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evident
Original paper
1989NEJMCardiology

CAST

Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction

RCTArrhythmia after myocardial infarction

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Overview

Suppressing post-MI ventricular ectopy with class IC drugs increased mortality.

Clinical takeaway

CAST is the canonical surrogate-outcome cautionary tale: drugs that suppressed ventricular ectopy after MI caused excess arrhythmic death and cardiac arrest.

Key result

Arrhythmic death or nonfatal cardiac arrest occurred in 4.5% with encainide/flecainide vs 1.2% with placebo (RR 3.6, 95% CI 1.7-8.5); total mortality 7.7% vs 3.0% (RR 2.5, 95% CI 1.6-4.5).

Practice impact

Ended routine class IC antiarrhythmic suppression of asymptomatic ventricular ectopy after MI.

Evidence

Study design

Randomized, double-blind, placebo-controlled trial stopped early for harm.

Enrollment

1,455

Follow-up

Mean about 10 months at preliminary report.

Geography

United States

Clinical question

Does suppressing asymptomatic or mildly symptomatic ventricular ectopy after MI with class IC antiarrhythmics improve survival?

Population

  • Post-myocardial infarction patients with asymptomatic or mildly symptomatic ventricular arrhythmia (six or more ventricular premature beats per hour) that could be suppressed during open-label titration.
  • Of 2309 patients entering titration, 1727 had initial suppression and were randomized to active drug or placebo; the encainide/flecainide comparison included 730 active-drug and 725 placebo patients.

Intervention

Encainide or flecainide.

Comparator

Placebo.

Primary outcome

Arrhythmic death or nonfatal cardiac arrest.

Class IC antiarrhythmic therapy increased arrhythmic death or cardiac arrest despite suppressing ventricular ectopy.

Relative risk / 3.6 / 95% CI 1.7-8.5

Key results

  • Arrhythmic death or nonfatal cardiac arrest: 33 of 730 (4.5%) with encainide/flecainide vs 9 of 725 (1.2%) with placebo (RR 3.6, 95% CI 1.7-8.5).
  • Total mortality: 56 of 730 (7.7%) vs 22 of 725 (3.0%) (RR 2.5, 95% CI 1.6-4.5).
  • The encainide and flecainide arms were discontinued early because of these results.

Harms

  • Excess arrhythmic death and nonfatal cardiac arrest.
  • Excess total mortality.

Clinical Use

Practice impact

  • Changed arrhythmia management by prioritizing patient-centered outcomes over suppression of ventricular ectopy.
  • Contraindicated class IC agents in many patients with structural heart disease or prior MI.

Applicability

  • Most relevant to post-MI or structural-heart-disease patients with ventricular ectopy.

Limitations

  • Studied older post-MI care before contemporary reperfusion, ICD, and heart-failure therapy.
  • Does not prohibit class IC drugs in carefully selected patients without structural heart disease.

Common misinterpretations

  • The lesson is not that all antiarrhythmics are harmful; the lesson is that surrogate rhythm suppression can worsen survival.

Related evidence

AFFIRM - ContextSCD-HeFT - Later Trial

Citation

Cardiac Arrhythmia Suppression Trial (CAST) Investigators. Preliminary report: effect of encainide and flecainide on mortality in a randomized trial of arrhythmia suppression after myocardial infarction. N Engl J Med. 1989;321(6):406-412. doi:10.1056/NEJM198908103210629

Encainide and flecainide accounted for the excess of deaths from arrhythmia and nonfatal cardiac arrests (33 of 730 patients taking encainide or flecainide [4.5 percent]; 9 of 725 taking placebo [1.2 percent]; relative risk, 3.6; 95 percent confidence interval, 1.7 to 8.5).