The search for novel antiarrhythmic strategies. Sicilian Gambit.

The past fifty years of antiarrhythmic drug development have seen limited success in prolonging life and reducing morbidity. It is likely that arrhythmias are in most instances final common pathways through which changes in the cardiac substrate and in trigger mechanisms are expressed. We propose that the development and administration of therapies for the arrhythmias themselves, while offering a panacea for a disease entity that has evolved and is being overtly manifested, is also an admission of failure to identify and prevent evolution of the substrate and triggers such that arrhythmias can occur. We suggest that while strategies for treatment and prevention of recurrence of arrhythmias still warrant exploration, greater hope for the future lies in identifying means for earlier diagnosis of the arrhythmogenic substrate and triggers, and in developing therapies that are "upstream" to the arrhythmia and prevent their initial expression. Means to achieve this end are suggested, using specific arrhythmias as examples. Similarly, to increase the likelihood that clinical studies of new therapies can be successfully concluded and interpreted, we suggest new approaches to patient selection, risk stratification, trial endpoints, outcome events and trial methodologies.