Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial

Authors (Top 5): D. S. Echt, P. R. Liebson, L. B. Mitchell, R. W. Peters, D. Obias-Manno

Journal Name, Year, Volume, Issue: New England Journal of Medicine, 1991, Volume 324, Issue 12

Type of Study: Multicenter, randomized, placebo-controlled clinical trial

DOI/PMID: 10.1056/NEJM199103213241201, PMID: 1900101

Quick Reference Summary

Treatment with encainide or flecainide significantly increased mortality due to arrhythmia and cardiac causes compared to placebo in post-myocardial infarction patients.

Relative risk of death or cardiac arrest due to arrhythmia was 2.64 (95% CI: 1.60-4.36, P = 0.0004), and due to all causes was 2.38 (95% CI: 1.59-3.57, P = 0.01) for active drug groups versus placebo.

Core Clinical Question

Does the use of encainide or flecainide in post-myocardial infarction patients with suppressed ventricular ectopy reduce mortality and morbidity compared to placebo?

Background

Disease Overview: Ventricular premature depolarizations (VPDs) are a risk factor for sudden and nonsudden cardiac death post-myocardial infarction.

Prior Data:

• VPDs associated with a fourfold higher mortality rate when exceeding 10 per hour.
• Previous studies failed to demonstrate that antiarrhythmic therapy reduces long-term sudden death risk.

Current Standard of Care: Management of VPDs often includes antiarrhythmic drugs; beta-blockers are commonly used.

Knowledge Gaps Addressed:

• Efficacy of encainide and flecainide in reducing mortality by suppressing VPDs.
• Safety profile of these antiarrhythmic agents in post-MI patients.

Study Rationale: To test the hypothesis that suppression of ventricular ectopy reduces sudden death incidence and to evaluate the safety of encainide and flecainide.

Methods Summary

Study Design:

Randomized, placebo-controlled trial with an intention-to-treat analysis.

Setting and Time Period:

Multicenter study from June 1987 to April 1989.

Population Characteristics:

1,498 post-myocardial infarction patients with ≥6 VPDs/hour and specific ejection fraction criteria.

Inclusion/Exclusion Criteria:

• Inclusion: 6 days to 2 years post-MI, ≥6 VPDs/hour, specific ejection fraction thresholds.
• Exclusion: Runs of ventricular tachycardia ≥15 beats at ≥120 bpm, ejection fraction below specified limits for flecainide use.

Intervention Details:

Active drugs: Encainide, flecainide, or moricizine based on initial open-label titration.

Control/Comparison Group Details:

Corresponding placebos for each active drug.

Primary and Secondary Outcomes:

• Primary: Death or cardiac arrest due to arrhythmia.
• Secondary: All-cause death or cardiac arrest, nonlethal arrhythmic events, syncope, need for pacemaker, recurrent MI, congestive heart failure, angina, revascularization procedures.

Statistical Analysis Approach:

Kaplan–Meier method for actuarial curves; log-rank tests for comparison; caution for multiple comparisons.

Sample Size Calculations:

Based on initial power assessments to detect differences in mortality.

Ethics and Funding Information:

Conducted with ethics approval; specific funding sources not detailed in provided text.

Detailed Results

Participant Flow and Demographics:

Total Patients: 1,498

Encainide/Placebo: 857 (432 active, 425 placebo)

Flecainide/Placebo: 641 (323 active, 318 placebo)

Primary Outcome Results:

Total Deaths/Cardiac Arrests: 89 patients

• Arrhythmia-Related: 59 (43 drug vs. 16 placebo, P = 0.0004)
• Nonarrhythmic Cardiac Causes: 22 (17 drug vs. 5 placebo, P = 0.01)
• Noncardiac Causes: 8 (3 drug vs. 5 placebo)

Relative Risks:

• Death/Cardiac Arrest due to Arrhythmia: 2.64 (95% CI: 1.60-4.36)
• Death/Cardiac Arrest due to All Causes: 2.38 (95% CI: 1.59-3.57)

Effect Sizes:

Significant increase in mortality with active drugs.

Confidence Intervals:

Provided for relative risks as above.

Secondary Outcome Results:

No significant differences in nonlethal arrhythmic events between drug and placebo groups.

Subgroup Analyses:

Similar relative risks in patients with ejection fraction <0.30 (1.97) and ≥0.30 (3.38).

Adverse Events/Safety Data:

No increase in nonlethal disqualifying ventricular tachycardia, proarrhythmia, syncope, need for a pacemaker, etc., with active drugs.

Results Tables: Referenced but detailed data not provided in text.

Authors' Conclusions

Primary Conclusions: Treatment with encainide or flecainide led to excess deaths due to arrhythmia and shock post-MI without reducing nonlethal arrhythmic events.

Interpretation of Results: The increased mortality may be attributable to proarrhythmic effects or exacerbation of myocardial ischemia by the study drugs.

Clinical Implications: Use of encainide or flecainide in suppressing VPDs post-MI increases mortality risk; emphasizes the need for cautious use of antiarrhythmic agents.

Future Research Recommendations: CAST II to evaluate the efficacy of moricizine in preventing arrhythmic death post-MI.

Literature Review

Not explicitly detailed beyond the background and discussion sections provided.

Critical Analysis

A. Strengths:

• Large Sample Size: Inclusion of 1,498 patients enhances statistical power.
• Randomized, Placebo-Controlled Design: Minimizes bias and allows for causal inferences.
• Blinded Classification of Outcomes: Reduces assessment bias in determining cause of death.
• Comprehensive Outcome Assessment: Inclusion of both mortality and a range of morbidity endpoints.

B. Limitations:

• Early Termination of Drug Use: Encainide and flecainide were discontinued partway through, potentially affecting long-term outcome assessment.
• Limited Monitoring Post-Event: Lack of continuous or thorough monitoring may have missed proarrhythmic events.
• Generalizability Issues: Study population restricted to specific post-MI patients with suppressed VPDs; results may not apply to broader populations.
• Potential for Unmeasured Confounders: Although randomization was used, some factors influencing mortality may not have been accounted for.

C. Literature Context:

• Previous Studies: Referenced failures of prior antiarrhythmic therapies to reduce sudden death risk.
• Comparison with Current Guidelines: Implicitly suggests reevaluation of antiarrhythmic use post-MI.
• Contribution to Existing Evidence: Demonstrates increased mortality with encainide and flecainide, challenging the efficacy of VPD suppression for mortality reduction.

Clinical Application

• Practice Change: Avoid using encainide or flecainide for suppressing VPDs in post-MI patients due to increased mortality risk.
• Applicable Populations: Post-myocardial infarction patients with suppressed ventricular ectopy and left ventricular dysfunction.
• Implementation Considerations: Shift towards beta-blockers and other safer alternatives for managing arrhythmias post-MI.
• Integration with Existing Evidence: Aligns with emerging data questioning the safety and efficacy of certain antiarrhythmic drugs.

How To Use This Info In Practice

Practitioners should refrain from using encainide or flecainide for VPD suppression in post-MI patients, opting for safer alternatives instead.