Circulation, Vol 90, 2843-2852, Copyright © 1994 by American Heart Association
JL Anderson, EV Platia, A Hallstrom, RW Henthorn, TA Buckingham, MD Carlson and PE Carson
BACKGROUND: The Cardiac Arrhythmia Suppression Trial (CAST) was designed to
test the hypothesis that suppression of ventricular ectopy with
antiarrhythmic drugs after a myocardial infarction reduces the incidence of
sudden arrhythmic death. Patients in whom ventricular ectopy could be
suppressed with encainide, flecainide, or moricizine were randomly assigned
to receive either active drug or placebo. The encainide and flecainide arms
of the study were discontinued in 1989 (CAST-I) and the moricizine arm in
1991 (CAST-II) because of excess mortality. To explore the mechanisms of
these adverse outcomes, we examined the interaction of baseline
characteristics with the hazard of therapy with encainide, flecainide, or
moricizine compared with their respective placebos. METHODS AND RESULTS:
CAST-I comprised 755 patients assigned to flecainide or encainide and 743
patients assigned to placebo, whereas in CAST-II, 502 patients received
moricizine and 491 patients received placebo. Clinical and laboratory
baseline variables of patients receiving active drug and those receiving
placebo were similar. In CAST-I patients, there was a significant
interaction of active therapy with both all-cause death/cardiac arrest and
arrhythmic death/cardiac arrest for non-Q-wave myocardial infarction (total
mortality hazard ratios, 1.8 versus 7.9 for Q-wave versus non-Q-wave
infarction, P = .03). Ventricular premature depolarization (VPD) frequency
> or = 50/h and heart rate > or = 74 beats per minute each interacted
significantly with total mortality/cardiac arrest only. In the sicker
CAST-II patients (ejection fraction < or = 40%), only diuretic use at
baseline interacted significantly with moricizine use for both all-cause
death/cardiac arrest and arrhythmic death/cardiac arrest (total mortality
hazard ratios, 1.9 versus 0.7 for diuretic use versus no use, P = .01).
CONCLUSIONS: Although active treatment in CAST- I was associated with
greater mortality than placebo with respect to almost all baseline
variables, the therapeutic hazard was more than expected in patients with
non-Q-wave myocardial infarction and (for total mortality) frequent
premature VPDs and higher heart rates, suggesting that the adverse effect
of encainide or flecainide therapy is greater when ischemic and electrical
instability are present. The relative hazard of therapy with moricizine in
the sicker CAST-II population was greater in those using diuretics. Thus,
although these drugs have the common ability to suppress ventricular ectopy
after myocardial infarction, their detrimental effects on survival may be
mediated by different mechanisms in different populations, emphasizing the
complex, poorly understood hazards associated with antiarrhythmic drug
treatment.
ARTICLES
Interaction of baseline characteristics with the hazard of encainide, flecainide, and moricizine therapy in patients with myocardial infarction. A possible explanation for increased mortality in the Cardiac Arrhythmia Suppression Trial (CAST)
University of Utah, LDS Hospital, Salt Lake City 84143.
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