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In the past 10 years, major randomized clinical trials
have profoundly effected the use and perception of antiarrhythmic drugs in the treatment
of ventricular arrhythmias. Trials have addressed primary prevention, prophylaxis against
an episode of sustained ventricular tachycardia or ventricular fibrillation (VT/VF) and
secondary prevention, the prevention of recurrences in survivors of episodes of VT/VF. The
CAST trial1, published in 1989, was the first major
randomized trial to radically change the perception and use of pharmacotherapy for
ventricular arrhythmias. Predicated on the premise that suppression of spontaneous
ventricular ectopy in patients with coronary artery disease would protect patients from
sudden arrhythmic death, the study used generally accepted and widely used indicators of
risk for VT/VC:\WWW recent prior myocardial infarction, quantified spontaneous ventricular
ectopy, and reduced ejection fraction. The newly developed sodium channel blocking agents,
encainide and flecainide, powerfully effective in suppressing premature ventricular
contractions, were used, as well as moricizine, a somewhat less efficacious PVC
suppressor, to test the hypothesis that suppression of spontaneous ventricular ectopy
could improve survival in patients at increased risk for arrhythmic death.
With the introduction of quinidine near the beginning of this century2, it was recognized that antiarrhythmic drug therapy
could be associated with anecdotal severe adverse actions including paradoxic induction of
life-threatening arrhythmias. The development of antiarrhythmic agents continued through
the century and their use expanded, reaching a peak in the 1980's. During that time, a
heightened general awareness of arrhythmias and the magnitude of the problem of sudden
arrhythmic death led to feverish development of new agents, especially those of Class IC3 (sodium blocking agents with slow kinetics of channel
binding and unprecedented clinical potency) and to wholesale and cavalier use of
antiarrhythmic agents. PVC's, recognized as triggers and harbingers of VT/VF were widely
targeted for therapeutic suppression.
CAST, carefully designed and controlled, was a landmark in antiarrhythmic
pharmacotherapy. It revealed undeniably the lethal potential of antiarrhythmic drugs. In
so doing, it highlighted the importance and deficiencies of identifying a population at
sufficient risk to be subjected to a risky therapy. In CAST, the notably low mortality in
the placebo group highlighted fallacies of widely accepted risk indicators. CAST disclosed
an adverse interaction between acute ischemia and antiarrhythmic drugs that facilitates
lethal proarrhythmia4, one of multiple possible but
unidentified adverse interactions between pathophysiology and drug action. Faced with
disappointment and concern after CAST, the investigators made the decision to continue
with CAST II5, utilizing moricizine and changing the
inclusion criteria to target a group at greater risk. CAST II also was prematurely
terminated with slight but significant early proarrhythmic risk and no significant chance
of long-term benefit.
The shocking and dismaying results of CAST and CAST II had multiple, far-reaching
consequences. Development of new sodium channel blocking agents virtually ceased. The
concept of primary prevention was approached with anxiety rather than enthusiasm;
recognition of the risks of therapy led to an acute appreciation of the importance of
defining a level of risk higher than the risk of the treatment. The deficiencies of widely
accepted risk indicators was perceived.
The discouragement that followed the CAST trials was partially alleviated by the
publication of the results of two relatively small primary prevention post-infarction
trials conducted in Europe with amiodarone, an agent with multiple actions including a
powerful Class III action, antiadrenergic action, calcium channel blocking action, and
sodium channel blocking action3. BASIS6 and the Polish post-infarction7
showed reductions in mortality at one year at a barely significant level in patients
treated with amiodarone.
The publication of these encouraging results was followed by the report of a secondary
prevention trial, ESVEM8,9, demonstrating a superiority
of another agent with prominent Class III actions plus beta receptor blocking action,
dl-sotalol, compared with a broad array of sodium channel blocking agents, in secondary
prevention of life-threatening ventricular tachyarrhythmias. This trial had the primary
goal of comparing two methods for predicting efficacy: electrophysiological study with
suppression of inducible ventricular arrhythmias versus suppression of spontaneous ectopy
on Holter monitoring and exercise tolerance testing. The secondary goal to compare sotalol
to the group of sodium channel blockers was approached by randomly assigning agents for
testing, and tracking outcomes according to the class of agent as well as the method of
efficacy prediction. Sotalol was approximately twice as efficacious and better tolerated
than the sodium channel blockers and the superiority occurred with both methods of
efficacy prediction 9.
Another secondary prevention trial, CASCADE10,
compared amiodarone with an array of Class I agents. This trial enrolled patients
resuscitated from cardiac arrest, in contrast to ESVEM which enrolled predominantly
patients with sustained ventricular tachycardia. CASCADE favored electrophysiological
study for efficacy prediction but utilized suppression of spontaneous ectopy in patients
non-inducible at electrophysiological study. While the inducibility protocol for ESVEM was
widely criticized11, that of CASCADE is generally
accepted as comparable to protocols in widespread usage at the time. Despite these
differences, recurrence rates with Class I agents in CASCADE were very similar to those in
ESVEM and amiodarone, like sotalol, was about twice as effective. However, amiodarone,
unlike sotalol in ESVEM, was not as well tolerated long-term as the Class I agents.
The results of these trials caused a resurgence of interest in antiarrhythmic drugs,
in primary prevention, and in the Class III action. A flurry of development of agents with
Class III actions occurred. While amiodarone and sotalol both have potent other actions,
there was emphasis on agents with strongly dominant or exclusive Class III action.
Unfortunately, recent trials have dampened the enthusiasm generated by the earlier trials
with the complex agents amiodarone and sotalol, and the Class III action also has been
stigmatized with this specter of proarrhythmia.
The primary prevention trial, SWORD12, was
conducted with the relatively "pure" Class III agent, d-sotalol, the isomer
lacking the clinically significant beta blocking action. It was conducted in patients with
recent infarction or remote infarction and congestive heart failure. Like CAST, it too was
prematurely terminated because of excess mortality in the d-sotalol treated group,
primarily lethal proarrhythmia. An older trial with dl-sotalol had shown a favorable trend
(non-significant) toward improved survival13.
The type of proarrhythmia with the Class III action is thought to be the induction of
the ventricular tachyarrhythmia, torsade de pointes, triggered by early
afterdepolarizations generated in the condition of prolonged repolarization14, as opposed to the proarrhythmia produced by sodium
channel blockers thought to be the facilitation of reentry consequent to reduction in
conduction velocity. In each case, the proarrhythmia is an adverse consequence intimately
linked to the therapeutic action.
Larger trials with amiodarone in post-infarct patients have failed to verify the
positive results in earlier trials. EMIAT15, a European
trial with the primary endpoint of total mortality, and CAMIAT16,
with the primary endpoint of arrhythmia mortality. Both failed to show a survival benefit.
However, both showed similar reductions in arrhythmic death. Skepticism regarding the
precision of the endpoint of arrhythmic death related to the uncertainty of classification
of arrhythmic death has limited acceptance of the arrhythmic death endpoint.
Two primary prevention trials of amiodarone in congestive heart failure have produced
disparate results. GESICA17, conducted in Argentina in
patients with predominately non-ischemic cardiomyopathy, found a significant reduction in
mortality in the treated group but STAT-CHF18,
conducted in the Veterans Administration Medical Centers in the United States in patients
with mostly ischemic cardiomyopathy, showed no survival benefit. A positive finding of
that trial was the low incidence of identified proarrhythmia with amiodarone. The
discontinuance rate with amiodarone was 40% in STAT-CHF, as opposed to 6% for GESICA.
GESICA investigators have argued the benefit of amiodarone is primarily in patients with
higher heart rates19. Heart rates in GESICA were
overall higher than STAT-CHF, and the congestive heart failure was generally more severe.
Pharmacotherapy suffered another setback with the recent publication of the results of
the primary prevention trial, MADIT20, and the
secondary prevention trial, AVID21. In the MADIT trial,
high risk patients were selected on the basis of the demonstration of spontaneous,
non-sustained ventricular tachycardia plus inducible, sustained ventricular
tachy-arrhythmias not suppressible by procainamide. Defibrillator implantation resulted in
significantly better survival rates than antiarrhythmic drugs of which amiodarone was used
in about 75%. In AVID, patients with cardiac arrest or hemodynamically unstable
ventricular tachycardia fared better with implantable cardioverter defibrillators than
with pharmacotherapy which consisted of amiodarone in more than 90% of the patients. These
trials showed a superiority of implantable cardioverter defibrillators over amiodarone in
survivors of sustained ventricular tachyarrhythmias but left the issue unsettled with
respect to sotalol or other agents.
The status of pharmacotherapy is now compromised in large part because of the unsolved
problem of proarrhythmia and the demonstrated superiority of implantable cardioverter
defibrillators in patients at high risk for lethal ventricular arrhythmias. If the large
numbers of people suffering arrhythmic death and the relatively small number of patients
identifiable as being at high risk, argue for continuing pursuit of pharmacotherapy in
order to achieve substantial reduction in the great numbers of people dying suddenly each
year. This endeavor will be facilitated by clarification of the molecular mechanisms of
proarrhythmia and its prevention. It may be advanced by the development of agents with
favorable combination of actions rather than "pure" agents with single actions.
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