Risk Of Drug-induced Arrhythmias Research Articles

Cardiotoxicity risk assessment of anti-cancer drugs and future perspectives

Cardiotoxicity is a serious adverse effect of anti-cancer drugs. Anti-cancer drug-induced cardiotoxicity are arrhythmia, cardiac contractile dysfunction, coronary artery disease, and hypertension, which affect to the quality of life in patients with cancer. In particular, cardiac contractile dysfunction is a life-threatening symptom leading to heart failure, suggesting that it is very important to predict the risk of developing the contractile dysfunction by anti-cancer drugs. Recently, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can be used to assess the risk of drug-induced arrhythmias. This prompts us to evaluate other cardiotoxic effects such as contractility dysfunction and structural toxicity with hiPSC-CMs. Since anti-cancer drug-induced contractility dysfunction are considered to be induced by chronic exposure, we have developed a method to assess chronic contractility dysfunction by imaging analysis of hiPSC-CMs. BMS-986094, which failed in clinical trials due to the occurrence of heart failure, was used as a positive compound. We found that chronic exposure to BMS-986094 decreased the contraction and relaxation velocity in hiPSC-CMs. Doxorubicin was observed to decrease cytotoxicity and both contraction and relaxation velocities in hiPSC-CMs. We are currently further evaluating other anti-cancer drugs with different mode-of-actions using hiPSC-CMs and assess the predictivity and utility of contractile assessment using hiPSC-CMs by comparing with real-world data. Here, we introduce our novel method to assess the chronic contractility of hiPSC-CMs by imaging analysis and discuss the future perspectives for assessing the anti-cancer drug-induced cardiotoxicity.

A deep learning platform to assess drug proarrhythmia risk.

Drug safety initiatives have endorsed human iPSC-derived cardiomyocytes (hiPSC-CMs) as an invitro model for predicting drug-induced cardiac arrhythmia. However, the extent to which human-defined features of invitro arrhythmia predict actual clinical risk has been much debated. Here, we trained a convolutional neural network classifier (CNN) to learn features of invitro action potential recordings of hiPSC-CMs that are associated with lethal Torsade de Pointes arrhythmia. The CNN classifier accurately predicted the risk of drug-induced arrhythmia in people. The risk profile of the test drugs was similar across hiPSC-CMs derived from different healthy donors. In contrast, pathogenic mutations that cause arrhythmogenic cardiomyopathies in patients significantly increased the proarrhythmic propensity to certain intermediate and high-risk drugs in the hiPSC-CMs. Thus, deep learning can identify invitro arrhythmic features that correlate with clinical arrhythmia and discern the influence of patient genetics on the risk of drug-induced arrhythmia.

Computational investigation of drug-induced effects on human cardiac electro-mechanics

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): NC3Rs Infrastructure for Impart Award (NC/P001076/1) Wellcome Trust Senior Research Fellowship in Basic Biomedical Sciences (214290/Z/18/Z) Background Human-based computer modelling and simulations have been widely used in cardiac electrophysiology, to provide a better understanding of the ionic mechanisms underlying risk of arrhythmias, and their modulation by drugs and diseased conditions. More recently, multiscale computer models of human cardiac electro-mechanics have been developed. These models provide the means for a comprehensive investigation of action potential, calcium transient, active force, and their variability in the population, and can predict drug-induced contractility changes in humans. Purpose This study aims to perform a computational investigation of variability in human cardiac contractility biomarkers and their modulation by well-known drugs. Methods We considered the most recent model of human ventricular electro-mechanics (Margara et al. 2020). We constructed a population of 300 cells by randomly varying the main ionic currents in the model, to represent the biological variability observed in human experimental data. We then simulated the effect of 10 reference compounds, 6 of which with known pro-arrhythmic risk. Simulations were performed at 1 Hz for multiple drug concentrations, using the Virtual Assay software. A set of action potential, calcium transient and active force biomarkers were computed, as well as the electro-mechanical window, and the occurrence of early after-depolarisations and after-contractions in the virtual population. Simulation results were compared against clinical risk of drug-induced arrhythmias and experimental recording from human ventricular myocytes from literature. Results Overall, biomarker variability in the virtual population increased following drug application compared to control conditions. All compounds had a negative inotropic effect in simulation, with a marked decrease of the active tension peak, e.g. -80% for nifedipine 8 nM. This is in agreement with human experimental data for all compounds except Dofetilide, for which no inotropic effect was observed in vitro. Compounds with known risk of arrhythmias provoked early after-depolarisations, which in turn caused after-contractions. Their occurrence in the population increased together with the drug concentration, e.g. 3.6% at 0.16 µM and 48% at 0.48 µM for droperidol. In addition, these compounds also displayed prolonged action potential and calcium transient, and a shortening of the electro-mechanical window, all known biomarkers of pro-arrhythmia. Conclusions We evaluated the effect and the cardiac safety of 10 reference compounds in a population of 300 human ventricular electro-mechanical models. Simulation results were in good agreement with experimental data in human ventricular cardiomyocytes, and they allowed to identify the compounds with a known pro-arrhythmic risk based on drug-induced early after-depolarisations and after-contractions. This methodology provides new insights into variability in human cardiac contractility and its modulation by drugs.

Perioperative Implications of the 2020 American Heart Association Scientific Statement on Drug-Induced Arrhythmias—A Focused Review

The recently released American Heart Association (AHA) scientific statement on drug-induced arrhythmias discussed medications commonly associated with bradycardia, supraventricular tachycardias, and ventricular arrhythmias. The foundational data for this statement were collected from general outpatient and inpatient populations. Patients undergoing surgical and minimally invasive treatments are a unique subgroup, because they may experience hemodynamic changes associated with anesthesia and their procedure, receive multiple drug combinations not given in either inpatient or outpatient settings, or experience postprocedural inflammatory syndromes. Accordingly, the generalizability of the AHA scientific statement to this perioperative population is unclear. This focused review highlights important aspects of the new AHA scientific statement and their application to the perioperative setting. The authors review medications frequently encountered and given by anesthesiologists and their risk of drug-induced arrhythmias and discuss common anesthetic and adjunctive medications and their associated risks of bradycardia, atrial fibrillation, torsades de pointes, and drug-induced Brugada syndrome. In many instances, the risk of arrhythmia reported by the AHA scientific statement in the general population appeared to be higher than found in perioperative arenas. Furthermore, the authors discuss the arrhythmia risk of additional medications commonly ordered or administered by anesthesiologists that are not included in the AHA scientific statement. As patient and procedural complexity increases and novel anesthetic combinations propagate, further research and observational studies will be required to delineate further perioperative risks for drug-induced arrhythmia.

Human In Silico Drug Trials Demonstrate Higher Accuracy than Animal Models in Predicting Clinical Pro-Arrhythmic Cardiotoxicity.

Early prediction of cardiotoxicity is critical for drug development. Current animal models raise ethical and translational questions, and have limited accuracy in clinical risk prediction. Human-based computer models constitute a fast, cheap and potentially effective alternative to experimental assays, also facilitating translation to human. Key challenges include consideration of inter-cellular variability in drug responses and integration of computational and experimental methods in safety pharmacology. Our aim is to evaluate the ability of in silico drug trials in populations of human action potential (AP) models to predict clinical risk of drug-induced arrhythmias based on ion channel information, and to compare simulation results against experimental assays commonly used for drug testing. A control population of 1,213 human ventricular AP models in agreement with experimental recordings was constructed. In silico drug trials were performed for 62 reference compounds at multiple concentrations, using pore-block drug models (IC50/Hill coefficient). Drug-induced changes in AP biomarkers were quantified, together with occurrence of repolarization/depolarization abnormalities. Simulation results were used to predict clinical risk based on reports of Torsade de Pointes arrhythmias, and further evaluated in a subset of compounds through comparison with electrocardiograms from rabbit wedge preparations and Ca2+-transient recordings in human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs). Drug-induced changes in silico vary in magnitude depending on the specific ionic profile of each model in the population, thus allowing to identify cell sub-populations at higher risk of developing abnormal AP phenotypes. Models with low repolarization reserve (increased Ca2+/late Na+ currents and Na+/Ca2+-exchanger, reduced Na+/K+-pump) are highly vulnerable to drug-induced repolarization abnormalities, while those with reduced inward current density (fast/late Na+ and Ca2+ currents) exhibit high susceptibility to depolarization abnormalities. Repolarization abnormalities in silico predict clinical risk for all compounds with 89% accuracy. Drug-induced changes in biomarkers are in overall agreement across different assays: in silico AP duration changes reflect the ones observed in rabbit QT interval and hiPS-CMs Ca2+-transient, and simulated upstroke velocity captures variations in rabbit QRS complex. Our results demonstrate that human in silico drug trials constitute a powerful methodology for prediction of clinical pro-arrhythmic cardiotoxicity, ready for integration in the existing drug safety assessment pipelines.

Early assessment of proarrhythmic risk of drugs using the in vitro data and single-cell-based in silico models: proof of concept

Background and purpose: To determine the predictive performance of in silico models using drug-specific preclinical cardiac electrophysiology data to investigate drug-induced arrhythmia risk (e.g. Torsade de pointes (TdP)) in virtual human subjects.Experimental approach: To assess drug proarrhythmic risk, we used a set of in vitro electrophysiological measurements describing ion channel inhibition triggered by the investigated drugs. The Cardiac Safety Simulator version 2.0 (CSS; Simcyp, Sheffield, UK) platform was used to simulate human left ventricular cardiac myocyte action potential models.Results: This study shows the impact of drug concentration changes on particular ionic currents by using available experimental data. The simulation results display safety threshold according to drug concentration threshold and log (threshold concentration/ effective therapeutic plasma concentration (ETPC)).Conclusion and implications: We reproduced the underlying biophysical characteristics of cardiac cells resulted in effects of drugs associated with cardiac arrhythmias (action potential duration (APD) and QT prolongation and TdP) which were observed in published 3D simulations, yet with much less computational burden.

Drug-drug interactions and QT prolongation as a commonly assessed cardiac effect - comprehensive overview of clinical trials.

BackgroundProarrhythmia assessment is one of the major concerns for regulatory bodies and pharmaceutical industry. ICH guidelines recommending preclinical tests have been established in attempt to eliminate the risk of drug-induced arrhythmias. However, in the clinic, arrhythmia occurrence is determined not only by the inherent property of a drug to block ion currents and disturb electrophysiological activity of cardiac myocytes, but also by many other factors modifying individual risk of QT prolongation and subsequent proarrhythmia propensity. One of those is drug-drug interactions. Since polypharmacy is a common practice in clinical settings, it can be anticipated that there is a relatively high risk that the patient will receive at least two drugs mutually modifying their proarrhythmic potential and resulting either in triggering the occurrence or mitigating the clinical symptoms. The mechanism can be observed either directly at the pharmacodynamic level by competing for the molecular targets, or indirectly by modifying the physiological parameters, or at the pharmacokinetic level by alteration of the active concentration of the victim drug.MethodsThis publication provides an overview of published clinical studies on pharmacokinetic and/or pharmacodynamic drug-drug interactions in humans and their electrophysiological consequences (QT interval modification). Databases of PubMed and Scopus were searched and combinations of the following keywords were used for Title, and Keywords fields: interaction, coadministration, combination, DDI and electrocardiographic, QTc interval, ECG. Only human studies were included. Over 4500 publications were retrieved and underwent preliminary assessment to identify papers accordant with the topic of this review. 76 papers reporting results for 96 drug combinations were found and analyzed.ResultsThe results show the tremendous variability of drug-drug interaction effects, which makes one aware of complexity of the problem, and suggests the need for assessment of an additional risk factors and careful ECG monitoring before administration of drugs with anticipated QT prolongation.ConclusionsDDIs can play significant roles in drugs’ cardiac safety, as evidenced by the provided examples. Assessment of the pharmacodynamic effects of the drug interactions is more challenging as compared to the pharmacokinetic due to the significant diversity in the endpoints which should be analyzed specifically for various clinical effects. Nevertheless, PD components of DDIs should be accounted for as PK changes alone do not allow to fully explain the electrophysiological effects in clinic situations.Electronic supplementary materialThe online version of this article (doi:10.1186/s40360-016-0053-1) contains supplementary material, which is available to authorized users.

Risk of arrhythmia induced by psychotropic medications: a proposal for clinical management

Several drugs used in the treatment of mental diseases are associated with an increased risk of sudden cardiac death (SCD). A general cause-relationship between the intake of these drugs and SCD is unattainable, but numerous case reports of drug-induced malignant arrhythmia and epidemiological studies, associating the use of specific drugs with SCD, strongly support the presence of an increased risk. Whereas the absolute risk of drug-induced life-threatening arrhythmia may be relatively low, even small increments in risk of SCD may have a major health impact considering that millions of patients are treated with psychotropics. In subgroups of pre-disposed patients, e.g. patients with cardiac diseases or other co-morbidities, the elderly or patients treated with other negatively interacting drugs, the absolute risk of drug-induced arrhythmia may be considerable. On the other hand, several of the major mental disorders are associated with a large risk of suicide if untreated. The observed risk of malignant arrhythmia associated with treatment with psychotropic drugs calls for clinical guidelines integrating the risk of the individual drug and other potentially interacting risk factors. In this review, data from various authorities on the risk of arrhythmia associated with psychotropic medications were weighted and categorized into three risk categories. Additionally, we suggest a clinically applicable algorithm to reduce the risk of malignant arrhythmia in patients to be treated with psychotropic medications. The algorithm integrates the risk categories of the individual drugs and pre-disposing risk factors and suggests a prudent follow-up for patients with an increased risk. We believe this clinically manageable guideline might improve safety in the many and rapidly increasing number of patients on psychotropic drugs.

GW24-e2999 Proarrhythmic window of a drug determines the risk of multiple ion channel inhibitors

ObjectivesThe proarrhythmic risk of QT prolonging drugs varies significantly. However, the mechanisms responsible for the high or low risk of drug-induced arrhythmias remain unknown. In this study, we tested our...

Common Variation in the NOS1AP Gene Is Associated With Drug-Induced QT Prolongation and Ventricular Arrhythmia

This study sought to determine whether variations in NOS1AP affect drug-induced long QT syndrome (LQTS). Use of antiarrhythmic drugs is limited by the high incidence of serious adverse events including QT prolongation and torsades de pointes. NOS1AP gene variants play a role in modulating QT intervals in healthy subjects and severity of presentation in LQTS. This study carried out an association study using 167 single nucleotide polymorphisms (SNP) spanning the NOS1AP gene in 58 Caucasian patients experiencing drug-induced LQTS (dLQTS) and 87 Caucasian controls from the DARE (Drug-Induced Arrhythmia Risk Evaluation) study. The rs10800397 SNP was significantly associated with dLQTS (odds ratio [OR]: 3.3, 99.95% confidence interval [CI]: 1.0 to 10.8, p = 3.7 × 10(-4)). The associations were more pronounced in the subgroup of amiodarone users, in which 3 SNPs, including rs10800397, were significantly associated (most significant SNP: rs10919035: OR: 5.5, 99.95% CI: 1.1 to 27.9, p = 3.0 × 10(-4)). We genotyped rs10919035 in an independent replication cohort of 28 amiodarone dLQTS cases versus 173 control subjects (meta-analysis of both studies: OR: 2.81, 99.95% CI: 1.62 to 4.89, p = 2.4 × 10(-4)). Analysis of corrected QT interval among 74 control subjects from our dataset showed a similar pattern of significance over the gene region as the case-control analysis. This pattern was confirmed in 1,480 control subjects from the BRIGHT (British Genetics of Hypertension Study) cohort (top SNP from DARE: rs12734991 in meta-analysis: increase in corrected QT interval per C allele: 9.1 ± 3.2 ms, p = 1.7 × 10(-4)). These results provide the first demonstration that common variations in the NOS1AP gene are associated with a significant increase in the risk of dLQTS. This study suggests that common variations in the NOS1AP gene may have relevance for future pharmacogenomic applications in clinical practice permitting safer prescription of drugs for vulnerable patients.

Benefits and strengths of the disproportionality analysis for identification of adverse drug reactions in a pharmacovigilance database

Adverse drug reactions (ADRs) represent an important medical issue: they result in 3–7% of all hospital admissions and are associated with a substantial increase in morbidity and mortality. Numerous methods can be used to investigate ADRs. Each has its strengths and weakness. The insufficiencies of basic (experimental) pharmacology as well as clinical trials for studying ADRs are well known. Animal physiology often differs from that of humans. Clinical trials, although necessary, do not allow definite conclusions, because they are built to evaluate efficacy more than safety. Thus, spontaneous notifications remain the cornerstone for ADRs despite their mandatory limitations (under-reporting, selective reporting, lack of denominator etc.). Intensive studies could allow quantification of a specific problem of drug safety (i.e. drug admission into hospital for ADRs). For some years, several pharmacoepidemiological methods have been used to identify and also to quantify ADRs. Among thesse methods, case–control or cohort studies are most widely used. However, their setting up requires specific organization, delay, money and also use of large databases, which are not often specifically built for evaluation of ADRs. In the present issue of the journal, clinical pharmacologists and pharmacoepidemiologists from Poitiers University Hospital (France) have used another method, working from the French PharmacoVigilance database. They used disproportionality analysis for identification of memory disorders associated with drugs [1]. The present paper discusses the benefits and strengths of this method.

Electrophysiological Characterization of Cardiomyocytes Derived From Human Induced Pluripotent Stem Cells

Cardiomyocytes derived from human induced pluripotent stem cells (hiPS-CMs) hold great promise for development of in vitro research tools to assess cardiotoxicity, including QT prolongation. In the present study, we aimed to clarify the electrophysiological/pharmacological characteristics of hiPS-CMs using the patch-clamp technique. The hiPS cells were differentiated into beating cardiomyocytes by the embryoid body method. The expression of genes related to cardiac ion channels and differentiation markers in cardiomyocytes were detected by RT-PCR. Whole-cell patch-clamp recordings were performed using single hiPS-CMs dispersed from beating colonies. We confirmed voltage-dependence of major cardiac ion currents (I(Na), I(Ca), I(Kr), and I(Ks)) and pharmacological responses to ion-channel blockers. Action potential duration (APD) was prolonged by both I(Kr)/hERG and I(Ks) blockers, whereas it was shortened by an I(Ca) blocker, indicating that these ion current components contribute to action potential generation in hiPS-CMs. As for multiple ion channel blockers, terfenadine prolonged APD, but verapamil did not, results which were identical to clinically relevant pharmacological responses. These data suggest that patch-clamp assay using hiPS-CMs could be an accurate method of predicting the human cardiac responses to drug candidates. This study would be helpful in establishing an electrophysiological assay to assess the risk of drug-induced arrhythmia using hiPS-CMs.

Integrated risk assessment and predictive value to humans of non‐clinical repolarization assays

The potential for drugs to be associated with the life-threatening arrhythmia, Torsades de Pointes (TdeP), continues to be a topic of regulatory, academic and industrial concern. Despite being an imperfect biomarker, prolongation of the QT interval of the surface ECG is used to assess the risk of a drug being associated with TdeP such that a thorough examination of drug effects on the QT interval is required for all new chemical entities. Numerous studies have investigated the relationship between non-clinical findings and the risk of TdeP and QT prolongation in the general population. There are many literature references supporting the strong correlation between the clinical safety margin over human ether-a-go-go (hERG) inhibitory potency and the risk of drug-induced arrhythmia and sudden death. A quantitative analysis of the relationship between non-clinical studies and the outcome of a human Thorough QT study has also been reported. In the current manuscript, based on the outcome of the non-clinical assays the sensitivity and specificity of each assay and an integrated risk assessment for predicting the outcome of the human Thorough QT study has been conducted. The data suggest that for QT prolongation mediated through inhibition of the hERG current the non-clinical assays are highly predictive of drug effects on the QT interval. Based on the literature review and specific quantitative analysis reported above it is concluded that non-clinical assays predict the risk of compounds to prolong the QT interval and cause TdeP in humans if the mechanism is through inhibition of the hERG current.

Sertindole causes distinct electrocardiographic T-wave morphology changes

Sertindole's propensity to prolong the QT interval relates to blockade of the KCNH2 (HERG) encoded Ikr potassium channel, but there has been limited detailed data on T-wave morphology changes. Digital 12-lead ECG was recorded at baseline and at steady-state in 37 patients switched to sertindole. ECG was analyzed for quantitative T-wave morphology changes and Fridericia-corrected QT duration (QTcF). Prominent T-wave morphology changes occurred during sertindole treatment and in some cases without concomitant prolongation of the QTcF interval. Four patients developed notched T-waves during sertindole treatment. Mean QTc prolongation was 19 ms. The mean effect size was higher for T-wave morphology combination score (MCS) (ES=1.92; 95% CI: 1.35-2.49) compared to the mean effect size for QTcF (ES=0.88; 95% CI: 0.52-1.24). The use of T-wave morphology analysis may become clinically relevant, particularly if shown to be associated with drug-induced arrhythmia risk.

DARE: the Drug-Induced Arrhythmia Risk Evaluation Study

DARE: the Drug-Induced Arrhythmia Risk Evaluation Study

Methodology of the Ongoing Drug-Induced Arrhythmia Risk Evaluation (DARE) Study

Methodology of the Ongoing Drug-Induced Arrhythmia Risk Evaluation (DARE) Study

Anti-HERG Activity and the Risk of Drug-induced Arrhythmias and Sudden Death

Anti-HERG Activity and the Risk of Drug-induced Arrhythmias and Sudden Death

The negative effect of red tape on research

To describe the kind of the difficulties encountered when seeking research governance approval for a nationwide public health and genetic study-the Drug-Induced Arrhythmia Risk Evaluation study-in England. Description of the processes followed when seeking research governance approval for the Drug-Induced Arrhythmia Risk Evaluation study-a case control study with annual follow-up of cases and controls over 5 years, set in the English National Health Service (NHS). The authors describe wide variations in NHS research governance approval procedures in England. NHS research governance procedures in England are impeding the process of epidemiological studies; there is the need for a centralised NHS R&D approval of studies, which is analogous to MREC for ethical approval.

The degree of potassium channel blockade and the risk of torsade de pointes: the truth, nothing but the truth, but not the whole truth

This editorial refers to ‘Anti-HERG activity and the risk of drug-induced arrhythmias and sudden death’† by M.L. De Bruin et al. , on page 590 Several anti-arrhythmic drugs, as well as medications not intended for cardiac indications, block a specific potassium channel named IKr (the rapid delayed rectifying potassium current). In the case of the anti-arrhythmic drugs, IKr channels are purposely targeted. By blocking potassium outflow currents, the anti-arrhythmic drugs prolong the action potential. This action (depicted in the electrocardiogram as prolongation of the QT interval) can be advantageous given that prolongation of the action potential also lengthens the refractory period, thereby suppressing common arrhythmias. Unfortunately, by a mechanism explained elsewhere,1 IKr blockade may lead to excessive QT prolongation and trigger a polymorphic ventricular tachyarrhythmia (torsade de pointes) that may degenerate into ventricular fibrillation. Furthermore, because of its unique three-dimensional characteristics,2 IKr channels are very easily blocked by the small molecules of numerous non-cardiac drugs. The result is that otherwise harmless and valuable drugs, like the non-sedative antihistamines and the quinolone-antibiotics, become potentially lethal pro-arrhythmic medications.3 An important study by De Bruin et al .4 suggests that a strong correlation exists between the strength of IKr blockade caused by a given drug and its pro-arrhythmic potential. The concept that stronger IKr blockers will lead not only to more QT prolongation but also to higher arrhythmic risk is so logical that the reader will be left wondering why this study was ever conducted, let alone published. In reality, however, this concept has been difficult to prove.5 Amiodarone, ranolazine, and verapamil illustrate that the correlation between IKr … *Corresponding author. Tel: +972 524266859; fax: +972 36974416. E-mail address : saviskin{at}tasmc.health.gov.il

Predicting Cardiac Arrhythmias and Sudden Death in Diabetic Users of Proarrhythmic Drugs

In diabetic patients, the corrected QT (QTc) interval is relatively long (1). In accordance with the concept of “reduced repolarization reserve” (2), a subsequent increase in QTc interval by proarrhythmic drugs may lead to cardiac arrhythmias and sudden death. Recently, it was shown that patients with diabetes are at increased risk of drug-induced arrhythmias (3). We developed a decision tool to predict the risk of serious ventricular arrhythmias and sudden death among diabetic users of nonantiarrhythmic proarrhythmic drugs. A cohort study among 61,280 diabetic patients using nonantiarrhythmic proarrhythmic medication (amitriptyline, astemizole, chloroquine, chlorpromazine, cisapride, clarithromycin, clomipramine, cotrimoxazole, diphenhydramine/dimenhydrinate, domperidone, doxepine, droperidol, erythromycin, grepafloxacin, halofantrine, haloperidol, indapamide, ketanserin, lidoflazine, mianserine, pentamidine, pimozide, probucol, promethazine, protriptyline, sulfamethoxazole, sultopride, tacrolimus, terfenadine, terodiline, thioridazine, trimethoprim, and zimeldine) (4) in the General Practice Research Database (1987–2001) was performed. This database contains computerized medical records of ∼650 general practices, including ∼6.5% of the population of England and Wales. Diabetic patients were followed from the 1st day of prescription of any nonantiarrhythmic proarrhythmic drug. Follow-up was censored when the duration of (one of) the prescription(s) had elapsed, when the study outcome occurred, in case of death, upon exit from the study population, or at the end of the study period, whichever of these events came first. The combined study outcome included ventricular tachycardia, ventricular fibrillation and flutter, cardiac arrest, and sudden death. …