Week 11 – CAST

“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.

Population:     

·       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

Outcome:

Primary – death or cardiac arrest with resuscitation “either of which was due to arrhythmia”

Secondary
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
4. syncope
5. permanent pacemaker implantation
6. recurrent MI
7. CHF
8. angina pectoris
9. coronary artery revascularization

Results:
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.

Implication/Discussion:
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.”

Further Reading:
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

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