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FDA CARDIO-RENAL ADVISORY COMMITTEE WILL REVIEW CAST STUDY

Executive Summary

FDA CARDIO-RENAL ADVISORY COMMITTEE WILL REVIEW CAST STUDY findings at its upcoming Oct. 5-6 meeting. Initiated in 1987 by the National Heart, Lung and Blood Institute, the Cardiac Arrhythmia Suppression Trial (CAST) was designed to determine whether antiarrhythmic drugs reduce sudden cardiac death in post-myocardial infarction patients with non-life-threatening arrhythmias. In April, labeling was modified for two anti-arrhythmic products -- Bristol-Myers' Enkaid (encainide) and Riker's Tambocor (flecainide) -- to restrict their use to life-threatening arrhythmias ("The Pink Sheet" May 1, p. 10). The label modification followed the announcement of interim data on approximately 1,500 patients taking the drugs. Investigators determined that 56 deaths or non-fatal cardiac arrests could be attributed to either of the two drugs compared to 22 events in the placebo group. However, an editorial in the Aug. 10 New England Journal of Medicine cautions against discontinuing the anti-arrhythmics in patients "treated effectively for prolonged periods." Discussing the combined flecainide/encainide data, the editorial acknowledges that the "substantial" increase in mortality among patients taking the drugs for asymptomatic or minimally symptomatic ventricular arrhythmias. However, the article continues: "Discontinuing encainide or flecainide in patients with sustained ventricular arrhythmias who have been treated effectively for prolonged periods is unwarranted and potentially dangerous." The editorial is authored by CAST data and safety monitoring board member Jeremy Ruskin, MD, Massachusetts General Hospital. He is a member of FDA's Cardio-Renal Drugs Advisory Committee. The unexpected results of the CAST study make the trial "an important milestone" in cardiology, Ruskin said. "Rather than serving as the definitive study of asymptomatic ventricular arrhythmias, CAST has instead upended old landmarks, challenged our preconceptions, and set new standards for research on cardiac arrhythmias," the editorial states. Specifically, the persistence of sudden death throughout the 10-month follow-up period among the drug group runs against the long-held assumption that patients are susceptible to drug-induced arrhythmias only in the early period of drug exposure, Ruskin noted. In addition, the trial's preliminary results "raise important questions" about the value of suppressing ventricular premature beats as a therapeutic endpoint in the post-MI patient population, he said. "Like other Class 1C agents, encainide and flecainide appear to exert proarrhythmic effects in patients with sustained ventricular arrhythmias more frequently than other classes of antiarrhythmic drugs," Ruskin continued. "In patients with a history of myocardial infarction, it seems prudent to reserve Class 1C agents for those in whom other antiarrhythmic drugs are ineffective or poorly tolerated." In an Aug. 4 "Dear Doctor" letter, Riker Medical Services Director George Eagleton, MD, noted that the company supplied Tambocor and a placebo for CAST but otherwise "did not participate" in the study. The company has submitted "data to regulatory authorities throughout the world" upon receiving it from the study, Eagleton said, adding that Riker looks forward to the FDA advisory committee's review of CAST results and to "clarification of this difficult area of medical therapeutics."
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