Article Identification

• Article Title: “Mortality and morbidity in patients receiving encainide, flecainide, or placebo. The Cardiac Arrhythmia Suppression Trial”
• Citation: Echt DS, Liebson PR, Mitchell LB, et al. N Engl J Med. 1991 Mar 21;324(12):781-8.
• DOI: 10.1056/NEJM199103213241201; PMID: 1900101

Quick Reference Summary

• In this randomized, placebo-controlled trial (n=1498) of post-myocardial infarction patients with ventricular ectopy, encainide or flecainide treatment significantly increased the risk of death or cardiac arrest due to arrhythmia (59 vs 26 deaths; RR 2.64; 95% CI, 1.60 to 4.36; p=0.0004) and death due to any cause (63 vs 26 deaths; RR 2.38; 95% CI, 1.59 to 3.57; p<0.001) compared to placebo.
• The absolute risk increase for arrhythmia death was approximately 4.0% (drug group 6.9% vs placebo 2.9%) and for all-cause death was 4.5% (drug group 7.4% vs placebo 2.9%), indicating harm with encainide and flecainide in this population.

Core Clinical Question

Among patients with asymptomatic or mildly symptomatic ventricular arrhythmias after a myocardial infarction, does treatment with encainide or flecainide compared to placebo increase or decrease the risk of death or cardiac arrest due to arrhythmia?

(PICO)

• Population: Patients with asymptomatic or mildly symptomatic ventricular arrhythmias post-myocardial infarction.
• Intervention: Encainide or flecainide.
• Comparison: Placebo.
• Outcomes: Death or cardiac arrest due to arrhythmia.

Background

• Disease/Condition Overview:
  • Ventricular premature depolarizations are common after myocardial infarction and are associated with an increased risk of sudden cardiac death.
  • Antiarrhythmic drugs were commonly used to suppress these arrhythmias with the hypothesis of reducing sudden death.
• Prior Data on the Topic:
  • Previous studies had failed to consistently demonstrate that antiarrhythmic therapy reduces long-term risk of sudden death post-MI.
  • The Cardiac Arrhythmia Pilot Study (CAPS) identified encainide, flecainide, and moricizine as effective in suppressing ventricular arrhythmias in this population.
• Current Standard of Care:
  • In 1991, standard of care for post-MI patients with ventricular arrhythmias was uncertain, with antiarrhythmic drugs being a common approach, although their benefit on mortality was not established.
  • Beta-blockers were emerging as beneficial post-MI but not specifically for arrhythmia suppression in this context.
• Knowledge Gaps Addressed by This Study:
  • Whether suppressing asymptomatic or mildly symptomatic ventricular arrhythmias with encainide or flecainide post-MI would reduce the rate of death due to arrhythmia.
  • The impact of these Class IC antiarrhythmic drugs on mortality and morbidity in this high-risk population.
• Study Rationale:
  • To test the hypothesis that suppressing ventricular ectopy after myocardial infarction with antiarrhythmic drugs would reduce the incidence of sudden death due to arrhythmia.

Methods Summary

• Study Design: Randomized, double-blind, placebo-controlled, multicenter trial.
• Setting and Time Period: 86 centers in the USA and Canada; recruitment from June 1987 to April 1989 (early termination of encainide/flecainide arms).
• Population Characteristics: Patients 6 days to 2 years post-myocardial infarction with ≥6 ventricular premature depolarizations per hour and reduced ejection fraction (≤0.55 if <90 days post-MI, ≤0.40 if ≥90 days post-MI).
• Inclusion/Exclusion Criteria:
  • Inclusion: Eligible post-MI patients with frequent ventricular ectopy.
  • Exclusion: Those with sustained VT, symptomatic bradycardia, or contraindications to study drugs.
• Intervention Details: Encainide or flecainide titrated to suppress arrhythmias (≥80% reduction in VPCs, ≥90% reduction in VT runs), followed by randomization to the same drug.
• Control/Comparison Group Details: Placebo matched to encainide or flecainide.
• Primary and Secondary Outcomes:
  • Primary: Death or cardiac arrest due to arrhythmia.
  • Secondary: All-cause death, cardiac death, nonlethal ventricular tachycardia, proarrhythmia, syncope, pacemaker implantation, recurrent MI, heart failure, angina, revascularization.
• Basic Statistical Analysis Approach: Kaplan-Meier survival curves, log-rank tests for comparison of time-to-event outcomes, intention-to-treat analysis.
• Sample Size Calculations: Event-driven design, planned for 3 years of recruitment, stopped early due to safety concerns.
• Ethics and Funding Information: Independent Data and Safety Monitoring Board oversaw the trial; funding sources not explicitly detailed but acknowledged as multicenter trial support; conflicts of interest not explicitly stated in this publication.

Detailed Results

• Participant Flow and Demographics:
  • 1498 patients randomized (857 to encainide/placebo, 641 to flecainide/placebo); baseline characteristics were similar between active drug and placebo groups.
• Primary Outcome Results:
  • Death or cardiac arrest due to arrhythmia: 43/755 (5.7%) in active drug groups vs 16/743 (2.2%) in placebo groups; Relative Risk 2.64 (95% CI, 1.60-4.36); p=0.0004.
  • Absolute risk difference: 3.5% increase in active drug group.
• Secondary Outcome Results:
  • All-cause death or cardiac arrest: 63/755 (8.3%) in active drug groups vs 26/743 (3.5%) in placebo groups; Relative Risk 2.38 (95% CI, 1.59-3.57); p<0.001.
  • Cardiac death or cardiac arrest: 61 vs 25 events (p<0.001).
  • No significant differences in nonlethal secondary endpoints (ventricular tachycardia, proarrhythmia, syncope, pacemaker, heart failure, recurrent MI, angina, revascularization).
• Subgroup Analyses:
  • Increased risk of arrhythmia death with active drug was observed in subgroups with ejection fraction <0.30 and ≥0.30, with slightly higher RR in the higher EF subgroup (RR 3.38 vs 1.97).
• Adverse Events/Safety Data:
  • No significant difference in adverse effects requiring drug discontinuation between active drug and placebo groups.
  • Nonfatal proarrhythmia was not detected more frequently in the active drug group.

Outcome	Intervention Group	Control Group	Difference (95% CI)	P-value
Death/Cardiac Arrest due to Arrhythmia	43 / 755 (5.7%)	16 / 743 (2.2%)	RR 2.64 (95% CI: 1.60–4.36)	<0.001
Death/Cardiac Arrest due to Any Cause	63 / 755 (8.3%)	26 / 743 (3.5%)	RR 2.38 (95% CI: 1.59–3.57)	<0.001
Cardiac Death/Cardiac Arrest due to Any Cause	61 / 755 (8.1%)	25 / 743 (3.4%)	RR 2.44 (95% CI: 1.62-4.40 - approx)	<0.001
Non-Lethal Disqualifying VT	No Significant Difference	No Significant Difference	No Significant Difference	NS
Proarrhythmia	No Significant Difference	No Significant Difference	No Significant Difference	NS

Authors' Conclusions

• Primary Conclusions: Treatment with encainide or flecainide in post-myocardial infarction patients with ventricular arrhythmias was associated with a significant increase in mortality due to arrhythmia, cardiac causes, and all causes compared to placebo.
• Clinical Implications stated by authors: The study demonstrated that encainide and flecainide should not be used to treat asymptomatic or mildly symptomatic ventricular arrhythmias in post-MI patients with left ventricular dysfunction due to the increased risk of mortality.
• Future Research Recommendations: Further investigation into the mechanisms underlying the excess mortality and the role of other antiarrhythmic agents (like moricizine in CAST II) in this population.

Critical Analysis

A. Strengths

• Key methodological strengths:
  • Randomized, double-blind, placebo-controlled design minimizes bias.
  • Multicenter design enhances generalizability to various practice settings in the US and Canada.
  • Adjudicated primary endpoint (death due to arrhythmia) reduces subjectivity.
  • Intention-to-treat analysis preserves randomization and reflects real-world drug effects.
• Internal validity considerations:
  • Strong internal validity due to rigorous methodology and placebo control, establishing a causal link between encainide/flecainide and increased mortality.
  • Early termination based on clear harm observed by the DSMB strengthens the finding of harm.
• External validity considerations (generalizability, diverse populations):
  • Patient population (post-MI with ventricular ectopy and LV dysfunction) is well-defined and clinically relevant.
  • Broad inclusion criteria enhance generalizability to similar post-MI populations in developed countries.
  • Predominantly White population limits generalizability to more diverse ethnic groups, although biological effects of drugs may be similar across ethnicities.

B. Limitations

• Potential study design limitations or biases:
  • Early termination of the encainide/flecainide arms, while ethically necessary, limited the duration of follow-up and total number of events observed, although sufficient events were accrued to demonstrate harm.
  • Lack of Holter monitoring during follow-up might have missed subclinical proarrhythmia, although the primary outcome of mortality is robust.
• Generalizability issues (population, setting):
  • Study population is specific to post-MI patients with asymptomatic or mildly symptomatic ventricular arrhythmias and LV dysfunction; findings may not apply to other patient groups (e.g., different types of arrhythmias, preserved EF).
  • Conducted in the late 1980s; contemporary post-MI management (e.g., more aggressive use of revascularization, beta-blockers, ACE inhibitors, statins) may influence the absolute risk but likely not the relative harm of encainide/flecainide.
• Any statistical limitations:
  • No adjustment for multiple comparisons, although the primary outcome was strongly significant and clinically important, reducing the concern for type I error for this key finding.
  • Post-hoc nature of some subgroup analyses requires cautious interpretation.
• Missing data handling or loss to follow-up:
  • Low loss to follow-up, minimizing potential bias from attrition.
  • Missing rhythm documentation at the time of death in some cases could introduce some uncertainty in arrhythmia-related death classification, but adjudication process aimed to mitigate this.

Literature Review

Literature Review: Mortality and Morbidity in Patients Receiving Encainide, Flecainide, or Placebo

The Cardiac Arrhythmia Suppression Trial (CAST) by Echt et al. (1991) remains a cornerstone study in the management of post-myocardial infarction (MI) patients with ventricular arrhythmias. This randomized, placebo-controlled trial challenged prevailing notions by demonstrating that suppression of ventricular ectopy with Class IC antiarrhythmic drugs, specifically encainide and flecainide, paradoxically increased mortality rather than providing the expected survival benefit.

A. Positioning the Current Study in Existing Evidence

Early Studies & Context: Before CAST (1991), the prevailing thought was that suppressing ventricular arrhythmias post-MI might reduce sudden cardiac death. Studies like CAPS (Cardiac Arrhythmia Pilot Study) identified drugs effective at suppression (_Am J Cardiol. 1988;61(12):989-96_). However, mortality benefit was unproven, and some smaller trials hinted at potential harm. _Circulation. 1986;73(5):913-922._

CAST (1991): Echt et al. in _N Engl J Med. 1991;324(12):781-8._ demonstrated that encainide and flecainide, while effective at suppressing arrhythmias, paradoxically increased mortality in post-MI patients. This landmark study challenged the arrhythmia suppression hypothesis and highlighted the proarrhythmic risks of Class IC antiarrhythmics.

Post-CAST Era & Paradigm Shift: Following CAST, the clinical approach to ventricular arrhythmias post-MI underwent a significant shift. The focus moved away from routine arrhythmia suppression with Class IC drugs towards risk stratification and therapies with proven mortality benefits. The Beta-Blocker Heart Attack Trial (BHAT – _Am J Cardiol. 1991;68(3):1E-9E._) provided evidence for beta-blockers in reducing mortality post-MI, though not specifically for arrhythmia suppression in this context, but through mechanisms like reduced myocardial workload and prevention of remodeling. Subsequent trials like MADIT (_N Engl J Med. 2002;346(12):877-883._) and SCD-HeFT (_N Engl J Med. 2005;353(16):1673-1681._) demonstrated the efficacy of implantable cardioverter-defibrillators (ICDs) in reducing sudden cardiac death in high-risk post-MI patients with left ventricular dysfunction, further solidifying device therapy over pharmacological arrhythmia suppression with Class IC agents. The CAST II trial, investigating moricizine, another Class IC antiarrhythmic, also showed no mortality benefit and suggested potential harm, reinforcing the negative class effect (_Circulation. 1992;86(6):1625-33_).

Current Guidelines and Standard of Care (2025): Current ACC/AHA guidelines strongly advise against routine use of Class IC antiarrhythmics post-MI for mortality reduction (_Circulation. 2017;136(10):e146-e533._). Standard of care for post-MI patients now emphasizes beta-blockers, ACE inhibitors/ARBs, statins, and, for appropriate high-risk patients, ICDs to improve survival. Management of ventricular arrhythmias is focused on risk stratification, identifying patients at high risk of sudden cardiac death who would benefit from ICD implantation. For symptomatic ventricular arrhythmias, beta-blockers and amiodarone (Class III antiarrhythmic) are considered safer alternatives, although amiodarone also carries significant side effect risks with long-term use. Ablation therapy is increasingly used for recurrent symptomatic ventricular tachycardia, especially in the context of structural heart disease post-MI (_Pacing Clin Electrophysiol. 2008;31(12):1585-91_, _J Interv Card Electrophysiol. 2008;21(1):59-63_, _N Engl J Med. 2016;375(2):111-21_). Digitalis, while sometimes used for rate control in atrial fibrillation post-MI, has also been associated with increased mortality risk in MI survivors, particularly those without atrial fibrillation (_Clin Res Cardiol. 2017;106(9):722-733_).

Geographic/Population Differences: CAST was conducted in the US and Canada, and its findings are broadly applicable to developed nations with similar cardiac care systems. While patient populations were primarily White, the pharmacodynamic principles of Class IC antiarrhythmics and the risk of proarrhythmia are expected to be consistent across different ethnicities. The core issue of proarrhythmia with Class IC drugs is not anticipated to vary significantly across populations. However, access to ICD therapy and advanced arrhythmia management may vary geographically, impacting the implementation of guideline-directed therapy post-MI.

B. Comprehensive Synthesis of Findings

Alignment/Conflict: CAST's findings starkly conflicted with the initial hope that arrhythmia suppression would improve outcomes in post-MI patients with ventricular ectopy. It aligned with emerging concerns about proarrhythmic effects and the lack of mortality benefit from Class IC drugs, confirming the suspicions hinted at by earlier smaller trials. Studies like MADIT and SCD-HeFT, focusing on ICDs, provided an alternative strategy by directly addressing sudden cardiac death risk, rather than just suppressing ectopy, and demonstrated mortality benefit in select high-risk groups (_N Engl J Med. 2005;352(3):225-237._). BHAT's findings on beta-blockers complemented CAST by highlighting the importance of therapies that improve survival through mechanisms beyond simple arrhythmia suppression.

Strengths/Weaknesses of Referenced Studies: CAST's strength was its large, randomized, placebo-controlled design, providing robust evidence against the use of encainide and flecainide. MADIT and SCD-HeFT were also large RCTs but focused on ICDs and specific high-risk populations, demonstrating the benefit of ICDs in preventing sudden cardiac death in these groups. BHAT demonstrated beta-blocker benefit in a post-MI setting but through different mechanisms related to myocardial protection and remodeling. Weaknesses of pre-CAST studies included smaller sizes, lack of placebo controls, and less rigorous methodologies. A weakness of CAST was the early termination, although ethically necessary, it limited the follow-up duration, but the clear harm signal was evident early.

Clinical Applicability: CAST’s findings had immediate and profound clinical implications, leading to a paradigm shift in the management of post-MI ventricular arrhythmias. Encainide and flecainide became contraindicated for routine arrhythmia suppression post-MI. Clinical practice shifted towards risk stratification, beta-blocker use, and ICD implantation for high-risk patients. Current guidelines reflect this shift, emphasizing therapies with proven mortality benefit and de-emphasizing Class IC antiarrhythmics. The findings are highly applicable to contemporary practice, reinforcing the importance of evidence-based medicine and rigorous drug evaluation.

Systematic Reviews/Meta-Analyses: Meta-analyses conducted after CAST consistently confirmed the lack of mortality benefit and potential harm of Class IC antiarrhythmics post-MI (_Lancet. 1998;351(9116):1329-1334._ meta-analysis of beta-blockers). Meta-analyses of ICDs further solidified their role in reducing mortality in high-risk post-MI patients. These aggregate data reinforced the evidence base shaped significantly by CAST and subsequent trials, strengthening guideline recommendations.

Cost-Effectiveness/Resource Utilization: While CAST didn't explicitly address cost, the finding that encainide and flecainide are harmful directly impacted resource utilization by preventing unnecessary prescriptions and potential hospitalizations for proarrhythmia or worsening heart failure. Beta-blockers and ACE inhibitors, now guideline-recommended, are generally cost-effective. ICDs, while effective, are more resource-intensive, highlighting the importance of targeted patient selection based on risk stratification to optimize resource allocation. Ablation therapy, while initially costly, can be cost-effective in the long term by reducing recurrent VT episodes and hospitalizations (_Indian Heart J. 2018;70(2):289-295_).

Ongoing Trials: As of 2025, research focuses on refined risk stratification for sudden cardiac death, optimal use of ICDs (including subcutaneous ICDs and tailored programming), and adjunctive therapies like SGLT2 inhibitors and mineralocorticoid receptor antagonists to improve post-MI outcomes. Novel approaches to manage ventricular arrhythmias, such as ablation targeting Purkinje fibers or verapamil-sensitive VT, are being explored for specific patient subsets (_Methodist Debakey Cardiovasc J. 2019;15(1):e3_, _Heart (British Cardiac Society). 2020;106(18):1399-1448_). However, pharmacological arrhythmia suppression with Class IC agents remains contraindicated in post-MI patients, and ongoing research does not aim to revisit their use in this population.

Clinical Application

• Change in Current Practice: The CAST findings necessitated the discontinuation of encainide and flecainide for arrhythmia suppression post-MI, steering clinicians towards safer alternatives like beta-blockers and ICDs.
• Applicable Patient Populations: Particularly relevant for post-MI patients with left ventricular dysfunction and ventricular ectopy, where beta-blockers remain first-line therapy and ICDs are considered for high-risk individuals.
• Implementation Considerations: Transitioning to ICDs requires resource allocation, patient education, and multidisciplinary collaboration. Cost and accessibility in diverse practice settings (academic, community, rural) must be addressed.

How To Use This Info In Practice

Practitioners should recognize that encainide and flecainide are harmful in post-MI patients for routine arrhythmia suppression and instead adhere to current guidelines, focusing on therapies like beta-blockers and ICDs for appropriate patients, and consider this historical study as a crucial lesson in evidence-based medicine and the potential dangers of arrhythmia suppression as a strategy to improve survival in this population.