Antiarrhythmic Drugs for All Patients With an ICD?

Abstract

IN THE EARLY STAGES OF IMPLANTABLE CARDIOVERTER DEfibrillator (ICD) use, the combination of antiarrhythmic drug concurrent with the device seemed redundant, akin to “a belt plus suspenders.” Before long it was discovered that, over time, most patients eventually required antiarrhythmic medication in addition to the ICD. In this issue of JAMA, the results of the Optimal Pharmacological Therapy in Cardioverter Defibrillator Patients (OPTIC) trial reported by Connolly and colleagues raise the issue of whether antiarrhythmic therapy, plus a -blocker, should be initiated at the time of initial ICD implantation in an effort to reduce the likelihood of ICD shock. To respond to this question, it is important to examine the interaction of antiarrhythmic drug therapy with the ICD, and the consequences of such a combination. Antiarrhythmic medication is administered in patients with an ICD for a number of reasons. Most importantly, drug therapy can reduce or eliminate ICD shocks by suppressing ventricular arrhythmias, or by slowing ventricular tachycardia (VT) to such a degree that it can be terminated with programmed antitachycardia pacing. In addition to the suppression of such “appropriate” shocks, antiarrhythmic therapy may suppress the “inappropriate” shocks precipitated by supraventricular arrhythmias (primarily atrial fibrillation). Because ICD shocks have been associated with reduced physical capacity and impaired quality of life, suppression of such events may have important clinical benefits. Antiarrhythmic agents may also be added to suppress symptomatic ventricular and supraventricular arrhythmias that are neither fast enough nor sustained to the degree that they cause the ICD to discharge. A further benefit is that, in some cases, these drugs may reduce the defibrillation threshold (defined as the energy required to defibrillate the ventricles) and as such allow for successful defibrillation when the defibrillation threshold is otherwise increased to a level that does not provide an adequate margin of safety (the difference between the defibrillation threshold and maximum output). On the other hand, antiarrhythmic drugs can interfere with ICD function. Proarrhythmic effects of such drugs include torsades de pointes and stabilization of otherwise nonsustained VT. Furthermore, the cycle length of VT can become prolonged to a point that the heart rate no longer exceeds the programmed rate cutoff of the ICD, leaving the arrhythmia unrecognized by the device. In addition, the pharmacological agent may increase, rather than decrease, the defibrillation threshold, in the worst case rendering the ICD ineffective in defibrillating the ventricles. Whenever an antiarrhythmic agent is administered to a patient with an ICD, the effect on device function must be considered. Both animal and clinical studies provide insights to help predict such interactions. As a drug class effect, the category III antiarrhythmic agents (potassium channel blockers), such as sotalol, tend to lower defibrillation threshold, although this finding is variable. In a human study, the defibrillation threshold was lowered acutely by 32% with the addition of D-sotalol (the pure class III enantiomer of D,L-sotalol). This property of lowering the defibrillation threshold may be used clinically to improve the defibrillation threshold when the margin of safety is insufficient. In contrast with potassium channel blocking drugs, the category IC sodium channel blocking agents (flecainide acetate, propafenone hydrochloride) have shown variable effects in animal and human defibrillation threshold. Amiodarone, which shares membrane properties of all the antiarrhythmic drug classes, has been shown to increase the defibrillation threshold in animal models and in some (but not all) human studies. Owing to the often unpredictable effects of antiarrhythmic drugs on ICD function and defibrillation threshold, some clinical electrophysiologists advocate testing of the ICD, and even induction of VT in patients with clinical arrhythmia, before discharging a patient with a new antiarrhythmic agent. In general, -adrenergic blocking agents are considered to have a neutral effect on defibrillation threshold. In routine practice, adjunctive antiarrhythmic therapy is administered to between 49% and 69% of patients who have an ICD. In the Multicenter Automatic Defibrillator Implantation Trial (MADIT) I study, which compared standard therapy with the ICD, 46% of the patients enrolled in