CAST I

Published

Echt DS, et al. "Mortality and morbidity in patients receiving encainide, flecainide, or placebo". The New England Journal of Medicine. 1991. 324(12):781-788.
PubMed • Full text • PDF

Clinical Question

Among patients with recent MI and increased ventricular ectopy, do antiarrhythmic agents improve survival?

Bottom Line

Among patients with recent MI and increased ventricular ectopy, use of antiarrhythmics suppresses ventricular ectopy, but increases mortality.

Major Points

The significance of post-MI ventricular ectopy depends on the timing of the arrhythmia following a myocardial infarction. NSVT within the first 24 hours of an infarction is probably related to reperfusion ischemia and is commonly felt to be less prognostic. However, data from the Multicenter Post-Infarction Program has demonstrated that NSVT found more than one week after an infarction carries a two-fold increased risk of sudden cardiac death with the greatest risk in the first 6 months. In patients post-MI with LVEF≤40, the risk is increased more than five-fold. In the 1970-1980s, studies attempted to assess whether suppression of ventricular ectopy could improve outcomes following MI, but these were too small to be conclusive.

The Cardiac Arrhythmia Suppression Trial (CAST I) randomized 1,500 post-MI patients with increased ventricular ectopy and depressed LV function to either encainide, flecainide or placebo. The trial was stopped early. Despite suppression of the original ventricular ectopy, treatment with encainide or flecainide was associated with significantly increased rate of arrhythmic deaths or cardiac arrests (5.7% vs. 2.2%) with a NNH of 29 patients at a mean follow-up period of 10 months. There was also an increase in nonarrhythmic death due to MI complicated by cardiogenic shock (1.5% vs. 0.4%). Overall, the administration of these class IC antiarrhythmic drugs was associated with excess all-cause mortality (8.3% vs. 3.5%) with a NNH of 21.

Subsequently, CAST II, which randomized 1325 post-MI patients with increased ventricular ectopy to either moricizine or placebo, was also stopped early when treatment with moricizine was associated with increased all-cause mortality. As a result, this led to a paradigm shift in the treatment of MI patients. Encainide and moricizine were withdrawn from the market, and these class IC antiarrhythmic drugs are contraindicated in patients with coronary heart disease.

Guidelines

Modern guidelines from the ACC/AHA do not comment on the use of antiarrhythmic medications in ACS care.

Design

• Multicenter, double-blind, parallel-group, randomized, placebo-controlled trial
• N=1,498 patients with recent MI and increased ventricular ectopy
  • Encainide (n=432)
  • Flecainide (n=323)
  • Placebo (n=743)
• Setting: 27 centers
• Enrollment: 1987-1989 (stopped early)
• Mean follow-up: 10 months
• Analysis: Intention-to-treat
• Primary outcome: Death or cardiac arrest due to arrhythmia

Population

Inclusion Criteria

• MI in prior 6 days to 2 years
• Mean ≥6 asymptomatic PVCs per hour on ambulatory EKG monitor
• LVEF <55% if <90 days since MI
• LVEF <40% if >90 days since MI

Exclusion Criteria

• Symptomatic ventricular arrhythmias
• NSVT ≥15 PVCs per hour at rate of ≥120 bpm
• If study medications did not effectively suppress the arrhythmias in pilot study

Baseline Characteristics

Medications:

• Aspirin: 67%
• ß-blocker: 27%
• CCB: 49%
• Digitalis: 20%
• Diuretic: 35%
• Nitrate: 40%

Interventions

• Initial, open-label titration identified patients who responded to suppression of PVCs and NSVTs; flecainide was not given to patients with LVEF≤30%
• Patients whom responded were randomized to either encainide, flecainide or placebo

Outcomes

Comparisons are encainide or flecainide vs placebo.

Primary Outcome

Death or cardiac arrest due to arrhythmia

5.7% vs. 2.2% (RR 2.64; 95% CI 1.60-4.36; P=0.0004; NNH=29)

Secondary Outcomes

Death or cardiac arrest due to all causes

8.3% vs. 3.5% (RR 2.38; 95% CI 1.59-3.57; P=0.0001; NNH=21)

Death or cardiac arrest due to MI complicated by cardiogenic shock

1.5% vs. 0.4% (P=0.01; NNH=91)

Funding

National Heart, Lung and Blood Institute