Clinical trial design to evaluate the effects of drugs on cardiac repolarization: current state of the art.
Prolongation of the QT interval associated with the potentially fatal arrhythmia known as torsades de pointes has been a common cause of the withdrawal of several promising drugs from the market. Many antihistamines, antibiotics, antimalarials, antidepressants, neuroleptics, antipsychotics, and imidazole antifungal agents have been shown to produce torsades, and all by the same mechanism. Advances in basic science and preclinical testing have begun to provide a scientific basis for distinguishing arrhythmogenicity from drug-induced QT effects. Many new techniques have been developed, and many others currently are being developed to facilitate the design of clinical trials to evaluate the effects of drugs on cardiac repolarization. The improvements in clinical trial design may help identify drugs that could induce torsades, halting futile research, potentially saving lives, and saving hundreds of millions of dollars in drug development. In the absence of any completely reliable surrogate measure for the arrhythmogenic potential of a drug, regulators have determined that QT interval prolongation should be intensively investigated in every drug that is developed. This article presents the basic mechanics of QT interval assessment and describes new developments that may make this measure a more accurate predictor of the effects of drugs on cardiac repolarization. It is absolutely essential that trial designs incorporate many ECG recordings, consistent QT interval measurement, and appropriate control or correction of the QT interval for heart rate in order to provide reproducible, scientifically meaningful results.
Camm
A John
AJ
St. George's Hospital Medical School, University of London, Cranmer Terrace, London SW17 0RE, UK. jcamm@sghms.ac.uk
D014150:Antipsychotic Agents / Q000009:adverse effects; D002986:Clinical Trials as Topic; D024841:Fluoroquinolones / Q000009:adverse effects; D006329:Heart Conduction System / Q000187:drug effects* / Q000503:physiopathology*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced; D012107:Research Design; D016171:Torsades de Pointes / Q000139:chemically induced
D014150:Antipsychotic Agents; D024841:Fluoroquinolones