CAST: Arrhythmia Suppression after Myocardial Infarction (1991)

“The results of the Cardiac Arrhythmia Suppression Trial (CAST) indicate that two such drugs, encainide and flecainide, do not improve survival in this group of patients and, in fact, are harmful.”

  • The CAST Investigators

1. Publication Details

  • Trial Title: Preliminary Report: Effect of Encainide and Flecainide on Mortality in a Randomized Trial of Arrhythmia Suppression after Myocardial Infarction
  • Citation: The Cardiac Arrhythmia Suppression Trial (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. 1989;321(6):406-412. DOI: 10.1056/NEJM198908103210629. Note: The definitive final report was published in 1991, but the 1989 preliminary report is the most cited as it announced the early termination for harm.
  • Published: August 10, 1989, in The New England Journal of Medicine
  • Author: The Cardiac Arrhythmia Suppression Trial (CAST) Investigators
  • Funding: The National Heart, Lung, and Blood Institute (NHLBI).

2. Keywords

  • Myocardial Infarction, Arrhythmia, Antiarrhythmic Drugs, Flecainide, Encainide, Sudden Cardiac Death, Randomized Controlled Trial

3. The Clinical Question

  • In patients with asymptomatic or mildly symptomatic ventricular arrhythmias after a recent myocardial infarction (Population), does treatment with antiarrhythmic drugs (encainide or flecainide) to suppress arrhythmias (Intervention) compared to placebo (Comparison) reduce the rate of death or cardiac arrest (Outcome)?

4. Background and Rationale

  • Existing Knowledge: It was well-established that patients who had frequent premature ventricular contractions (PVCs) after a myocardial infarction (MI) were at a much higher risk of sudden cardiac death. The prevailing “arrhythmia suppression hypothesis” was that these PVCs were not just markers of risk, but were triggers for fatal arrhythmias.
  • Knowledge Gap: It was a widespread and logical assumption that if you could suppress the “benign” PVCs with antiarrhythmic drugs, you would prevent sudden cardiac death. However, this physiologically plausible hypothesis had never been proven in a large, definitive randomized controlled trial.
  • Proposed Hypothesis: The authors hypothesized that suppressing ventricular arrhythmias with encainide or flecainide would reduce the rate of death from arrhythmia in post-MI patients.

5. Study Design and Methods

  • Design: A multicenter, prospective, randomized, double-blind, placebo-controlled trial (used to test the effectiveness of interventions).
  • Setting: Multiple clinical centers in the United States.
  • Trial Period: Enrollment ran from June 1987 to April 1989 (when the trial was stopped).
  • Population:
    • Inclusion Criteria: Adult patients who had a myocardial infarction 6 days to 2 years previously, had an average of 6 or more PVCs per hour, and had a left ventricular ejection fraction of ≤55%.
    • Exclusion Criteria: Included patients with sustained ventricular tachycardia or fibrillation.
  • Intervention: Patients who showed suppression of their PVCs during an open-label run-in phase were randomized to receive active treatment with either encainide or flecainide.
  • Control: Patients were randomized to receive a matching placebo.
  • Management Common to Both Groups: All patients received standard post-myocardial infarction care according to the practices of the time.
  • Power and Sample Size: The trial was designed to enroll 4400 patients to have sufficient power to detect a clinically meaningful reduction in mortality.
  • Outcomes:
    • Primary Outcome: A composite of death from arrhythmia or cardiac arrest.
    • Secondary Outcomes: Included total mortality.

6. Key Results

  • Enrollment and Baseline: 1498 patients were randomized before the trial was stopped (755 to active drug and 743 to placebo). The groups were well-matched at baseline.
  • Trial Status: The encainide and flecainide arms of the trial were stopped early by the data and safety monitoring board due to a significant increase in mortality in the active treatment group.
  • Primary Outcome: The rate of death from arrhythmia or cardiac arrest was significantly higher in the active-drug group: 33 of 755 patients (4.5%) died or had a cardiac arrest, compared with 9 of 743 patients (1.2%) in the placebo group (p=0.0006).
  • Secondary Outcomes: Total mortality was also significantly higher in the active-drug group (7.7% vs. 3.0%; p=0.0006).
  • Adverse Events: The primary adverse event was death, which was significantly more common in the active-drug group.

7. Medical Statistics

  • Analysis Principle: The trial was analyzed using an intention-to-treat principle.
  • Statistical Tests Used: The primary outcome was analyzed using a time-to-event analysis with a log-rank test.
  • Primary Outcome Analysis: The primary outcome was a comparison of the rates of death or cardiac arrest between the two groups.
  • Key Statistic(s) Reported: Relative Risk (RR) for death from arrhythmia: 3.6 (95% CI, 1.7 to 8.5).
  • Interpretation of Key Statistic(s):
    • Relative Risk (RR):
      • Formula: Conceptually, RR = (Risk in Intervention Group) / (Risk in Control Group).
      • Calculation: The paper reports the result as 3.6.
      • Clinical Meaning: The RR of 3.6 means that patients in the active-drug group had a 3.6 times higher risk of dying from an arrhythmia compared to the placebo group.
    • Confidence Interval (CI):
      • Formula: Conceptually, CI = (Point Estimate) ± (Margin of Error).
      • Calculation: The 95% CI was 1.7 to 8.5.
      • Clinical Meaning: Since this entire range is well above the line of no effect (1.0), it confirms that the result is highly statistically significant and demonstrates a profound level of harm.
    • P-value: The p-value of 0.0006 is extremely low, indicating the result is highly statistically significant (a result is conventionally considered statistically significant if the p-value is less than 0.05).
  • Clinical Impact Measures:
    • Absolute Risk Increase (ARI):
      • Formula: ARI = (Risk in Intervention Group) – (Risk in Control Group)
      • Calculation: ARI = 4.5% – 1.2% = 3.3%.
      • Clinical Meaning: For every 100 patients treated with these antiarrhythmic drugs, about 3 additional deaths or cardiac arrests occurred.
    • Number Needed to Harm (NNH):
      • Formula: NNH = 1 / ARI
      • Calculation: NNH = 1 / 0.033 = 30.
      • Clinical Meaning: You would only need to treat 30 patients with encainide or flecainide to cause one additional death or cardiac arrest.
  • Subgroup Analyses: The harm was consistent across all subgroups.

8. Strengths of the Study

  • Study Design and Conduct: The large, multicenter, randomized, double-blind, placebo-controlled design is the gold standard and was essential for uncovering this unexpected harm.
  • Generalizability: The inclusion of multiple centers increased the applicability of the findings.
  • Statistical Power: The study was large enough to detect a clear and definitive signal of harm, leading to its early termination.
  • Patient-Centered Outcomes: The study focused on the most important outcome: mortality.

9. Limitations and Weaknesses

  • Internal Validity (Bias): The study was well-conducted with a very low risk of bias.
  • External Validity (Generalizability): The findings are specific to the Class IC antiarrhythmic drugs studied (encainide and flecainide) in the post-myocardial infarction population.
  • Other: The trial was stopped early for harm, which was ethically necessary.

10. Conclusion of the Authors

  • The authors concluded that the antiarrhythmic drugs encainide and flecainide, despite being effective at suppressing PVCs, caused a significant increase in the risk of death from arrhythmia and total mortality in patients after myocardial infarction.

11. To Summarize

  • Impact on Current Practice: This was a profoundly practice-changing trial and one of the most important in the history of cardiology and evidence-based medicine. It completely overturned the “arrhythmia suppression hypothesis” and led to the immediate cessation of this widespread and harmful practice.
  • Specific Recommendations:
    • Patient Selection: For adult patients with asymptomatic or mildly symptomatic ventricular arrhythmias after a myocardial infarction.
    • Actionable Intervention: Do not administer Class IC antiarrhythmic drugs (flecainide, encainide) for the purpose of suppressing PVCs.
    • Expected Benefit: Avoiding this therapy prevents one additional death or cardiac arrest for every 30 patients.
  • What This Trial Does NOT Mean: This trial does NOT mean that all antiarrhythmic drugs are harmful in all situations. However, it serves as a powerful cautionary tale.
  • Implementation Caveats: This trial is a classic example of the “do not treat” lesson in medicine. It highlights the danger of relying on surrogate markers (like PVC suppression) instead of patient-centered outcomes (like survival).

12. Context and Related Studies

  • Building on Previous Evidence: The CAST trial (1989) was designed to definitively test a widely held belief that was based on physiological reasoning but lacked high-quality evidence.
  • Influence on Subsequent Research: The shocking results of CAST had a chilling effect on the development of antiarrhythmic drugs and fundamentally changed the way all new therapies are evaluated. It cemented the principle that a therapy must be proven to improve patient-centered outcomes, not just physiological or surrogate markers.

13. Unresolved Questions & Future Directions

  • Unresolved Questions: This trial definitively answered its primary question with a clear finding of harm.
  • Future Directions: The results of this trial shifted the focus of post-MI risk stratification away from PVC suppression and towards other strategies, such as assessing left ventricular function and, later, the use of implantable cardioverter-defibrillators (ICDs).

14. External Links

15. Framework for Critical Appraisal

  • Clinical Question: The research question was highly relevant, as it tested a very common and accepted clinical practice.
  • Methods: The multicenter, double-blind RCT design was of the highest quality and was absolutely essential for uncovering this unexpected harm. Without a placebo group, the excess deaths would have been attributed to the patients’ underlying disease.
  • Results: The study reported a statistically significant and clinically profound increase in harm (NNH of 30). The finding was so clear that the trial was stopped early.
  • Conclusions and Applicability: The authors’ conclusion is strongly supported by the data. The trial is a landmark in evidence-based medicine, serving as the ultimate example of how a logical, physiologically-based therapy can be deadly, and how only a rigorous, placebo-controlled trial can reveal such a truth.

16. Disclaimer and Contact

  • This summary is provided by the Academic Committee of ESBICM (ACE) to facilitate the understanding of this study; readers are advised to refer to the original trial document for a deeper understanding. If you find any information incorrect, or missing, or it needs an update or have a request for a specific critical care trial summary, kindly write to us at academics[at]esbicm.org.
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