Thorough QT/QTc not so thorough: removes torsadogenic predictors from the T-wave, incriminates safe drugs, and misses profibrillatory drugs.
Drug-induced QT prolongation has such a strong correlation with torsade de pointes (TdP) that it comes to serve as a surrogate for TdP. As a result, drugs that prolong QT by as little as a few ms, even without any evidence of TdP, may get dropped from development or blocked from approval. However, measurement of QT with ms accuracy may be impossible to achieve. Worse, some drugs that lengthen the QT interval are not only not proarrhythmic, they may even be antiarrhythmic; while some that shorten the QT can be strongly proarrhythmic. Indeed, proarrhythmia related to repolarization disturbances is caused by triangulation, reverse use dependence, instability, and dispersion (TRIaD). When TRIaD is present with QT prolongation it commonly yields TdP, but when TRIaD is combined with QT shortening it preferentially leads to VF instead. While TdP is lethal in less than 20% of instances, VF is much more morbid. Worse, available evidence suggests that there is more death from drug-induced fibrillation than TdP. Thus, QT prolongation alone is not very useful. Instead, the T-wave should be used in alternate ways: extraction of TRIaD.
Hondeghem
Luc M
LM
Catholic University, Leuven, Belgium. Luc.Hondeghem@ScreenQT.com
D000200:Action Potentials / Q000187:drug effects; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology; D022062:Electrophysiologic Techniques, Cardiac; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000503:physiopathology*; D016171:Torsades de Pointes / Q000139:chemically induced* / Q000503:physiopathology
D000889:Anti-Arrhythmia Agents