Spectrum of drugs prolonging QT interval and the incidence of torsades de pointes

The incidence of drug-induced proarrhythmias in the general population is largely unknown. Knowledge regard-ing incidence and risk factors is mainly derived from studies during clinical development of drugs and is therefore limited to antiarrhythmic compounds with a relatively high incidence. For non-cardiovascular drugs, proarrhythmias are rarely seen during clinical development but usually appear later, several years after registration. Both spontaneous adverse reaction reports and epidemiological studies have severe limitations when used to estimate the incidence of proarrhythmias with non-cardiovascular compounds. QT prolongation and torsades de pointes have been associated with non-sedating antihistamines, antibiotics, antipsychotics, antidepressants and a gastro-intestinal prokinetic agent; drugs within these classes constitute the vast majority of non-cardiovascular compounds associated with this potentially serious side-effect. Epidemiological studies on non-sedating anti-histamines and on cisapride have largely failed to demonstrate an increased risk for sudden death or ventricu-lar arrhythmias, which is most likely due to the low specificity of the end-points studied. A careful case ascertainment, which requires access to electrocardiograms and clinical records, and prospectively defined, strict definitions for the classification of proarrhythmias, is of great importance in these studies.