Related Experiment Videos
[Intermediary and substitution criteria in the development of anti-arrhythmia agents]
M Lièvre1, A Leizorovicz, J P Boissel
1Unité de pharmacologie clinique, Lyon.
Insights
Suppressing arrhythmias after myocardial infarction is not always beneficial, as shown by the Cardiac Arrhythmia Suppression Trial (CAST). Reducing arrhythmias does not reliably substitute for mortality as a measure of drug efficacy.
Area of Science:
- Cardiology
- Clinical Trials
- Pharmacology
Context:
- The Cardiac Arrhythmia Suppression Trial (CAST) challenged the traditional view that suppressing post-myocardial infarction arrhythmias is always beneficial.
- Methodologies in secondary prevention trials have led to anti-arrhythmia reduction being used as a surrogate for mortality.
- The efficacy of antiarrhythmic drugs has been historically assessed by their ability to suppress arrhythmias.
Purpose:
- To analyze the validity of using anti-arrhythmia suppression as a surrogate endpoint for mortality in myocardial infarction secondary prevention trials.
- To define and evaluate the advantages of "substitutive criteria" in clinical trial endpoints.
- To re-evaluate the relationship between anti-arrhythmic drug efficacy and mortality reduction.
Summary:
- A meta-analysis of 6 trials involving Class I antiarrhythmics post-myocardial infarction was conducted.
- Anti-arrhythmia effects were monitored using Holter monitoring, in parallel with mortality data.
- Results showed a significant reduction in arrhythmias (nearly 60%) but no significant change in mortality (p=0.41).
Impact:
- The study suggests that reducing arrhythmias is not a suitable surrogate endpoint for mortality in myocardial infarction trials.
- Findings indicate that anti-arrhythmia suppression may not accurately reflect overall patient benefit or mortality reduction.
- The research provides a critical perspective on clinical trial endpoint selection in cardiovascular medicine.
Abstract:
The traditional view that the suppression of arrhythmias (risk factor) after myocardial infarction can only be beneficial, has been queried by the results of the Cardiac Arrhythmia Suppression Trial (CAST) which showed increased mortality in two treatment groups. The methodology of trials of secondary prevention of myocardial infarction by antiarrhythmic agents partially explains why the reduction of anti-arrhythmias has come to be considered as a substitute for mortality in the assessment of drug efficacy. The authors define substitutive criteria and describe their three advantages (facility, correspondence, estimation). A meta-analysis of 6 trials of secondary prevention of myocardial infarction by Class I antiarrhythmics, in which the antiarrhythmic effect was evaluated (Holter monitoring) in parallel with mortality, shows that anti-arrhythmias were significantly reduced by nearly 60% (p = 10-8) whereas mortality remained unchanged (p = 0.41). A special graphic presentation of the results of these 6 trials shows that, even before the results of the CAST, it was clear that the suppression of antiarrhythmics was not a suitable substitutive end point for mortality.