sample, and the testing was performed on a test sample with the construction of an ROC curve, calculation of AUC, sensitivity, and specificity.Results. The training and test samples were comparable in terms of the main clinical and anamnestic parameters and features of the pharmacological history. Patients with QT interval prolongation had significantly lower levels of magnesium (p=0.001), NOS1 (p=0.015) and NOS1AP (p=0.035). The discriminant analysis algorithm was stopped at the fourth step, as a result of which four statistically significant predictors were included in the model: thiazide or loop diuretic intake, blood serum magnesium level, plasma NOS1 and NOS1AP levels, each of which was assigned a certain number of points according to the received standardized coefficients. When conducting an ROC analysis on the initial sample, a threshold value of the scale of 6 points was obtained (AUC 0.848 (0.759 0.937, p=0.002), sensitivity 73.81%, specificity 85.71%). The use of the scale on the test sample showed sensitivity of 77.27%, specificity of 77.77% and AUC of 0.834 (0.721 0.965, p=0.001), which corresponds to the good quality of the prognostic model.Conclusion. Patients with a total score of ≥6 points have a high risk of drug-induced QT interval prolongation while taking class III AAD.

The Association of Proton Pump Inhibitors and QT Interval Prolongation in Critically Ill Patients.

Drug-induced QT interval prolongation has been reported to be related to life-threatening polymorphic ventricular tachycardia (torsade de pointes). Proton pump inhibitors (PPIs) are prescribed widely for hospitalized patients; the QT interval prolongation and torsade de pointes caused by PPIs were reported. We conducted a study to determine the association between PPI treatment and QT interval prolongation in critically ill patients. This study included patients with electrocardiography (ECG) reports from the Medical Information Mart for Intensive Care III database (MIMIC-III). Patients younger than 18years, missing baseline laboratories and with QT interval prolongation before intensive care unit (ICU) admission were excluded. The end point was the diagnosis of QT interval prolongation reported by ECG. This study included 24,512 ICU patients. Of them, 11,327 patients were treated with PPIs, 4181 with histamine 2 receptor antagonists (H2RAs) and 6351 without acid suppression therapy (non-AST); the incidence of QT interval prolongation were 8.5%, 3.3% and 3.4% respectively. After adjustment for demographics, electrolytes, comorbidities and medications, PPIs were associated a higher risk of QT interval prolongation compared with H2RAs (OR 1.66, 95% CI 1.36 - 2.03) and non-AST (OR 1.54, 95% CI 1.31 - 1.82), while there was not significant difference between H2RAs and non-AST (OR 0.93, 95% CI 0.73 - 1.17). In the propensity score matching population, the results were consistent. Pantoprazole (OR 2.14, 95% CI 1.52 - 3.03) and lansoprazole (OR 1.80, 95% CI: 1.18 - 2.76) showed a higher QT prolongation risk than omeprazole. Several drugs caused higher QT prolongation risk when used in combination with PPIs. In ICU patients, the association between PPI prescription and increased risk of QT interval prolongation was independent of known QT-prolonging factors; pantoprazole and lansoprazole had a higher risk compared with omeprazole. The combination of PPIs and other QT-prolonging drugs should be avoided.

Association of QT interval-prolonging drugs with clinical trial eligibility in patients with advanced cancer.

Drug-induced prolongation of the heart rate-corrected QT interval (QTc) is associated with increased risk for the potentially fatal arrhythmia torsades de pointes. Due to arrhythmia risk, clinical trials with cancer therapeutics often exclude patients based on thresholds for QTc prolongation. Our objective was to assess associations between prescriptions for QT-prolonging drugs and the odds of meeting cancer trial exclusionary QTc thresholds in a cohort of adults with advanced cancer. Electronic health records were retrospectively reviewed for 271 patients seen at our institutional molecular solid tumor clinic. Collected data included demographics, QTc measurements, ventricular arrhythmia-related diagnoses, and all inpatient and outpatient prescriptions. Potential associations were assessed between demographic and clinical variables, including prescriptions for QT-prolonging drugs, and QTc measurements. Women had longer median QTc measurements than men (p = 0.030) and were prescribed more QT-prolonging drugs during the study (p = 0.010). In all patients, prescriptions for QT-prolonging drugs were associated with longer median and maximum QTc measurements at multiple assessed time points (i.e., for QT-prolonging drugs prescribed within 10, 30, 60, and 90 days of QTc measurements). Similarly, the number of QT-prolonging drugs prescribed was correlated with longer median and maximum QTc measurements at multiple time points. Common QTc-related exclusionary criteria were collected from a review of ClinicalTrials.gov for recent cancer clinical trials. Based on common exclusion criteria, prescriptions for QT-prolonging drugs increased the odds of trial exclusion. This study demonstrates that prescriptions for QT-prolonging drugs were associated with longer QTc measurements and increased odds of being excluded from cancer clinical trials.

Gender electrocardiographic features in patients with drug-induced long QT syndrome caused by antiarrhythmic therapy

Female gender is traditionally considered to be a risk factor for the QT interval prolongation and polymorphic ventricular tachycardia «torsades de pointes». However, despite a large number of studies on electrocardiographic features in patients with congenital long QT interval syndrome, there is relatively little information on gender ECG differences in the drug-induced QT interval prolongation.The aim of this study is to evaluate the gender characteristics of electrocardiographic parameters characterizing myocardial depolarization and repolarization in patients with drug-induced QT interval prolongation induced by class III antiarrhythmic drugs.67 patients with drug-induced QT interval prolongation induced class III antiarrhythmic drugs (amiodarone or sotalol) were examined, of which 38 (56.8 %) women and 29 (43.2 %) men, mean age – 57.1 ± 9.5 years. All patients underwent clinical laboratory and non-invasive electrophysiological studies, which included 12-lead ECG recording and 24-hour Holter monitoring. The patients of both genders were comparable in age and clinical characteristics, with the exception of a higher prevalence of AF in men (82.7 % vs 52.6 %, p = 0.03). The total duration of taking class III antiarrhythmic drugs in male patients was 3.79 ± 1.49 days, which significantly differed from female patients (3.11 ± 1.15 days, p = 0.044). When analyzing the initial standard ECG of patients recorded before starting antiarrhythmic drugs, there were no statistically significant differences between the groups, with the exception of large values of the corrected cardioelectrophysiological balance index (QTc/QRS) in female patients ( p = 0.037). While taking class III antiarrhythmic drugs, women had a higher duration of QTc ( p = 0.03) and JTc ( p = 0.023) intervals, as well as a dispersion of QT ( p = 0.012) and JT ( p = 0.006) intervals. According to Holter monitoring data, female patients were more likely to have an increased risk of developing non-sustained polymorphic VT ( p = 0.105).These results suggest a complex interplay between gender and repolarization that needs further investigation. Considering the gender characteristics of the process of myocardial repolarization, it should be taken into account not only when prescribing class III antiarrhythmic drugs to women, but also during preclinical and clinical development of drugs that have the QT interval prolonging effect.

Prevalence of Drugs and Drug Combinations that Increase Risk of Prolonged QT Time Among People with Major Neurocognitive Disorder Living in Sweden: A Cross-Sectional Registry Study.

People with major neurocognitive disorder might be susceptible to drug-induced QT interval prolongation due to the presence of a number of concomitant risk factors. The aim of this study was to investigate the prevalence of QT-prolonging drugs and QT-prolonging drug-drug interactions and associated factors among older people with major neurocognitive disorder. In this register-based study, we obtained information regarding QT-prolonging drug use in a large population of older people with major neurocognitive disorder, through record linkage between the Swedish registry for cognitive/dementia disorders, and the Swedish Prescribed Drug Register. QT-prolonging drugs were identified according to the CredibleMeds online database and interactions using the Janusmed interaction database. Drug use was defined as one or more filled prescriptions during a 6-month timeframe, July 01 to December 31, 2017. Associations between people with a QT-prolonging drug and the factors of age and gender were analysed through multiple logistic regression. Of 35,212 people included in the study, 41.6% had one or more QT-prolonging drug prescribed. The most commonly prescribed drug was donepezil, with a prevalence of 25.0%, followed by citalopram and escitalopram, representing 14.5% and 3.9% of prescriptions in the study population, respectively. Significant associations were found between QT-prolonging drug use and the factors of younger age and female gender. The most prevalent interaction was between citalopram and donepezil (2.7%), followed by the combination of escitalopram and donepezil (0.7%). In this population of olderpeople with major neurocognitive disorder, QT-prolonging drugs and interactions that increase the risk of torsade de pointes were prevalent. Due to the presence of many risk factors in this population, it is important to continuously evaluate current QT-prolonging drugs and concomitant drug treatment in each individual.

Abstract 13289: Risk of QT Interval Prolongation Associated With Dofetilide and Sotalol in Patients With Heart Failure With Preserved Ejection Fraction

Introduction: Heart failure (HF) with reduced ejection fraction (HFrEF) is a risk factor for drug-induced QT interval prolongation. It is unknown if HF with preserved ejection fraction (HFpEF) also increases the risk. Dofetilide (D) and sotalol (S) are potent QT interval-prolonging agents that are commonly used in patients with HFpEF, in whom atrial fibrillation is a common comorbidity. Hypothesis: The risk of QTc prolongation associated with D or S (D/S) is increased in patients with HFpEF. Methods: The data source was electronic health records from the Indiana Network for Patient Care (February 2010 to May 2021). After removing patients with overlapping diagnoses of HFpEF and HFrEF, no diagnosis code, absence of QT interval records, and no validated record of using D/S, we identified patients taking D/S among three groups: HFrEF (n=138), HFpEF (n=109), and no HF (n=729). Cochran-Mantel-Haenszel statistics were used to compare baseline characteristics. QT interval prolongation was defined as heart rate-corrected QT (QTc) &gt; 500 ms during D/S therapy. Unadjusted odds ratios (OR) of QT interval prolongation were determined by univariate analysis, and adjusted ORs were determined by generalized estimating equations (GEE) with logit link to account for an individual cluster with different times of hospitalization and covariates. Results: QTc prolongation associated with D/S occurred in 51.2% of patients with HFpEF, 70.1% of patients with HFrEF, and 29.4% of patients with no HF. After adjusting for age, sex, race, serum potassium and magnesium concentrations, kidney function, concomitant drug therapy, and comorbid conditions, the adjusted odds of QTc prolongation were significantly higher in patients with HFpEF, as well as in those with HFrEF, compared to those with no evidence of HF (Table). Conclusions: The odds of QT interval prolongation among inpatients receiving D/S were increased in patients with HFpEF and HFrEF compared to those who did not have HF.

ПРОГНОСТИЧЕСКОЕ ЗНАЧЕНИЕ ДЕФИЦИТА МАГНИЯ СЫВОРОТКИ КРОВИ У ПАЦИЕНТОВ С НАРУШЕНИЯМИ РИТМА СЕРДЦА, ПРИНИМАЮЩИХ АНТИАРИТМИЧЕСКИЕ ПРЕПАРАТЫ III КЛАССА

Aim: To determine the prevalence of serum magnesium deficiency in patients with ischemic heart disease and/or arterial hypertension and cardiac arrhythmias taking class III antiarrhythmic drugs and to establish the prognostic value of hypomagnesaemia for the development of drug-induced QT prolongation and ventricular arrhythmias. Material and Methods: The study included 117 patients with ischemic heart disease and/or arterial hypertension and cardiac arrhythmias taking class III antiarrhythmic drugs (amiodarone or sotalol). All patients underwent clinical, laboratory and instrumental studies, including the determination of serum magnesium levels. Depending on the magnesium levels, all patients were divided into 3 groups. Group A (n=21) included patients with serum magnesium below the reference values (&lt;0.75 mmol/l), group B (n=77) – patients with normal magnesium levels (0.75 – 1.0 mmol/l), group C (n=19) – those with magnesium levels above the reference values (≥ 1.0 mmol/l). Results: The incidence of hypomagnesaemia among patients with cardiac arrhythmias was 18%. Serum magnesium levels significantly correlated with the intake of loop diuretics (R=-0.3, p=0.001). In patients with serum magnesium deficiency, higher values were observed for the duration of the corrected QT and JT interval (p&lt;0.001), the interval T peak - T end (p&lt;0.01), as well as the cardiac electrophysiological balance index (p&lt;0.001). Magnesium level &lt;0.75 mmol/l was associated with a risk of drug-induced QT interval prolongation greater than 500 ms in patients receiving antiarrhythmic therapy (OR - 5.87 [95% CI 2.45–13.99]), life-threatening ventricular arrhythmias (OR - 3.81 [95% CI 1.90-7.62]) and non-sustained polymorphic ventricular tachycardia (OR - 4.06 [95% CI 1.77-9.29]). Conclusion: In patients with cardiac arrhythmias taking class III antiarrhythmic drugs, hypomagnesaemia is a predictor of the development of drug-induced QT interval prolongation and life-threatening ventricular arrhythmias including non-sustained polymorphic ventricular tachycardia. Routine determination of serum magnesium levels in patients taking antiarrhythmic drugs may be of value in predicting and preventing drug-induced life-threatening ventricular arrhythmias.

Cancer treatment and drug-induced QT interval prolongation: A review

Anticancer drugs can cause drug-induced prolongation of the QT interval. Prolongation of the QT interval is a known risk factor and an independent predictor of the development of life-threatening ventricular arrhythmias (polymorphic ventricular tachycardia, also called Torsades de Pointes), and sudden cardiac death in patients with and without structural heart disease. Healthcare practitioners should constantly evaluate the benefit/risk ratio prior to initiating treatment as well as continuing the chosen one. Some patients need particular attention, especially those who have risk factors such as comorbidities, taking drugs associated with QT interval prolongation, dehydration and electrolyte imbalance, etc. Despite apparent increase in the awareness among the patients and medical professionals, many scientists suggest that there is a lack of awareness about the true prevalence of these adverse events, which are at least 10 times greater than reported cases. This article discusses anticancer drugs that have an association with QT interval prolongation, and also possible strategies in the treatment of the patients with drug-induced QT interval prolongation.

Traditional and new electrocardiographic predictors of non-sustained polymorphic ventricular tachycardia caused by drug-induced long QT syndrome

Aim. To identify electrocardiographic (ECG) predictors of drug-induced non-sustained polymorphic ventricular tachycardia (PVT).Material and methods. The study included 110 patients with ischemic heart disease and /or arterial hypertension and cardiac arrhythmias who were taking class III antiarrhythmic drugs (amiodarone or sotalol). According to the presence or absence of the drug-induced QT interval prolongation (Bazett) (greater than 450 ms in men and greater than 470 ms in women), the patients were divided into 2 groups: «LQTS» (n=64) and «Non LQTS» (n=46). According to the presence or absence of non-sustained PVT, patients with drug-induced LQTS were additionally divided into the «PVT» (n=17) and «Non PVT» (n=47) groups. All patients underwent clinical, laboratory and instrumental examinations, which included taking anamnesis, physical examination, echocardiography, Holter monitoring, general clinical laboratory examinations, 12-lead ECG recording before and while taking antiarrhythmic drugs.Results. In the «LQTS» group of patients, PVT was significantly more common than in the «non LQTS» group (p=0.017). When analyzing the baseline ECG parameters recorded before the initiation of antiarrhythmic therapy, no significant differences were found between the groups except for a greater QT interval dispersion in the group of patients with LQTS and non-sustained PVT compared with patients without LQTS (p=0.03). While receiving antiarrhythmic therapy, patients with LQTS and non-sustained PVT had a longer duration of the QT interval (p&lt;0.05), as well as the duration of the corrected QT and JT intervals (p&lt;0.001) compared with group of patients without LQTS and subgroup without non-sustained PVT. The values of the parameters of the balance of depolarization and repolarization of the ventricular myocardium (iCEB and iCEBc) were significantly higher in patients with LQTS and non-sustained PVT (p&lt;0.001). Based on the results of the analysis of contingency tables, the most effective predictor of non-sustained PVT was an iCEBc value ≥5.81 (OR=7.294, 95% CI [4,245-11,532]). According to the results of one-way ROC-analysis, the iCEBc value ≥5.81 demonstrated high sensitivity (94.1%) and specificity (84.9%), as well as a fairly high area under the ROC-curve (0.901).Conclusions. Our results indicate that the value of the corrected index of the cardioelectrophysiological balance ≥5.81 can be used in the prediction of non-sustained PVT in patients with QT interval prolongation induced by amiodarone and sotalol in addition to the existing ECG parameters.

E2027 Cardiac Safety Evaluation With Concentration-Response Modeling of ECG Data to Inform Dose Selection in Studies in Patients With Dementia With Lewy Bodies.

E2027 is a novel, highly selective and potent inhibitor of phosphodiesterase 9 in development for dementia with Lewy bodies. Cardiac safety assessments for emerging agents are essential to avoid drug-induced QT interval prolongation, which may predispose individuals to potentially fatal ventricular arrhythmias. To evaluate the cardiac safety of E2027 and to inform dose selection for the phase 2 study of E2027 in dementia with Lewy bodies, we evaluated concentration-response modeling of pooled electrocardiogram data. A post hoc concentration-QTc analysis evaluated potential QT effects using data from 2 randomized, double-blind studies in healthy subjects: a single ascending dose (SAD) study and a multiple ascending dose (MAD) study. Daily E2027 doses ranged from 5 to 1200 mg. A linear mixed-effects model was used to establish the relationship between plasma concentrations of E2027 and change from the baseline of QTcF (ΔQTcF). A significant but shallow relationship was observed in the estimated slope of the concentration-ΔQTcF: 0.002 ms/ng/mL (90% confidence interval: 0.0007-0.0031) with a small, nonsignificant treatment effect-specific intercept of -0.6 ms. Based on this pooled concentration-QTc analysis, an effect on the QTcF interval >10 ms can be excluded up to E2027 plasma concentrations of ∼3579 ng/mL, corresponding to a dose at least 4-fold larger than the 50 mg phase 2 dose. This pooled post hoc analysis evaluating cardiac safety of E2027 demonstrated that clinically concerning QTcF prolongation and related cardiac complications are highly unlikely with proposed E2027 doses planned for phase 2.

Drug-Induced QT Interval Prolongation

The correct measurement of the QT interval (using the QT correction formulas, preferably Fridericia and Framingham) as well as a correct interpretation of the causes and of the clinical consequences of a QT prolongation is very important in clinical practice. Drug-induced long QT syndrome (DILQTS) is one of the most common causes of LQTS. In the diagnosis and management of the DILQTS, it can be useful to follow the three-step rule presented in this article: detailed pharmacological anamnesis and correct ECG interpretation; database search and clinical interpretation; confirmatory test.

Prevalence of drug to drug induced QT interval prolongation in critically Ill cardiac patients in a tertiary cardiac center in Malaysia

Drug-drug interactions (DDIs) involving CYP3A4 are particularly concerning, in view of their enzyme system which could metabolize up to 50% of utilized medications which could predispose to the hazard of QT prolongation. Some drugs do not affect the repolarization or affect the QT interval themselves. However, it can increase the risk of QT prolongation when taken with drugs that block the metabolic breakdown particularly. Predisposing factors of QT prolongation include female sex, age over 65 years, brady-arrhythmia, electrolyte disturbances (hypokalemia, hypomagnesaemia), cardiac disease (congestive heart failure, ventricular hypertrophy, myocardial infarction, and atrial fibrillation), impaired hepatic/renal function and hypothyroidism.

Drug-Induced QT Interval Prolongation

Drug-Induced QT Interval Prolongation

Use of automated patch clamp in cardiac safety assessment: Past, present & future perspectives

There is no doubt that automated patch clamp (APC) technology has revolutionized research in biomedical science. High throughput ion channel screening is now an integral part of the development and safety profiling of the majority of new chemical entities currently developed to address unmet medical needs. The increased throughput it provides has significantly improved the ability to overcome the time-consuming, low throughput bottlenecks resulting from the more conventional manual patch clamp method, considered the ‘gold standard’, for studying ion channel function and pharmacology. While systems offering the luxury of automation have only been commercially available for two decades, the road leading to this new technology is long and rich in seminal, hands-on, studies dating back as far as the 18th century. So where does this technology currently stand, and what will it look like in the future? In the current article, we review the scientific history leading to the development of APC systems, examine key drivers in the rapid development of this technology (such as failed ion channel programmes and the issue of drug-induced hERG inhibition and QT interval prolongation), highlight key capabilities and finally provide some perspective on the current and future impact of the technology on cardiac safety assessment and biomedical science.