The potential for QT prolongation and proarrhythmia by non-antiarrhythmic drugs: clinical and regulatory implications. Report on a Policy Conference of the European Society of Cardiology

Abstract

The scientific and clinical basis of drug-induced QT prolongation and proarrhythmia was summarized by formal presentations. The speakers were chosen for their particular competence in the relevant field. Furthermore, selected topics were discussed in detail in separate workshops. This document represents the executive summary of the Conference. It is based on written reports composed by the speakers and the chairs of the workshops. Before preparation of the final version of the document, a draft was circulated to all participants of the Conference for suggestions and comments. The opinions expressed in this document are those of the participants and do not necessarily reflect the official position of their organisations or agencies. The meeting was made possible by unrestricted educational grants to the Committee for Scientific and Clinical Initiatives of the ESC from several companies listed in the Appendix. The problemQT interval prolongation, and possibly increased QT dispersion, are risk factors in a number of cardiovascular as well as non-cardiovascular diseases. A variety of drugs prolong the QT interval, although the major examples are the so-called class III antiarrhythmics. These drugs generally exert their therapeutic effect by affecting potassium ion channels, thereby reducing outward, repolarizing current, and prolonging action potential duration and the QT interval. Many of these drugs have been developed for conversion of atrial fibrillation and/or maintenance of sinus rhythm in patients with recurrent atrial fibrillation. Such patients are at low risk of potentially fatal arrhythmias, at least in the absence of antiarrhythmic drug therapy.However, antiarrhythmic drugs which prolong cardiac repolarization are not harmless, as they may induce

QT PRODACT: In Vivo QT Assay in the Conscious Dog for Assessing the Potential for QT Interval Prolongation by Human Pharmaceuticals

“…A variety of drugs can prolong the QT interval of the electrocardiogram (ECG) and lead to torsade de pointes (TdP), a polymorphic ventricular tachycardia that can progress to ventricular fibrillation and sudden death (1). Therefore, much emphasis has been placed on the assessment of the potential risk for QT interval prolongation caused by pharmaceuticals both in clinical and non-clinical tests.…”

Analysis of West Virginia medicaid claims data for the prevalence of medical conditions and use of drugs likely to cause QT prolongation in patients with schizophrenia

“…4,32,33 The QT-prolongation potential of each drug was based on either US Food and Drug Administration-approved drug labeling or case reports of QT prolongation/torsades de pointes. These drugs were identified in the prescription claims data using their specific NDC codes.…”

“…Of the atypical antipsychotics, quetiapine, risperidone, and ziprasidone have been shown to cause QT prolongation. [3][4][5] This issue of antipsychotic-induced arrhythmia has assumed paramount importance, especially in light of a high incidence of cardiovascular mortality and morbidity in patients with schizophrenia, with 1 study 6 estimating the incidence to be nearly 1.5-fold higher in these patients compared with controls. An important reason for this elevated cardiac risk may be frequent overdose of medications and high prevalence of comorbid substance abuse disorder, with studies 3,7 estimating nearly 50% of schizophrenic patients to be experiencing comorbid substance abuse disorders.…”

Sensitivity of T-wave morphology and the QT interval to small drug-induced electrocardiographic changes

“…Most drugs that cause disturbed repolarization and arrhythmias inhibit the I Kr current and have a QT prolonging effect [3]. As a consequence, the electrocardiographic QT interval is presently used as the golden standard by which cardiac safety is assessed in "Thorough QT Studies".…”