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Shock Inhibition Evaluation With Azimilide - SHIELD
Description:
The goal of the trial was to evaluate treatment with the antiarrhythmic drug azimilide compared with placebo in patients with ventricular arrhythmias already treated with implanted cardioverter defibrillator (ICD) therapy.
Study Design
Study Design:
Patients Enrolled: 633
Mean Follow Up: 1 year
Mean Patient Age: 63 years
Female: 10
Mean Ejection Fraction: 34% at baseline
Patient Populations:
Within 42 days preceding first ICD implant, documented episode of sustained VT or episode of cardiac arrest/ventricular fibrillation (VF) with ejection fraction ≤40%; or pre-existing ICD implant with an ICD shock triggered by spontaneous VT or VF
Exclusions:
New York Heart Association class IV heart failure, unstable angina, recent myocardial infarction, prolonged QTc intervals at baseline or JTc, or a major illness
Primary Endpoints:
All-cause shocks plus symptomatic tachyarrhythmias terminated by ATP, and all-cause shocks
Secondary Endpoints:
Appropriate ICD therapies, defined as shocks or VT terminated by ATP
Drug/Procedures Used:
Patients were randomized to azimilide 75 mg/day (n = 220), azimilide 125 mg/day (n = 199), or placebo (n = 214). All patients also had an ICD implanted, and uniform programming of the ICD was used, with the "floor" for ventricular tachycardia (VT) detection specified according to the slowest documented VT rate, and a ceiling set at 200 bpm.
Concomitant Medications:
Beta-blockers (78%), angiotensin-converting enzyme inhibitors (74%), diuretics (62%), statins (60%), digoxin (38%), and aspirin (38%)
Principal Findings:
Compared with placebo, the primary endpoint of recurrent all-cause shocks plus symptomatic arrhythmias terminated by antitachycardia pacing (ATP) was significantly lower in the azimilide 75 mg group (52% vs. 58%, hazard ratio [HR] 0.43, p = 0.0006) and the azimilide 125 mg group (50% vs. 58%, HR 0.53, p = 0.0053). For the coprimary endpoint of all-cause shocks, the difference was not statistically significant for the comparison of placebo (53%) with azimilide 75 mg (48%, HR 0.72, p = 0.13) or azimilide 125 mg (46%, HR 0.83, p = 0.36). Recurrence of all appropriate ICD therapies occurred less frequently in the azimilide 75 mg group compared with placebo (61% vs. 63%, HR 0.52, p = 0.017) and the 125 mg group compared with placebo (55% vs. 63%, HR 0.38, p = 0.0004).
A cardiac emergency department (ED) visit or hospitalization occurred less frequently in the azimilide 75 mg group compared with placebo (21.8% vs. 38.3%, p < 0.001), and the 125 mg group compared with placebo (27.6% vs. 38.3%, p < 0.05). Most ventricular tachyarrhythmia events terminated by shocks or ATP were clustered together, with 79% of interevent intervals less than one day in the placebo group compared with 73% for azimilide 75 mg and 57% for azimilide 125 mg.
Adverse event rates were similar for the three treatment groups, with the exception of heart failure, which occurred more frequently in the placebo group (16%) compared with the azimilide 75 mg group (9%) or 125 mg group (11%). Study drug discontinuation also did not differ by treatment group (40% for placebo, 36% for azimilide 75 mg, and 35% for azimilide 125 mg). There were five patients in the azimilide groups and one in the placebo group with torsade de pointes, all of which were successfully treated by the ICD.
Interpretation:
Among patients with ventricular arrhythmias already treated with ICD therapy, use of the antiarrhythmic drug azimilide was associated with a reduction in the primary endpoint of all-cause shocks plus symptomatic tachyarrhythmias terminated by ATP compared with placebo. Furthermore, it is associated with a decrease in the incidence of cardiac ED visits or hospitalization compared with placebo. There was no difference in the incidence of all-cause shocks.
Azimilide is a class III antiarrhythmic agent that is still investigational and not yet approved by the FDA. Sotalol, another class III antiarrhythmic drug, but with blocking activity, has also been shown in studies to be associated with a reduction in the number of all-cause shocks in ICD patients.
References:
Dorian P, Al-Khalidi HR, Hohnloser SH, et al., on behalf of the SHIELD (SHock Inhibition Evaluation with AzimiLiDe) Investigators. Azimilide reduces emergency department visits and hospitalizations in patients with an implantable cardioverter-defibrillator in a placebo-controlled clinical trial. J Am Coll Cardiol 2008;52:1076-83.
Dorian P, Borggrefe M, Al-Khalidi HR, et al. Placebo-controlled, randomized clinical trial of azimilide for prevention of ventricular tachyarrhythmias in patients with an implantable cardioverter defibrillator. Circulation 2004;110:3646-54.
Presented by Paul Dorian at the American Heart Association Scientific Sessions, November 2004, New Orleans, LA.
Keywords: Tachycardia, Ventricular, Imidazolidines, Ventricular Fibrillation, Heart Failure, Piperazines, Sotalol, Emergency Service, Hospital, Heart Arrest, Defibrillators, Implantable, Torsades de Pointes, Calcium Channel Blockers
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