The present and future of antiarrhythmic drugs

The saga of antiarrhythmic drug (AAD) therapy reflects a field shaped by empiricism and burdened by challenges related to safety. The Singh-Vaughan-Williams classification was a timely necessity that eventually slowed pharmacological innovation by prioritizing electrophysiologic properties over arrhythmogenic mechanisms. The present, limited pharmacological armamentarium demands efforts to reassess legacy antiarrhythmics, repurpose non-antiarrhythmic agents as upstream or downstream therapy, and develop novel compounds. Flecainide, propafenone, and dronedarone have demonstrated their reliable efficacy and safety, even in patients with structural heart disease, which should allow clinicians to reduce their reliance on amiodarone. Previous concerns regarding the proarrhythmic risk of dofetilide and ibutilide are currently managed through careful patient selection and adequate QT interval monitoring. Novel targeted AADs are advancing through the development pipeline, of which etripamil and landiolol have already been approved. Other emerging drugs, such as SK channel blockers (AP30663 and AP31969), RyR2 blockers, CaMKII inhibitors, and TASK-1 blockers (doxapram), are aligned with the new paradigm of atrial fibrillation that focuses on triggers and re-entry. Once triggered, arrhythmias are perpetuated by the underlying substrate, which could be directly targeted by antifibrotic therapy. Developing concepts such as atrial cardiomyopathy allows clinicians to characterize substrate objectively, in order to assess disease severity and individualize antiarrhythmic treatment. The future of antiarrhythmic therapy will be reshaped by artificial intelligence and digital twinning, which allow precise phenotyping and a tailored approach based on individual patient profiles, complemented by rhythm monitoring through wearables.