Sotalol: An important new antiarrhythmic

Progress in Cardiology

Sotalol: An important new antiarrhythmic Jeffrey L. Anderson, MD, and Eric N. Prystowsky, MD Salt Lake City, Utah, and Indianapolis, Ind.

Sotalol, the most recently approved oral antiarrhythmic drug, has a unique pharmacologic profile. Its electrophysiology is explained by nonselective β-blocking action as well as class III antiarrhythmic activity (including fast-activating cardiac membrane–delayed rectifier current blockade), which leads to increases in action potential duration and refractory period throughout the heart and in QT interval on the surface electrocardiogram. Its better hemodynamic tolerance than other βblockers may be a result of enhanced inotropy associated with class III activity. Sotalol’s ability to suppress ventricular ectopy is similar to that of class I agents and better than that of standard β-blockers. Unlike class I agents, its use in a postinfarction trial was not associated with increased mortality rate. Therapeutically, it has shown superior efficacy for prevention of recurrent ventricular tachycardia and ventricular fibrillation, which was the basis for its approval. In a randomized study, the Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) trial , sotalol was associated with an increased in-hospital efficacy prediction rate (by Holter monitor or electrophysiologic study), reduced long-term arrhythmic recurrence rate with superior tolerance, and lower mortality rate than class I (“standard”) antiarrhythmic drugs. Sotalol was 1 of 2 drugs selected for comparison with implantable defibrillators in the recent National Institutes of Health Antiarrhythmics versus Implantable Defibrillator (AVID) study. Sotalol appears to be a preferred drug for use with implantable defibrillators; unlike some other agents (eg, amiodarone) it does not elevate and, indeed, may lower defibrillation threshold. Although unapproved for this use, sotalol is active against atrial arrhythmias. It has shown efficacy equivalent to propafenone and quinidine in preventing atrial fibrillation recurrence, but it is better tolerated than quinidine and provides excellent rate control during recurrence. Sotalol’s major side effects are related to β-blockade and the risk of torsades de pointes (acceptably small if appropriate precautions are taken). Unlike several other antiarrhythmics (eg, amiodarone), it has no pharmacokinetic drug-drug interactions, is not metabolized, and is entirely renally excreted. Initial dose is 80 mg twice daily, with gradual titration to 240 to 360 mg/day as needed. The daily dose must be reduced in renal failure. On the basis of favorable clinical trials and practice experience, sotalol has shown a steadily growing impact on the treatment of arrhythmias during its 5 years of market availability, a trend that is likely to continue. (Am Heart J 1999;137:388-409.)

Sotalol hydrochloride is a water-soluble, racemic mixture of D- and L-isomers in an approximate ratio of 1:1.1,2 Sotalol displays β-blocker activity that is almost entirely caused by the L-isomer. The β-blocking effect is nonselective and is without intrinsic sympathomimetic or membrane-stabilizing activity. The β-blocking potency on a milligram basis is approximately one third to one fourth that of propranolol. Sotalol also displays class III antiarrhythmic activity, defined as lengthening of cardiac repolarization. This action is exerted by both the D- and L-isomers. Sotalol has been studied for many years, having been synthesized in the United States in 1960 (before propranolol)3; marketing began in 1974 in Europe for treatment of hypertension.4 However, interFrom the University of Utah and St. Vincent’s Hospital, Northside Cardiology. Portions of this manuscript are based on the book chapter JL Anderson: “Sotalol, bretylium, and other class III antiarrhythmic agents,” used with permission from Lippincott, Williams, & Wilkins. In: Podrid P, Kowey P, editors. Cardiac arrhythmias—mechanism, diagnosis and management. Philadelphia: Williams & Wilkins; 1995. p. 450-65. Reprint requests: Eric N. Prystowsky, MD, 958 Laurelwood, Carmel, IN 46032. Copyright © 1999 by Mosby, Inc. 0002-8703/99/$8.00 + 0 4/1/87148

est in sotalol’s unique antiarrhythmic properties was delayed until the early 1980s. Arrhythmia studies beginning in 1982 led to Food and Drug Administration approval of sotalol for treatment of life-threatening ventricular arrhythmias (ventricular tachycardia [VT] and ventricular fibrillation [VF]) in the United States in late 19921; marketing began in 1993. Sotalol is now available in many areas of the world, including Europe, Australia, Southeast Asia, and North and South America. The use of class III antiarrhythmic agents in clinical therapeutics is increasing, given recent negative studies (eg, the Cardiac Arrhythmia Suppression Trial [CAST])5 of class I antiarrhythmic agents. Sotalol ranks within the top 3 drugs in sales in many countries where it has market history; its use in the United States is growing.

Chemistry and clinical pharmacology Fig 1 shows the structure of sotalol. Chemically, it is a methane sulfonamide-substituted phenethalomine.1 Sotalol is a white, crystalline solid of molecular weight 308.8 that is hydrophilic and

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readily soluble in water, propylene glycol, and ethanol.1 Sotalol is marketed in the United States exclusively as an oral formulation. It also can be given parenterally, however, and is marketed for intravenous adminstration in several countries. The clinical pharmacokinetics have been well defined and are summarized in Table I.2,6 The bioavailability of orally administered sotalol is high. Sotalol tablets are virtually completely absorbed after ingestion on an empty stomach and approximately 80% absorbed when taken with food. After absorption, sotalol undergoes no significant first-pass metabolism and so is almost completely bioavailable. Sotalol shows negligible protein binding; its apparent volume of distribution is 2 L/kg. Circulating sotalol is not subject to biotransformation by the liver or other organs. Elimination is almost entirely (80% to 90% of a dose) by renal excretion of unchanged drug, with a terminal elimination half-life ranging between 10 and 20 hours. The pharmacokinetics of sotalol are unchanged with long-term administration. As a consequence of its lack of protein binding and biotransformation, sotalol is devoid of significant pharmacokinetic drug interactions. Sotalol is a racemic mixture of D- and L-isomers, which are handled identically by the kidney. Its β-blocker and class III activities show separate dose-response relations with plasma concentration of drug. Maximal β-blockade is achieved at lower concentrations than maximal class III effects.7-10 On a milligram basis, oral sotalol has one third to one fourth the potency of oral propranolol.2,8,11,12 Given intravenously, sotalol is one eighth to one sixteenth as potent as intravenous propranolol.8,12 The Dand L- isomers differ in their β-blocking and class III actions. The β-blocking effects of racemic sotalol are accounted for almost entirely by actions of the levo-compound, the relative β-blocking activities of the L- versus D-isomer being ≥50:1.12-14 In contrast, both isomers contribute substantially to its class III effects. The usual antiarrhythmic dose of sotalol hydrochloride is 160 mg to 320 mg daily, given in 2 or 3 divided doses.1 The clearance of sotalol is decreased in renal insufficiency, and adjustment in dosing interval is necessary. Because of age-related reductions in renal clearance, the elderly also may experience decreased elimination of sotalol.1

Inotropic and hemodynamic effects Experimental hemodynamic studies. The experimental in vitro inotropic effects of sotalol include a concentration-dependent increase in contractility in isolated

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Figure 1

Structure of sotalol.

ventricular tissue associated with an increase in action potential duration.8 (Kaumann and Olson first observed this ability of sotalol to improve contractility while lengthening the action potential duration almost 30 years ago.9) In whole animals, sotalol decreases heart rate, blood pressure, and ventricular contractility (as measured by left ventricular [LV] dP/dt), and reduces cardiac output.8 Sotalol causes greater decreases in heart rate than propranolol, but there is less cardiac depression at equieffective β-blocking doses in dogs without autonomic influences.8 This reduced cardiac depressant effect is believed to be explained by the enhanced inotropy associated with class III activity, partially counterbalancing the negative inotropic effects of β-blockade.

Clinical hemodynamic studies In clinical hemodynamic studies, sotalol has shown fewer negative inotropic effects than anticipated for the degree of β-blockade achieved.15,16 Hemodynamics of intravenous sotalol. Thumala et al17 studied the effects of acutely administered, intravenous sotalol in 24 patients who were undergoing catheterization. Given in a mean dose of 0.34 mg/kg, sotalol reduced heart rate, cardiac index, and LV dP/dt, both at rest and during exercise.17 Stroke volume was unchanged, although cardiac index fell in parallel with heart rate. Total systemic resistance (and LV end-diastolic pressure) increased, whereas total pulmonary resistance, mean arterial pressure, and pulmonary arterial pressure showed little change. Lloyd et al18 gave intravenous sotalol in a dose of 40 mg to 120 mg to 28 patients with acute myocardial infarction and arrhythmias and observed a reduction in heart rate and mean arterial pressure but no change in pulmonary capillary wedge pressure or systemic vascular resistance. Stroke volume remained constant and LV end-diastolic volume was unchanged or decreased.18 Hemodynamics of oral sotalol. Mahmarian et al19 compared long-term administered oral sotalol, quinidine,

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Table I. Clinical pharmacokinetic profile of sotalol Rate of absorption (time to peak Cp) Extent of absorption Bioavailability of absorbed drug Binding to plasma proteins Apparent volume of distribution Biotransformation Metabolites Total body clearance (with normal renal function) Percentage of drug eliminated renally (unchanged) Plasma elimination half-life (patients) Therapeutic plasma concentration range* Pattern/model of elimination kinetics Dose proportionality of Cp? Special features

2.5-4 h 90%-100% Approximately 100% 0% 2.0 ± 0.4 L/kg 0% None detected 150 mL/min >75% 15 (10-20 h) ~1-4 µg/mL First order/2-compartment Yes (linear) Water soluble, little CNS penetration Primary renal elimination Accumulates in patients with renal failure, not in patients with hepatic failure No pharmacokinetic drug interactions†

Cp, Concentration of drug in plasma; CNS, central nervous system. *Therapeutic Cp range not well established; limited clinical use. †Pharmacodynamic interactions are possible.

Table II. Hemodynamic effects of oral sotalol in 27 patients with complex ventricular arrhythmias*

Table not available

and placebo in a double-blind, randomized, crossover trial in 27 patients with complex ventricular arrhythmias. The majority (85%) had structural heart disease. Table II shows hemodynamic effects of placebo and sotalol (320 mg to 640 mg per day for 4 weeks). The small decline in cardiac index was accounted for primarily by a reduction in heart rate. Reductions in systolic blood pressure were modest: 7 mm Hg at rest, 9 mm Hg with exercise. Stroke volume tended to increase (by 11 mL/m2 at rest, 8 mL/m2 with exercise). Sotalol increased LV ejection fraction (LVEF) at rest (47% ± 13% to 51% ± 15%, P < .002) and favorably influenced exercise ejection fraction (52% ± 15% to 55% ± 14%, P = not significant) measured by radionuclide ventriculography. Sotalol also was generally well tolerated clinically; however, 2 patients with

markedly depressed LVEF at rest (18%, 23%) and markedly dilated LV chambers (end-diastolic volume indexes >200 mL/m2) had congestive heart failure develop. Winters et al16 assessed the hemodynamic effects of oral sotalol in 12 patients with moderate LV dysfunction (mean LVEF, 37%) undergoing electrophysiologic testing. Nine of these had life-threatening ventricular arrhythmias. Sotalol was given in a mean dose of 160 mg every 12 hours for at least 4 doses and tested for peak effects 2 hours after dosing. Heart rate was observed to decrease by 28% (21 beats/min) and cardiac index by 24% (0.8 L/min · m2). Compared with baseline measurements, increases were observed in systemic vascular resistance (by 25%), stroke volume (by

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Table III. Electrophysiologic effects of intravenous sotalol in 33 patients with ventricular tachyarrhythmias* Measurement (ms) RR interval QTc interval AH interval HV interval Atrial effective refractory period AV nodal effective refractory period Ventricular effective refractory period Sinus node recovery time AV node block (Wenkebach) CL

Baseline

After sotalol*

Change, %

P value

738 ± 163 397 ± 50 86 ± 20 60 ± 18 248 ± 39 346 ± 59 241 ± 29 870 ± 275 371 ± 65

955 ± 182 440 ± 40 101 ± 24 61 ± 20 309 ± 52 431 ± 61 277 ± 28 1150 ± 405 466 ± 84

+29.4 +10.8 +17.8 +2.2 +24.6 +24.9 +14.9 +32.0 +25.6

<.01 <.05 <.01 NS <.01 <.01 <.01 <.01 <.01

AV, Atrioventricular; CL, cycle length; NS, not significant; RR, respiratory rate; QTc, corrected QT interval. *Sotalol dose, 1.5 mg/kg intravenous. Adapted with permission from the American Heart Association. Nademanee K, Feld G, Hendrickson JA, Singh PN, Singh BN. Electrophysiologic and antiarrhythmic effects of sotalol in patients with life-threatening ventricular tachyarrhythmias. Circulation 1985;72:555-64.

8%), and pulmonary capillary wedge pressure (from 6.4 to 11.8 mm Hg). Mean systemic arterial pressure, pulmonary artery pressure, and stroke work index did not change. Therapy was associated with worsening heart failure in only one patient and was discontinued. Overview of hemodynamic effects. In relatively small but carefully performed studies, acute, intravenously dosed sotalol caused negative chronotropic but relatively modest negative inotropic effects. Multiple dosing with oral sotalol was associated with good tolerance in patients with mild to moderately compromised systolic function. Exacerbation of congestive heart failure was uncommon and, when observed, occurred in patients with severely reduced cardiac function (ejection fraction <25%) and markedly increased LV end-diastolic volume (>200 mL/m2). The reduced cardiac depressant effects of sotalol relative to other β-blockers (eg, propranolol) may be caused by enhanced inotropy associated with class III activity that partially counterbalances the negative inotropic effect of β-blockade. Thus despite its β-blocking activity, sotalol can be used (with some caution) in patients with mildly or moderately compromised LV systolic function. However, caution should be exercised in prescribing sotalol to patients with a history of congestive heart failure and avoided in those with decompensated failure.

Cellular electrophysiology Electrophysiologic effects in cardiac cells and tissues: Combined class II and class III activity The β-blocking actions of sotalol have been well demonstrated and have been shown to be noncardioselective and unassociated with intrinsic sympathomimetic or local anesthetic activity.8,11,12 Apart from β-blockade, electrophysiologic studies of sotalol dating

back almost 30 years have shown that it causes a concentration-dependent increase in action potential duration in all cardiac tissues with lengthening of effective and absolute refractory periods.12,13 Classical antiarrhythmic agents with sodium-channel blocking activity depress action potential upstroke (phase 0) velocity and slow conduction. In contrast, sotalol has no effect on the upstroke velocity of the action potential, except at very high concentrations. Thus sotalol has combined class II (β-blocking) and class III (action potential prolonging) electrophysiologic effects as the basis for its antiarrhythmic actions. The concentrationresponse curves of these 2 actions differ, however, with β-blockade beginning and reaching maximum effect at lower concentrations than the class III effect.

Cellular basis for electrophysiologic actions The cellular electrophysiologic actions of sotalol consist of blockade of both β1 and β2 adrenoreceptors as well as blockade of myocardial outward potassium currents.12,13 The importance of blockade of each specific channel receptor to its overall antiarrhythmic activity is not yet completely understood. Carmeliet20 interpreted voltage-clamp studies to indicate that lengthening of the action potential duration by sotalol may be primarily caused by reductions in the cardiac membrane–delay-ed rectifier current (Ik) associated with a smaller decrease in the inward rectifier current (Ik1).20 Recently, the Ik current has been resolved into at least 2 components, a fast-activating (Ikr) current and a slow-activating current (Iks).21 In guinea pig myocytes, sotalol selectively blocked Ikr.21 Both D- and L-isomers contribute to class III effects, whereas β-blocking activity is almost entirely caused by actions of the L-isomer and is dose dependent.12-14

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Figure 2

Comparison of survival with sotalol versus vehicle (left) and flecainide versus vehicle (right) in conscious canine model of sudden death (ischemic VF). (Left reprinted with permission from the American Society for Pharmacology and Experimental Therapeutics. Patterson E, Lynch JJ, Lucchesi BR. Antiarrhythmic and antifibrillatory actions of the beta adrenergic receptor antagonist, dl-sotalol. J Pharmacol Exp Ther 1984;230:519-26. Right, reprinted with permission from the American College of Cardiology [Journal of the American College of Cardiology], 1987;9:359-65.)

Reverse use dependence Studies of sotalol’s effect on the action potential duration have demonstrated that it is reduced in magnitude as the stimulus frequency is increased. This phenomenon is referred to as reverse use dependence.13,22 Reverse use dependence has now been reported with many newer agents with class III action, a notable exception being amiodarone.13,22 With therapy that causes reverse use dependence, action potential prolongs to a greater extent at slower physiologic rates than at faster rates. Whether reverse use dependence has clinically important consequences is unknown, but the possibility arises of attenuation of antiarrhythmic action during clinical tachyarrhythmias that occur at rapid rates (that is, at short cycle lengths).13 The reverse use dependence phenomenon associated with sotalol appears to be attenuated in infarcted compared with normal ventricular myocardium.23 Intravenous sotalol increased monophasic cardiac action potential duration similarly in chronically infarcted and normal canine myocardium during sinus rhythm (by +22% and +22%, respectively) and after a long coupling interval during ventricular pacing (by +11% and +13%, respectively). However, after a short coupling interval (200 msec) during pacing, a differential response was observed, with a 10% increase in the infarct zone (P < .05) versus a 5% increase in normal myocardium (P =

not significant). This preserved class III action at short coupling intervals in infarcted myocardium may lend to sotalol’s antiarrhythmic actions in this substrate.

Clinical electrophysiology Electrophysiology of intravenous sotalol The electrophysiologic effects of intravenous sotalol were studied by Nademanee et al24 in 33 patients with life-threatening ventricular arrhythmias. Table III gives a summary of their results (sotalol dose, 1.5 mg/kg, infused over a 5- to 10-minute period). Lengthening of effective refractory periods was observed throughout the heart, including in the atrium and atrioventricular node (each by 25%) and in the right ventricle (by 15%). These global increases in effective refractory periods have been replicated in several studies of intravenous sotalol.25-29 In other studies, the effects on refractoriness were shown to be associated with lengthening of the monophasic cardiac action potential in human atria and ventricles.29-32 Sotalol’s ability to prolong refractoriness in accessory pathways has been shown in still other studies.33-35 A reflection of this effect on the surface electrocardiogram is lengthening of the QT and QTc intervals. The most common class II (β-blocking) actions observed with sotalol were prolongation of the sinus node recovery time (a measure of latency of sinus node automaticity) and lengthening of conduction

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Table IV. Comparative electrophysiologic effects of sotalol and propranolol

Table not available

time through the atrioventricular node (as reflected by the AH interval). In contrast, conduction times through the His-Purkinje system (as measured by the HV interval) and ventricle (assessed by the QRS interval), which are largely independent of sympathetic tone, were unchanged.

Electrocardiography of long-term oral sotalol administration The electrocardiographic effects of oral sotalol, administered long term in 114 patients with chronic premature ventricular complexes (PVCs) who were enrolled in a randomized, blinded, multicenter study were evaluated. Sotalol, in daily doses of 320 mg, 640 mg, or placebo, was given for 4 weeks.36 Heart rate significantly decreased similarly with both doses of sotalol—by an average of 19 beats/min, or 25%, with 320 mg/day, and by 16 beats/min, or 24%, with 640 mg/day—and was unchanged with placebo. Therapy increased PR intervals, but only slightly (by 6%) and, again, similarly with each dose. QRS duration was unchanged. However, QT intervals lengthened and showed a dose-dependent trend: increases averaged 80 ms (21%) with 320 mg/day and 91 ms (23%) with 640 mg/day. When corrected for heart rate changes, the changes in QT were more moderate, with QTc increases averaging 21 ms (5%) and 30 ms (7%) for the 2 doses, respectively. Effects of long-term therapy on LVEF were also measured, which increased an average of 3 to 4 percentage points.

Electrophysiologic comparisons with propranolol Table IV summarizes the electrophysiologic effects of sotalol versus propranolol. Creamer et al37 compared the actions of equiactive β-blocking doses of sotalol and pro-

pranolol in 8 patients with permanent pacemakers. Sotalol prolonged paced QTc both after intravenous administration (by 6.5%) and after 4 weeks of oral therapy (by 11.5%). In contrast, QRS duration was unchanged. Propranolol did not change QT or JT intervals in the short term but did tend to increase QTc, although not significantly, with long-term therapy. Neither drug affected pacing threshold after intravenous drug administration. Echt et al32 measured cardiac monophasic action potential duration in 8 patients before and after intravenous propranolol (0.15 to 0.2 mg/kg) and sotalol (0.3 to 0.6 mg/kg). Monophasic action potential duration increased only after sotalol, both in atrium (by 17%, P = .01) and in ventricle (by 10%, P = .005).

Sotalol’s effect on dispersion of ventricular recovery The QT interval measures the composite of ventricular activation and recovery times. Prolongation of QT interval associated with minimal changes in QRS, as occurs with sotalol, thus primarily reflects changes in ventricular recovery time. Increased dispersion of ventricular recovery time may provide a substrate that facilitates the development of serious ventricular arrhythmias. Antiarrhythmic agents may either increase or decrease dispersion of recovery as they lengthen recovery time. Day et al38 studied the effects of sotalol on QTc interval dispersion on the 12-lead surface electrocardiogram (defined as the QTc maximum minus the QTc minimum among the leads) in 67 patients after myocardial infarction who had been randomly assigned to a 6-month treatment period with either sotalol or placebo. Throughout treatment, the maximum QTc was found to be significantly greater, but the QTc dispersion significantly less, in patients treated with sotalol compared with placebo. By reducing abnormal QTc dispersion, despite increasing

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Figure 3

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which also exhibit class III and/or class II activity, were also variably effective in this model.43

Clinical ventricular antiarrhythmic activity Efficacy and tolerance in patients with chronic complex ventricular ectopy

Suppression of PVCs by sotalol compared with propranolol. (Adapted with permission from Kluwer Academic Publishers: Anderson J, et al. Sotalol versus class I and II antiarrhythmics. In: Hanyod JJ et al, editors. Cardiovascular drugs and therapy. 4th ed. Kluwer Academic Publishers, 1990. p. 603-11.)

maximum QTc, sotalol may increase electrical stability and exert an antiarrhythmic effect.38,39

Animal models of antiarrhythmic activity Sotalol has been shown to exhibit potent antiarrhythmic activity in several experimental arrhythmia models, including methylchloroform, halogen-catecholamine, ouabain, and coronary ligation.8,40 Sotalol also was evaluated in a canine post–myocardial infarction model in which VT is induced by programmed electrical stimulation (PES).40,41 In this model, sotalol was effective, and metoprolol ineffective, in suppressing VT inducibility.40 Sotalol also has been shown to be effective in preventing ischemia-related VF in a conscious dog model mimicking the conditions of clinical sudden death.41 In this model, a reperfused myocardial infarction (MI) is created by coronary ligation and release. After MI healing, recurrent coronary ischemia is induced in another vascular bed by electrically stimulating an acute coronary thrombosis. VF results within 3 to 8 hours in 90% to 100% of untreated animals.41-43 In contrast, survival at 24 hours was 65% (13 of 20) in animals pretreated with intravenous sotalol (2 mg/kg or 8 mg/kg) (Fig 2); only 1 (7%) of 15 parallel controls survived.41 Unlike sotalol, flecainide (a class IC agent) did not prevent sudden death (90% fatality); indeed, time to VF was shortened (Fig 2).42 Bretylium, amiodarone, D-sotalol, and nadolol,

Placebo-controlled observations. To determine the ability of sotalol to suppress ventricular ectopic activity, 2 dosages (320 mg/day and 640 mg/day, divided into 2 doses) were compared with placebo.36 One hundred fourteen patients with chronic, frequent PVCs (≥30/hour) were enrolled and treated for 6 weeks in a randomized, parallel group, double-blind design.36 Sotalol in both dosages was effective in reducing PVCs (by 75% with 320 mg/day and 85% with 640 mg/day, compared with only 10% for placebo [P < .001 vs either dose of sotalol]). With 320 mg/day, 34% of patients achieved the individual efficacy criterion of ≥75% PVC reduction; with 640 mg/day, 71% achieved efficacy, and with placebo, only 6% were effectively treated (P < .003, sotalol versus placebo groups). Repetitive PVCs were suppressed equally effectively by both doses of sotalol (80% and 78%, respectively, versus 25% by placebo, P < .005 vs each sotalol dose). Non-life-threatening proarrhythmia occurred in 3 patients receiving sotalol and 2 receiving placebo. Tolerance was dose dependent: 8 receiving 640 mg/day but only 1 receiving 320 mg/day discontinued therapy because of an adverse reaction (P < .02). In summary, sotalol was an effective antiarrhythmic for suppressing complex PVCs; 320 mg/day was as effective in suppressing repetitive ventricular ectopy and was better tolerated than 640 mg/day. Hohnloser et al44 reviewed 13 controlled trials in which complex but nonsustained ventricular arrhythmias were treated with sotalol (n = 626 patients) and used either placebo (n = 114 patients) or active treatment controls (n = 395 patients). Efficacy (>75% PVC suppression) was achieved in a median of 58% of patients, and proarrhythmia was observed in only 3.6%. LVEF effects were evaluated in 6 of these studies. None of the studies showed worsening in LVEF, and 3 showed increases (31% ± 8% to 35% ± 12%, P < .05). These data demonstrate that sotalol has substantial ventricular antiarrhythmic activity. However, as is the case with other antiarrhythmics, PVC suppression alone does not establish a clinical or survival benefit of sotalol. Comparison of sotalol with primary β-blockers.

Sotalol suppresses ventricular ectopy more than drugs

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Table V. Summary of major trials of sotalol for sustained VT or VF Long-term outcome Study

n

Multicenter IV sotalol vs PCA49

110

Refractory arrhythmia study53

479

Boston long-term study54 ESVEM Study57,58

161 486

Drug IV sotalol IV PCA PO sotalol PO sotalol PO sotalol C I drug

Method EPS EPS EPS Holter EPS EPS sotalol/C I Holter sotalol/C I

Acute response 30%* 20%* 35%*/25%† 39%* 34% 36%/13% 41%/45%

VT recurrence

Death

— — 16%/y‡§

— — 4%/y‡§

16%/y‡ 15% /30%/y§

5%/y‡ 6%/11%/y§

IV, Intravenous; PCA, procainamide; EPS, electrophysiologic study; PO, orally; ESVEM, Electrophysiologic Study versus Electrocardiographic Monitoring; C I, class I. *Complete response rate. †Partial response rate. ‡Partial and selected “nonresponders” also qualified for chronic therapy. §Combined response rates for electrophysiology study and Holter guided therapy (which did not differ).

with exclusive β-blocker activity. Deedwania45 reported a double-blind, placebo-controlled, parallel study that compared the antiarrhythmic effects of sotalol (160 mg twice daily) and propranolol (40 mg 3 times a day) in 172 patients with frequent PVCs (≥30/hr). The efficacy goal was >75% PVC suppression. Those not achieving “efficacy” were advanced to doses of 320 mg twice daily for sotalol and 80 mg 3 times daily for propranolol. Sotalol reduced PVCs to a greater extent (by 80%, from 274 to 54 per hour) than propranolol (59% reduction, from 255 to 104 per hour; P < .002, sotalol vs propranolol). Also, a greater percentage of patients showed effective suppression with sotalol (56%) than propranolol (29%) (P < .001) (Fig 3). Comparisons with other antiarrhythmic agents.

Sotalol suppresses ventricular ectopy favorably when compared with commonly used class I antiarrhythmic agents. Lidell et al46 compared sotalol with procainamide therapy in 33 patients in an open, randomized, crossover study. Sotalol achieved the goal of 75% reduction in PVCs in 67% of patients (n = 22) versus 39% (13 patients) with procainamide. Sotalol was compared with quinidine in 144 patients in a placebo-controlled, multicenter, randomized, double-blind crossover study.15,19 Sotalol was titrated to a dose of 320 mg to 640 mg daily, based on tolerance and antiarrhythmic effect, and quinidine sulfate to 800 mg to 1600 mg daily. Based on a preliminary report, sotalol reduced mean PVC frequency from 245 per hour to 54 per hour and quinidine from 262 per hour to 33 per hour, a similar result. These observations suggest that sotalol is approxi-

mately as effective in PVC suppression as are class IA agents, with similar or better tolerance.46 However, PVC suppression has not been shown to be an effective marker for risk reduction.5 Therefore antiectopic activity, although a marker of drug effect, cannot be used as a surrogate for mortality outcome in patients with symptomatic, potentially life-threatening arrhythmias.

Sotalol for sustained VT or VF Sotalol has been efficacious when used in the prevention of recurrent VT or VF (Table V). Early studies reported on the ability of sotalol to treat sustained VT or VF, as guided by PES. Observational studies. In an initial European experience in 18 patients, Senges et al25 reported that 61% (n = 11) were rendered noninducible by intravenous sotalol. (Sustained VT was induced at baseline in 15 of these patients.) Responding patients were discharged receiving oral sotalol in doses designed to achieve matching plasma drug concentrations during intravenous testing. Nine of the 11 patients discharged receiving sotalol were free of arrhythmia recurrence at 8 to 18 months. In an early U.S. experience, Nademanee et al24 tested intravenous sotalol (1.5 mg/kg) in 37 patients with clinical VT or VF. Thirty-three patients had inducible VT/VF at electrophysiologic study. Sotalol prevented induction of VT or VF in 15 (45%) of these. Oral sotalol was given to them and initially controlled arrhythmias in 13 (87%). During long-term (>1 month) therapy in 12, 2 had arrhythmia recurrence, 2 had adverse effects, and 8 remained arrhythmia free after 2 to 23 months (mean 15 months). Holter monitoring was performed before and after oral sotalol in 21 patients. Suppression of sponta-

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Figure 4

Suppression of ventricular tachyarrhythmias induced at PES by sotalol given in different doses. (Reprinted with permission of the publisher from Kehoe: Safety and efficacy of oral sotalol for sustained ventricular tachyarrhthmias refractory to othe rantiarrhythmic agents, American Journal of Cardiology Supplement, 72:56A-60A. Copyright 1993 by Excerpta Medica Inc.)

neously occurring ventricular arrhythmias (by ≥85%) with sotalol showed a fair but imperfect correlation with PES-defined efficacy of intravenous drug: sotalol prevented reinduction of VT at PES in 9 of 11 with Holter suppression versus 2 of 10 without Holter suppression. During clinical follow-up, 7 of 9 patients without adverse effects were arrhythmia free if suppressed by Holter versus 2 of 9 who were not suppressed. Roden48 has summarized these and other small, open studies of sotalol for sustained ventricular tachyarrhythmias. The other reported results were favorable and in keeping with those presented. Controlled comparison of sotalol with procainamide. Singh et al49 undertook a prospective,

double-blind, randomized multicenter trial comparing intravenous sotalol with intravenous procainamide in 110 patients.4,48,49 Ventricular tachyarrhythmias were induced with an EP protocol using up to three ventricular extrastimuli. Sotalol suppressed inducible VT or VF in 15 (30%) of 50 patients, and procainamide suppressed induction in 10 (20%) of 50 evaluable patients (P = .19). Oral sotalol was tested in 11 PES responders and found to be effective in 8, suggesting a good (although imperfect) correlation between responses to intravenous and oral therapy. Comparisons of sotalol and amiodarone. Direct comparisons of sotalol and amiodarone are limited. Sotalol

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and amiodarone were compared in 59 patients with sustained VT or VF unassociated with acute MI in a randomized, open European multicenter study.50 Therapy was empiric and dosing was guided by clinical tolerance. Sixteen of 29 patients assigned to sotalol completed 12 months of therapy, 1 had arrhythmia recurrence, 9 were withdrawn (because of adverse effects), and 5 died (3 during therapy and 2 after withdrawal). Similarly, 16 of 30 randomly assigned to amiodarone completed 12 months of therapy, 5 had arrhythmia recurrence, 9 were withdrawn, and 4 died (each after withdrawal). No significant differences in recurrence rates (which favored sotalol), withdrawals, or deaths were noted between amiodarone and sotalol, but the study was unblinded and its size was relatively small. In a smaller study, Man et al51 compared sotalol (titrated to 240 mg twice daily over 7 days) and amiodarone (600 mg 3 times daily for 10 days) in 34 patients with coronary artery disease and sustained monomorphic VT who were evaluated with electrophysiologic studies. An adequate response to therapy was defined as inability to induce VT or induction of only a slow, stable VT. Therapy with sotalol and amiodarone caused similar effects on ventricular effective refractory periods. Few patients were rendered noninducible with either sotalol (n = 4) or amiodarone (n = 3), but amiodarone prolonged VT cycle length to a greater extent than sotalol (by 75 msec versus 32 ms, respectively). Thus an “adequate” antiarrhythmic response was achieved in 24% with sotalol and 41% with amiodarone (P = .30). Clinical outcomes were not compared. Refractory arrhythmia study. The safety and efficacy of oral sotalol were evaluated in an open-label, multicenter, historically controlled study in 481 patients with drug-refractory, sustained ventricular tachyarrhythmias.52,53 After a drug-free baseline evaluation, sotalol therapy was initiated at 80 mg every 12 hours, with upward dose titration in increments of 160 mg/day every 72 hours, as required for efficacy and tolerated, to a maximum dose of 480 mg every 12 hours. Efficacy was predicted either by PES or by Holter monitor responses; the most appropriate monitoring method was chosen for each patient based on individual baseline PES and Holter results. PES was used to make an efficacy prediction in 269 patients, of whom 94 (35%) showed complete suppression of inducible VT. The efficacy response by sotalol dose is shown in Fig 4 and demonstrates a reduction in rate below the 30% to 40% overall mean only for the lowest dose group studied (160 mg/day). Holter monitoring was used to

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Figure 5

Patients free of arrhythmia recurrence in the Refractory Arrhythmia Study of sotalol. (Reprinted with permission of the publisher from Kehoe: Safety and efficacy of oral sotalol for sustained ventricular tachyarrhthmias refractory to othe rantiarrhythmic agents, American Journal of Cardiology Supplement, 72:56A60A. Copyright 1993 by Excerpta Medica Inc.)

make an efficacy prediction in 109 patients, of whom 34 (39%) showed a complete response. In-hospital discontinuation of sotalol was required in 123 (26%) patients because of lack of efficacy and in 42 (9%) because of adverse effects. Proarrhythmia was observed in 23 (4.8%) patients and was manifest as either torsades de pointes (n = 12) or an increase in episodes of clinical VT (n = 11). Exacerbation of heart failure was an uncommon cause for early discontinuation: only 3 (1%) stopped drug for this reason. A total of 268 patients entered long-term therapy and were monitored for arrhythmia recurrence. At 12, 18, and 27 months, 76%, 72%, and 66% of patients, respectively, remained arrhythmia free (Fig 5). For patients discharged receiving drugs, differences in outcomes were predicted by whether PES or Holter monitoring during drug testing showed a partial versus a complete response, or by the baseline ejection fraction. Among the 70 (24%) patients who had an arrhythmia recurrence, sudden death occurred in 16 (23% of arrhythmic events). Annual all-cause mortality rate averaged 4% per year. During follow-up (mean 1.2 ± 0.3 years), late onset heart failure was reported in 7 (2%) patients and proarrhythmia (primarily new onset torsades de pointes) in 8 (3%). No organ toxicity was reported. Long-term study of sotalol. A 5-year prospective observational study was performed in Boston to assess the efficacy and safety of sotalol, guided by PES, in 161 patients with life-threatening ventricular tachyarrhyth-

Anderson and Prystowsky 397

Figure 6

Failure time curves in patients with VT and with or without complete suppression of VT at PES in the long-term study of sotalol. (Personal communication, Brian A. McGovern, MD, November 6, 1998.)

mias shown to be refractory to at least one class I antiarrhythmic drug.54 Most patients (87%) had coronary artery disease, the great majority (82%) with a history of MI; many had substantial LV dysfunction (LVEF ≤30% in 41). Follow-up electrophysiology studies were completed in 132 patients and performed on a median sotalol dose of 240 mg/day (range 160 mg/day to 960 mg/day). Sotalol suppressed inducible VT by PES in 45 (34%) patients. Long-term sotalol administration was given to the 45 PES responders and to 34 others (who were partial responders) in whom sotalol was regarded as the best therapeutic option. After 1 and 2 years of follow-up, 79% and 67% of patients, respectively, were free from recurrence of VT or VF. In contrast to results of the Refractory Arrhythmia Study,52,53 recurrence rates were lower in patients who had shown complete VT suppression at PES (86% versus 52% at 2 years) (Fig 6).54 Despite VT recurrence in some, actuarial survival was excellent: 98% at 1 year and 90% at 2 years. Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) Study. The ESVEM trial

provided an opportunity to compare outcomes with sotalol (class II/III) and class I antiarrhythmic agents in patients with life-threatening, sustained ventricular tachyarrhythmias.55-58 Two questions were assessed in ESVEM55: (1) are more accurate predictions of antiarrhythmic drug efficacy obtained with an electrophysiology study or with Holter monitoring, and (2) what is the relative effectiveness of various agents used to treat

398 Anderson and Prystowsky

ventricular tachyarrhythmias? The results showed minor differences by testing method but major differences in outcome by drug. In ESVEM, 486 patients with sustained VT or VF whose antiarrhythmic therapy could be assessed by either Holter monitoring or electrophysiologic study were randomly assigned to have drug efficacy assessed by one or the other of these two methods. The incidence of efficacy predictions was greater with Holter monitoring (77%) than electrophysiology study (45%, P < .001).56 Difference in outcome by method in ESVEM. A total of 296 patients with efficacy predictions were discharged receiving medication predicted to be “effective” by one or the other technique. During follow-up, an early trend in freedom from a ventricular arrhythmia (VT/VF) recurrence favored the electrophysiology study arm, but the curves merged together within 2 years and the 6-year actuarial recurrence rate was similar for the two techniques (P = .69).57 The study was not powered to compare mortality rates, although these also did not differ among patients with predicted efficacy. When event rates were separately analyzed for all 486 randomly assigned patients (“intention-to-treat” analysis) there was still no difference in arrhythmia recurrence rate (P = .23), but a trend favoring the electrophysiology arm was observed for cardiac death (P = .06). When the analysis of mortality rate was further restricted to patients with coronary artery disease (85% of patients), survival was found to be significantly better in patients randomly assigned to the electrophysiology study group (P = .02). (It should be stressed that >50% of the intended patients in the electrophysiology group were being treated with off-protocol therapies, including amiodarone and defibrillators.) In contrast, those with no coronary artery disease tended to have better survival if assigned to the Holter monitor group (P = not significant). Significant differences in outcome by drug class in ESVEM. In contrast to the lack of difference in outcome

by evaluation method, substantial outcome differences by drug treatment class were observed (Table IV). 57,58 In a Cox proportional hazards model, the recurrence of arrhythmia was predicted to be increased only in those using drugs other than sotalol (risk ratio 2.5, P < .001) and in those with a history of previous drug failure (risk ratio 1.8, P = .001). No other baseline or treatment factors were significantly associated with an increased risk of arrhythmia recurrence. Also, all-cause death was predicted to be increased by the use of a drug other than sotalol (risk ratio 1.9, P = .07) as well as by advanced (>1) functional class (risk ratio 2.1, P = .07). The trends toward better outcomes were consistent for

American Heart Journal March 1999

sotalol within both the Holter monitor and electrophysiology groups. These findings showed, importantly, that sotalol was associated with a better clinical outcome than agents primarily causing sodium-channel blockade, even when each therapy had been predicted to be “effective” by Holter or electrophysiology testing. In-hospital versus outpatient efficacy in ESVEM.

ESVEM also assessed the relative rates of achieving an “efficacy prediction” with antiarrhythmic therapy during both in-hospital testing and outpatient therapy and the relative tolerance rates among the antiarrhythmic drugs, both initially and long term. During in-hospital evaluation, no significant differences in efficacy predictions emerged in the Holter monitor arm among the 7 drugs tested (sotalol plus 6 class I antiarrhythmic agents, including quinidine, procainamide, mexiletine, and propafenone), whereas in the electrophysiology arm, sotalol achieved a significantly greater proportion of efficacy predictions (35%) than the class I antiarrhythmic agents (averaging <20%). Sotalol also was associated with the greatest proportion of patients predicted to be effectively treated overall (43%). During up to 6 years of follow-up, arrhythmia recurrence among the 296 patients with an efficacy prediction was significantly less frequent in patients assigned to sotalol than to any of the other drugs (P < .001, failure-time analysis). A trend toward a lower mortality rate in the sotalol group was seen for all-cause death, cardiac death, and arrhythmic death (P < .07), even though the study was not powered as a mortality trial. Indeed, when an uncensored (intention-to-treat) analysis was undertaken that included all patients by their original long-term drug assignment, antiarrhythmic recurrence continued to be substantially lower in the sotalol group (P < .001), and all-cause death (P = .004), cardiac death (P = .02), and arrhythmic death (P = .04) were all significantly lower (Fig 7). Short- and long-term antiarrhythmic safety in ESVEM. Sotalol also was associated with a low rate of

discontinuation because of adverse drug-related effects during both initial drug titration and long-term therapy. During in-hospital titration, adverse events required drug discontinuation in 16% of the sotaloltreated group compared with a range of 23% to 43% of patients receiving one of six other antiarrhythmic agents (P < .001, sotalol versus other drugs). During long-term therapy, discontinuation was required in 7% of sotalol patients, less than one half of the average discontinuation rate in patients treated with the other (class I) antiarrhythmic agents (P = .003) (eg, mexile-

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Anderson and Prystowsky 399

Figure 7

Arrhythmia recurrence and cause-specific mortality in the ESVEM study by intention-to-treat with sotalol (class II/III) or class I antiarrhythmic therapy. (Reprinted by permission of the New England Journal of Medicine. Mason JW for the electrophysiologic study versus electrocardiographic monitoring investigators. A comparison of seven antiarrhythmic drugs in patients with ventricular tachyarrhythmias. N Engl J Med 1993;329:452-8. Copyright 1993 by the Massachusetts Medical Society.)

tine, 19%; procainamide, 31%; quinidine, 32%; and propafenone, 13%) (Fig 8).58 Overall antiarrhythmic efficacy in ESVEM. Complete efficacy, defined as drug tolerance during titration, achievement of an efficacy prediction during inhospital drug testing, no arrhythmia recurrence, and drug not discontinued during long-term therapy because of an adverse effect was substantially and significantly better with sotalol than with other drugs, both in the electrophysiology study arm (P < .001) and the Holter monitor arm (P = .002) (Fig 9). Thus in ESVEM, treatment with sotalol (a drug with both β-blocker [class II] and potassium-channel block-

ing [class III, repolarization-prolonging] activity), compared with other drugs, was associated with increased efficacy predictability (particularly by electrophysiologic study, which may be preferred in patients with coronary artery disease), reduced arrhythmia recurrence rates, and reduced mortality rate during outpatient therapy, even though the outcome comparisons were restricted to patients whose drugs were predicted to be effective. These important results, derived from a randomized, controlled trial of moderate size in patients with lifethreatening ventricular arrhythmias, provide a useful basis for treatment recommendations in this patient population.

400 Anderson and Prystowsky

Figure 8

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the study design limited the number of patients treated long term with sotalol, conclusions about sotalol therapy are limited.60 However, the ICD was associated with a lower mortality rate than drug therapy (primary empiric amiodarone). Empirical versus electrophysiologic study or Holter-guided therapy for sotalol. Whether sotalol is

Discontinuation by drug class (sotalol versus class I) during long-term antiarrhythmic therapy in ESVEM. (Personal communication, Jay W. Mason, MD, November 6, 1998.)

The Antiarrhythmics versus Implantable Defibrillator (AVID) study: A comparison of antiarrhythmic drug therapy versus implantable cardioverter-defibrillators (ICD). An important question for therapy of

life-threatening ventricular tachyarrhythmias in the current decade is: what are the appropriate therapeutic roles of ICDs and drug therapy? To study the question of benefits of management of life-threatening ventricular arrhythmias with antiarrhythmic drugs versus ICDs, the National Institutes of Health initiated a multicenter randomized study in 1993, AVID. Patients surviving primary VF or hemodynamically compromising VT are candidates for the study. Randomization of qualifying patients is initially between a nonthoracotomy ICD system and drug therapy. Noting the results of studies such as ESVEM and the Cardiac Arrest in Seattle: Conventional versus Amiodarone Drug Evaluation (CASCADE) study,59 the AVID planning committee selected sotalol (as guided in ESVEM, by either Holter monitor or electrophysiology study) and amiodarone (as given in CASCADE [empirically]) as the test drugs. Thus, in patients assigned to the drug arm, a second randomization to sotalol or amiodarone occurred. No class I agents were chosen for AVID because of clinical trial data suggesting lesser predicted efficacy and greater recurrence risk. AVID finished in 1997, but because

effective when used empirically (as amiodarone was in CASCADE59), and, if so, to what extent it is effective as compared with guided therapy, has not been determined by well-controlled studies. Data from the Refractory Arrhythmia Study52,53 and, to some extent, from a prophylactic postinfarction study60 can be cited to support the likelihood of benefit from unguided (empirical) therapy, whereas another longterm study54 suggested a better outcome in patients showing arrhythmia suppression at electrophysiologic study after sotalol than in those remaining unsuppressed. (Better outcomes for patients treated with amiodarone showing suppression at electrophysiologic study also have been observed.) As noted above, empirical therapy was accepted in the AVID study for amiodarone but not for sotalol.61 The authors believe sotalol is likely to be of benefit when begun under careful monitoring and continued empirically in high-risk patients, but given the better established role of guided sotalol, they prefer a guided approach in current clinical practice. Clinical trials testing empirical sotalol would be welcome. Sotalol for right VT in patients with normal hearts. The pathophysiologic characteristics and

response to therapy of VT occurring in otherwise normal hearts differ. Gill et al62 tested sotalol, verapamil, and flecainide in 23 patients with VT originating from the right ventricule and associated with a clinically normal heart. Efficacy was assessed by suppression of sustained and unsustained VT on Holter monitor recording, exercise testing, and PES. All 3 drugs were effective, regardless of monitoring method. However, sotalol was effective somewhat more frequently (88% to 91% of patients) than the other drugs (65% to 83% response rates) (P = not significant). In current therapeutics, radiofrequency catheter ablation also is viewed as an excellent therapy for patients with right ventricular outflow tract VT.63

Studies of sotalol for prevention of post-MI death Studies of racemic sotalol. Class I antiarrhythmic agents (eg, encainide, flecainide, moricizine) have been

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Anderson and Prystowsky 401

Figure 9

Overall efficacy (absence of efficacy failure or intolerance) of sotalol versus class I drugs in ESVEM.(Reprinted by permission of the New England Journal of Medicine. Mason JW for the electrophysiologic study versus electrocardiographic monitoring investigators. A comparison of electrophysiologic testing with Holter monitoring to predict antiarrhythmic-drug efficacy for ventricular tachyarrhythmias. N Engl J Med 1993;329:445-51. Copyright 1993 by the Massachusetts Medical Society.)

shown to increase (or provide no benefit) rather than reduce mortality rate when used for prevention of death in patients after infarction with ventricular ectopy.5 In contrast, several β-blockers have been shown to reduce mortality rate when used after MI in patients not selected by presence or absence of ventricular arrhythmias.64 Sotalol, which combines β-blocking and class III effects, was evaluated by Julian et al60 in a double-blind, placebo-controlled, secondary prevention trial in 1456 patients after MI. Sotalol was begun in a dose of 320 mg given once daily, whereas 80 mg is the currently recommended initial dose for arrhythmia indications, given twice daily. With this large initial dose, a trend toward an increased early death was observed. However, this finding was reversed with time so that long-term mortality rate (at approximately 1 year) tended to be favorable affected by sotalol (18% reduction: 8.9% to 7.3%, P = .3). Together with the favorable mortality rate trend, a significant reduction in recurrent MI was associated with sotalol therapy (Fig 10). The Timolol, Encainide, Sotalol Trial (TEST),65 was another smaller postinfarction study. Entry criteria included MI within 1 month, LVEF ≤40%, and ≥10 PVCs per hour or nonsustained VT on Holter recording. TEST used an even larger dose of sotalol (320 mg twice daily) and was prematurely stopped because of safety concerns that arose after 20 patients had been entered into

the sotalol arm and 6 events (4 deaths, 2 proarrhythmic events) had occurred within 2 weeks of initiating sotalol therapy. The conclusions of TEST were limited by its small size, short follow-up, and lack of a placebo arm. Considering these studies, it appears likely that sotalol can be given to patients with previous MI without an overall adverse effect on mortality rate (or with the possibility of modest benefit) if started in small initial and target daily doses (eg, approximately 80 mg and 160 mg twice daily, respectively) at >1 month after infarction. Conversely, sotalol appears to have adverse potential if given in large single and daily doses early after MI. Similarly, recent post-MI trials with amiodarone from Europe and Canada have failed to establish a general indication for amiodarone for prophylaxis of all-cause mortality, despite beneficial effects on arrhythmic events.66 Thus, of drugs with antiarrhythmic effects, standard β-blockers alone continue to be preferred for routine postinfarction prophylaxis. Prophylactic D-Sotalol after MI. A “pure” class III drug (devoid of β-blocker or other antiarrhythmic activity) might be better tolerated than one with mixed β-blocking and class III effects and might potentially improve survival in high-risk patients. This hypothesis recently was tested using D-sotalol in the multicenter SWORD (Survival With Oral D-sotalol) study in 3121 patients with recent MI and LV dysfunction.67 Unfortunately, an adverse effect on

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Figure 10

Mortality and morbidity rates (recurrent MI) after MI in patients treated with sotalol or placebo. (Reprinted with permission from Julian DG, Prescott RJ, Jackson FS, Szekely P. Controlled trial of sotalol for one year after myocardial infarction. Lancet 1982;i:1142-7. Copyright © by The Lancet, Ltd, 1982.)

mortality rate was noted (5.0% vs 3.1% at an average of 5 months of therapy, relative risk 1.65, confidence interval 1.15 to 2.36, P = .006), which led to premature study termination. Surprisingly, the hazard of therapy was greater in those with better cardiac function, suggesting that the competing risk of proarrhythmia outweighed any antiarrhythmic benefit, especially in those at inherently lower risk, whereas neither substantial risk nor benefit was observed in higher risk patients. Consistent with this, a Danish study in a higher risk population of patients after MI with heart failure, testing a closely related “pure” class III drug (dofetilide), has been completed without evidence of overall harm (DIAMOND). Nevertheless, the negative findings of SWORD lend support to the concept that the β-blocking activity of D- and L-sotalol is of importance to its overall clinical use.

Use of sotalol in patients with an ICD Antiarrhythmic drug therapy is used in combination with ICDs to reduce the frequency of serious ventricular arrhythmias requiring defibrillation, to slow sustained VT to allow antitachycardia pace conversion, and to prevent sustained supraventricular arrhythmias (eg, atrial fibrillation). Some drugs used for this purpose (eg, class I drugs and amiodarone) may increase the electrical threshold for defibrillation and reduce the efficacy of defibrillation shocks. In contrast, sotalol has been found to lower defibrillation threshold in experimental models. In human studies, Dorian and Newman68 determined

the lowest energy required for defibrillation in 25 consecutive patients who received ICDs and were treated with oral sotalol (171 ± 58 mg daily). Defibrillation threshold was found to average 5.9 ± 3.4 J (range, 2 to 15 J), which compared favorably (P < .01) with the average defibrillation threshold of 16 ± 10 J in a nonrandomized but concurrent comparison group of 23 patients (18 treated with amiodarone) (Fig 11). In 5 patients given sotalol, VF could not be induced at all (n = 1) or no more than 2 to 3 times (n = 4) at the time of postoperative VF threshold testing. Sotalol’s effectiveness for preventing supraventricular and ventricular arrhythmias, for reducing heart rate during atrial fibrillation, and reducing defibrillation threshold all appear to support its use as adjunctive therapy for appropriate patients with ICDs. However, because sotalol does not substantially slow the rate of sustained VT,51 it may be less effective in increasing the success of antitachycardia pacing. Also, its relative benefits compared with those of standard βblockers used in this setting need to be evaluated.

Summary of ventricular antiarrhythmic drug actions of sotalol On the basis of reported clinical experience, sotalol shows good suppression of ventricular ectopy, with >75% to 80% suppression of PVCs being achieved in ≥65% of patients (Table VI). Its antiarrhythmic effects on sustained VT are excellent compared with other agents, with approximately 35% of patients showing

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suppression of induced VT at PES. Finally, it has very good to excellent antifibrillatory effects, leading to favorable results in animal models of ischemic sudden death (VF), in patients with sustained ventricular tachyarrhythmias, in secondary prevention trials after MI, and as adjunctive therapy in patients with ICDs.

Anderson and Prystowsky 403

Figure 11

Clinical supraventricular antiarrhythmic activity The electrophysiologic effects of sotalol include significant increases in atrial, atrioventricular nodal, and accessory pathway refractory periods. Given this profile, sotalol would be expected to have antiarrhythmic activity against supraventricular arrhythmias. Intravenous and oral sotalol have proven effective in terminating and preventing supraventricular tachyarrhythmias, including atrioventricular nodal and atrioventricular reentrant forms of paroxysmal supraventricular tachycardia (PSVT) and paroxysmal atrial fibrillation (PAF) and flutter. Because sotalol (but not other β-blockers) prolongs accessory pathway refractoriness, sotalol also may substantially decrease the preexcited ventricular response in atrial fibrillation.

Early studies of supraventricular tachyarrhythmia therapy Small and open design studies. Camm and Paul69

have summarized early studies of sotalol therapy for supraventricular tachyarrhythmias. In an overview of seven open trials in 106 patients, intravenous sotalol in a dose of 0.4 mg/kg to 1.5 mg/kg converted 46% (n = 47) episodes of PSVT or PAF. Six studies evaluated the ability of intravenous sotalol (0.6 mg/kg to 2.75 mg/kg) to prevent the reinduction of sustained PSVT by PES in 74 patients. Sotalol was successful in 59% (n = 44). Oral therapy with sotalol was subsequently given to prevent reinduction of PSVT in three trials and was successful in 19 of 28 patients (68%). Sotalol was more effective at PES than metoprolol in preventing reinduction of PSVT (59% versus 28%, P < .05) in another study. Several small open design studies reported clinical experience with oral sotalol therapy: of 74 patients with resistant PSVT, 29 (39%) responded to sotalol. Another small study using a crossover design compared sotalol with atenolol. Sotalol was more successful in preventing clinical recurrences of PSVT (62% versus 31%).

Comparisons of intravenous sotalol with placebo Jordaens et al70 compared intravenous sotalol and placebo in a multicenter efficacy and safety study in

Defibrillation threshold in patients with implantable cardioverter-defibrillators treated with sotalol (n = 23) and in concurrent controls (n = 25); 18 were undergoing amiodarone therapy. (Data adapted from reference 68.)

43 patients with ongoing surpraventricular tachyarrhythmia caused by atrioventricular nodal reentry (n = 27), atrioventricular reentry with an accessory connection (n = 11), or other causes (n = 5). Sotalol was given in a dose of 1.5 mg/kg over a 10-minute period and efficacy (conversion to sinus rhythm) was assessed at 30 minutes. Sotalol was well tolerated, and proarrhythmic effects did not occur. Sinus rhythm was achieved in 83% of patients receiving sotalol compared with 16% receiving placebo (P < .0001). Another double-blind, parallel-design, multicenter study compared the effectiveness of two doses of sotalol (80 mg or 160 mg twice daily) with placebo in 37 patients with a variety of paroxysmal supraventricular tachyarrhythmias.69 Entry required at least one arrhythmia attack during each of three consecutive baseline periods of 1 to 4 weeks. Efficacy was then evaluated during double-blind treatment phases lasting two baseline periods or until an event occurred. Arrhythmias recurred significantly more frequently (P < .01) in patients receiving placebo (95%, 20 of 21) than in those receiving either dose of sotalol: 69% (11 of 16) of patients receiving a lower dose and 57% (12 of 21) receiving a higher dose. The relative risks of recurrence were 0.61 for sotalol 80 mg twice daily and 0.41 for 160

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Table VI. Summary of ventricular antiarrhythmic activity of sotalol Model

Success rate (% patients responding)

Experimental (canine) VF threshold39,41 Prevention of sudden cardiac death (ischemic VF)39 Clinical Suppression of ventricular ectopy (>75%)36,47 Suppression of VT/VF By Holter monitor (salvos >90%, runs 100%)1,36,44,53,56 By PES1,53,54,56 Complete suppression Partial suppression VT with normal hearts (Holter, exercise, PES)56,62 Defibrillation threshold68 Mortality trends* Postinfarction (vs placebo)60 In VT patients (vs class I drugs)1,57,58

Increased 65% 65%-70% 40%-50% 30%-40% 20%-30% Approximately 90% Unchanged or reduced 18% reduction* 41% reduction*

*Mortality effects are inadequately studied; patient groups are limited for mortality comparisons and differences do not always reach significance.

mg twice daily. PAF is known to be more resistant to pharmacologic therapy than PSVT. Indeed, a larger percentage of patients with PSVT (61%) remained event free during sotalol therapy than patients with PAF (16%). A U.S. multicenter study evaluated two doses of intravenous sotalol (1.0 and 1.5 mg/kg) versus placebo in the acute treatment of 93 patients with either spontaneous or induced PSVT (n = 45) or PAF (n = 48) and ventricular rates >120 beats/min.71 Efficacy was assessed after 30 minutes. Sotalol was well tolerated, and hypotension and dyspnea were reported in a small and equal percentage (approximately 10%) of each group. Sotalol in both doses was effective in terminating PSVT, with 67% converting to normal rhythm compared with 14% after placebo (P < .05, each dose versus placebo). Sotalol in both doses was also effective in controlling ventricular response rates (>20% reductions) in patients with atrial fibrillation (72% to 75% responded) compared with placebo (0% response). However, early (30minute) conversion rates from atrial fibrillation were low and similar among the three treatment groups (11% to 14%, P = not significant). Intravenous amiodarone also has failed to show acute efficacy in PAF conversion, although it too is effective in long-term atrial fibrillation management.

Postoperative supraventricular arrhythmias Postoperative supraventricular arrhythmia (primarily atrial fibrillation) is a major clinical problem. Janssen et al72 studied 161 patients and found sotalol (80 mg 3 times daily) to be more effective than metoprolol (50

mg 3 times daily) or control in a randomized open study. Postoperative arrhythmias occurred less frequently with sotalol (2%) than with metoprolol (16%) or control therapy (37%), and they reverted more rapidly when tachyarrhythmia occurred. In another study of 429 consecutive patients undergoing coronary bypass grafting, two doses of sotalol (40 mg and 80 mg 3 times daily) were compared with 2 doses of propranolol (10 mg and 20 mg 4 times daily) for prevention of supraventricular tachyarrhythmias.73 Supraventricular tachyarrhythmia occurred in 14% and 19% of patients, respectively, receiving low- and highdose sotalol, and 11% and 14% of patients, respectively, receiving low- and high-dose propranolol. There were no differences in efficacy between the 2 drugs at either dose. Additional comparative studies of sotalol and standard β-blockers as well as other antiarrhythmic drugs in the postoperative setting would be welcome.

Efficacy of sotalol versus quinidine for preventing af recurrence Sotalol was compared with sustained-release quinidine sulfate for maintenance of sinus rhythm after cardioversion from chronic atrial fibrillation in 183 patients in an open, randomized, parallel design Swedish study.74 After 6 months of treatment, approximately half the patients in each group remained in sinus rhythm (sotalol, 52%; quinidine, 48%; P = not significant). However, patients relapsing were less tachycardic while receiving sotalol than those receiving quinidine (average ventricular rates, 109 versus 78 beats/min) and less symptomatic. Sotalol

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also was better tolerated with fewer adverse effects and a lower rate of withdrawal (11% versus 26%).

Comparisons of sotalol and propafenone for atrial fibrillation al75

Reimold et compared sotalol with propafenone for prevention atrial fibrillation in a randomized study of 99 patients with paroxysmal or persistent atrial fibrillation. Patients had not been responsive to an average of 2 class I agents. All patients were returned to sinus rhythm at the start of the study. A failure-time analysis of response over a 6-month period was made (Table VII). Overall, 41% of patients remained in sinus rhythm, with no significant difference between drugs. Sotalol was discontinued because of side effects in 8% of patients receiving propafenone and 12% of patients receiving sotalol. In another study from the same group,76 a staged-care approach to therapy of refractory, symptomatic atrial fibrillation was tested using propafenone and sotalol sequentially or together in 109 patients who had not been responsive to 1 to 5 previous antiarrhythmic drug trials. Propafenone was given as initial therapy. Sotalol was substituted if atrial fibrillation recurred. A combination was used in each individual. After 6 months of propafenone treatment courses, 39% were free of recurrent atrial fibrillation; after sotalol treatment courses, 50% remained in normal rhythm. The cumulative success rate with sequential treatment with propafenone or sotalol, or both, at 6 months was 55%, with little further decline during subsequent follow-up. Therapy was discontinued because of intolerable side effects in 8% of patients.

Comparisons of sotalol and amiodarone for atrial fibrillation Only preliminary and relatively small comparisons of sotalol and amiodarone for long-term therapy of atrial fibrillation are currently available.77 Neither is FDAapproved for treatment of atrial fibrillation in the United States. However, interest in the use of these drugs is widespread, especially for patients refractory to class I antiarrhythmics76 and for those with significant structural heart disease, in whom class I drugs appear to pose excessive proarrhythmic risk.5,78 Hence, additional studies would be welcome. Indeed, additional comparisons are forthcoming, including a substudy of the ongoing National Institutes of Health supported Atrial Fibrillation Follow-up: Investigation of Rhythm Management (AFFIRM) study.

Anderson and Prystowsky 405

Table VII. Comparison of propafenone and sotalol for preventing recurrence of atrial fibrillation75 Propafenone

Sotalol

P value

50 46 ± 8 41 ± 8 30 ± 8 8 0 4 8 0

50 49 ± 7 46 ± 8 37 ± 8 8 4 6 12 4

NS NS NS NS NS NS NS NS

No. patients NSR at 3 mo (%) NSR at 6 mo (%) NSR at 12 mo (%) Bradycardia (%) CHF (%) Proarrhythmia (VA) (%) AE (discontinue) (%) Death (%) AE, Adverse effect. Data adapted from reference 75.

Summary of supraventricular arrhythmia efficacy and safety Sotalol appears to have potential for supraventricular arrhythmia therapy, but this indication has been less well studied than that for ventricular arrhythmias. Sotalol is as yet unapproved for a supraventricular indication in the United States. Both intravenous and oral sotalol may be effective in terminating or slowing ongoing supraventricular tachyarrhythmias, with PSVT being more responsive than PAF. Efficacy in terminating and preventing PSVT and preventing atrial fibrillation recurrence appears to be good and comparable with class IA and IC agents and superior to primary βblockers. Ongoing atrial fibrillation is effectively slowed, but sotalol’s potential to rapidly terminate atrial fibrillation remains to be clearly defined. The safety of sotalol’s use in supraventricular arrhythmias needs to be further defined but appears to be generally adequate, with proarrhythmia (torsades de pointes) remaining of greatest concern. As recorded in the sotalol package insert, serious proarrhythmias have been reported in 1.9% (n = 13) of patients treated for supraventricular arrhythmias in the sponsor’s database (n = 682)1 compared with 5.7% of those treated for sustained VT/VF (58 of 1024). Specifically, torsades de pointes occurred in 1.3% of patients with supraventricular arrhythmia (n = 9) versus 3.9% of those treated for sustained VT/VF (n = 40).

Adverse effect profile Adverse reactions to sotalol are accounted for almost entirely by events related to β-blocker activity and, in addition, events associated with QT prolongation (a result of its class III effects), specifically torsades de pointes (Table VII).1,79 The risk of torsades de pointes

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406 Anderson and Prystowsky

Table VIII. Summary of common adverse effects of sotalol* Adverse effect Cardiac Proarrhythmia Torsades de pointes (overall) With h/o VT/VF With No VT/VF Worsened VT (h/o VT) CHF h/o VT/VF h/o CHF Bradycardia Sinus node arrest 2nd- or 3rd-degree heart block Syncope General adverse effects Dyspnea Fatigue Dizziness Asthenia Light-headedness Hypotension

Incidence (patients discontinued), %

4.3 (3) 2.4 4 1-1.4 1 3.3 (1) 4.6 7.3 13 (3) ≤1 (<1) ≤1 (<1) 5 (1) 21 (3) 20 (4) 20 (2) 13 (2) 12 (1) 6 (2)

h/o, History of; CHF, congestive heart failure. *Adverse effects given that were associated with discontinuations in 1% or patients.

is a major reason why hospitalization in a monitored setting is recommended for initiation of therapy and continued until a steady state drug level is approached, usually within a few days. During premarketing trials, more than 3000 patients with cardiac arrhythmias received oral sotalol (about 1400 for sustained ventricular tachyarrhythmia). Of these, approximately 2500 received therapy for at least 2 weeks. The risk of proarrhythmia depended on the reason for therapy. In patients with a history of sustained ventricular tachyarrhythmia, the risk of torsades de pointes was 4% and the risk of worsening of clinical VT was 1% (Table VIII). 1,79 In patients with less serious ventricular arrhythmias, or supraventricular arrhythmias, risk decreased to 1% to 1.4%. The risk of proarrhythmia was also dependent on drug dose: the incidence of torsades increased with doses >320 mg/day, especially in the VT/VF population. In clinical trials experience, sotalol discontinuation was required because of side effects in 17% of all patients and in 13% of those treated for at least 2 weeks. Adverse reactions leading to discontinuation of oral sotalol (with discontinuation rates) included fatigue (4%), bradycardia (3%), dyspnea (3%), proarrhythmia (3%), asthenia (2%), and dizziness (2%). Organ toxic effects that could be ascribed to sotalol were not observed in short- or long-term trials. How-

ever, elevated blood glucose levels and increased insulin requirements relating to β-blockade may occur.1

Contraindications/precautions Sotalol, as with other β-blockers, is contraindicated in patients with bronchial asthma, severe sinus bradycardia, second- and third-degree atrioventricular block (unless protected with a pacemaker), uncontrolled congestive heart failure, and cardiogenic shock. It is also contraindicated in congenital or acquired long QT syndrome and in those with previous evidence of sotalol hypersensitivity or allergy.1 In premarketing studies, new or worsened heart failure occurred in 3.3% of 3257 patients and required sotalol discontinuation in 1%. Heart failure was more likely to occur in those with sustained VT/VF (4.6%) or a history of prior heart failure (7.3%), with an annualized risk of new or worsened heart failure of 3% without and 10% with history of heart failure. Sotalol should be avoided in the setting of uncorrected hypokalemia or hypomagnesemia. Electrolyte imbalance should first be corrected because of the otherwise increased risk of augmenting QT prolongation and causing torsades de pointes proarrhythmia. Prolongation of QTc interval to >520 msec should be regarded as excessive and avoided during sotalol therapy because of an increased associated risk of proarrhythmia. Bradycardia (defined as a heart rate consistently <50 beats/min) has been reported in 13% of patients, but frank sinus node dysfunction or sinus node arrest as a consequence of sotalol therapy is uncommon (≤1%), as is second- or third-degree atrioventricular block (≤1%). However, treatment with sotalol in patients with sick sinus syndrome should be avoided in the absence of a pacemaker. β-Blockers, including sotalol, may mask premonitory signs of hypoglycemia in patients with labile diabetes or a history of episodes of spontaneous hypoglycemia and should be used with caution in this setting. Renal function should be an important consideration in dosing sotalol. Sotalol is eliminated primarily by renal excretion of unchanged drug; consequently, dose modification is necessary with renal impairment. Otherwise, excessive drug accumulation and an increased risk of proarrhythmia and other adverse effects may occur. Sotalol is not known to cause pharmacokinetic interactions with other drugs. However, adverse pharmacodynamic interactions may be anticipated in some settings, for example, if sotalol is given with antiarrhythmics or other drugs that prolong the QT interval. Prescription and over-the-counter drugs (eg,

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certain antihistamines) that can prolong the QT interval should be avoided as concomitant therapies. Caution should be used with drugs that also possess negative inotropic or chronotropic effects, such as calcium channel blockers and other β-blockers.

Indications/dosing Indications In the United States, oral sotalol administration is indicated for the prevention and treatment of documented ventricular arrhythmias, such as sustained VT, that in the judgment of the physician are life threatening.1 Because of the proarrhythmic potential of sotalol, including a 1% to 2% rate of torsades de pointes or new VT/VF in those with either unsustained ventricular tachyarrhythmias or supraventricular arrhythmias, its use in patients with less severe arrhythmias is not approved.

Initiation of therapy: Setting and dose Given the small but real risk of proarrhythmia (torsades), sotalol should generally be initiated and doses increased in a monitored hospital setting, with patients observed until a steady-state blood level is approached. The recommended initial dose of sotalol is 80 mg given twice daily, with the dose being increased (generally allowing 2 to 3 days between dosing increments), if necessary, to 240 mg or 320 mg, given in 2 or 3 divided doses. (More rapidly up-titrated regimens are used clinically by some physicians, on the basis of patient tolerance during careful observation, but are not yet approved.) Some patients with life-threatening refractory ventricular arrhythmias may require doses as high as 480 mg/day to 640 mg/day. However, these doses are associated with an increased risk of adverse events, including proarrhythmia.

Dosing modifications Because sotalol is predominantly excreted in the urine and its terminal half-life is prolonged in conditions of renal impairment, dosing intervals of sotalol should be modified from every 12 hours for creatinine clearance >60 mL/min to every 24 hours for a clearance of 30 ml/min to 60 mL/min, every 36 to 48 hours for a clearance of 10 mL/min to 30 mL/min, and individualized for those with a creatinine clearance of <10 mL/min.

Addendum A double-blind, multicenter, dose-response trial of sotalol for the maintenance of sinus rhythm in patients with a history of symptomatic atrial fibrillation or flutter

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has been completed recently.80 Two-hundred fifty-three patients were randomly assigned into 4 groups that received sotalol 80, 120, or 160 mg twice daily, or placebo. All patients were in sinus rhythm at randomization; 58% had structural heart disease. Patients were followed up for 12 months or until the first recurrence of symptomatic arrhythmia. There were no deaths or episodes of torsades de pointes, sustained ventricular tachycardia, or ventricular fibrillation. Adverse events were dose dependent and reflected the β-blocking properties of the drug. Time to first recurrence of symptomatic atrial arrhythmia was dose dependent, and the 120 mg dose provided the best benefit/risk ratio. In another recently completed double-blind, prospective study of 82 patients, sotalol was associated with a 73% reduction in risk of atrial fibrillation after cardiac surgery.81 Patients were given 80 to 120 mg sotalol twice daily or placebo, starting 48 hours before surgery and continuing 72 hours after surgery.

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