Drug-Induced QT/QTc Interval Shortening: Lessons from Drug-Induced QT/QTc Prolongation

The review discusses safety implications of drugs found to shorten the QT/QTc interval. It uses parallels with drug-induced QT/QTc prolongation. It summarizes the evidence that increases in repolarization heterogeneity are likely more important for arrhythmia induction and maintenance than the absolute changes in the QT/QTc duration. The review further compares the direct evidence of proarrhythmia caused by QT-prolonging and -shortening drugs. At present, there is little proof of QT-shortening drugs causing ventricular fibrillation in more than rare isolated instances. Comparisons of the incidence of the congenital syndromes show that short QT syndrome is much rarer than long QT syndrome, similar to the findings of short QT intervals compared with long QT intervals in the general population. Nevertheless, potential concerns come from experimental drugs developed to increase the current of potassium-rectifying channels. Some of these drugs were found to cause ventricular fibrillation in isolated hearts. Still, population exposure to drug-induced QT shortening is likely substantially lower compared with QT prolongation, especially if considering that most of the processes that decrease the so-called repolarization reserve are associated with QT prolongation. Finally, the review lists reasons why purely theoretical concepts of pharmaceutical risk cannot be used to develop regulatory guidance and concludes that at present, no additional tests and/or general acceptance restrictions are needed for the approval of QT-shortening drugs.