Current and Emerging Antiarrhythmic Drug Therapy for Ventricular Tachycardia

Cardiol Ther (2013) 2:27–46 DOI 10.1007/s40119-013-0012-5 REVIEW Current and Emerging Antiarrhythmic Drug Therapy for Ventricular Tachycardia Eric S. Williams • Mohan N. Viswanathan To view enhanced content go to www.cardiologytherapy-open.com Received: November 28, 2012 / Published online: February 20, 2013 Ó The Author(s) 2013. This article is published with open access at Springerlink.com ABSTRACT events continue to be a source of morbidity and impaired quality of life in such patients. Ventricular arrhythmias, including ventricular Antiarrhythmic therapy is indicated in select fibrillation (VF) and sustained ventricular patients to treat symptomatic VT episodes, to tachycardia (VT), are the principal causes of reduce the incidence of ICD shocks, and sudden cardiac death in patients with structural potentially to improve quality of life and heart disease. While coronary artery disease is reduce hospitalizations related to cardiac the predominant substrate associated with the arrhythmia. The primary adverse effects of development of VT, these arrhythmias are antiarrhythmic medications are related to both known to occur in a variety of disorders, cardiac and extracardiac toxicity, including the including dilated cardiomyopathy, valvular risk of proarrhythmia. Current drug therapy for and congenital heart disease, and cardiac ion ventricular arrhythmia has been limited by channelopathies such as the long QT syndrome. suboptimal efficacy in many patients, resulting In a minority of patients, VT occurs in the in recurrent VT/VF events, and by drug toxicity absence of structural heart disease. Despite the or intolerance leading to discontinuation in a established mortality benefit of the implantable large percentage of patients. Amiodarone cardioverter defibrillator (ICD) in patients at and sotalol are the principal agents used in risk of lethal arrhythmias, recurrent VT/VF the chronic treatment of VT. In addition, dronedarone and dofetilide, agents approved for the treatment of atrial fibrillation, and E. S. Williams (&) Á M. N. Viswanathan Division of Cardiology, University of Washington ranolazine, an antianginal agent, have been Medical Center, Seattle, WA, USA demonstrated to be protective against e-mail: [email protected] ventricular arrhythmia in small clinical studies. Finally, advances in basic electrophysiology have uncovered new molecular targets for the treatment of ventricular arrhythmia, and Enhanced content for this article is available on the journal web site: pharmacologic agents directed at these targets www.cardiologytherapy-open.com 123 28 Cardiol Ther (2013) 2:27–46 may emerge as promising VT treatments in the The principal mechanisms of future. The roles of these current and emerging arrhythmogenesis in the heart are abnormal therapies for the treatment of VT in humans will automaticity, triggered activity from after- be summarized in this review. depolarizations, and myocardial reentry [2]. Triggered activity and abnormal automaticity are the most important mechanisms of focal VT Keywords: Antiarrhythmic medications; arising from the ventricular outflow tracts, Ventricular fibrillation; Ventricular tachycardia although microreentrant circuits may also play a role. In the setting of myocardial scar from CAD, macroreentry is the most common INTRODUCTION mechanism contributing to VT [7, 8]. It is estimated that 1–5% of all patients with a Ventricular arrhythmias, including ventricular history of previous myocardial infarction (MI) tachycardia (VT) and ventricular fibrillation (VF), will develop VT. In the setting of acute MI, on are the leading cause of sudden cardiac death the other hand, the incidence of VT/VF ranges (SCD), which in turn represents about half of all from 2% to 10% [9, 10]. This upfront cardiovascular mortality and accounts for over arrhythmic risk has been reduced by early 350,000 deaths annually in the United States [1]. coronary reperfusion strategies, such as VT can be either sustained (lasting [30 s) thrombolytics and primary angioplasty, in the or nonsustained, and can have a uniform QRS acute phases of MI [2, 11]. The electrical morphology (monomorphic) or a variable substrate for VT following acute MI is morphology (polymorphic). It is the most established as early as 2 weeks postinfarction, common wide complex tachycardia seen in based on programmed ventricular stimulation association with structural heart disease [2]. The studies, and presumably is present indefinitely vast majority of VT is related to myocardial [12]. The abnormal substrate is characterized by pathologic processes that promote cardiac inflammation and fibrosis, cardiac hypertrophy, fibrosis or inflammation, most commonly from abnormal cell coupling, and ion channel coronary artery disease (CAD) in over 80% expression in the myocardium that promote of patients [3]. However, myocarditis, dilated ventricular arrhythmia [5]. The subsequent cardiomyopathy, congenital heart disease, development of VT in at-risk patients results cardiac infiltrative diseases, arrhythmogenic from the interplay of the abnormal myocardial right ventricular cardiomyopathy, and substrate and arrhythmogenic triggers. The hypertrophic cardiomyopathy are also known roles played by the autonomic nervous system, to contribute to an arrhythmogenic substrate. In hemodynamic stress, metabolic abnormalities, about 10% of patients, VT occurs in the absence and ventricular premature depolarizations as of structural heart disease [4]. This subset of proarrhythmic triggers have all been well VT is thought to be either idiopathic or described [6, 13]. related to primary electrical disease, such as The only intervention demonstrated to the long QT syndrome, Brugada syndrome, improve survival in patients at risk of SCD catecholaminergic polymorphic ventricular from ventricular arrhythmias is the implantable tachycardia (CPVT), or other cardiac ion cardioverter defibrillator (ICD). It is indicated channelopathies [5, 6]. for secondary prevention in patients with a 123 Cardiol Ther (2013) 2:27–46 29 history of sustained VT/VF, and for primary potentially to reduce hospitalizations related to prevention in patients with a history of heart cardiac arrhythmia [18]. failure or previous MI and left ventricular Current antiarrhythmic therapy for VT is ejection fraction (LVEF) of 35% or less [14]. limited by its potential for both cardiac and There are several limitations, however, with the extracardiac toxicity, including the risk of ICD as primary therapy for VT/VF. First, and proarrhythmia, and by its limited efficacy. In most important, is that although the ICD the Optimal Pharmacological Therapy in effectively terminates ventricular arrhythmias, Cardioverter Defibrillator Patients (OPTIC) it does not prevent them. Second is the trial, amiodarone and sotalol were each morbidity associated with both appropriate significantly more effective in preventing ICD and inappropriate ICD shocks. Third, the shocks compared to beta-blockers alone, but current selection criteria for ICD candidacy are 1-year shock rates were still 10% in the imperfect, as many ICD recipients never receive amiodarone arm and 24% in the sotalol arm, appropriate ICD therapy for VT/VF, whereas with drug-related adverse effects leading to many other patients with LVEF greater than discontinuation in one in five patients [19]. 35% who are not eligible for the ICD go on to No new antiarrhythmic agents have yet been experience SCD [15]. In addition, the benefit of approved for the treatment for VT in the past the ICD is not established in the early post-MI decade; however, novel concepts in the period; despite an increased risk of arrhythmic understanding of ventricular arrhythmogenesis death in this population, there was no have the potential to deliver new therapeutic difference in total mortality in patients within targets for VT that balance antiarrhythmic 6 and 40 days of acute MI treated with the ICD efficacy against the risks of organ toxicity, vs. medical therapy in a randomized trial [16]. negative inotropy, and proarrhythmic effects Antiarrhythmic drug therapy is commonly seen with contemporary drug therapy. used as adjunctive treatment in ICD recipients for Several clinical trials have evaluated the the suppression of VT/VF episodes. In the efficacy and safety of various antiarrhythmic Antiarrhythmic Versus Implantable Defibrillator medications used for the treatment of VT in (AVID) trial of secondary prevention ICD patients with established cardiovascular disease. therapy, the 1-year arrhythmia event rate was This review will summarize their findings and 90% in the ICD arm, and was reduced to 64% discuss more recent data on emerging with concurrent antiarrhythmic therapy [17]. pharmacotherapies for ventricular arrhythmia. Overall, up to 70% of patients with an ICD receive adjuvant antiarrhythmic drug therapy, even though there is no medication formally METHODS approved for this indication [18]. The indications for adjunctive antiarrhythmic therapy are: to The following review article incorporates data reduce the incidence of appropriate and from clinical trials, review articles, and inappropriate ICD shocks; to slow the rate of textbooks to provide a comprehensive and up- spontaneous VT episodes to improve their to-date summary of antiarrhythmic drug hemodynamic tolerance and to facilitate pace therapy for VT. Emerging antiarrhythmic termination by the ICD; to treat symptomatic therapies include those agents that have not VT episodes; to improve quality of life; and yet been approved for clinical use in VT but

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