Cardiol Ther (2013) 2:27–46 DOI 10.1007/s40119-013-0012-5

REVIEW

Current and Emerging Antiarrhythmic Drug Therapy for Ventricular

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 , 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 disease. While coronary artery disease is reduce hospitalizations related to cardiac the predominant substrate associated with the . 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. cardioverter defibrillator (ICD) in patients at and are the principal agents used in risk of lethal arrhythmias, recurrent VT/VF the chronic treatment of VT. In addition, and , agents approved for the treatment of atrial fibrillation, and E. S. Williams (&) M. N. Viswanathan Division of Cardiology, University of Washington , 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 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

123 30 Cardiol Ther (2013) 2:27–46 have been tested in clinical investigations or such as congenital long QT syndrome and CPVT early phase clinical trials in humans in the past [41]. decade (2002–2012). In the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II), bisoprolol reduced all-cause mortality by 34% and sudden cardiac death by DISCUSSION 44% in patients with heart failure [30]. The Clopidogrel and in Myocardial Current Antiarrhythmic Therapy Infarction Trial (COMMIT) randomly assigned over 45,000 patients to either a combination of Classification of Antiarrhythmic Agents intravenous and oral metoprolol or placebo The most common classification scheme for within 24 h of acute MI, and showed that the antiarrhythmic agents is the Vaughan Williams use of early beta-blocker therapy reduced the classification, which characterizes drugs based risk of VF development, although this was on their ability to block specific ion currents counterbalanced by an increase in cardiogenic or cell receptors [20]. Table 1 summarizes shock, especially during the first day after these agents and their use in the treatment admission [31]. Overall, a meta-analysis of of ventricular arrhythmias, and Table 2 beta-blocker studies in post-MI patients summarizes the results of select clinical trials suggests a significant relative benefit in with these medications. Class I agents are preventing SCD and all-cause mortality [42]. blockers, further divided into Class IA (, and Amiodarone ), Class IB (, ), Amiodarone is an iodinated and Class IC (flecainide, ). Class II derivative that is highly lipophilic. It combines agents are beta-adrenergic blockers, properties of all Vaughan Williams such as . Class III agents are classifications, possessing sodium channel, blockers, such as potassium channel, , and amiodarone, sotalol, dofetilide, and beta- blocking activity. It dronedarone. Class IV agents are calcium accumulates in a variety of organ tissues, channel blockers, such as . The including adipose, leading to an elimination Vaughan Williams classification does not, half-life of over 30 days. In fact, amiodarone can however, account for the complex actions of be detected in plasma up to 9 months after certain antiarrhythmics, such as amiodarone, discontinuation [22]. which is known to have multichannel blocking In the pre-ICD era, amiodarone had an properties [38]. established use for the prevention of SCD in high-risk patients with a history of previous MI Beta-Blockers or aborted SCD [43]. Meta-analysis showed a Beta-blockers are considered first-line therapy modest reduction in all-cause mortality with for patients with systolic heart failure and amiodarone vs. placebo [44]. A pooled analysis following acute MI for their established of the European Amiodarone Myocardial survival benefit in these populations [30, 31, Infarction Trial (EMIAT) and the Canadian 39, 40]. In addition, beta-blockers are indicated Amiodarone Myocardial Infarction Trial in the treatment of certain ion channelopathies, (CAMIAT) that evaluated amiodarone use in

123 Table 1 Summary of antiarrhythmic medications used for ventricular tachycardia 2:27–46 (2013) Ther Cardiol Drug V-W Dosage (oral) Metabolism Adverse effects Drug–drug interactions [reference] class Quinidine IA 324–648 mg q8h (gluconate) Hepatic Diarrhea, stomach cramps, tinnitus, ; dose by 50%; ; warfarin and [21] 300–600 mg q6h (sulfate) (CYP3A4) fever, rash, thrombocytopenia, beta-blocker dose; amiodarone, and renal hemolytic anemia, QT prolongation, cimetidine and verapamil may : torsades quinidine levels Disopyramide IA 150–300 mg q6h (150 mg q12–24h in Primarily Urinary retention, blurred vision, may ; disopyramide levels; [21] moderate–severe CKD) renal constipation, dry mouth, QT use caution with co-administration of prolongation, torsades other QT prolonging medications Mexiletine IB 150–300 mg q8h Hepatic Nausea, stomach cramps, tremor, Cimetidine and quinidine may : [21] (CYP2D6) blurred vision, ataxia, confusion mexiletine levels IC 50–200 mg q12h (50–200 mg q24h in Hepatic Tremor, blurred vision, headache, Amiodarone, cimetidine, propranolol [21] significant CKD) (CYP2D6) ataxia, PR and QRS prolongation, and quinidine may : flecainide levels and renal proarrhythmia Propafenone IC 150–300 mg q8h Hepatic Constipation, dizziness, headache, ; digoxin dose by 25–50%; cimetidine [21] (CYP2D6, metallic taste, bronchospasm, and quinidine may : propafenone 3A4, 1A2) , PR and QRS levels prolongation, proarrhythmia Amiodarone III Loading dose 400 mg q6–12h for 10 g Hepatic Pulmonary toxicity, hypo/ ; digoxin and warfarin dose by [22] Maintenance dose 200–600 mg/day (CYP3A4) hyperthyroidism, hepatic toxicity, 25–50% neuropathy, corneal deposits, bradycardia, prolongation of PR, QRS, QT Sotalol [22] III Start 80 mg q12h (80 mg q24h if Renal Bradycardia, fatigue, bronchospasm, Use caution with co-administration of moderate CKD) Maintenance dose heart failure, QT prolongation, other QT prolonging medications

123 80–160 mg q12h (40–80 mg q12h in torsades CKD). Avoid in severe CKD 31 32 123 Table 1 continued Drug V-W Dosage (oral) Metabolism Adverse effects Drug–drug interactions [reference] class

Dofetilide III 500 lg q12h if CrCl[60; 250 lg q12h Renal and Headache, chest pain, dizziness, Do not administer dofetilide with [23–25] if CrCl 40–60; 125 lg q12h if CrCl hepatic respiratory tract infection, dyspnea, cimetidine, , 20–39. Avoid in severe CKD (CYP3A4) nausea, QT prolongation, torsades prochlorperazine, megestrol, verapamil, trimethoprim or hydrochlorothiazide Dronedarone III 400 mg q12h Hepatic Diarrhea, nausea, stomach cramps, Verapamil and may : [26, 27] (CYP3A4) QT prolongation, bradycardia, heart dronedarone levels; dronedarone may failure, hepatic toxicity : digoxin, beta-blocker and simvastatin levels Ranolazine IB 500–1,000 mg q12h Hepatic Dizziness, headache, nausea, QT Ranolazine may : digoxin and [28, 29] (CYP3A4) prolongation simvastatin levels; diltiazem and verapamil may : ranolazine levels CKD chronic kidney disease, CrCl creatinine clearance, CYP cytochrome P450, q6h, q8h, q12h, q24h dosing every 6, 8, 12, 24 h, respectively, V-W Vaughan Williams ado hr(03 2:27–46 (2013) Ther Cardiol Table 2 Summary of clinical trials of antiarrhythmic medications 2:27–46 (2013) Ther Cardiol Study Population N Agent(s) studied Follow-up Primary endpoint Results [reference] CIBIS II Heart failure with 2,647 Bisoprolol vs. placebo Mean of All-cause mortality Mortality was lower with [30] NYHA Class 3 or 4 1.3 years bisoprolol compared to placebo symptoms, ejection (11.8% vs. 17.3%; hazard ratio fraction B35% 0.66, P\0.0001). Sudden death was lower with bisoprolol compared to placebo (3.6% vs. 6.3%; hazard ratio 0.56, P = 0.0011) COMMIT Acute MI patients within 45,852 Metoprolol (IV plus oral) 28 days 1. Death, reinfarction, or No significant difference in either [31] 24 h of suspected onset vs. placebo cardiac arrest primary outcome. Fewer patients 2. Death from any cause had ventricular fibrillation with metoprolol vs. placebo (2.5% vs. 3.0%; odds ratio 0.83, P = 0.001) but more developed cardiogenic shock (5.0% vs. 3.9%; odds ratio 1.30, P\0.00001) OPTIC Secondary prevention 412 Amiodarone ? beta- 1 year ICD shock for any reason Fewer shocks with [19] ICD recipients blocker vs. sotalol vs. amiodarone ? beta-blocker beta-blocker (10.3%) compared to sotalol (24.3%) or beta-blocker alone (38.5%)

Pacifico Secondary prevention 302 D,L-sotalol vs. placebo 1 year Death or ICD shock from any Lower risk of death or ICD shock et al. [32] ICD recipients cause with sotalol over placebo (reduction in risk, 48%, 123 P\0.001). Sotalol also reduced the mean frequency of shocks due to any cause (1.43 vs. 3.89 shocks per year, P = 0.008) 33 34 123 Table 2 continued Study Population N Agent(s) studied Follow-up Primary endpoint Results [reference]

SWORD Previous MI, ejection 3,121 D-Sotalol vs. placebo Mean of All-cause mortality Higher risk of death with D-sotalol [33] fraction B40% 148 days over placebo (5.0% vs. 3.1%; relative risk 1.65, P = 0.006). Arrhythmic deaths accounted for the increased mortality EMIAT/ Survivors of acute MI 2,687 Beta- 2 years All-cause mortality, cardiac Event rates were significantly lower CAMIAT with either ejection blockers ? amiodarone, death, arrhythmic cardiac for patients receiving beta- pooled fraction B 40% beta-blockers alone, death, nonarrhythmic blockers ? amiodarone compared analysis (EMIAT), or with amiodarone alone vs. cardiac death, arrhythmic to beta-blockers alone, [34] frequent ventricular placebo death, or resuscitated cardiac amiodarone alone, or placebo ectopy (CAMIAT) arrest CAST [35] Survivors of acute MI 1,498 or flecainide vs. Mean of All-cause mortality Increased mortality with encainide with frequent placebo 10 months or flecainide compared to ventricular ectopy placebo, including both arrhythmic death (P = 0.0004), and nonarrhythmic cardiac death (P = 0.01) SHIELD ICD recipients with 633 Aimilide vs. placebo 1 year 1. All-cause shocks plus All-cause shocks plus symptomatic [36] history of VT/VF symptomatic ventricular tachycardia tachyarrhythmias terminated by antitachycardia terminated by pacing were significantly reduced

antitachycardia pacing by (hazard ratio 0.43, 2:27–46 (2013) Ther Cardiol 2. All-cause shocks P = 0.0006 on 75 mg dose; hazard ratio 0.53, P = 0.0053 on 125 mg dose). The reductions in all-cause shocks on azimilide were not statistically significant Cardiol Ther (2013) 2:27–46 35

patients recovering from MI (EMIAT enrolled patients with LVEF B40% and CAMIAT enrolled patients with frequent or repetitive ventricular ectopy) found that incidences of cardiovascular death and arrhythmic death or resuscitated cardiac arrest were significantly lower in ventricular fibrillation, patients receiving both beta-blockers and VF amiodarone than in those not receiving beta-

primary outcome with celivarone vs. placebo blockers, with or without amiodarone [34]. No significant difference in the Conversely, in the era of the primary prevention ICD, amiodarone did not confer a survival benefit over placebo in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) of symptomatic heart failure patients with LVEF of 35% or less [45]. New York Heart Association, Amiodarone plus beta-blockers was shown to be superior to monotherapy with sotalol or sudden death NYHA ICD therapy for VT/VF or beta-blockers in the OPTIC trial for the reduction of shocks in secondary prevention ICD recipients [19]. As a result of its greater

9 months efficacy, amiodarone is the most common used for suppression of

number of patients, VT in patients with structural heart disease and

N ICDs. In the AVID trial, nearly twice as many patients in the ICD arm who ultimately received adjuvant antiarrhythmic therapy were treated with amiodarone compared to either sotalol or mexiletine [17]. Amiodarone has a low risk of proarrhythmia, myocardial infarction, despite causing prolongation of the action 486 Celivarone vs. placebo Median of MI potential duration and QT interval, probably because it reduces heterogeneity of

40% depolarization. Torsade de pointes occurred in B less than 1% in the EMIAT and CAMIAT trials [46, 47]. Extracardiac toxicity, however, is well described, and is related to both a daily and cumulative dose effect of amiodarone. Clinical

history of VT/VF and ejection fraction hypothyroidism occurs in up to 32% of patients, ICD recipients with Population N Agent(s) studied Follow-up Primary endpoint Results and may require thyroxine supplementation continued even after drug discontinuation [22]. implantable cardioverter defibrillator, ] ventricular tachycardia Hyperthyroidism can also occur, but is less 37 [ ALPHEE VT Table 2 Study [reference] ICD common in the western world where dietary

123 36 Cardiol Ther (2013) 2:27–46 iodine intake is adequate. Pulmonary toxicity is chronic kidney disease (because of its less common but is among the most serious significant renal drug elimination) [48]. For adverse drug reactions, presenting as chronic this reason, it is common practice to initiate interstitial pneumonitis, bronchiolitis obliterans sotalol therapy in the inpatient setting with with organizing pneumonia, or the acute continuous ECG monitoring during the loading respiratory distress syndrome. Corneal deposits, phase for five doses in patients at higher risk. QT skin photosensitivity, neuropathy, and interval prolongation and bradycardia can gastrointestinal side effects have also been presage the development of proarrhythmia and reported [22]. may warrant a reduction of the sotalol dose. Other adverse effects include fatigue, Sotalol bronchospasm, dyspnea and heart failure. Sotalol is a potassium that Unlike amiodarone, these effects are related to prolongs action potential duration and is a the daily dose but not the cumulative dose, Vaughan Williams Class III agent. It is a racemic making sotalol a more attractive first-line mixture of D-sotalol, which has pure Class III therapy for younger patients or those for antiarrhythmic activity, and L-sotalol, which whom longer-term treatment is anticipated [22]. has Class III and beta-blocker effects. Doses less than 120 mg twice daily appear to have a primary beta-blocker effect, with higher doses Class I Antiarrhythmic Agents producing significant Class III activity [22]. The Cardiac Arrhythmia Suppression Trial (CAST) A placebo-controlled trial in 302 ICD compared Class IC agents to placebo in post-MI recipients showed that treatment with racemic patients with impaired LVEF (40% or less) for the sotalol significantly reduced the risk of death or suppression of ventricular ectopy, and was ICD shock (34% incidence with sotalol vs. 54% terminated prematurely due to excess mortality with placebo) at 1 year [32]. However, the rate of in the antiarrhythmic arm [35]. Both all-cause drug discontinuation in the sotalol arm was 27%. mortality and arrhythmic death were increased A similar finding was noted in the OPTIC trial, with both encainide and flecainide treatment. As with nearly a quarter of patients discontinuing such, Class IC antiarrhythmic agents are no sotalol therapy due to drug intolerance [19]. The longer recommended therapy for patients with most common adverse reactions in these trials ischemic heart disease or left ventricular were related to the beta-blocking effects of the dysfunction from any cause. Conversely, the risk drug; symptomatic bradycardia and torsade de of ventricular proarrhythmia with Class IC agents pointes were rare. Of note, in the Survival With in the absence of structural heart disease is low; Oral D-Sotalol (SWORD) trial, D-sotalol, which however, in patients with atrial arrhythmias, does not have significant beta-blocking effects, flecainide or propafenone may promote 1:1 was associated with increased mortality and atrioventricular nodal conduction with proarrhythmia in patients with post-MI left acceleration of the ventricular rate and a wide ventricular dysfunction [33]. QRS tachycardia [21]. The most significant adverse reaction Earlier studies that examined Class I agents associated with sotalol is torsade de pointes, for secondary VT/VF prevention in post-MI seen in 2–3% of patients; especially at risk are patients showed they were inferior in efficacy women and patients with heart failure or to both amiodarone and sotalol [49, 50]. The

123 Cardiol Ther (2013) 2:27–46 37 most commonly used Class I agent in this multichannel blocker similar in structure to setting is mexiletine, used in 20% of patients amiodarone but noniodinated. It was who received adjuvant antiarrhythmic developed with the potential to achieve treatment in the ICD arm of the AVID trial antiarrhythmic efficacy similar to that of [17]. As a Class IB antiarrhythmic agent, it does amiodarone, without the extracardiac toxicity not seem to carry the increased mortality risk seen with long-term amiodarone therapy [26, associated with the Class IC drugs, based on 52]. It is approved for the treatment of atrial observational data with the Class IB drug fibrillation, largely based on results of A Trial lidocaine from the Global Utilization of With Dronedarone to Prevent Hospitalization or Streptokinase and TPA for Occluded Coronary Death in Patients With Atrial Fibrillation Arteries (GUSTO-I and GUSTO-IIb) trials [51]. (ATHENA), a placebo-controlled, double-blind, Quinidine, procainamide, and disopyramide parallel arm trial to assess the efficacy of are Class IA antiarrhythmic agents that have dronedarone 400 mg b.i.d. for the prevention intermediate activity of cardiovascular hospitalization or death from (compared to Class IC agents) and also prolong any cause in patients with atrial fibrillation or action potential duration via potassium atrial flutter, which demonstrated significant channel blockade. They are indicated in the reductions in the composite endpoint of treatment of supraventricular arrhythmias and all-cause mortality and cardiovascular VT. Unfortunately, use of these agents is limited hospitalization with dronedarone vs. placebo by the risk of torsade de pointes (seen in [26]. In two earlier randomized trials of 0.5–8%) and the poor tolerability of these dronedarone in patients with atrial fibrillation agents, including drug-induced lupus with or flutter, rates of pulmonary, , and procainamide, anticholinergic effects with hepatic adverse effects were not significantly disopyramide, and a host of gastrointestinal, greater with dronedarone than with placebo at dermatologic and neurologic side effects seen 1 year follow-up [27]. After its approval in the with quinidine use [21]. United States, however, subsequent reports of While the lower efficacy and poor severe liver toxicity led to a warning by the US tolerability of the Class I agents has relegated Food and Drug Administration, recommending them to third-line therapy for the prevention that prescribing physicians follow hepatic and treatment of ventricular arrhythmia, there function tests routinely [53]. is evidence that combination therapy with a Although dronedarone has not been studied Class I and a Class III agent may be more specifically for the treatment of VT/VF, animal effective than monotherapy with either studies have demonstrated antiarrhythmic agent [43]. Common combinations include properties on ventricular myocardium, and amiodarone or sotalol plus mexiletine. subsequent reports in humans have supported its efficacy in select cases [54–56]. In addition, Emerging Antiarrhythmic Therapy in ATHENA, patients on dronedarone showed a reduction in arrhythmic death [26]. The use of Dronedarone dronedarone in patients with heart failure, Dronedarone is a recent addition to the however, is controversial in light of the antiarrhythmic armamentarium. A Vaughan Antiarrhythmic Trial with Dronedarone in Williams Class III agent, dronedarone is a Moderate to Severe CHF Evaluating Morbidity

123 38 Cardiol Ther (2013) 2:27–46

Decrease (ANDROMEDA) trial, whose results to have efficacy in the treatment of ventricular suggest dronedarone may lead to worsening arrhythmia. A randomized trial of patients with heart failure symptoms and a two-fold increase CAD and sustained VT showed that oral in mortality in this population [52]. As such, dofetilide was equally as effective as oral dronedarone is contraindicated in Class IV heart sotalol in the prevention of recurrent failure patients or in those who have had a recent ventricular arrhythmias and arrhythmic death hospitalization for decompensated heart failure. at 1 year [59]. A more recent study in 30 ICD The ANDROMEDA study authors recommend recipients with drug-refractory VT/VF episodes that ‘‘dronedarone should not be used in patients showed a significant reduction in both monthly with heart failure and reduced left ventricular ventricular arrhythmia episodes (from 1.8 ± 4.5 systolic function.’’ A more recent placebo- to 1.0 ± 3.5, P = 0.006) and monthly ICD controlled trial of dronedarone in patients with therapies (from 0.9 ± 1.4 to 0.4 ± 1.7, permanent atrial fibrillation and major vascular P = 0.037) after treatment with dofetilide. In risk factors (including CAD and heart failure) addition, 83% of patients had complete was stopped prematurely due to a two-fold suppression of VT/VF during their first month excess in cardiovascular mortality [57]. Stroke, of treatment [60]. hospitalization for heart failure, and arrhythmic Dofetilide is very well tolerated, although deaths were also significantly increased in the inpatient monitoring for 3 days is required dronedarone arm of the Permanent Atrial during the loading phase, given the risk of QT Fibrillation Outcome Study Using Dronedarone prolongation and the potential for torsade de on Top of Standard Therapy (PALLAS) [57]. While pointes (seen in 1–3%) [23, 24]. Dofetilide some of these adverse findings were unexplained, dosing is based on calculated creatinine it was postulated that the negative inotropic clearance, as a result of its renal drug effects of dronedarone, along with its drug–drug elimination. The safety of dofetilide has been interactions (notably with vitamin K antagonists established in patients with left ventricular and with digoxin) and potential proarrhythmic dysfunction and CAD [24, 25], and on the effects, may have contributed. basis of limited clinical experience in the In summary, while dronedarone has been treatment of ventricular arrhythmia, it may be shown to be effective in suppressing ventricular an alternative antiarrhythmic agent for such arrhythmia in animal studies and in case reports patients with VT/VF events refractory to of patients with refractory VT/VF episodes, the amiodarone and/or sotalol therapy. results of ANDROMEDA and PALLAS have raised doubts about the safety of this Ranolazine medication in patients with structural heart Ranolazine is a novel antianginal drug with disease. multiple ion channel blocking antiarrhythmic activity. It is a piperazine derivative with a Dofetilide chemical structure similar to lidocaine, and its Dofetilide is a Class III antiarrhythmic agent most potent ion channel blocking effect is on and a selective blocker of the rapid delayed late sodium current [28, 29, 61, 62]. It is thus rectifier potassium current, IKr [58]. It is considered a Vaughan Williams Class IB agent. approved in North America for the treatment Ranolazine also has effects on the delayed of atrial fibrillation; however, it has been shown rectifier current (IKr) and prolongs action

123 Cardiol Ther (2013) 2:27–46 39 potential duration, with corresponding QT action potential duration and refractory period interval prolongation on electrocardiography. [36]. As such, azimilide has demonstrated It has been shown in experimental animal action against both supraventricular and models to have antiarrhythmic effects in the ventricular arrhythmias. In the Shock ventricle [61, 62]. In the Metabolic Efficiency Inhibition Evaluation with Azimilide (SHIELD) With Ranolazine for Less Ischemia in trial, a randomized controlled trial of 633 Non-ST-Elevation Acute Coronary Syndrome– secondary prevention ICD recipients, the Thrombolysis in Myocardial Infarction 36 trial primary endpoint of all-cause shocks plus (MERLIN-TIMI 36), ranolazine was shown symptomatic tachyarrhythmias terminated clinically to reduce arrhythmia episodes, by antitachycardia pacing was significantly including nonsustained VT, on ambulatory reduced in patients receiving azimilide [36]. In cardiac monitoring in patients presenting with addition, the secondary endpoint of appropriate acute coronary syndrome [29]. It has ICD therapies for VT/VF episodes was reduced subsequently been used in the suppression of by 48% and 62%, with the 75 mg and 125 mg ectopic ventricular activity [63] and for the doses of azimilide, respectively. reduction in VT burden and prevention of Based on the concerning results from shocks in ICD recipients [64]. previous antiarrhythmic drug trials in patients Ranolazine in particular works synergistically with structural heart disease, such as CAST and with the Class III antiarrhythmic agents, most SWORD, azimilide was studied prospectively in commonly with amiodarone [65]. This has been the Azimilide Postinfarct Survival Evaluation demonstrated in animal models to have an (ALIVE) trial, in which 3,717 patients with antiarrhythmic effect in both the atrium and recent MI and an ejection fraction between ventricle. In rabbit treated with both 15% and 35% were randomly assigned to ranolazine and a Class III agent, there was no receive azimilide, 100 mg daily, vs. placebo. At increase in early after-depolarizations or 1 year of follow-up, there were no significant ventricular proarrhythmia associated with the differences in all-cause, cardiac, or arrhythmic addition of ranolazine [61]. In addition, in the mortality between the azimilide and placebo MERLIN-TIMI 36 trial, despite causing modest groups [67]. QT prolongation, ranolazine use was not Overall, azimilide was well tolerated in associated with an increased risk of SCD clinical trials. In the SHIELD trial, its compared with placebo [66]. Based on limited discontinuation rate was similar to the placebo but positive clinical experiences with ranolazine, arm. Adverse events with azimilide include it appears to be beneficial as add-on therapy in neutropenia (seen in 1% of patients) and QT patients with recurrent VT events while on a prolongation leading to torsade de pointes (seen Class III antiarrhythmic agent. in up to 1–2% of patients). It is not currently approved for use in North America or Europe. Azilimide Azimilide is an investigational Class III Celivarone antiarrhythmic agent that blocks both the Celivarone is a noniodinated benzofuran rapid (IKr) and slow (IKs) components of the derivative that is in investigational use for delayed rectifier cardiac potassium current. It its action against atrial and ventricular causes prolongation of the atrial and ventricular arrhythmias [37]. Similar to amiodarone and

123 40 Cardiol Ther (2013) 2:27–46 dronedarone, it has Class I, II, III and IV Intracellular Calcium antiarrhythmic activity, but with different Altered intracellular calcium handling has been relative potencies for the various channels and implicated in ventricular arrhythmogenesis in a receptors. Also, its structure and kinetics differ number of models [6]. Two important proteins from those of amiodarone and lend itself to an in myocardial calcium homeostasis are the improved side effect profile and reduced sarcoplasmic reticulum (SR) calcium ATPase potential for drug interactions [68]. It was (SERCA2a) and the ryanodine receptor (RyR2). shown in a small phase 2 clinical study of ICD The former promotes calcium reuptake into the recipients to trend toward fewer VT and VF SR and the latter is a SR calcium release channel episodes at the higher dose of celivarone that promotes an increase in cytosolic calcium, (300 mg daily), although the 46% relative risk which in turn activates myocardial contractile reduction at 6 months was not statistically proteins. Diastolic calcium leakage via RyR2 is significant [69]. A larger trial of 486 patients thought to contribute to proarrhythmia, with LVEF of 40% or less and at least one VT/VF notably by promoting after-depolarizations in episode within a month of enrollment, the cardiomyocyte. CPVT is one cardiac however, did not find that celivarone was any electrical disorder characterized by leaky more effective for the prevention of ICD RyR2, resulting in delayed after-depolarizations interventions or sudden death than placebo and polymorphic VT triggered by exercise [68]. In both studies, celivarone was well and adrenergic stimulation [6, 41]. The tolerated and had an acceptable safety profile. antiarrhythmic agent flecainide targets RyR2, Nonetheless, in light of the disappointing and was shown to prevent arrhythmias in a clinical data to date, it is not currently mouse model of CPVT, by inhibiting RyR2- approved for use in humans. mediated calcium release. Now this agent has found a role clinically to suppress VT events in Future Antiarrhythmic Targets patients with CPVT in conjunction with beta- blockers [70]. Novel targets for the treatment of ventricular Pharmacotherapies to normalize intracellular arrhythmia continue to be explored, and it is calcium handling by either stabilizing RyR2 likely that pharmacologic agents directed at some activity or modulating associated proteins of these targets will enter clinical trials in the next involved in diastolic SR calcium leakage in few years. The commonly used antiarrhythmic order to prevent arrhythmia may prove to be medications for VT/VF primarily target sodium novel antiarrhythmic agents in the future. In a channels (Class I agents) or potassium channels recent report, a pharmacologic RyR2 stabilizer (Class III agents), but are limited by variable was investigated in both a mouse model and in efficacy and the potential for ventricular human nonfailing myocardium, and was found proarrhythmia. Newer therapeutic approaches to be effective in reducing SR calcium leak [71]. to cardiac arrhythmias have focused on the Another recent report showed that inhibition of roles of intracellular calcium, gap junctions, calcium/calmodulin-dependent kinase (CaMKII) sodium–calcium exchange, and was able to reduce cardiac arrhythmias and SCD triphosphate (ATP)-sensitive potassium channel in a proarrhythmic mouse model similar to that blockade, and will be reviewed briefly [37]. seen in CPVT [72].

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Gap Junctions calcium ion in exchange for the import of Cell–cell coupling in the heart acts to maintain three sodium ions, while operating in the synchronization of depolarization and forward mode. Increased expression or activity repolarization between myocytes, and of NCX has been associated with impaired disruption of this coupling is thought to cardiac contractility and an increased risk of contribute to arrhythmogenesis. It has been arrhythmias in the setting of heart failure [75]. proposed that restoration or enhancement of NCX also operates in the reverse mode, coupling via gap junctions may be an effective promoting intracellular calcium loading, antiarrhythmic target [37]. Connexin 43 is the during conditions of high cytosolic sodium principal gap junction protein responsible for concentration, or in the setting of digitalis use cell–cell coupling in ventricular myocardium, (which antagonizes the sodium/potassium and its function is impaired during acute ATPase). Excessive calcium loading can also be ischemia and acidosis [73]. Rotigaptide, an proarrhythmic, as it promotes triggered activity antiarrhythmic peptide that improves through delayed after-depolarizations [6, 75]. conduction across gap junctions, has been NCX blockade has been considered to be a shown in experimental animal models to potential therapeutic strategy for cardiac suppress ischemia-induced proarrhythmia [73]. arrhythmias, in particular with agents that The proposed mechanism of action of rotigaptide predominantly inhibit the reverse mode over the is prevention of the dephosphorylation of forward mode. To date, there has been limited connexin 43 that accompanies acute metabolic progress in the development of clinically useful stress. By maintaining gap junction conductance, agents. Two drugs, KBR-7943 and SEA-0400, have this peptide in turn both prevents conduction been shown to prevent calcium overload in slowing in the cardiomyocytes, and synchronizes models of ischemia/reperfusion injury, and the action potentials thereby reducing dispersion appear to reduce after-depolarizations in models of refractoriness [74]. of vulnerable cardiac tissue [75]. These findings While the concept of normalizing gap are promising but await further in vivo junction conductance with an antiarrhythmic confirmation in animal models. agent is a promising one, there are multiple mechanisms by which gap junction physiology ATP-Sensitive Potassium Channel Blockade can be impaired in disease states other than by Myocardial ischemia is associated with increases dephosphorylation. The roles of myocyte in extracellular potassium, which is believed to fibrosis, connexin protein downregulation and contribute to ventricular proarrhythmia. The trafficking in the remodeling of gap junctions activation of cardiac ATP- have all been appreciated and may pose sensitive potassium channels during myocardial challenges to the development of a single ischemia promotes potassium efflux and pharmacotherapeutic target or agent [73]. reductions in action potential duration; impaired function of the sodium/potassium Sodium–Calcium Exchange ATPase may also contribute [76]. In addition, The sodium–calcium exchanger (NCX) is the ischemia-induced potassium accumulation is primary pathway for intracellular calcium heterogeneous, which leads to dispersion of removal in the cardiomyocyte. It is a cell repolarization and thereby creates a substrate membrane protein that removes a single for reentrant arrhythmias.

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ATP-sensitive potassium channel activity is often limited by suboptimal effectiveness and inhibited by ATP but activated by adenosine 50- drug intolerance or toxicity leading to diphosphate (ADP). Therefore, with a fall in the discontinuation. ATP:ADP ratio during myocardial ischemia, the Newer and emerging antiarrhythmic ATP-sensitive potassium channel opens and therapies must meet the challenge of potassium leaves the cell. Increases in effectively suppressing drug-refractory VT/VF extracellular potassium are known to promote without promoting proarrhythmia or other perturbations in cardiac electrical activity, such cardiovascular adverse events. While dofetilide as increased excitability of normal ventricular and ranolazine hold promise, and merit further tissues, leading to premature ventricular investigation in large prospective studies of ICD complexes, and a reduction in action potential patients, dronedarone use in atrial fibrillation duration. Regional dispersion of the refractory has been associated with a disturbing signal of period, especially during periods of myocardial harm in patients with structural heart disease. ischemia, is a major contributor to the Therefore its use in patients with VT should be development of VF. is an ATP- carefully considered or avoided in the absence sensitive potassium channel inhibitor that has of prospective data establishing its safety and been shown to attenuate reductions in action efficacy in this population. Azimilide and potential duration in models of ischemia, and celivarone await more convincing efficacy data suppress extrasystoles and VF [76]. in humans before they are approved for clinical Glibenclamide is a sulfonylurea that also use. provokes hypoglycemia due to its effects on A better understanding of the molecular noncardiac tissue [76]. For ATP-sensitive mechanisms of ventricular arrhythmogenesis potassium channel inhibition to become an has provided basic electrophysiologists with attractive therapeutic option, cardioselective new antiarrhythmic targets related to pharmaceuticals must be developed and intracellular calcium handling, gap junctions, tested. Currently, the agents HMR-1883, HMR- sodium–calcium exchange, and ATP-sensitive 1098 and HMR-1402 have been developed and potassium channel activity. Further advances in studied in animals, with favorable results on the this field will undoubtedly spur novel drug reduction of ischemic cardiac arrhythmias [77]. therapies for patients with refractory ventricular arrhythmias in the future.

CONCLUSION ACKNOWLEDGMENTS In patients with structural heart disease at risk of ventricular arrhythmias, the ICD continues to be Dr. Williams is the guarantor for this article, the gold standard therapy for the reduction of and takes responsibility for the integrity of the SCD and improved long-term survival. work as a whole. No extramural funding was Antiarrhythmic medication is indicated as add- used in the preparation of this manuscript. on therapy in those with VT events to reduce the morbidity associated with recurrent arrhythmic Conflict of interest. Dr. Williams declares he episodes. While amiodarone and sotalol are the has no conflicts of interest. Dr. Viswanathan principal agents used in this setting, their use is declares he has no conflicts of interest.

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