RT-182
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The impact of major clinical
trials on pharmacotherapy of ventricular arrhythmias
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Ralph Lazzara.
Cardiovascular Section, University of Oklahoma Health Sciences Center, Oklahoma
City, USA
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Abstract
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Major randomized clinical trials of pharmacotherapy
for primary (prevention of the first episode) and secondary (prevention of recurrences)
prevention of sustained ventricular tachyarrhythmias (VT/VF) have revealed the risk of
proarrhythmia and the superior efficacy of agents with Class III and antiadrenergic
actions over sodium channel blockers (Class I). CAST and CAST II tested the hypothesis
that suppression of spontaneous ectopy with Class I agents in patients at increased risk
for VT/VF (recent infarction, PVCs, reduced ejection fraction) would improve survival.
CAST was discontinued because of excess mortality with Class IC agents and CAST II was
terminated because of slight early harm and long-term inefficacy of moricizine. However,
BASIS and a Polish arrhythmia trial demonstrated improved survival in post-infarct
patients treated with amiodarone. ESVEM showed superior efficacy of dl-sotalol over an
array of Class I agents in secondary prevention in patients with predominant VT, and
CASCADE demonstrated superior efficacy of amiodarone over Class I agents in cardiac arrest
survivors. However, SWORD showed an enhanced mortality of d-sotalol, lacking
antiadrenergic action, in patients with recent infarction or with remote infarction and
congestive heart failure.
EMIAT and CAMIAT, larger placebo-controlled studies of post-infarct patients, failed
to show survival benefit with amiodarone although sudden death was reduced in both trials.
Trials of amiodarone in patients with heart failure showed disparate results; GESICA, in
Argentina, showed reduced mortality while STAT-CHF, in the United States, showed no
benefit with amiodarone. In GESICA, there were more non-ischemic cardiomyopathy, higher
heart rates, and a much lower discontinuation rate than in STAT-CHF. Comparison of
pharmacotherapy with implanted defibrillators in MADIT, a primary prevention trial of high
risk patients (spontaneous non-sustained VT, inducible non-suppressible sustained VT) and
AVID, a secondary prevention trial, showed superiority of implanted defibrillators over
amiodarone.
Despite the disappointing results of the trials, pharmacotherapy has the best promise
for substantial reduction of the large numbers of arrhythmia deaths because of the
feasibility of voluminous applicability. The Class III action plus antiadrenergic action
appears most beneficial but the problem of proarrhythmia remains to be solved.
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Key Words
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Major clinical trials
primary prevention of ventricular tachyarrhythmias, secondary prevention of ventricular
tachyarrhythmias, CAST trial, CAST II trial, BASIS trial, Polish arrhythmia trial, CASCADE
trial, SWORD trial, ESVEM trial, EMIAT trial, CAMIAT trial, GESICA trial, CHF STAT trial,
MADIT trial, AVID trial, class I, Ic, III drugs, moricizine, amiodarone, dl-sotalol,
d-sotalol, ICD, antiadrenergic action, proarrhythmia, R
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