Hopes and disappointments with antiarrhythmic drugs

Abstract

Ventricular arrhythmias such as sustained ventricular tachycardia and ventricular fibrillation account for two thirds of sudden cardiac deaths. Most ventricular tachyarrhythmias have well understood mechanisms such that it is theoretically possible to conceive of an antiarrhythmic drug-based intervention that would prevent arrhythmias that cause sudden cardiac death. Pharmaceutical agents which interfere with ion channel activity are known as antiarrhythmic drugs.Acute experiments showing antiarrhythmic effects in the basic science laboratory have often not translated into clinical effectiveness. Evidence of efficacy has been difficult to assess and appears to be sparse. However, proarrhythmia is common and complicates assessment of the potential value of antiarrhythmic drugs. Important studies such as the Cardiac Arrhythmia Suppression Trial and the Survival With ORal d-sotalol study confirmed that antiarrhythmic drugs could kill rather than cure patients at risk of sudden cardiac death, and spelled the death knell for widespread use of antiarrhythmic drugs for the primary prevention of sudden cardia death in high risk patients.However, when the implantable cardioverter defibrillator was introduced into clinical practice the situation changed - a drug that generally suppressed ventricular tachyarrhythmias was needed, but safety concerns were alleviated because the ICD could reverse proarrhythmic adverse effects. The accent changed towards the development of drugs that might reduce the prevalence or the symptomatic burden of ventricular arrhythmias. Similarly, antiarrhythmic drug development progressed towards finding an agent that might reduce symptoms associated with recurrent atrial fibrillation rather than for the treatment of ventricular arrhythmia.In recent times the goal of antiarrhythmic therapy has changed again. No longer is it thought necessary to develop blockbuster therapies, but to concentrate on the specific mechanisms of cardiac arrhythmias in individuals and to develop therapies that can be specifically engineered to help carefully defined phenotypes. Personalised or precision medicine is now guiding the development of antiarrhythmic agents that are directed to very specific targets and arrhythmia mechanisms and are without off-target effects that may compromise their efficacy.The value of antiarrhythmic medical therapy has raised great hopes which have been followed by disillusionment. Now hopes and needs are rising again, and we are better prepared to make this therapy successful. If we understand the arrhythmias we may be able to design effective and uncomplicated therapy.