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The Cardiac Arrhythmia Suppression Trial: first CAST ... then CAST-II
H L Greene1, D M Roden, R J Katz
1Department of Medicine, University of Washington, Seattle.
Insights
The Cardiac Arrhythmia Suppression Trial found that suppressing ventricular premature complexes after heart attack worsened survival. CAST-II was terminated early due to increased cardiac mortality with moricizine.
Area of Science:
- Cardiology
- Clinical Trials
- Pharmacology
Background:
- The Cardiac Arrhythmia Suppression Trial (CAST) investigated if suppressing ventricular premature complexes post-myocardial infarction improved survival.
- Initial CAST results indicated that encainide and flecainide worsened survival, leading to the CAST-II trial.
Purpose of the Study:
- To test the hypothesis that suppressing ventricular premature complexes after myocardial infarction improves survival.
- To evaluate the efficacy and safety of moricizine compared to placebo in patients post-myocardial infarction.
Main Methods:
- CAST-II modified enrollment criteria to include patients with a higher likelihood of serious arrhythmias.
- Protocol changes included a narrowed enrollment window (4-90 days post-MI), lower ejection fraction threshold (≤0.40), and adjusted ventricular tachycardia definitions.
- Drug titration was double-blinded against placebo.
Main Results:
- CAST-II was terminated prematurely due to excessive cardiac mortality observed in patients treated with moricizine within the first two weeks.
- There was a low probability of demonstrating a long-term survival benefit with moricizine treatment.
Conclusions:
- Suppression of ventricular premature complexes after myocardial infarction may not improve, and could potentially worsen, survival.
- Moricizine demonstrated an unacceptable cardiac mortality risk in the early post-MI period.
- The CAST and CAST-II trials highlight the complexities and risks associated with antiarrhythmic drug therapy in post-MI patients.
Abstract:
The Cardiac Arrhythmia Suppression Trial (CAST) was a study designed to test the hypothesis that suppression of ventricular premature complexes after a myocardial infarction would improve survival. Preliminary results showed that suppression of ventricular premature complexes with encainide and flecainide worsened survival, and the CAST continued as the CAST-II with moricizine compared with its placebo. The protocol for the CAST-II was changed to attempt to enroll patients more likely to experience serious arrhythmias. The enrollment time was narrowed to 4 to 90 days after myocardial infarction; the qualifying ejection fraction was lowered to less than or equal to 0.40; a higher dose of moricizine could be used; early titration itself was double-blind with a placebo, and the definition of disqualifying ventricular tachycardia was changed to allow patients with more serious arrhythmias to be entered into the trial. The Cardiac Arrhythmia Suppression Trial-II was subsequently terminated prematurely because 1) patients treated with moricizine had an excessive cardiac mortality rate during the 1st 2 weeks of exposure to the drug, and 2) there appeared to be little chance of showing a long-term survival benefit from treatment with moricizine. This report outlines the rationale behind the Cardiac Arrhythmia Suppression Trial and the reasons for selection of the drugs used in the CAST and CAST-II.