“Mortality and Morbidity in Patients Receiving Encainide, Flecainide, or Placebo”
The Cardiac Arrhythmia Suppression Trial (CAST) [free full text]
N Engl J Med. 1991 Mar 21;324(12):781-8.
Ventricular arrhythmias are common following MI, and studies have demonstrated that PVCs and other arrhythmias such as non-sustained ventricular tachycardia (NSVT) are independent risk factors for cardiac mortality following MI. As such, by the late 1980s, many patients with PVCs post-MI were treated with antiarrhythmic drugs in an attempt to reduce mortality. The 1991 CAST trial sought to prove what predecessor trials had failed to prove – that suppression of such rhythms post-MI would improve survival.
· post-MI patients with ≥ 6 asymptomatic PVCs per hour and no runs of VT ≥ 15 beats, LVEF < 55% if within 90 days of MI, or LVEF < 40% if greater than 90 days since MI
o patients were further selected by an open-label titration period in which patients were assigned to treatment with encainide, flecainide, or moricizine
o “responders” had at least 80% suppression of PVCs and 90% suppression of runs of VT
Intervention: continuation of antiarrhythmic drug assigned during titration period
Comparison: transition from titration antiarrhythmic drug to placebo
Primary – death or cardiac arrest with resuscitation “either of which was due to arrhythmia”
1. all-cause mortality or cardiac arrest
2. cardiac death or cardiac arrest due to any cardiac cause
3. VT ≥ 15 or more beats at rate ≥ 120 bpm
5. permanent pacemaker implantation
6. recurrent MI
8. angina pectoris
9. coronary artery revascularization
The trial was terminated early due to increased mortality in the encainide and flecainide treatment groups. 1498 patients were randomized following successful titration during the open-label period, and they were reported in this paper. The results of the moricizine arm were reported later in a different paper (CAST-II).
RR of death or cardiac arrest due to arrhythmia was 2.64 (95% CI 1.60–4.36). The number needed to harm was 28.2. See Figure 1 on page 783 for a striking Kaplan-Meier curve.
RR of death or cardiac arrest due to all causes was 2.38 (95% CI 1.59–3.57). The number needed to harm was 20.6. See Figure 2 on page 784 for the relevant Kaplan-Meier curve.
Regarding the other secondary outcomes, cardiac death/arrest due to any cardiac cause was similarly elevated in the treatment group, and there were no significant differences in non-lethal endpoints among the treatment and placebo arms.
Treatment of asymptomatic ventricular arrhythmias with encainide and flecainide in patients with LV dysfunction following MI results in increased mortality.
This study is a classic example of how a treatment that is thought to make intuitive sense based on observational data (i.e. PVCs and NSVT are associated with cardiac death post-MI, thus reducing these arrhythmias will reduce death) can be easily and definitively disproven with a placebo-controlled trial with hard endpoints (e.g. death). Correlation does not equal causation.
Modern expert opinion at UpToDate notes no role for suppression of asymptomatic PVCs or NSVT in the peri-infarct period. Indeed such suppression may increase mortality. As noted on Wiki Journal Club, modern ACC/AHA guidelines “do not comment on the use of antiarrhythmic medications in ACS care.”
1. CAST-I Trial at ClinicalTrials.gov
2. CAST-II trial publication, NEJM (1992)
3. Wiki Journal Club
4. 2 Minute Medicine
5. UpToDate “Clinical features and treatment of ventricular arrhythmias during acute myocardial infarction”
Summary by Duncan F. Moore, MD