Clinical Trial Issues

Currently, clinical trials are required to assess effects of both acute and chronic drug treatments for the termination, prophylaxis, or prevention of the first presentation, or repeated episodes, of an arrhythmia. The ultimate measure of a drug's effectiveness is, of course, reductions in morbidity and mortality. It has to be remembered that in the past we fell into the trap of treating the ECG, but not the patient's arrhythmias. Thus we concentrated on ECG surrogates rather than true clinical outcomes. There are no surrogates for the actual arrhythmias, and so we ultimately always have to determine whether a new drug produces real beneficial clinical outcomes by improving quality of life and saving lives. One clear example of this is a recent trial to determine whether, in atrial fibrillation, it is better to re-establish sinus rhythm or simply use a drug to control ventricular rate - the so-called 'rate versus rhythm' controversy.15 It seems that there is no clear advantage of rhythm control over rate control. Such a finding reflects the reality of a situation in which there are complex interplays between disease, patient, and drug. The importance of death as an unambiguous endpoint cannot be minimized, especially when a drug's disease target is, in the final analysis, a reduction in cardiac sudden death. The logistics and expense of using death as an endpoint is a further reason for the current lack of enthusiasm for antiarrhythmic drug discovery programs.

The easiest type of clinical trial for an antiarrhythmic drug is where it is given intravenously to terminate an arrhythmia. The endpoint is unequivocal, especially when the arrhythmia has been present for a period of hours, or longer. Since the drug is given intravenously, its presence at a potentially effective concentration ensures the most reliable type of clinical trial for an antiarrhythmic drug. This represents one end of the spectrum, as opposed to the other end where the endpoint of death is used.

A major problem with arrhythmias is their nature. Some arrhythmias are transient, others are chronic, and sometimes they subtly change their nature over time. Thus, recent-onset atrial fibrillation is electrophysiologically different from chronic atrial fibrillation as a result of remodeling. It appears that atrial fibrillation begets atrial fibrillation16 and thereby ensures its continuation albeit in a slightly different form.

Given such problems with antiarrhythmic clinical trials, there is a clear need for arrhythmia surrogates, analogous to the manner in which blood pressure changes over a limited period can be used as a surrogate for the morbid and lethal adverse effects of sustained hypertension. Unfortunately, even for hypertension, this most obvious surrogate is inadequate, and can give a false picture. There are, of course, a number of potential surrogates for antiarrhythmic trials, but their validity has to be questioned. For example, the electrophysiological actions of an ion channel blocker can be shown explicitly in man by relatively noninvasive electrophysiological studies. For example, an IKr blocker can prolong the QT interval and change refractoriness thereby revealing its electrophysiological actions in normal myocardium, but whether such actions necessarily result in antiarrhythmic effects still has to be tested in humans with arrhythmias.

Table 2 outlines the type of trial that could be used for particular arrhythmias and the difficulties encountered with such trials.

Table 2 The various factors encountered in clinical trials of antiarrhythmic drugs

Arrhythmia

Endpoint

Patient population

Outcome measure

A1: Acute atrial tachycardia

Termination of arrhythmia

Those with recent (hours)

Termination of arrhythmia in

and/or fibrillation

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