Cardiovascular Diseases Clinical Trial
To determine whether drug treatment of asymptomatic ventricular arrhythmias in post-myocardial infarction patients reduced the incidence of sudden cardiac death and total mortality.
BACKGROUND:
Each year over 400,000 people in the United States die suddenly of coronary heart disease.
The majority have known coronary heart disease. Of these, the post-myocardial infarction
population constitutes a large proportion. About 8 to 15 percent of patients who recover
from an acute myocardial infarction die in the subsequent year. Half of these deaths are
usually sudden, presumably due to arrhythmia. Advanced age, poor ventricular function, and
presence of ventricular arrhythmias can identify post-MI patients at high risk of sudden
cardiac death and all-cause mortality.
A number of clinical trials have evaluated whether acute or chronic anti-arrhythmic drug
therapy can reduce mortality in post-MI patients. Of these, only the use of acute
intravenous and long-term beta-blockers, independently and in combination, had been shown to
reduce mortality. However, beta-blockers have many actions in addition to being
anti-arrhythmic agents and it is possible that these other effects may have been
particularly important in prolonging life.
None of the clinical trials of other antiarrhythmic drugs had shown significant benefits
from treatment, and a number had even failed to show a positive trend. It was certainly
possible that treatment of ventricular premature depolarizations, in itself, did not lead to
a reduction in mortality, or even sudden death. The studies that had been done, however, had
not adequately addressed the issue. Most of the studies were small and did not select
patients on the basis of frequent ectopic beats. Moreover, appropriate drugs in optimal
doses may not have been used, and adverse effects may well have outweighed any potential
benefit. Poor compliance, perhaps due to adverse effects, may also have limited the
opportunity for a beneficial outcome.
In an effort to address some of these points, the National Heart, Lung, and Blood Institute
initiated the Cardiac Arrhythmia Pilot Study in 1982. The objectives were to assess: whether
post-MI patients with documented ventricular arrhythmia could be identified and enrolled
into a double-blind clinical trial; whether one or more drugs could be found to effectively
and safely reduce ventricular premature depolarizations over a one-year period; whether
dose-adjustment could be carried out, using ambulatory ECG's; and whether good patient
compliance could be maintained. The Cardiac Arrhythmia Pilot Study, which enrolled 500
patients, evaluated four active drugs (encainide, ethmozine, flecainide, imipramine) against
placebo. The study was too small to determine whether any of these drugs had an effect on
mortality or major morbidity. The study was completed in July 1986.
The pilot study demonstrated that patient recruitment was feasible, that dose-adjustment
could be accomplished, and that good compliance to the protocol could be achieved. Because
of the encouraging results of the pilot study, the NHLBI conducted a full-scale trial.
DESIGN NARRATIVE:
Randomized, double-blind. Enrollment began in June 1987 when twenty-seven clinical centers
began to randomize 4,400 post-myocardial infarction patients to placebo or treatment with
encainide, flecainide, or moricizine. Prior to actual randomization, there was an open-label
titration period to identify patients who responded to treatment. A total of 1,727 patients
who responded were randomized: 1,455 to encainide, flecainide, or placebo, and 272 to
moricizine or placebo. In April 1989, encainide and flecainide were discontinued because of
increased total mortality and sudden arrhythmic death. CAST continued to compare moricizine
to placebo in 1,300 patients for 18 months until August 1991 when the moricizine portion of
the trial was stopped early because of excess deaths. The primary outcome variable in the
full-scale trial was sudden cardiac death, with total mortality a secondary endpoint. Data
analysis continued through March 1998.
;
Allocation: Randomized, Masking: Double-Blind, Primary Purpose: Prevention
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