Drug-induced QT interval prolongation: An important evaluation for drug approval

Torsade de pointes, a potentially fatal arrhythmia, may be induced by prolongation of the QT interval and may be triggered by cardiac or noncardiac drugs. Guidelines do not currently exist to assess the cardiac proarrhythmic potential of a new drug, the degree of risk or the implications for drug labeling; however, these are of importance to both drug developers and regulatory agencies. Suggestions for clinical trial assessment may be made from present experience. The clinical proarrhythmic properties of a drug may be correctly predicted by in vitro and in vivo preclinical models of cardiac toxicity, but shortcomings have been demonstrated with all available models. In general, cardiac toxicity in humans is less likely to be caused by compounds that do not generate any adverse preclinical signal. Nevertheless, both false positive and false negative conclusions may result. Phase I and II studies need to consider the cardiac proarrhythmic safety of every investigational drug. The quality of electrocardiographic data and the appropriateness of electrocardiographic analyses are crucial to assess drug-induced QT interval prolongation. Large numbers of electrocardiograms are required to correct the QT interval by heart rate in each study participant. Less strict monitoring can be used in phase III studies and post-marketing surveillance once proarrhythmic safety has been established. Assessment of QT interval prolongation, an indirect indicator of predisposition for torsade de pointe inductions, is relied on in clinical premarketing evaluation. Nevertheless, no guarantee is offered by the absence of torsade de pointes tachycardia during large phase III studies and no conclusions of a drug's proarrhythmic toxicity should be made until postmarketing surveillance data have been reviewed.