Abstract
Anti-arrhythmic drugs are a mainstay in the management of symptoms related to arrhythmias, and are adjuncts in prevention and treatment of life-threatening ventricular arrhythmias. However, they also have the potential for pro-arrhythmia and thus the prediction of arrhythmia predisposition and drug response are critical issues. Clinical trials are the latter stages in the safety testing and efficacy process prior to market release, and as such serve as a critical safeguard. In this review, we look at some of the lessons to be learned from approaches to arrhythmia prediction in patients, clinical trials of drugs used in the treatment of arrhythmias, and the implications for the design of pre-clinical safety pharmacology testing.
Highlights
Cardiac arrhythmias range from the benign to the life-threatening. The former typically arise in patients with structurally and functionally normal hearts, while the latter more commonly arise in those with acquired or genetically-determined abnormalities in cardiac structure or cellular electrophysiology
Even more problematic is that non-cardiac drugs sometimes developed for relatively benign conditions can lead to malignant ventricular arrhythmias (Bednar et al, 2002)
We focus on anti-arrhythmic drugs, and the role of clinical data in informing our approaches to assessment of their risks of pro-arrhythmia
Summary
Cardiac arrhythmias range from the benign to the life-threatening. The former typically arise in patients with structurally and functionally normal hearts, while the latter more commonly arise in those with acquired or genetically-determined abnormalities in cardiac structure or cellular electrophysiology. TdP is characteristic of non-cardiac drug-induced long QT in patients with normal hearts With these considerations in mind, estimates have been made (Sarganas et al, 2014). The challenge is to set the threshold at the correct level, so as to allow safe drugs to continue through development and on to the market, and this is dependent on the methods employed in risk assessment. These methods are in the process of being modified, in light of advances in our understanding of cellular electrophysiology, and the models available. We adhere to the Vaughan-Williams classification system in referring to drugs by class, acknowledging its limitations
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