Acquired (Drug-Induced) Long and Short QT Syndromes

Abstract

This chapter is presented in two parts – QT interval prolongation and QT interval shortening. Part 1 begins with a historical perspective on the consequences of drug-induced QT prolongation and its frequency in patient population at large. There is in depth discussion of various molecular and electrophysiological mechanisms that underpin induction of torsade de pointes, the relationship between QT interval and the proarrhythmic risk it poses and how this relationship is modulated by a number of ancillary properties of a drug. The authors also summarize some of the novel markers of clinical risk in a setting of QT interval prolongation. Regulatory initiatives, including the studies required and their interpretation with regard to clinical risk, are covered in great detail with reference to the two guidelines (ICHS7B and ICH E14) from International Conference on Harmonization. Risk factors for drug-induced QT prolongation and torsade de pointes and the potential mechanisms underpinning each risk factor are discussed in detail, together with a balanced discussion of evidence on why females are at a greater risk. Pharmacogenetic factors and the available evidence concerning potential inter-ethnic differences in drug-related QT response are discussed at length. The authors highlight how drug-induced prolongation of QT interval fits into overall risk/benefit assessment of a drug and its labeling implications. Part 2 is comparatively shorter and begins with the rationale for drugs as a cause of QT shortening and discusses the diagnostic dilemmas and defining normal lower values of QTc interval and the threshold value for diagnosing short QT interval. It then summarizes the epidemiological evidence linking short QT interval with potentially fatal ventricular arrhythmias. Nonclinical data on drugs implicated in QT shortening are reviewed followed by clinical evidence and industry experience, especially taking account of drugs such as the anticonvulsants lamotrigine, rufinamide and BAY-79, a highly selective tyrosine kinase inhibitor. This is followed by a summary of regulatory perspectives in the context of ICH E14 and risk/benefit of drugs that may be found to shorten QT interval