Abstract & Commentary
Synopsis: Data indicate that azimilide is a well-tolerated antiarrhythmic drug that decreases the frequency of ICD discharges or pacing in patients with ventricular tachycardia.
Source: Singer I, et al. J Am Coll Cardiol. 2004;43: 39-43.
Azimilide is a new antiarrhythmic drug that is being developed for treatment of primarily supraventricular, but also ventricular, arrhythmias. In this study, Singer and colleagues report the results of a multicenter, double-blind, placebo-controlled trial of azimilide for reduction of antiarrhythmic therapy in patients with implantable cardioverter defibrillators (ICDs). A total of 172 patients were recruited from 37 centers in the United States and randomly assigned to receive placebo, 35 mg, 75 mg, or 100 mg oral azimilide daily. Patients could be included in the study if they met one of the following criteria: an ICD implantation had occurred 30 days or more before randomization and the patient had had at least one ICD shock within the preceding year; or an ICD had been implanted for symptomatic VT within 30 days of randomization and the patient had an inducible sustained monomorphic VT. Patients with a history of class IV New York Heart Association failure, those taking other antiarrhythmic drugs, with unstable or recent ischemia, with a QTc longer than 440 msec or a history of polymorphic VT, hypertrophic cardiomyopathy or restrictive heart disease, or significant liver and renal dysfunction were excluded. After beginning therapy, all patients were evaluated at 0.5, 1, 3, 6, 9, and 12 months after beginning azimilide or placebo. Noninvasive electrophysiologic testing was performed to determine the defibrillation threshold at baseline and at the 1-month visit. The ICD was interrogated at every visit, and stored electrograms were retrieved. Patients were also seen after a documented ICD shock. An Andersen-Gill proportional hazard model was used to analyze recurrent ICD therapies. Only tachycardia detections that were treated appropriately with either shocks or antitachycardia pacing (ATP) were used in the analysis. The ICD therapy rates per patient-year exposure across treatment groups were compared using the log-rank test.
Of the 172 patients randomized in the study, 37 patients received placebo, 45 patients received 35 mg of azimilide, 45 patients received 75 mg of azimilide, and 46 patients received 125 mg of azimilide. A total of 2011 appropriate ICD therapies were detected in this study with a mean number per patient of 18 ± 50 and a median of 4. A total of 358 appropriate ICD shocks were detected with a mean number of shocks per patient of 4 ± 5 with a median of 2.
There was no difference between the groups in terms of age, left ejection fraction, or gender. Ten percent of patients had class III New York Heart Association congestive heart failure. No differences were observed in blood pressure, heart rate, or ECG variables. The use of concomitant medication was similar among the groups.
The overall proportion of patients who reported adverse events was similar across all groups. Seven (19%) were withdrawn from placebo and 33 (24%) from the 3 azimilide groups. There were 3 reported episodes of torsades de pointes in 2 patients. Both patients were receiving 125 mg of azimilide daily. Azimilide significantly reduced the frequency of appropriate ICD therapies in all active drug groups compared to placebo by 69%. There was no difference between the 3 doses. The hazard ratio for all 3 groups was 0.31. Azimilide therapy at these doses was not associated with any significant changes in defibrillation threshold or pacing threshold.
Singer et al conclude that their data indicate that azimilide is a well-tolerated antiarrhythmic drug that decreases the frequency of ICD discharges or pacing in patients with ventricular tachycardia.
Comments by John DiMarco, MD, PhD
Azimilide is an investigational class III antiarrhythmic drug currently undergoing clinical trials as a treatment of supraventricular and ventricular arrhythmias. It is unique in that it blocks both the rapid (IKr) and the slow (IKs) components of the delayed rectifier cardiac potassium channel. The data presented here, however, are quite surprising. There was no dose response over a greater than 3-fold dose range of 35-125 mg daily. In trials for therapy of atrial fibrillation, azimilide has only consistently shown effects at doses of 100 mg or 125 mg per day. If the data presented here are to be accepted at face value, that azimilide would seem to be effective in ventricular arrhythmias at lower doses with no greater effect at higher doses remains to be explained.
The population in this study is quite unusual. The patients had a very large total and mean number of VT or VF events. Although many of these events were probably terminations of runs of ventricular tachycardia with ATP in a few individuals, the median numbers of ATP therapies and the numbers of appropriate shocks are still quite substantial. This raises the possibility that the placebo group was just a true outlier and what we’re seeing in the other 3 groups is just an absence of meaningful drug effect.
There is currently a larger study, the Shock Inhibition With Azimilide (SHIELD) study in progress to confirm the results of this pilot study. It will be interesting to see if the data presented here can be confirmed in this larger trial.
Dr.DiMarco, Professor of Medicine, Division of Cardiology, University of Virginia, Charlottesville, is on the Editorial Board of Clinical Cardiology Alert.