This post was authored by John Camm, MD, St. George's University of London, London, United Kingdom.

The principle of reducing or eliminating arrhythmias that arise from disturbances of ion channel function by adjusting the electrophysiological properties of the myocardium with drugs that modify one or more ion channel is appealing and seemed likely to be successful. For example, the effect of an antiarrhythmic drug may be to directly reverse abnormal electrophysiology or to induce compensatory effects to indirectly re-balance cardiac electrophysiology.  There are occasional examples of the direct approach, for example by inhibiting the gain of function in sodium channels responsible for long QT type 3. More often a “downstream” electrophysiological effect such as shortening of the atrial refractory period, due to multiple, and often incompletely understood, ion channel abnormalities, which gives rise to atrial arrhythmias can be reversed by an ion channel blocking agent that leads to action potential and refractory period prolongation, but in a manner independent of the action(s) that led to shortening of refractoriness. However, given the complexity and multiplicity of effects that may in combination lead to a clinical arrhythmia it is unlikely that, in most cases, targeting a single ion channel, as for example by inhibiting the rapid component of the delayed rectifier (iKr) will lead to efficient anti-arrhythmic treatment and suppress the atrial tachyarrhythmia. As a consequence multichannel blockers are often used, rather like a blunderbuss, in the hope that their multiple effects will somehow reverse or compensate for the underlying pathophysiology in a both safe and effective manner. This approach has certainly led to some success, but has often proved unsafe.

When the specific target(s) that give rise to arrhythmia is unknown it is highly likely that many non-specific “off-target” drug effects will result from non-specific drug therapy. Thus it is hardly surprising that our unsophisticated approach to the pharmacotherapy of arrhythmias often leads to the development of “proarrhythmia.” Although a drug action is intended to affect abnormal tissue it may also disturb normal tissue. An atrial arrhythmia may be the focus of treatment but ventricular myocardium may also be affected.  Thus an attempt to prolong the refractoriness of abnormal atrial tissue with drugs that extends the atrial action potential in order to prevent recurrences of atrial fibrillation may at the same time lead to an increase of the duration of the ventricular action potential and give rise to a long QT interval and polymorphic ventricular tachycardia, if not worse.

Although a potential proarrhythmic action of antiarrhythmic drugs had been acknowledged for many years it was not until the CAST study that the extent of this problem was understood. In this study powerful drugs inhibiting the sodium current, in order to block conduction from an ectopic focus or within a re-entry circuit, were given to patients with a high density of ventricular extrasystoles and underlying structural heart disease. The intention was to prevent sudden death. Not only did proarrhythmic risk subtract from the potential beneficial actions of antiarrhythmic therapy but proarrhythmia dominated, rendering the therapy distinctly harmful. At first this serious adverse effect was thought to be related to the specific agents tested in the CAST, but then a ‘class effect’ was mooted.  At this stage an extensive development program of antiarrhythmic therapy which concentrated on sodium channel blockers was stopped in its tracks and this was eventually followed by progressive abandonment of already established and approved therapies. Today, few of these agents remain on the pharmacopeia and the use of those that endure is strictly controlled and limited to those without structural heart disease.

However, there was another type of antiarrhythmic drug which was designed predominantly to prolong the refractoriness of the myocardium rather than to slow conduction. A beta-blocker which also had this effect (racemic sotalol) had reduced mortality in high risk post myocardial infarction patients, although it was perhaps no better than more simple beta-blocking agents. Nevertheless another drug which prolonged refractoriness was then investigated in a wide range of patient groups vulnerable to sudden death. The results with amiodarone were generally, although not always, favorable. They were sufficiently compelling, however, to cause a major change in clinical practice towards the ready application of amiodarone and to launch the investigation of many antiarrhythmic drugs which relied on action potential prolongation, most specifically by inhibiting potassium repolarising currents: iKr, iKs or both.

A large randomised trial with d-sotalol in patients with poor left ventricular function following recent or remote myocardial infarction (MI) was stopped prematurely because of many more presumed arrhythmic deaths in the d-sotalol rather than the placebo treated group. Trials with dofetilide in patients with heart failure or reduced left ventricular function post MI were both neutral with regard to mortality, but at the expense of prolonged in-hospital monitoring which detected far more patients in the dofetilide groups with polymorphic ventricular tachycardia – clearly a proarrhythmic effect related to this therapy. Azimilide in post MI patients at high risk of sudden death was not effective in reducing mortality, but its proarrhythmic effect was not demonstrated until it was tried as a therapy for atrial fibrillation (AFib). However, this brought to an end the search for an inhibitor of the delayed potassium current which might reduce the burden of sudden death in high risk post MI or heart failure populations.  The development of many new compounds was abandoned, and attention turned to so-called multi-channel blockers.

The possible prognostic use of an antiarrhythmic drug found a new target, when the safety of an agent designed primarily for the suppression of symptomatic recurrences of AFib had to be investigated. Previous experience with dofetilide in a high risk acute heart failure population had shown that the occurrence/recurrence of AFib and related hospitalizations could be effectively suppressed.  A similar “model” (class IV NYHA heart failure, or recent decompensation, in patients with an ejection fraction ≤35 percent) was used to test dronedarone, but again the trial was terminated early because of more deaths in the dronedarone compared with the placebo group. However, based on intriguing results from a meta-analysis of AFib recurrence trials in less sick patients it seemed that dronedarone might reduce both hospitalisations and mortality. A subsequent trial, at the time the largest ever conducted in an AFib population, clearly demonstrated that dronedarone use was associated with a reduction of unplanned cardiovascular hospitalisations. All-cause mortality was numerically less with dronedarone but this effect was not significant. Investigators and clinicians were impressed with the results, and the drug was approved in North America for the purpose of reducing cardiovascular hospitalisations. A new era of antiarrhythmic care seemed to have begun.

Out in the real world, as with any new drug, adverse effects associated with dronedarone began to accumulate, some of which had not been anticipated. Rare cases of hepato-toxicity came to light and led to warnings and relabeling. But, the real blow came with the news of another trial which was terminated prematurely because of an excess of outcome events, predominantly sudden death and stroke, in a population of patients with permanent AFib. The trial was based on results from ATHENA where such patients had seemed to derive benefit, not from rhythm control, but perhaps from rate control, ventricular antiarrhythmic effects, lowered blood pressure, reduced coronary events or fewer strokes. This speculation proved to be very wrong, but the adverse results remain unexplained. It is true that the patients had worse heart failure and more structural heart disease, but events did not seem to cluster in such patients. Theories relating to unanticipated pharmacological cardioversion leading to stroke, negative inotropic effects of dronedarone or interactions between dronedarone and anticoagulants or digoxin could explain part but not all. All of this might have been foreseen with drugs that had multiple actions especially when the therapeutic index was low and the clinical investigation was incomplete.

Antiarrhythmic drug therapy had hit an all-time low, but another possibility suggested itself. Ranolazine is an agent approved for use in chronic stable angina and long QT type 3 syndrome. The drug selectively blocks the slow more than the fast component of the sodium current, but also has some effect on the rapid phase of the delayed potassium current. Preliminary studies showed that the drug might prevent AFib and specifically designed studies were launched to investigate this.  However, results from the basic science laboratory had shown that the combination of ranolazine with low dose dronedarone, theoretically well below that needed to cause adverse effects, might be a highly effective combination and clinical studies have now turned towards the design and conduct of novel trials to explore combination therapy.

It is far too soon to write the final chapter on antiarrhythmic drug therapy, although presently overtaken by better ablation and device therapy for both atrial and ventricular arrhythmias. In the end, therapy will be preventive, pharmacologic and given sufficiently early to prevent progression which renders the substrate for arrhythmia “incurable.” Despite many setbacks antiarrhythmic agents may well have their day before too long.

Camm will give the 13th Annual Maseri-Florio International Lecture today from 2 – 3:30 p.m. in Room 152 B.

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