Magnitude of QT prolongation associated with a higher risk of Torsades de Pointes

Drug induced Torsades de Pointes (TdP) is a major concern for new drugs seeking regulatory approval. Prolongation of QT intervals greater than 60 millisecond or to longer than 500 millisecond in an individual patient has been considered to be associated with a higher risk. The purpose of this study is to identify values inferred from a population that predict a stronger potential for TdP.

Prolongation data of 30 non-antiarrhythmic QT prolonging drugs were analysed. Depending on how strong the drugs were associated with TdP, they were categorized as strong or borderline torsadogens. The differences in mean QTc increases between the two groups were compared and cut-off values that distinguished strong from borderline drugs were searched for.

The average QTc increase of 19.3 millisecond of strong torsadogens was significantly greater than the 8.0 millisecond of borderline torsadogens. Prolongation greater than 12 millisecond in the context of monotherapy or 25 millisecond in the presence of metabolic inhibition and an upper bound of 95% confidence interval (CI) for the mean QTc increase greater than 14 millisecond in monotherapy or 30.1 millisecond in combination therapy with metabolic inhibitors favoured a stronger association with TdP.

Drugs strongly associated with TdP have greater QTc increases than those with less concern. Several cut-off values have been noted to distinguish between them. These values may be helpful for evaluation of TdP risk for future QT prolonging drugs.