Prevention of Implantable Defibrillator Shocks with Sotalol
Abstract & commentary
Synopsis: Sotalol decreases the risk of death or the delivery of a first defibrillator shock among patients with prior sustained ventriculator tachyarrhythmias who have ICDs in place. Sotalol should be considered as adjunctive therapy in such patients.
Source: Pacifico A, et al. N Engl J Med 1999;340: 1855-1862.
This study reports the results of a multicenter trial conducted in 44 U.S. and European centers on the effects of sotalol in patients with implantable cardioverter defibrillators (ICDs). Patients were eligible for inclusion in the trial if they had received their first or a replacement ICD within three months before enrollment. Patients who had received a replacement ICD must have received one shock during the preceding six months. All patients had an ICD that provided both antitachycardia pacing and high-energy shock therapy and also had the capacity to store electrograms from therapy episodes. The trial was a double-blind, placebo-controlled trial in which patients were randomized to receive sotalol or matching placebo with block stratification according to left ventricular ejection fraction at each site. The initial sotalol dose was 120 mg twice daily. The dose could be titrated either up or down according to electrocardiographic changes, either bradycardia or QT interval changes. The minimum dose allowed was 80 mg bid and the maximum dose was 160 mg bid. Sotalol was given once daily in patients with reduced renal function (i.e., creatinine clearance between 30-60 mL per minute). The primary end point was death from any cause plus delivery of a first appropriate shock. To exclude shocks delivered for supraventricular arrhythmias or device malfunction, stored electrograms from all events were analyzed by members of an events committee who made the final determination. Results were analyzed both according to an intention to treat principle as well as according to actual treatment at the time the end point was reached.
The study randomized 302 patients with 151 in each group. The clinical characteristics of the two groups were similar to those reported by other studies dealing with patients with sustained ventricular arrhythmias. The mean age was 62 years. More than 80% of the entire study group were male. Two-thirds of the patients had ejection fractions greater than 30%. More than 90% of the patients were in New York Heart Association class I or II. About 70% of the patients had coronary artery disease. About one-third of the patients had been resuscitated from cardiac arrest, while two-thirds of the patients had symptomatic or inducible ventricular tachycardia.
During the course of the study, the median daily dose of sotalol was 242 mg. Thirty-four percent of patients assigned to receive sotalol and 35% assigned to receive placebo discontinued double-blind therapy during the course of the 12-month trial. The most common reasons for discontinuation were presumed adverse effects in the sotalol group or recurrent arrhythmia in the placebo group.
Concomitant drug therapy other than beta blockers was similar between the groups. Although the proportion of patients receiving beta blockers at the start of the study was similar between the placebo group and the sotalol group, more patients had concurrent beta-blocker therapy discontinued in the sotalol group.
There were few deaths in the study. Four patients in the sotalol group died and seven patients in the placebo group died. Only two and three patients, respectively, died of cardiac causes. There were no deaths due to arrhythmia.
Kaplan-Meier life-table analysis of time to event for the combined end point of death plus delivery of shock for any reason differed significantly between the groups. Sixty-six percent of the patients in the sotalol group and 46% of the patients in the placebo group remained free of events at the end point at 12 months. Patients with low ejection fractions were more likely to receive shocks but sotalol had similar protective effects in both ejection fraction strata. The concurrent use of beta blockers other than sotalol had no significant effect on the risk of death or the delivery of first shock for any reason. When patients were censored at the time of discontinuation of therapy, the Kaplan-Meier analysis still showed benefit in the sotalol group.
Adverse events, including dizziness, fatigue, dyspnea, and heart failure, were frequent in both groups. Bradycardia was more frequent in the sotalol group (9% vs 2%). Only two patients in the study, one in each group, developed torsade de pointes.
Pacifico and colleagues conclude that sotalol decreases the risk of death or the delivery of a first defibrillator shock among patients with prior sustained ventricular tachyarrhythmias who have ICDs in place. They propose that sotalol be considered as adjunctive therapy in such patients.
Comment by John P. DiMarco, MD, PhD
Trials such as the Antiarrhythmics vs. Implantable Defibrillators Trial (AVID) (N Engl J Med 1997;337:1576-1583) have suggested that the ICD is the best initial therapy in patients with life-threatening ventricular tachyarrhythmias. However, the role of added therapy with antiarrhythmic drugs in such patients remains controversial. Initially, after the ICD was introduced, more than two-thirds of patients received concomitant antiarrhythmic drug therapy. In AVID, however, antiarrhythmic drug therapy was discouraged and usually introduced to decrease the frequency of shocks for recurrent ventricular arrhythmias or supraventricular arrhythmias. However, many patients who might otherwise have been eligible for AVID were excluded because investigators believed there was a need for some antiarrhythmic drug therapy prior to enrollment in the trial.
This study shows that selected use of antiarrhythmic therapy does have some benefits. In this well-designed trial, sotalol was begun in-hospital and an electrophysiologic study was performed before hospital discharge. The paper unfortunately does not tell us if the electrophysiologic study provided useful information. However, with the period of in-hospital monitoring, Pacifico et al were able to tailor the dose of sotalol to achieve antiarrhythmic benefit without excess toxicity. The data also clearly show that antiarrhythmic drug therapy alone is probably not adequate. The total event rates are high enough that one should be convinced that sotalol alone is inferior to the ICD even if it provides some improvement over placebo.
The role of sotalol as an antiarrhythmic drug, however, is still not certain. Some data have suggested that sotalol is not more effective than metoprolol in patients with sustained ventricular arrhythmias (Seidl K, et al. Am J Cardiol 1998;82:744-748). A prospective trial is now under way to compare these two agents. The relatively slow enrollment in this trial also raises questions about pre-enrollment bias. For example, in the AVID study, relatively few patients were randomized to sotalol in contrast to amiodarone. It is possible that only patients whom the investigators believed were "healthy" enough to tolerate sotalol were enrolled. It is also unfortunate that systematic quality of life assessments were not reported in this paper. Finally, Pacifico et al included only shocks and not episodes of antitachycardia pacing in their end point. Therefore, it is possible that sotalol changed the type of arrhythmia without preventing all types of recurrence.
This study supports the practice of depending on the ICD as primary therapy for patients with prior sustained ventricular arrhythmias. When needed, sotalol may be safely used to increase patient tolerance of this form of therapy.
In ICD patients, sotalol may be useful to:
a. reduce unnecessary shocks due to supraventricular arrhythmias.
b. reduce proarrhythmia associated with ICDs.
c. eliminate bradycardia in patients on beta blockers.
d. reduce appropriate shocks.
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