Drug-induced proarrhythmic effects: assessment of changes in QT interval.

Abstract

During the past decade interest in the potential for drugs to have proarrhythmic effects has increased substantially. The evidence which has lead to this comes from a number of sources. For example, in a study that identified over 24 000 medicolegal postmortems between 1985 and 1988 in Finland, 49 cases were detected in patients receiving psychotropic drugs, in whom the cause of death could not be determined. Analysis of drug treatment in these subjects revealed that a substantially greater proportion had been receiving the drug thioridazine than could be accounted for by consumption of this drug in the general population [1]. While this evidence does not establish causality of a proarrhythmic effect of thioridazine, it identified the need for investigation of such an effect. In a further study based on a database of over 33 000 ECGs recorded between 1975 and 1983, 183 recordings with QTc prolongation based on an arbitrary threshold of 470 ms were identified. These were compared with 187 recordings from matched subjects in which QTc values were normal. Comparison of diagnoses and drug treatment revealed hypertension to be significantly more common in those with QTc prolongation [2]. This is consistent with the QT prolongation reported in left ventricular hypertrophy [3]. In addition the drug sotalol (known to prolong action potential duration) was used more frequently in patients with QT prolongation. Mortality rates were significantly higher in patients with QT prolongation, although, this could not be explained by the increased use sotalol or other drugs. These data suggest that QT prolongation is a risk marker for increased cardiac mortality due to the prevalence of coexisting disease, although they do not define a precise risk threshold for QTc intervals. Interest in drug effects on the QT interval was further increased following reports that terfenadine, a widely used histamine 1 receptor antagonist may cause Torsade de Pointes and QT prolongation [4]. In addition interaction studies showed that the use of terfenadine with drugs known to inhibit hepatic cytochrome P 450 caused accumulation of terfenadine and greater QT prolongation [5]. The relationship between proarrhythmic effects and QT prolongation is complicated since other drugs that prolong the QT interval show no evidence of proarrhythmic activity and may in fact possess potent antiarrhythmic properties. Thus amiodarone causes significant prolongation of QT and QTc intervals and is perhaps the most effective antiarrhythmic agent available [6, 7]. There is a need for greater clarity of the electrophysiological basis for proarrhythmic drug action and more detailed studies of the cardiac effects of new therapeutic substances are required.