Risk Factors For Torsades De Pointes Research Articles

Sex-Specific Classification of Drug-Induced Torsade de Pointes Susceptibility Using Cardiac Simulations and Machine Learning.

Torsade de Pointes (TdP), a rare but lethal ventricular arrhythmia, is a toxic side effect of many drugs. To assess TdP risk, safety regulatory guidelines require quantification of hERG channel block in vitro and QT interval prolongation in vivo for all new therapeutic compounds. Unfortunately, these have proven to be poor predictors of torsadogenic risk, and are likely to have prevented safe compounds from reaching clinical phases. Although this has stimulated numerous efforts to define new paradigms for cardiac safety, none of the recently developed strategies accounts for patient conditions. In particular, despite being a well-established independent risk factor for TdP, female sex is vastly under-represented in both basic research and clinical studies, and thus current TdP metrics are likely biased toward the male sex. Here, we apply statistical learning to synthetic data, generated by simulating drug effects on cardiac myocyte models capturing male and female electrophysiology, to develop new sex-specific classification frameworks for TdP risk. We show that (i) TdP classifiers require different features in females vs. males; (ii) male-based classifiers perform more poorly when applied to female data; and (iii) female-based classifier performance is largely unaffected by acute effects of hormones (i.e., during various phases of the menstrual cycle). Notably, when predicting TdP risk of intermediate drugs on female simulated data, male-biased predictive models consistently underestimate TdP risk in women. Therefore, we conclude that pipelines for preclinical cardiotoxicity risk assessment should consider sex as a key variable to avoid potentially life-threatening consequences for the female population.

Survey concerning internal medicine physicians and prolonged QT interval: Knowledge and treatment practices.

Prolongation of the QT interval is associated with adverse cardiac events specifically Torsades de pointes (TdP). There are multiple mediations that have a known, possible, or conditional risk for prolonged QT interval, but general practitioners’ knowledge of these medications is unknown. We conducted a survey to assess internal medicine (IM) providers’ knowledge of risk factors and medications associated with prolonged QT as well as provider experience and comfort when treating patients with prolonged QT. A 17-question, anonymous survey was constructed in 2019 and distributed to IM providers and residents at a tertiary care center. Questions included demographic information, 6 Likert-scale questions gauging provider experience with prolonged QT, and 10 multiple choice clinical vignettes to assess clinical knowledge. Data was analyzed descriptively. Knowledge was assessed via clinical vignettes and compared by level of training. Forty-one responses were received out of a total of 87 possible respondents (47.1% response rate). About 70% of respondents see patients with acquired prolonged QT once monthly or more. 95% rarely see congenital prolonged QT. When presented with QTc drug issues, 73% of providers seldom or sometimes consulted pharmacy, but about half used online resources. The average correct score on the clinical vignettes was 5.59/10, with the highest scores seen in attending physicians in their first five years of practice (6.96/10). Our survey suggests that IM providers commonly encounter QT prolonging drugs. Educational efforts to improve knowledge of drug and patient risk factors for TdP may be needed.

QT interval prolongation and Torsades de Pointes with donepezil, rivastigmine and galantamine.

Background:Acetylcholinesterase inhibitors (AChEis) including donepezil, galantamine and rivastigmine are used to treat Alzheimer’s disease (AD). This study aimed to evaluate evidence from the case report literature for an association between these agents and risk of QT interval prolongation and Torsades de Pointes (TdP) arrhythmia.Methods:Published literature was mined with predetermined MeSH terms for each of donepezil, galantamine and rivastigmine, to identify cases of QT interval prolongation and TdP. Case reports were analysed using causality scales and a QT interval nomogram.Results:A total of 13 case reports were found (10 for donepezil, 2 for galantamine and 1 for rivastigmine) with rate corrected QT interval (QTc) prolongation. Five cases with donepezil exhibited TdP. TdP was not reported in the cases with galantamine and rivastigmine. The use of a QT heart rate nomogram highlighted risk with donepezil compared with the other two drugs and the application of the Naranjo causality scale suggested probable or possible causation for all donepezil cases. All patients had at least two other risk factors for TdP, including modifiable risk factors such as electrolyte disturbances, bradycardia, co-administration of QT prolonging drugs. A number of recent cases involved recent changes in medication.Conclusion:Our evaluation of the case report literature suggests that there is evidence for a causal association between donepezil and QTc/TdP risk. Attention to risk factors for QTc prolongation/TdP should be exercised when prescribing donepezil and modifiable risk factors corrected. Owing to the low number of cases with galantamine and rivastigmine, further work is needed to establish whether these drugs may be more suitable than donepezil for patients with other risk factors for TdP.

Reining in the QTc: reducing the risk of Torsades de Pointes across a major health system.

Hospitalized patients have a high prevalence of prolonged QTc and are a high-risk population for Torsades de Pointes (TdP). One modifiable risk factor for TdP is the use of QT prolonging drugs. Electronically alerting providers who are ordering QT prolonging drugs in at-risk patients may help to achieve safer prescribing practices. Our previous study decreased inappropriate prescription of IV haloperidol by 36% using a targeted "smart" electronic alert. We wanted to assess an approach to expanding this type of electronic alert to commonly used QT prolonging medications and evaluate how this would affect prescribing practice. This retrospective cohort study evaluated the impact of these alerts for 12 frequently prescribed high-risk medications across a major health system. Between October 2016 and June 2017, a total of 6453 alerts fired and resulted in 3020 (46.8%) orders being cancelled by the provider. Our focused electronic alert significantly decreased prescribing of QT prolonging medications in high-risk patients.

The Identification of Torsades de Pointes via CEEG: A Case Report on a Patient with Physiologically Provoked Nonepileptic Events

ABSTRACTContinuous electroencephalography (CEEG) is chiefly performed at The Medical University of South Carolina (MUSC) for identifying seizures, including its refined use within the epilepsy monitoring unit (EMU) as a differentiator between epileptic and psychogenic etiologies. CEEG also provides critical data that carry implications outside the bounds of both epilepsy and psychogenic events, such as the characterization of unorthodox clinical phenomena that are of physiological (though nonepileptic) origins. Although nonepileptic events (NEEs) are primarily linked with psychogenic phenomena (conversion disorder, malingering) that can mimic epileptic activity, they, like seizures, have diverse semiologies and etiologies. Although it is reasonable for seasoned neurodiagnostics professionals to develop an expectation that NEEs are of psychogenic origin, it is essential to acknowledge that they include etiologies that lay beyond those of psychiatric influence. Such a case is presented in which a 74-year-old female patient who, though initially suspected of having either psychogenic or epileptic seizures, was found to be having frequent episodes of the life-threatening cardiac convulsive syncope torsades de pointes (TdP). The patient had several known risk factors for TdP, including a prolonged QT complex, female gender, advancing age, active medications known to provoke TdP, and electrolyte imbalances (low magnesium and potassium) (Trinkley et al. 2013). TdP was first suspected through the CEEG by a combination of remarkable EEG background changes, recorded video evidence of clinical features, and accompanying single-lead electrocardiogram (ECG) data captured during the events. Upon proper diagnosis, the patient was urgently treated with restorative measures, including electrolyte replenishment, pacemaker implantation, and cessation of provocative medications.

A new paradigm for predicting risk of Torsades de Pointes during drug development: Commentary on: "Improved prediction of drug-induced Torsades de Pointes through simulations of dynamics and machine learning algorithms".

Drug-induced long QT syndrome (diLQTS) is a clinical entity in which administration of a drug produces marked prolongation of the QT interval on the ECG. DiLQTS places a patient at risk of developing Torsades de Pointes (TdP), a malignant polymorphic ventricular tachycardia associated with arrhythmic sudden cardiac death (SCD). In addition to diLQTS, other clinical risk factors for TdP include female gender, bradycardia, electrolyte disturbances, recent conversion to normal (sinus) rhythm, and congenital LQTS.

Drug-induced QT interval prolongation and torsades de pointes: Role of the pharmacist in risk assessment, prevention and management.

Torsades de pointes (TdP) is a life-threatening arrhythmia associated with prolongation of the corrected QT (QTc) interval on the electrocardiogram. More than 100 drugs available in Canada, including widely used antibiotics, antidepressants, cardiovascular drugs and many others, may cause QTc interval prolongation and TdP. Risk factors for TdP include QTc interval >500 ms, increase in QTc interval ≥60 ms from the pretreatment value, advanced age, female sex, acute myocardial infarction, heart failure with reduced ejection fraction, hypokalemia, hypomagnesemia, hypocalcemia, bradycardia, treatment with diuretics and elevated plasma concentrations of QTc interval-prolonging drugs due to drug interactions, inadequate dose adjustment of renally eliminated drugs in patients with kidney disease and rapid intravenous administration. Pharmacokinetic drug interactions associated with the highest risk of TdP include antifungal agents, macrolide antibiotics (except azithromycin) and drugs to treat human immunodeficiency virus interacting with amiodarone, disopyramide, dofetilide or pimozide. Other important pharmacokinetic interactions include antidepressants (bupropion, duloxetine, fluoxetine, paroxetine) interacting with flecainide, quinidine or thioridazine. Pharmacists play an important role in minimizing the risk of drug-induced QTc interval prolongation and TdP through knowledge of drugs that are associated with a known or possible risk of TdP, individualized assessment of risk of drug-induced QTc interval prolongation, awareness of drug interactions most likely to result in TdP and attention to dose reduction of renally eliminated QTc interval-prolonging drugs in patients with kidney disease. Treatment of hemodynamically stable TdP consists of discontinuation of the offending drug(s), correction of electrolyte abnormalities and administration of intravenous magnesium sulfate 1 to 2 g.

Drug safety of macrolide and quinolone antibiotics in a tertiary care hospital: administration of interacting co-medication and QT prolongation.

Some macrolide and quinolone antibiotics (MQABs) are associated with QT prolongation and life-threatening torsade de pointes (TdP) arrhythmia. MQAB may also inhibit cytochrome P450 isoenzymes and thereby cause pharmacokinetic drug interactions (DDIs). There is limited data on the frequency and management of such risks in clinical practice. We aimed to quantify co-administration of MQAB with interacting drugs and associated adverse drug reactions. We conducted an observational study within our pharmacoepidemiological database derived from electronic medical records of a tertiary care hospital. Among all users of MQAB associated with TdP, we determined the prevalence of additional QT-prolonging drugs and risk factors and identified contraindicated co-administrations of simvastatin, atorvastatin, or tizanidine. Electrocardiographic (ECG) monitoring and associated adverse events were validated in medical records. Among 3444 administered courses of clarithromycin, erythromycin, azithromycin, ciprofloxacin, levofloxacin, or moxifloxacin, there were 1332 (38.7%) with concomitant use of additional QT-prolonging drugs. Among those, we identified seven cases of drug-related QT prolongation, but 49.1% had no ECG monitoring. Of all MQAB users, 547 (15.9%) had hypokalemia. Forty-four MQAB users had contraindicated co-administrations of simvastatin, atorvastatin, or tizanidine and three of those related adverse drug reactions. In the studied real-life setting, we found a considerable number of MQAB users with additional risk factors for TdP but no ECG monitoring. However, adverse drug reactions were rarely found, and costs vs. benefits of ECG monitoring have to be weighted. In contrast, avoidable risk factors and selected contraindicated pharmacokinetic interactions are clear targets for implementation as automated alerts in electronic prescribing systems.

Current use of domperidone and co-prescribing of medications that increase its arrhythmogenic potential among older adults: a population-based cohort study in Ontario, Canada.

Domperidone is commonly used to treat nausea and gastrointestinal disorders. Recent data suggests that it may increase the risk of sudden cardiac death, particularly in older people. Little is known about how it is used in contemporary practice. This study sought to characterize the population of older adults newly dispensed domperidone, describe dosages of domperidone used, and determine the frequency of co-prescribing domperidone with medications that may increase the arrhythmogenic potential of domperidone. This is a retrospective cohort study using administrative health database information from Ontario, Canada. Prescription medication records were obtained from the Ontario Drug Benefit Claims Database. Diagnostic codes were obtained from the Ontario Health Insurance Plan Database, the Canadian Institute for Health Information Discharge Abstract Database, and the same-day surgery database. Patients who received a new prescription for domperidone between April 1, 2003 and March 31, 2010 were included. A total of 122,233 patients met inclusion criteria; 85 % were between 66 and 84 years old and 63 % were female. The mean estimated daily domperidone dose was 35 mg, and the estimated daily dose was <40 mg for 62 % of users. Strong or moderately strong cytochrome P-450 (CYP) 3A4 inhibitors were co-prescribed for 4.3 and 10.7 % of users, while medications with a known risk or possible risk for torsades de pointes (TdP) were co-prescribed to 18.3 and 18.8 % of users. Older domperidone users were commonly co-prescribed drugs with the potential to increase the risk for TdP. These combinations should be avoided, as iatrogenic QT prolongation is a modifiable risk factor for TdP.

Assessment of Drug-Induced Torsade de Pointes Risk for Hospitalized High-Risk Patients Receiving QT-Prolonging Agents

Although risk factors for torsade de pointes (TdP) are known, identifying hospitalized patients at greatest risk for QTcP who should receive cardiac monitoring is poorly defined. Describe the prevalence of risk for TdP in patients and associations between risk factors and QTc prolongation (QTcP) at a tertiary teaching hospital. This retrospective analysis assessed physiological and pharmacological risk factors for TdP of adult patients receiving ≥1 QTc-prolonging medications (QTcMed) during hospitalization. The QTcMeds were stratified by risk for causing TdP (probable, possible, and conditional). Baseline electrocardiograms (ECGs) were assessed for QTcP associated with risk for TdP. During a 6-month period, 12,401 (51%) hospitalizations received ≥1 QTcMed. A baseline ECG was obtained for 2381 (19%) patients. A total of 386 (16%) patients with a baseline ECG were found to have QTcP. Significant associations for QTcP were found with the following physiological risk factors: female (P = .021), left-ventricular ejection fraction <40% (P < .0001), cardiac arrest (P < .0001), and cardioversion (P = .007). Significantly more patients with QTcP (n = 209, 54%) received probable-risk QTcMeds than those without QTcP (n = 542, 27%; P < .0001). Probable-risk QTcMeds administered alone or concomitantly with other QTcMeds were more frequently associated with QTcP. No documented cases of TdP were identified. Of the population receiving QTcMeds, only a small portion had a baseline ECG, identifying a large population at risk of QTcP without appropriate monitoring. Patients with cardiac disease receiving probable-risk QTcMeds were associated with the highest risk of QTcP and should be monitored closely.

Drug-induced QT interval prolongation: mechanisms and clinical management.

The prolonged QT interval is both widely seen and associated with the potentially deadly rhythm, Torsades de Pointes (TdP). While it can occur spontaneously in the congenital form, there is a wide array of drugs that have been implicated in the prolongation of the QT interval. Some of these drugs have either been restricted or withdrawn from the market due to the increased incidence of fatal polymorphic ventricular tachycardia. The list of drugs that cause QT prolongation continues to grow, and an updated list of specific drugs that prolong the QT interval can be found at www.qtdrugs.org. This review focuses on the mechanism of drug-induced QT prolongation, risk factors for TdP, culprit drugs, prevention and monitoring of prolonged drug-induced QT prolongation and treatment strategies.

Risk Management of QT-prolonging Drugs by Community Pharmacists by Using a Mobile Electrocardiograph

Prolongation of the QT interval is associated with a high risk of serious arrhythmia, i.e., torsades de pointes (TdP). However, in many cases, the QT-prolonging drug(s) is prescribed without performing a thorough check-up of the patient's condition, especially an electrocardiogram. In addition to patient interview, we used an electrocardiogram obtained with a mobile electrocardiograph (RMH-ECG) in a community pharmacy in order to improve the risk management for QT-prolonging drugs. A comparison of the results obtained using RMH-ECG (modified I) and 12-lead ECG (I) revealed that both corrected QT (QTc) values were almost identical, and the correlation coefficient was 0.96. In one month, 5 of 948 patients who visited our pharmacy and continuously took QT-prolonging drugs had additional risk factors for TdP (advanced age, female, and drug-drug interaction). We monitored the QT interval of one of these patients. She had received erythromycin for 19 months along with other drugs metabolized by a P450 (CYP3A4); benidipine and prednisolone (for over 2 years), and tacrolimus (for 13 weeks). Three RMH-ECG tests at every 2 weeks revealed that QTcs were normal (0.43-0.45 s); therefore, we dispensed drugs without any change in the prescription. Approximately 1 in 1200 individuals has a prolonged QT interval without any subjective symptoms, and the time window of drug-induced TdP is considered to be from several hours to months after taking these drugs. Therefore, we think that an ECG test should be performed in community pharmacies before dispensing QT-prolonging drugs and that the QT interval should be monitored.

Le syndrome du QT long chez les patients psychiatriques chimiorésistants : prévalence, facteurs de risque, et implications thérapeutiques

Patients with psychiatric illness have an increased cardiovascular mortality, partly due to sudden death and increased by taking certain antipsychotics and other psychotropic drugs. Poor cardiac safety of these drugs is associated with prolongation of the QT interval of the electrocardiogram (ECG), causing an arrhythmia called Torsade de Pointes (TdP). Units for Difficult Patients receive patients whose care is complicated in a usual psychiatric ward, due to agitation or violence. There are currently five of these psychiatric units in France. These units therefore welcome the chemo-resistant patients, that is to say, resistant to many neuroleptics, or associations of major psychotropic drugs. They also accommodate patients whose condition is not compatible with care in prisons. The hospitalization lasts for 10 months on average. The distinctive feature of these units is that they treat patients with reinforced human resources, psychotherapies, and above all psychotropic drugs. ObjectivesA study was conducted at the unit in Villejuif, Paris, to measure the prevalence of long QT syndrome and its risk factors in connection with drug prescription. Material and methodAn ECG and serum electrolytes were made in the same time for each patient. The data collected are: QT, heart rate, QTc by the formulas of Bazett and Fridericia, QTc given by the device. Conduction disorders were sought for exclusion. Prescriptions were analyzed, sorted by drug therapeutic class, according to the risk of QT prolongation, and dosage levels. PatientsThe analysis results of 63 patients aged 19 to 64 years. The average age is 33 years and the sex ratio is 11 women (17%) and 52 men (83%). The most frequent diagnosis was paranoid schizophrenia, representing over 50% of the patients. It is followed by specific disorders of personality. The mood disorders are less frequent. The pervasive developmental disorders are absent. Some patients also have comorbid psychiatric diagnoses. ResultsThese results show: prevalence of long QT syndrome by 40% according to the formula of Bazett (including 6 %>500ms, major risk of TdP); the preponderance of medicinal risk factor, present in all patients. Other risk factors for QT prolongation are rare (hypokalaemia and bradycardia: 1.6%, female: 17%). The risk factors for TdP are frequent (hypomagnesemia: 8%, hypocalcemia: 46%, renal dysfonction 11%), some of which can be corrected; a measurement variability of the QT interval with significant differences (p<0.001) by the operator and the method of calculation used (Bazett, Fridericia…); increase in the number and average values of long QTc with the number of drugs associated with QT lengthening; lastly, an increase of number and average values of long QTc with high doses. ConclusionsThe prevalence of long QT syndrome in our study is higher than that usually found in the literature. The associations of psychotropic drugs are many, evidence that drug resistance is present. These treatments involve many molecules presented as lengthening the QT. Patients with the longest QT, are those having most associated drugs and higher doses. However, despite the proven toxicity of these treatments, it must be remembered that the QT prolongation does not necessarily a negative risk-benefit balance. This is assessed on a case-by-case basis to determine the right practice. These results emphasize the need for increased surveillance of risk associated with long QT patients on psychotropic associations. They now have awareness of carers and the establishment of a protocol for enhanced surveillance in the service.

Proarrhythmic Risk with Antipsychotic and Antidepressant Drugs

The quinidine-like effects of some antidepressant drugs (particularly tricyclic antidepressants) and many antipsychotic drugs (particularly the phenothiazines) confound treatment of psychosis and depression in patients with major mental illness. This is especially true among elderly patients with existing risk factors for corrected QT (QTc) interval prolongation. We used PubMed, previously reported review articles and the extensive personal files of the authors to identify cases of subjects aged>or=60 years who developed QTc interval prolongation, polymorphic ventricular tachycardia (PVT)/torsade de pointes (TdP) and/or sudden cardiac death while taking antipsychotic or antidepressant drugs or a combination of these medications. We identified 37 patients who had taken, in total, 46 antipsychotic or antidepressant drugs. Our most striking finding was that almost four-fifths of our cases involved women. When the 14 critically ill subjects receiving haloperidol intravenously were excluded, 91.3% of our subjects were women. Almost three-quarters of our study subjects had cardiovascular disease. Intravenous administration of haloperidol in the critically ill and profoundly agitated elderly warrants particular comment. Of the 14 subjects in this category identified, six were men and eight were women. In 13 cases, the drug dose far exceeded the 2 mg necessary to produce an antipsychotic effect. These clinicians were using an agent to achieve sedation that usually requires very high doses in the critically ill and profoundly agitated elderly to achieve this effect. Inclusion criteria for our literature review required antipsychotic and/or antidepressant drug-induced QTc interval prolongation. Even so, our finding that 31 of our 37 subjects developed PVT is sobering. However, the reader should not conclude that drug-induced QTc interval prolongation is highly predictive of PVT or its TdP subtype. All of our study subjects had at least two risk factors for TdP, with age and sex being the most common. We included the rare case of a patient with congenital long QT syndrome who developed further lengthening of the QTc interval and TdP when prescribed an antidepressant drug well known to produce QTc interval prolongation. We conclude with recommendations for clinicians not expert in the specialty of cardiology to deal with the many questions raised in this review. Specifically, such clinicians treating elderly patients with antipsychotic and antidepressant drugs that may prolong the QTc interval should aggressively obtain a baseline ECG for elderly female patients with additional risk factors such as personal or family history of pre-syncope or syncope, electrolyte disturbances or cardiovascular disease. Elderly male patients are also subject to QTc interval prolongation when such risk factors are present. It is important that the clinicians themselves inspect ECGs. If the QT interval is more than half the RR interval, QTc interval prolongation is likely to be present. In such cases, a cardiology colleague interested in QTc interval issues and TdP should be asked to review the ECG. Finally, nothing in our recommendations replaces meticulous attention to US FDA guidelines in the package insert of each drug.

Takotsubo cardiomyopathy and QT interval prolongation: who are the patients at risk for torsades de pointes?

Objectives QT interval prolongation is prevalent among patients with Takotsubo cardiomyopathy (TC), whereas torsades de pointes (TdP) has rarely been reported in these patients. We studied all peer-reviewed reports on TC-associated QT interval prolongation and all peer-reviewed reports on TC-associated TdP to characterize the clinical circumstances leading to TdP in patients with TC. Methods The literature search yielded 14 reports on TC-associated TdP and 26 reports on TC-associated QT interval prolongation. Overall, 15 patients with TC-associated TdP and 86 patients with TC-associated QT interval prolongation were reported. We systematically reviewed each report and recorded the risk factors for TdP as well as the clinical circumstances of TC. Results The prevalence of the male sex was higher among patients with TC-associated TdP relative to patients with TC-associated QT interval prolongation (26.7% vs 5.8%; P = .01). There was a trend in the mean maximal corrected QT interval being longer among patients with TC-associated TdP relative to patients with TC-associated QT interval prolongation (679.9 ± 230.6 vs 555.9 ± 63.8 milliseconds; P = .06). There were no differences between patients with TC-associated TdP and patients with TC-associated QT interval prolongation in mean age, maximal troponin levels, and lowest ejection fraction. Overall, 12 (80.0%) patients with TC-associated TdP had risk factors for TdP other than the female sex and systolic dysfunction, including suspicion of congenital long QT syndrome, bradycardia, hypokalemia, recent conversion from atrial fibrillation to sinus rhythm, and using QT prolonging agents. Conclusions Men with TC-associated QT interval prolongation are at risk for TdP. Most patients with TC-associated TdP have risk factors for TdP other than the female sex and systolic dysfunction.

An in vitro model for assessment of drug-induced torsade de pointes arrhythmia

Torsade de pointes (TdP) is a serious side effect of many drugs. We aimed to establish an in vitro TdP model for drug testing, which includes typical risk factors, such as female gender, hypokalemia, low magnesium levels, and bradycardia. Isolated, spontaneously beating rabbit hearts (female White New Zealand rabbits) were perfused according to the Langendorff technique and submitted to conditions known as risk factors for TdP, i.e., [K(+)](e) = 2.5 mM and [Mg(++)](e) = 0.5 mM, with 10(-8) M noradrenaline and 10(-7) M carbachol. Thereafter, cumulative concentration-response curves for haloperidol (10, 100, 200, 1,000, and 2,000 nM) and dofetilide (1, 10, 20, 100, and 200 nM) were performed, while cardiac activation and repolarization was measured at 256 ventricular sites (unipolar extracellular potentials). We found in three of six hearts under haloperidol TdP arrhythmias in supratherapeutic concentrations > or =100 nM. Dofetilide also induced TdP (three of seven) in concentrations > or =20 nM. The TdP showed a complex pattern being initiated in one region by an early R-on-T ventricular extrasystole, when in the other regions high activation-recovery interval (ARI) dispersion occurred, then spreading in complex beat-to-beat changing patterns until self-termination. Dofetilide and haloperidol significantly prolonged ARI and QTc. Haloperidol significantly increased dispersion predominantly at the right wall and prolonged basic cycle length. Dofetilide also increased dispersion and slowed basic cycle length. Haloperidol (> or =100 nM) and dofetilide (> or =20 nM) can induce TdP by prolongation of ARI, slowing of heart rate, and increasing repolarization inhomogeneities. The linear combination of the independent variables QTc, BCL and dispersion could highly significantly predict TaP (adjusted R(2): 0.896, p < 0.001) The model seems suitable to identify a pharmacological risk for TdP in vitro within a limited number of animals.

Torsade de pointes induced by systemic antifungal agents: lessons from a retrospective analysis of published case reports

Torsade de pointes (TdP) is a potentially fatal arrhythmia that might be associated with systemic antifungal agent (SAFAs) administration. The objective of this study was to investigate all published reports on TdP induced by SAFAs in order to characterise this association. Each original report was analysed for the presence of risk factors for TdP: female gender, structural heart disease, electrolyte imbalance, concomitant use of a QT interval prolonging agent which SAFA inhibits its liver metabolism, liver cirrhosis, renal failure and more. Naranjo probability scale for adverse drug reactions was applied for every full report. Twenty-one reports on 28 patients were analysed. All patients survived. Most patients (25/28; 89.2%) used one or more agents that might have prolonged the QT interval and their liver metabolism might have been inhibited by SAFA. Female gender was the second most common risk factor for TdP (20/28; 71.4%). All patients, including female patients, had one or more risk factors for TdP prior to SAFA administration. According to Narajno probability scale, there was no definite association between TdP and SAFA in any report. SAFA alone might seldom trigger TdP. We wish to raise the level of awareness of risk factors for TdP prior to SAFA administration and for concomitant use of other dysrhythmogenic agents in particular.

Methadone-associated Torsades de Pointes (polymorphic ventricular tachycardia) in opioid-dependent patients

We reviewed all the publications concerning methadone-associated Torsades de Pointes (TdP) (polymorphic ventricular tachycardia) in opioid-dependent patients in order to characterize the clinical circumstances leading to this serious complication. Our literature search yielded 14 reports on 40 patients with methadone-associated TdP. We gathered and recorded the risk factors for TdP mentioned in those reports, among other clinical aspects. The most prevalent risk factors for TdP were high-dose methadone (n = 39, 97.5%) and concomitant use of agents that increase serum methadone levels or trigger TdP (n = 22, 55%). HIV infection (n = 16), hypokalaemia (n = 14), female sex (n = 13), liver cirrhosis or renal failure (n = 11) and heart disease (n = 9) were also described. All the patients had at least one and 34 (85%) had two or more risk factors for TdP during methadone treatment. We wish to raise the level of awareness of risk factors for TdP among physicians in heroin-treatment clinics who frequently prescribe methadone.

Torsade de pointes induced by psychotropic drugs and the prevalence of its risk factors

To investigate all published case reports of torsade de pointes (TdP) induced by psychotropic drugs (PDs) in order to examine the prevalence of risk factors for TdP prior to the drug initiation. We found 45 reports on 70 patients with TdP induced by PDs. Each report was analyzed for the presence of risk factors for TdP: female gender, heart disease, hypokalemia, high doses of offending agent, concomitant use of a QT interval prolonging agent, and a history of long-QT syndrome. Female gender was the most common risk factor for TdP (71.4%). The other studied risk factors were also frequently present (34.2-14.2%). Nearly all patients had at least one and 51 (73%) patients had >2 risk factors for TdP prior to PD initiation. We wish to raise the level of awareness of risk factors for TdP in the psychiatric community.

Drugs that cause Torsades de pointes and increase the risk of sudden cardiac death.

Torsades de pointes (TdP) is a potentially life-threatening arrhythmia associated with not only antiarrhythmic drugs, but noncardiac drugs of many different classes. All these drugs prolong the QT interval by their blocking of the potassium channel I(Kr), and many are metabolized by the cytochrome P450 isoenzyme CYP3A4. Polypharmacy with other drugs utilizing the same enzyme, or inhibiting CYP3A4, can lead to TdP. A consistent finding of all the QT-prolonging drugs is predominance of TdP in women. Other risk factors for QT prolongation and TdP include hypokalemia, congestive heart failure, and structural heart disease. Knowledge of potential drug interactions and other risk factors for TdP can help in reducing the number of adverse events associated with the use of QT-prolonging drugs.