scholarly journals QT Interval Prolongation as a Biomarker for Torsades de Pointes and Sudden Death in Drug Development

2002 ◽  
Vol 18 (2) ◽  
pp. 57-62 ◽  
Author(s):  
Gregory D. Sides
Keyword(s):  
Sudden Death ◽  
Qt Interval ◽  
Drug Effect ◽  
Torsades De Pointes ◽  
Interval Prolongation ◽  
Drug Induced ◽  
Apparent Increase ◽  
Intrinsic Factors ◽  
Qt Interval Prolongation ◽  
Extrinsic And Intrinsic Factors

Prolongation of the QT interval on the surface 12-lead electrocardiogram is widely accepted as a biomarker for the potential of a drug to produce torsades de pointes and/or sudden death. Detection of drug-induced prolongation of the QT interval in animals and man is frequently confounded by extrinsic and intrinsic factors that limit the ability to detect a true drug effect. In particular drugs that increase heart rate show an apparent increase in QT interval that confounds assessment of a true drug effect on cardiac ventricular repolarization. The basis for the use of the QT interval as a biomarker will be examined.

scholarly journals Safety and effectiveness of drug therapy for the acutely agitated patient (Part I)

2013 ◽  
pp. 127-136
Author(s):  
Gianluca Airoldi
Keyword(s):  
Heart Rate ◽  
Qt Interval ◽  
Physical Restraint ◽  
Safety Data ◽  
Surrogate Marker ◽  
Diagnostic Procedures ◽  
Torsades De Pointes ◽  
Long Qt ◽  
Drug Induced ◽  
Qt Interval Prolongation

Acute agitation occurs in a variety of medical and psychiatric conditions, and the management of agitated, abusive, or violent patients is a common problem in the emergency department. Rapid control of potentially dangerous behaviors by physical restraint and pharmacologic tranquillization is crucial to ensure the safety of the patient and health-care personnel and to allow diagnostic procedures and treatment of the underlying condition. The purpose of this article (the first in a 2-part series) is to review the extensive safety data published on the antipsychotic medications currently available for managing situations of this type, including older neuroleptics like haloperidol, chlorpromazine, and pimozide as well as a number of the newer atypical antipsychotics (olanzapine, risperidone, ziprasidone). Particular attention is focused on the ability of these drugs to lengthen the QT interval in surface electrocardiograms. This adverse effect is of major concern, especially in light of the reported relation between QT interval and the risk of sudden death. In patients with the congenital long-QT syndrome, a long QT interval is associated with a fatal paroxysmal ventricular arrhythmia knownas torsades de pointes. Therefore, careful evaluation of the QT-prolonging properties and arrhythmogenic potential of antipsychotic drugs is urgently needed. Clinical assessment of drug-induced QT-interval prolongation is strictly dependent on the quality of electrocardiographic data and the appropriateness of electrocardiographic analyses. Unfortunately, measurement imprecision and natural variability preclude a simple use of the actually measured QT interval as a surrogate marker of drug-induced proarrhythmia. Because the QT interval changes with heart rate, a rate-corrected QT interval (QTc) is commonly used when evaluating a drug’s effect. In clinical settings, themost widely used formulas for rate-correction are those of Bazett (QTc=QT/RR^0.5) and Fridericia (QTc=QT/RR^0.33), both of which standardize themeasuredQTinterval to an RRinterval of 1 s (heart rate of 60 bpm).However, QT variability can also be influenced by other factors that are more difficult to measure, including body fat, meals, psycho-physical distress, and circadian and seasonal fluctuations.

scholarly journals Drug-induced QT interval prolongation in cancer patients

2011 ◽  
Vol 4 (4) ◽  
pp. 223
Author(s):  
Torben K. Becker ◽  
Sai-Ching J. Yeung
Keyword(s):  
Cancer Patients ◽  
Qt Interval ◽  
Alkylating Agents ◽  
Torsade De Pointes ◽  
Interval Prolongation ◽  
Drug Induced ◽  
Vascular Disruption ◽  
Qt Interval Prolongation ◽  
Increased Risk ◽  
Multiple Drugs

Cancer patients are at an increased risk for QT interval prolongation and subsequent potentially fatal Torsade de pointes tachycardia due to the multiple drugs used for treatment of malignancies and the associated symptoms and complications. Based on a systematic review of the literature, this article analyzes the risk for prolongation of the QT interval with antineoplastic agents and commonly used concomitant drugs. This includes anthracyclines, fluorouracil, alkylating agents, and new molecularly targeted therapeutics, such as vascular disruption agents. Medications used in the supportive care can also prolong QT intervals, such as methadone, 5-HT3-antagonists and antihistamines, some antibiotics, antifungals, and antivirals. We describe the presumed mechanism of QT interval prolongation, drug-specific considerations, as well as important clinical interactions. Multiple risk factors and drug–drug interactions increase this risk for dangerous arrhythmias. We propose a systematic approach to evaluate cancer patients for the risk of QT interval prolongation and how to prevent adverse effects.

Modelling of drug-induced QT-interval prolongation: estimation approaches and translational opportunities

2015 ◽  
Vol 42 (6) ◽  
pp. 659-679 ◽  
Author(s):  
Eleonora Marostica ◽  
Karel Van Ammel ◽  
Ard Teisman ◽  
Koen Boussery ◽  
Jan Van Bocxlaer ◽  
...  
Keyword(s):  
Qt Interval ◽  
Interval Prolongation ◽  
Drug Induced ◽  
Qt Interval Prolongation

Torsades de pointes complicating complete heart block with QT interval prolongation

2016 ◽  
Vol 71 (5) ◽  
pp. 627-627
Author(s):  
Ivan Stankovic ◽  
Biljana Putnikovic ◽  
Aleksandar N. Neskovic
Keyword(s):  
Qt Interval ◽  
Heart Block ◽  
Complete Heart Block ◽  
Torsades De Pointes ◽  
Interval Prolongation ◽  
Qt Interval Prolongation

scholarly journals Domperidone-Associated QT Interval Prolongation in Non-oncologic Pediatric Patients: A Review of the Literature

2016 ◽  
Vol 69 (3) ◽  
Author(s):  
Amy D Morris ◽  
Jennifer Chen ◽  
Elaine Lau ◽  
Jennifer Poh
Keyword(s):  
Qt Interval ◽  
Cardiac Death ◽  
Pediatric Patients ◽  
Heart Diseases ◽  
Torsades De Pointes ◽  
Qtc Interval ◽  
Interval Prolongation ◽  
Medical Subject Headings ◽  
Qt Interval Prolongation ◽  
Mort Subite

<p><strong>ABSTRACT</strong></p><p><strong>Background: </strong>Domperidone is a prokinetic agent used to treat pediatric gastroesophageal reflux disease. Health Canada has issued warnings about an increased risk of domperidone-associated ventricular arrhythmias and sudden cardiac death. However, the supporting data referred only to adult patients; therefore, extrapolating the safety risks to pediatric patients is difficult.</p><p><strong>Objective: </strong>To summarize and evaluate the evidence for domperidone associated QT interval prolongation, ventricular arrhythmias, and sudden cardiac death to determine the safety of this drug for pediatric patients.</p><p><strong>Data Sources: </strong>Two databases (MEDLINE [1946 to August 2015] and Embase [1980 to August 2015]) were searched with the following Medical Subject Headings and keywords: “domperidone”, “arrhythmias, cardiac”, “death, sudden, cardiac”, “electrocardiography”, “heart diseases”, “long QT syndrome”, “tachycardia, ventricular”, “torsades de pointes”, and “ventricular fibrillation”. The search was limited to studies conducted in humans under 18 years of age and published in English.</p><p><strong>Study Selection and Data Extraction:</strong> Original research included in this review reported on the cardiac-related safety of domperidone in nononcologic patients under 18 years of age.</p><p><strong>Data Synthesis: </strong>Of the 5 studies meeting the inclusion criteria (<em>n </em>= 137 patients), one reported a statistically significant change in the corrected QT (QTc) interval, but the clinical significance was unclear. Most of the studies reported rare occurrences of pathological QTc intervals in a limited number of patients. However, confounding factors (e.g., abnormal electrolyte level or concurrent medications) were not consistently considered. Potential bias might have been alleviated by blinding of electrocardiogram (ECG) assessors; however, this was not consistently implemented. The designs of the included studies did not allow assessment of causality. The results should be interpreted with caution.</p><p><strong>Conclusions: </strong>Although the available evidence is limited, pathological QTc intervals were noted among a small number of infants, which supports the possibility of domperidone-associated risk of prolonged QTc interval. Because of the potential severity of QT interval prolongation, individual assessment and routine ECG monitoring should be implemented for patients receiving domperidone.</p><p><strong>RÉSUMÉ</strong></p><p><strong>Contexte : </strong>La dompéridone est un agent gastroprocinétique utilisé pour traiter le reflux gastro-oesophagien chez l’enfant. Santé Canada a publié des mises en garde à propos d’un risque accru d’arythmies ventriculaires et de mort subite cardiaque associées à la dompéridone. Or, comme les données probantes ne concernent que l’adulte, il est difficile de généraliser les risques pour la santé à l’enfant.</p><p><strong>Objectif : </strong>Résumer et analyser les données probantes portant sur l’allongement de l’intervalle QT, les arythmies ventriculaires et la mort subite cardiaque associés à la dompéridone afin de déterminer le degré d’innocuité du médicament chez l’enfant.</p><p><strong>Sources des données : </strong>Deux bases de données (MEDLINE [1946 à août 2015] et EMBASE [1980 à août 2015]) ont été interrogées en utilisant les mots clés et les Medical Subject Headings (MeSH) suivants : « domperidone »  dompéridone), « arrhythmias, cardiac » (arythmies cardiaques), « death, sudden, cardiac » (mort, subite, cardiaque),« electrocardiography » (électrocardiographie), « heart diseases » (cardiopathies), « long QT syndrome » (syndrome du QT long), « tachycardia, ventricular » (tachycardie, ventriculaire), « torsades de pointes » (torsades de pointes) et « ventricular fibrillation » (fibrillation ventriculaire). La recherche se limitait aux études publiées en anglais et effectuées chez l’humain de moins de 18 ans.</p><p><strong>Sélection des études et extraction des données : </strong>Les études retenues dans la présente revue abordaient l’innocuité cardiaque de la dompéridone chez les patients de moins de 18 ans qui ne sont pas atteints d’un cancer.</p><p><strong>Synthèse des données : </strong>Parmi les cinq études qui répondaient aux critères d’inclusion (<em>n </em>= 137 patients), une indiquait un changement statistiquement significatif dans l’intervalle QT corrigé (QTc), mais la signification clinique demeurait floue. La plupart des études signalaient de rares cas d’intervalles QTc pathologiques chez un nombre limité de patients. Cependant, des facteurs de confusion (déséquilibre électrolytique ou emploi concomitant de médicaments, par exemple) n’étaient pas systématiquement pris en compte. Il aurait été possible d’éviter de potentiels biais en tenant les lecteurs d’électrocardiogramme (ECG) dans l’ignorance du traitement, mais cette mesure n’était pas toujours mise en oeuvre. Les plans des études retenues ne permettaient pas d’évaluer la causalité. Il faut donc interpréter les résultats avec prudence.</p><p><strong>Conclusions : </strong>Bien qu’il n’y ait que peu de données probantes, des cas d’intervalles QTc pathologiques ont été relevés chez un petit nombre de nourrissons, ce qui vient appuyer le risque possible d’allongement de l’intervalle QTc associé à la dompéridone. À cause de la potentielle gravité de l’allongement de l’intervalle QT, une évaluation individuelle et une surveillance ECG systématique doit être mise en place pour les patients qui reçoivent de la dompéridone.</p>

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