Do we need new antiarrhythmic compounds in the era of implantable cardiac devices and percutaneous ablation?

The past two decades have witnessed a major breakthrough in the treatment of cardiac arrhythmias. Owing to technical perfection of implantable cardioverter defibrillators (ICD), antitachycardic pacing (ATP), and radiofrequency catheter ablation, today's treatment of cardiac arrhythmias has reached an unprecedented level of efficacy and safety. At the same time, the use of antiarrhythmic drugs has declined because of their low efficacy and proarrhythmic potential. Do we actually need new antiarrhythmic compounds in the era of ICDs and percutaneous ablation? If the answer is yes, many additional questions come up: Which pharmacological targets should be modified? Are we merely looking for greater efficacy and safety in conventional antiarrhythmic principles 1 or do we need conceptually new approaches? Clearly, the therapeutic goals and the methods by which they are achieved differ in ventricular and in atrial tachyarrhythmias (Fig. 1). Schematic presentation of the relative importance (indicated by the size of the circles) of the therapeutic options for conversion of ventricular (VT/VF) and atrial (AF) tachyarrhythmias. While the use of an implantable cardioverter defibrillator (ICD) is unquestionably the therapy of choice for life-threatening ventricular tachyarrhythmias, its combination with ablation, antitachycardic pacing (ATP), and drugs may represent options for reducing the number of delivered shocks. Since atrial arrhythmia does not impose an acute threat to survival, atrial ICDs, though effective, are not acceptable. Therefore, conversion of this arrhythmia is the mainstay for drug therapy or ablation. ATP has been tried but appears to be ineffective. Unless ventricular fibrillation (VF) is effectively terminated, death occurs within a few minutes. Therefore, ICDs are the mainstay among the therapeutic options for ventricular tachyarrhythmias (see Fig. 1). The ICD reduces mortality in patients who have survived a potentially life-threatening arrhythmia but also produces a clear survival benefit when used as primary prevention for sudden cardiac death of various etiologies. Amiodarone is the only antiarrhythmic agent that was tested for its being putatively equieffective with ICD regarding survival rate; however, it did not turn out to be superior 2. Ablation techniques are curative for rare idiopathic ventricular tachyarrhythmias (VT), but are merely adjuvant to ICD therapy for ventricular tachycardia with left ventricular dysfunction. Since underlying heart disease can progress during prolonged survival, an increasing number of patients receive multiple, yet clinically appropriate shocks which they experience as painful or even traumatic. Antiarrhythmic drugs compete with antitachycardic pacing (ATP) and ablation procedures as add-on measures for reducing shock frequency and therefore improving quality of life. However, in contrast to ATP and ablation, amiodarone has never been tested in this setting. Of the newer compounds, dofetilide did not reduce event numbers 3, whereas azimilide showed a small effect 4. More efficacious yet safe drugs for this indication are highly desirable. Supraventricular tachyarrhythmias related to accessory bundles or ectopic foci firing from the pulmonary veins are curable with multiple ablation techniques (for review see 5), although long-term efficacy of treatment has not yet been assessed. Atrial ICDs have been tried for conversion of atrial fibrillation (AF) to sinus rhythm, but had to be abandoned again because the patients do not tolerate the shocks, even less so when AF is asymptomatic. Antitachycardic pacing to terminate or prevent AF is ineffective. Atrial tachyarrhythmias are not imminently life-threatening although they increase mortality because of associated stroke. Therefore, effective anticoagulation is required in addition to antiarrhythmic medication. Of the supraventricular tachyarrhythmias, AF is particularly difficult to treat because of its tendency to become persistent in the course of the disease. Intuitively, the optimal therapeutic goal would be conversion to stable sinus rhythm (SR) rather than normalization of ventricular excitation frequency in order to prevent tachycardic cardiomyopathy. However, no difference could be detected between these two options with respect to mortality 6, although it must be pointed out that anticoagulation was withdrawn in the putatively rhythm-stable group. It is desirable that drugs for the treatment of AF be more efficacious, show selectivity for atrial versus ventricular tissue, and meet the high demands for drug safety given the chronic character of AF. Safety and efficacy of ICDs preclude the use of antiarrhythmic agents alone in order to achieve stabilization in fast VT/VF, but reducing the number of clinically appropriate shocks is a valid therapeutic goal. Ion channels are classical targets for antiarrhythmic drugs 1. Treatment with Class I sodium channel blockers is limited by negative inotropic effects and by ventricular proarrhythmic effects particularly in patients with severe left ventricular dysfunction 7. In the wake of the CAST study, development of new antiarrhythmic agents was directed towards prolongation of effective refractory period (ERP) by selective block of individual K channels (e.g. the IKr blocker dofetilide). However, these compounds were not effective in reducing shock frequency but were related to an enhanced risk for torsades de pointes 3. Blockers of Ito to prolong action potential duration (APD) (e.g. tedisamil) turn out to be not as selective as anticipated, and the concomitant IKr block precluded further development for use in ventricular arrhythmias. Even unselective K+ channel block by new class III drugs is not sufficiently curative, because in the study with azimilide not a single patient remained free of interventional events 4. Lack of successful antiarrhythmic therapy with representatives of ion channel blockers necessitates the search for alternative mechanisms of action. Enhancing instead of blocking K+ channel activity in order to stabilize the resting membrane potential could be a useful putative antiarrhythmic principle. Indeed, several drug companies are at present investigating HERG channel openers for their antiarrhythmic potential 8. In addition, new antiarrhythmic concepts have evolved that focus on reversing impaired Ca2+ handling which may cause afterdepolarizations that can trigger a tachycardic episode 9. Owing to the tendency of AF to become permanent, recent-onset and paroxysmal AF are more easily treated than persistent AF. For safety reasons, pharmacological conversion of AF is usually carried out in hospitalized patients in order to safeguard against pro-arrhythmia and stroke. In this setting, the results with the old drug flecainide were not worse than with the new compound ibutilide (but 30 times less expensive, see Ref. 10). Based on the assumption that chances for successful pharmacological conversion are highest if treatment is initiated as rapidly as possible, self-medication with a single oral dose was propagated in selected patients with recent-onset AF (“pill in the pocket”). Here, flecainide, or propafenone, was shown to be not only highly effective for conversion but also safe 11. Conversion of recent-onset AF does not necessarily require new drugs. Why is persistent AF more resistant to conversion? Numerous studies have shown that chronic AF induces both electrical and structural remodeling. Electrical remodeling comprises triangularization of the action potential with a less prominent plateau phase and a shortened effective refractory period. The underlying mechanisms are complex and involve changes in regulation of channel expression and activity 12. Therefore, it may not be a particularly clever strategy to further depress the already down-regulated ion channel function with antiarrhythmic drugs. This also holds true for blockers of the ultrarapidly activating K+ current IKur, which is depressed during electrical remodeling. On the other hand, IKur blockers may provide a safety advantage because the underlying Kv1.5 channel is preferentially expressed in atria and little in the ventricle. In our own experience, selective IKur block has astonishingly small effects on atrial APD in patients with AF and even shortens APD in SR 13. Clinical studies with the selective HERG channel blocker dofetilide were not superior to other class III or class IC drugs in promoting sinus rhythm 14. Reduced atrial contractility facilitates thrombus formation, although a state of hypercoagulability induced by enhanced expression of endocardial tissue factor in the fibrillating atria may also contribute to the thrombogenic risk 15. Risk of stroke is not necessarily abolished by conversion into SR for two reasons: (i) Apparent maintenance of SR may be interrupted by frequent asymptomatic relapses into AF that go undetected but nevertheless may disturb recovery from contractile dysfunction. Unfortunately, only symptomatic episodes can be treated, and it is not clear whether the patients have asymptomatic AF that predisposes them to a high stroke risk. (ii) Even when regular electrical atrial activity can be demonstrated in the surface ECG, contractile dysfunction may still persist and continue to impose a thrombogenic risk. In summary, the answer to the question initially posed is “yes”. We think that useful therapeutic improvement could be provided by new antiarrhythmic agents that are more efficacious for hybrid therapy with ICDs and by drugs that enhance contractile recovery in addition to stable conversion into SR. Moreover, we need to explore the potential of antiarrhythmic concepts that include previously neglected processes such as modulation of gap junctions, receptor systems, neurohormones, or proteins involved in Ca2+ homeostasis. Last but not least, innovative strategies of K+ ion channel activation rather than block could lead to new drugs with the expected level of efficacy and safety.