CAST: Cardiac Arrhythmia Suppression Trial

1
CAST Cardiac Arrhythmia Suppression Trial

• Purpose
• To determine whether therapy with class Ic
  antiarrhythmics to suppress asymptomatic or
  mildly symptomatic ventricular arrhythmias after
  MI reduces mortality due to arrhythmia
• Reference
• The 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
  198932140612.

2
CAST Cardiac Arrhythmia Suppression Trial -
TRIAL DESIGN -

• Design
• Multicenter, multinational initial phase open
  main phase randomized, double-blind,
  placebo-controlled
• Patients
• 1725 patients with gt6 ventricular premature
  depolarizations/h (24h Holter recording) and
  left ventricular ejection fraction lt0.55 at lt90
  days after MI or lt0.40 at gt90 days after MI
• Follow up and primary end point
• Mean 10 months follow up. Primary endpoint death
  from arrhythmia
• Treatment
• Open titration phase (mean 15 days) to select
  patients in whom drug (encainide, flecainide or
  moricizine) suppressed arrhythmias
• Selected patients then randomized to three-times
  daily placebo, encainide 3550 mg, flecainide 100
  mg or moricizine 200250 mg (results for
  moricizine not reported here)

3
CAST Cardiac Arrhythmia Suppression Trial-
RESULTS -

• Study of encainide/flecainide vs. placebo halted
  at mean follow up of 10 months on recommendation
  of CAST Data and Safety Monitoring Board because
  in group taking encainide or flecainide,
  compared with placebo group
• All-cause mortality significantly higher
• Non-fatal cardiac arrest or death from arrhythmia
  significantly higher
• Death from other cardiac causes also higher
• Results consistent across all subgroups examined
• No confounding factors were identified to explain
  marked differences between encainide/flecainide
  and placebo
• Study subsequently modified to continue with
  moricizine (CAST II)

4
CAST Cardiac Arrhythmia Suppression Trial-
RESULTS continued-

All-cause mortality
Survival
100
()
95
90
85
Placebo (n725)
Encainide or flecainide (n730)
P0.0003
80
0
50
100
150
200
250
300
350
400
450
500
Days after randomization
CAST Investigators.
N Engl J Med
1989
321
406

12.
5
CAST Cardiac Arrhythmia Suppression Trial-
RESULTS continued-

Mortality and cardiac arrest
Placebo
Encainide/flecainide
Relative risk
(n725)
(n730)
(95 CI)
No. ()
No. ()
Non-fatal cardiac arrest
9 (1.2)
33 (4.5)
3.6 (1.7

8.5)
or death from arrhythmia



Other cardiac death
6 (0.8)
14 (1.9)

Non-cardiac or unclassified death
7 (1.0)
9 (1.2)

or cardiac arrest






Total death or cardiac arrest
22 (3.0)
56 (7.7)
2.5 (1.6

4.5)
300
293
Average days of exposure
CAST Investigators.
N Engl J Med
1989
321
406

12.
6
CAST Cardiac Arrhythmia Suppression Trial-
SUMMARY -

• In patients with asymptomatic or mildly
  symptomatic ventricular arrhythmias after MI,
  encainide or flecainide started at mean of 15
  days after MI caused
• Excessive mortality risk
• Excessive risk of death from arrhythmia