Antiarrhythmic Actions of Amiodarone: A Profile of a Paradoxical Agent

Antiarrhythmic Actkm of Amkdarone: A Profile of a Paradoxical Agent Bramah N Slngh, MD, PhD Amiadaronera complexcompoundwith variegated verter-defibrillator in patients withVT/VF and in survielectrapharmacologic and pharmacokinetic propeti’es vors of cardiacarrestremainsuncetiin when total and an equallycomplexside-effect profile,continues to mortali~isusedastheprima~ endpointof comparison. havea criticalrolein thecontrolof ventricular and su- Amiodaronesuppresses ventricular ectopyand markpraventricular tachyarrh miasas the useof classI edlysuppresses nonsustained VT. It preventsinducible P is alsothecasewithsotolol. VT/VF in a smallnumberof patients, agentshasdeclined.Suc butslowsVTmte Unlikeotherse-called classIIIagents,amiodaronenon- in a largernumber.Theroleof thedrug in prolonging competitively blockssympathetic stimulation, and itsef- survivalin thepos!myacardial infarctionpatientis unfeckon repdarizationare notassociated withreverse clear,althaughpreliminarydata from blindedstudies use dependency. Rarelydoes it producetorsadesde suggest thatthedrugdecreases arrhythmia-related morpointesdespiteitspropensity toinducesignificant brad- tality.Similarly,in heortfoilure, amiodarone hasthe ycardiaand markedprolongationof the QT interval. tentialto reducetotalmortalitybutappearsto beseE Duringlong-termthemp withthedrug,thereisno im- tivelyeffective in nonischemic ratherthan in ischemic pairmentaf ventricular L nction;in fact,thereare sig- cardiomyopathy. Intravenous amiodarone wasrecentiy nificantincreases in Iheleftventricular +&n fraction introduced in theUnitedStatesfar thecontrolof recurtmcledamiodaronetherapyin patients with rentdestabilizing W orW resistant toconventional therduring heart r ilure. long-term amiadaroneadministrationapy.Thereisalsoevolvingdataindicating thatthedrug consistently demansirates markedefficacyin a wide mightbe the mostpotentagentin maintainingsinus withatrialfibrillationor flutterconem of arrhythmias. Themaiarlimitation of amio- rhythmin patients daroneduringlong-termtherapyis itsunusualside-ef- vertedchemically ar electrically to sinusrhythm.Howfectprofile,althoughtheincreasing trendfor low-dose ever,blindedcontrolled compamtive studiesinvolving drug therapyhasdemons-ted a maiordeclinein the sotolol,quinidine,or pureclassIIIdrugshavenotbeen ovemll incidence of seriousadversereacfions. Amio- carriedout. The availabledata nevertheless suggest profile,amiadaroneisa dedaroneiseffective incontrolling symptomatic ventricular that,barringitsside-effect antifibrillatory tochycardia andfibrillation(VT/VF)in >60-70% of po- sirableprototypeof a broad-spectrum tientswhenconventional agents(especially class1)are and antiarrhythmic compound. (AmJ Cardiol1996;78(suppl 4A):41-53) ineffective or notwell tolerated.Theefficacyof amiodaranecomparedwith thatof an implantable cardio-

s

ynthesized in the early 1960s as a coronary vasodilator for the control of myocardial ischemia, amiodarone began to draw attention as a molecule with a complex biologic profile.l Recognition of its somewhat unique electropharmacologic properties in 19702 Ied to the exploration of its clinical antiarrhythmic potential a few years later.3’4Despite its complicated side-effect profile, which became evident with the’increasing use of the drug on both sides of the Atlantic as well as in South America, 3’4a compelling perception has developed that arniodarone is the most effective agent in the control of ventricular tachycardia and fibrillation (VT/VF), with efficacy comparable to that of implantable cardioverter-defibrillators (ICDS), and in maintaining sinus rhythm in From the Division Veterons UniversiV geles,

AHoirs

of California, for reprints:

y 691/1

Anqees, Y

and the De

Los Angelesl

of Medicine,

of Medicine, Schoo f of Medicine, Los An-

11301

Bramah

Affairs

Wilshire

Boulevard,

by Excerpta Medica, Inc.

All rights reserved.

N. Singh,

11 E, Veterons

90073.

01996

and the Department

Center

artment

California.

Address diolo

of Cardiology Medical

MD,

Medical 10S

PhD, Section Center Angeles,

of Car-

of West

10S

California

patients with atrial fibrillation. Amiodarone has also been believed to have the greatest potential of any antiarrhythmic drug (excluding P blockers) for effecting a beneficial impact on mortality in patients at the highest risk for m-rhythmic death. Whether these perceptions will be vindicated by the outcome of the results of ongoing controlled studies and those about to be initiated remains uncertain. However, the available data on the drug’s efficacy and antiarrhythrnic mechanisms, which determine the observed clinical effects, merit serious scrutiny. Aspects of these issues and the drug’s potential for expanding indications in controlling arrhythmias form the basis of this article.

PHARMACOLOGICCONSIDERATIONS h spiteof the.expanding knowledge from experimental and clinical studies in recent years, there have been few insights into the complexity of the broad-based electropharrnacologic profile of amiodarone. The enigma of the drug’s action continues to intrigue pharmacologists and cardiologists. As indicated elsewhere in this supplement,5 it is clearly 0002-9149/96/$15.00 Pll S0002-9149(96)00452-3

41

TABLE

1 Comparative

and Chronic

Oral

Electrophysiologic

Administration

and Pharmacadynamic

Properties

of Intravenous

of Amiodarorse Intravenous

Parameters

Amiodarone

Heart rate

* +

QT/QTc QRS:

intervals

Chronic Oral Amiodarone Reduced +++ Prolonged

+++

slow rate fast rate

t;

t:+

AV nodal conduction

Jz TI

t+++

Atrial ERP AV nodal ERP Ventricular

T++

ERP

t+++ T+++

tt

Bypass tract ERP

T+ ++

t+++

effect

++

+++

Inotropic effec!

+

Noncompetitive

/3 blockade

Net antiadrenergic Negative

1++

+++

[may be positiv~inotropic ~

Ndesethylamiodorone

effect)

+++

ERP = effective relractow period; Y = variable effec!; + to +++

,= gmded effect from minimal to wbftantial; T

= increase; 1 = decrease.

simplistic to continue classifying amiodarone as a class 111antiarrhythmic compound even though the most striking feature of its pharmacology is the consistent and marked lengthening of the action potential duration during long-term therapy. The compound appears to exhibit all 4 electrophysiologic classes of action—or all 5 if one includes its bradycardic action as a discrete mechanism. However, its overall net effects during chronic administration cannot be mimicked simply by combining sodium channel blockers, ~ blockers, so-called pure potassium channel blockers, and calcium channel antagonists. Its pharmacodynamic properties and therapeutic effects suggest the uniqueness of a complex molecule with interacting properties rather than an aggregate of individually-discrete actions. The acute and chronic actions of amiodarone in the heart are substantially different,Gbut the basis for such differences in terms of actions on ionic currents has not been established. Some of these differences are emphasized in Table I. The antiadrenergic effects of the drug, evident during short-term as well as

—+—— Baseline

m,

100 ~ 95

1

—3-6

Mos Amio

_

long-term drug administration, have come into sharp focus with the demonstration that rate-lowering @ blockers remain the only class of antiarrhythmic drugs that consistently reduces mortality in controlled clinical trials.7Without having intrinsic sympathomimetic effects, amiodarone reduces heart rate during long-term administration almost to the same extent as most @ blockers. However, amiodarone does not produce the so-called /3blocker side effects. When amiodarone is given intravenously, there is little or no effect on ventricular effective refractory pe@d in unanesthetized animals or conscious patients, despite plasma levels often >10 mg/rnL.8 The effect of intravenous amiodarone is dominated by significant changes in terms of decreases in anterograde conduction across the AV node with increases in the effective refractory period of the AV node. These acute effects are not accompanied by significant increases in repolarization, and yet the drug has recently been shown to be effective in the control of hemodynarnically destabilizing ventricular tachycardia and fibrillation.gIts efficacy exceeds that of inFIGURE 1.Effectsaf -km amiadaranehalmsnt an ci2 ifsfs *W

>1 Year Amio

~

S4(~ hearttula,(~ unmwctad ~ inQT/QTC in tervaf, and(clnammlized * withCard”m -b. l$m”~ raduced heartrataw theentins 24-haurpariad,butsffact ~ ~s ~ ~ -9 and2 w At 3 to 6 nsardha, amiada~ PfJA s“wnificnrst increases ~ QTandQT,m antire 24-hourperithe ods(p <0.001)Withauteffectssn

650 r

a

t’ 600

600 I

t-

-u b

cirwdian rhythmidty. Effectwus 01s0

450 -

signifkantly g~n~ ~~; of drugfmatmem tmalment (p<0.001).Simi400 manthsaf farthe br dikremesweremaintained I !,tl,l c-1,1 801$1, 16 24 12 18 24 O 6 12 06 0 6 12 18 24 QT.interwd, butthecirccrdian rhythmicity& 1ysarwusvirhsally atdished. Hour of Day Hour of Day Hour of Day “l-laws atwhichstatistical .- sirmificarrt werefoundbatweus treated groups andbasadirse. @daptsdwithPerrniss”km AmHearfJ.’2)

1

d“~

42

THE

AMERICAN

JOURNAL

OF

Cardiology@

“OL

VOL

78

(4A]

AUGUST

29,

1996

I

TABLE II Sotalol,

Possible

Mechanisms

and Pure Class

to Account

Ill Agents

to Cause

Effect

I

for the Differing Torsades

Potentials

of Amiodarone,

de Pointes

Amiodarorre

SOtalOl

Pure Claw Ill Agents

Bradyccmdia

Tt

ttt

Prolonged

TTT

tT

;

z t

TT

t

TT

QT/Q~C

QT/QT,

dispersion:

-Spatial -Temporal

11 ~

EAD generation Reverse use/rate

11 in PF or M cells

41

dependency of APD

++ * ++

Calcium channel antagonism K“ dependency of APD Tj interaction Incidence of torsades de poinfss

?

‘TT

Tt —

—

<1%

3-6%

3–A%

Abbreviations: * = vorioble effects; T = increase; 1 = decrwws; – = absent; + = present; EAD = early cdtwdePlorizotion; APD = action potantial duration; K = potassium;PF = Purkiniefibers; Tt = triiodo!hyronine.

travenous lidocaine and procainamide and is comparable to that of intravenous bretylium tosylate.10 In isolated tissues, amiodarone exerts a depressant effect on sinus node automaticity, but this is not translated into a significant bradycardic action in conscious animals or humans following intravenous injections of amiodarone. Presumably, the bradycardic action does not occur because sympathetic activation due to the peripheral vasodilator actions of the drug and the drug’s direct depressant effect on the sinus node are opposing influences and together produce the net effect.b In contrast, the electrophysiologic effects of longterrn administration of amiodarone are numerous and often striking. The drug predictably lengthens depolarization (QT.) and refractoriness in most cardiac tissues as a function of time, with little or no change in the QRS duration except at faster heart rates. There is a modest increase in the HV interval (a class I effect) with a significant prolongation of the AH interva18caused by the drug’s antiadrenergic and calcium channel blocking actions. The net effects on depolarization are consistent with those in animals chronically treated with amiodarone.2 The QTCinterval in humans increases progressively on a constant dose of amiodarone, 11reaching what appears to be a steady-state effect at 6–12 months.12Figure

1 illustrates the effects of the duration of drug treatment on the circadian rhythmicity of heart rate and the QT and QT. intervals. It is noteworthy that the depressant effect on the heart rate reaches steady state by 3 months of maintenance drug treatment. In contrast, increases in the QT and QT. intervals continue despite a constant dose during the period between 6 and 12 months of treatment. These effects are consistent with the long onset and offset times of drug action for the antiarrhythmic and antifibnllatory effects of the drug. Thus, as might be expected, after chronic treatment a marked increase occurs in the effective refractory periods in most cardiac tissues (atria, ventricles, AV node, His-Purkinje system, accessory tracts of the heart) as a function of time. There is usually little or no change in the QRS, but there is an increase in the HV interval.13>14 An increase in the QRS duration does, however, sometimes occur, 14as do increases in infranodal conduction (anterograde or retrograde) following fast stimulation frequencies, again reflecting effects on the fast-sodium channel.15It is clear that the overall electrophysiologic changes, which are accompanied by a progressive decrease in heart rate, are significantly greater during long-term therapy c,ompared with those found after short-term intravenous or oral administration. In part, this difference is caused by

FIGURE 2. Effects of amiadarane an corrected QT/QT,interval circadian variability. QT.isex ressed asa perI’ centage of meanvoueineach group.kksurfyvariability ofQT. v aboveandbelowmeanfar24 hours~ isnotalteredsignificantaher3-6 ~ 100 months ofdrug therapy t utismark- ~ edfyreduced aftertherupylasting ~ >1 year.& datasuggest that amiodorone facilitates temporal hoarizam~neity inven~icular Y Iatary tian-a potentially antiflbri mechanism. (Adapted withpermissionfromAmHeotiJ.’2)

~5~ 0

100

100

3

6

9

’11

~5tc11’11’1:’111 ~5tl’1’’llll’ll’l 12 15 1821

24

Hour of Day

A SYMPOSIUM:

0

3

6

9

12 15 1621

24

0

3

6

PHARMACOTHERAPY

9

12 15 1621

24

Hour of Day

Hour of Day

OF

CARDIAC

ARRHYTHMIAS

43

the properties of the drug’s major metabolize, Ndesethylamiodarone.lc There are a number of features of the drug’s effect on repolarization that differ from those of other so-called class III drugs (Table II). These variations may be of importance in accounting for the differences in proarrhythmic actions and rates of efficacy between amiodarone and other class 111agents or @blockers.5 The effects of arniodarone are not dependent on heart rate, in contrast to the reverse rate and reverse use dependent actions of class III agents in general. Arniodarone reduces temporal and spatial dispersion of depolarization (QT interval) 12,17and, despite a marked bradycardic effect and substantial prolongation of the QT interval, the incidence of torsades de pointes that the dmg produces is very 10W.18 Figure 2 shows that the temporal dispersion of the QTC interval is markedly reduced by amiodarone as a function of time. The precise electrophysiologic mechanism underlying the rare occurrence of torsades de pointes during amiodarone therapy remains unidentified. It is tempting to speculate that the temporal and spatial dispersion induced by the drug might contribute to a greater homogeneity of refractoriness in the myocardium, thereby reducing the possibility of focal excitation. To what extent the rare occurrence of torsades de pointes might be due to the drug’s calcium channel blocking action, which prevents early afterdepolarizations (EADs) and delayed afterdepolarizations (DADs), or to its differential effects on ventricular muscle, the Purkinje fibers, and the ventricular M cells, remains equally speculative.

HEMODYNAMICEFFECTSOF AMIODARONE There are few or no data on the inotropic effects of amiodarone in isolated cardiac muscle. Some reduction in cardiac contractility might be expected from the drug’s propensity to block sodium and calcium channels, especially since the drug, unlike sotalol and other class III agents, does not lengthen the action potential in isolated tissues during intravenous infusion in animals and in humans. On @e other hand, intravenous amiodarone does produce peripheral and coronary vasodilator effects. Therefore, the net hemodynamic effect of the compound derives from a complex interplay of simultaneous alterations in preload, afterload, ventricular contractility, and heart rate. The net effect may be further influenced by ischernia because amiodarone increases.coronary blood flow and may exert a cmdioprotective effect. In humans, amiodarone was found to increase cardiac’output and decrease the left ventricular filling pressure while decreasing systemic and coronary vascular resistance.lg Because arniodarone is most often used for longterm drug therapy, the effects of the drug on systolic and diastolic function are clinically relevant. In this setting, there is no significant decrease in the left’ ventricular ejection fraction (LVEF); in fact, there may bean increase, as recently confirmed in the CHF 44

THE

AMERICAN

JOURNAL

OF

CARDIOLOGY”

VOL

78

STAT trial,20 in which up to 40% increase in the LVEF was maintained for over 2 years. In another smaller study, a consistent increase in LVEF occurred, but an impairment of diastolic function, determined echocardiographically, also occurred.21 This impairment of diastolic function maybe the basis for the heart failure rarely associated with amiodarone treatment in patients with existing ventricular diastolic function. However, these cases are rare and the drug is usually well tolerated in patients with heart failure, in whom it may improve exercise capacity.22

AMIODARONE PHARMACOKINETICS Theclinical pharmacokinetics of amiodarone are not completely understood. The drug has a large volume of distribution (500 liters) and a long elimination half-life (35– 110 days) and requires many months for blood levels to reach equilibrium for optimal therapeutic effects. The bioavailability of orally administered amiodarone is about 30–50%. Excretion is minimal via the kidneys. Extensive hepatic metabolism occurs, with desethylamiodarone’ as the major metabolize.Desethylamiodarone is electropharmacologically active with a pattern similar to that of the parent compound with respect to the onset and offset times of drug action; thus, while the metabolize may contribute substantially to the overall effects of the parent compound, it does not appear to account for the delayed onset of action of amiodarone. Because of their strong lipophilic nature, amiodarone and its metabolizes accumulate extensively in liver, lung, fat, skin, and other tissues. Amiodarone and desethylamiodarone are not dialyzable, and doses of amiodarone need not be reduced. in patients with renal disease. The ventricular myocardium develops a concentration 10–50 times that found in the plasma. The onset of action after intravenous drug administration generally occurs within several hours, whereas the onset of action after oral administration may require 2–3 days and often requires 1–3 weeks. The use of higher loading doses reduces this time interval. Amiodarone elimination is biphasic; the initial 50% decrease in plasma levels over the first 3–10 days after cessation of therapy is probably a result of elimination from well-perfused tissues followed by an increased drug concentration rebound. This rebound is thought to be caused by elimination of the parent compound from poorly perfused tissues in which the drug has a mean terminal half-life of 53 days. The relationship between plasma drug concentrations and dose of arniodarone is reasonably linear, and the plasma levels of the drug in patients successfully treated with amiodarone are usually in the range of 1.5–2.5 pg/mL. Desethylamiodarone levels rise as a function of time and may either approximate those of the parent compound or exceed them. There is, however, some evidence that in the case of drug-induced organ toxicity, higher levels of the metabolizethan those of the parent compound are found in tissue. Because the drug has such a long

[4A)

AUGUST

29,

1996

TABLE IllClinical Absorption

Pharmacokinetic

Profile

of Amiodarone T~a,: 2-12

rate

h (log time, 0,4-3

Extent af absorption

Poor and slow

Bioavoilobility

Variable

Protein binding

96.3

(22-56%]

+ 0.6%

Volume of distribution

1.3-65.8

Elimination

Negligible

Biotronsfarmation Elimination

l/kg

3.2-20.7

Pattern of elimination

h (acute], 13.7-52.6

0.10-0.77 Major:

mon~Ndesethylamiodarane;

Minor:

bis-Ndesethylomiodarone,

Deiodinated 1.2-2.5

plasma ronge

Suggested

Tachycardia

metabolizes

pg/mL

Dose schedule

One daily

Special

Slaw anset ond oFfset af drug action

factors

half-life, plasma levels of amiodarone and desethylamiodarone can be detected as long as 9 months after cessation of therapy. The pharmacokinetic profile of amiodarone is summarized in Table III. Dosingschedules: An optimal standardized dosing regimen is difficult to develop for this complex compound. The overall philosophy of dosing has been to use the lowest dose that is consistent with the best clinical response and the least number of severe adverse reactions. An initial loading dose of 800– 1,200 mg daily for 1–3 weeks, followed by 400– 600 mg daily for 2–4 weeks, and then 200–400 mg or less a day is recommended for amiodarone. The regimen may need to be varied in relation to the clinical features of the patients and the early development of side effects. In general, lower loading and maintenance doses are desired for supraventricular than for ventricular arrhythmias. Amiodarone was recently approved for intravenous administration for the acute control of VT/VF refractory to conventional therapy (see below). The intravenous regimen (Table IV) can also be used for rapid loading. However, such a regimen does not shorten the time to steady state effect of the drug when it is used for prophylactic long-term therapy. Drug interactions: It should be emphasized that amiodarone interacts with a number of other cardioactive agents that are metabolized in the liver. The list includes digoxin, warfarin, quinidine, procainamide, N-acetylprocainamide (NAPA), flecainide, propafenone, and phenytoin. If digoxin is administered with amiodarone, plasma levels of digoxin double. Amiodarone administered conTABLE IV

days (chranic)

l/rein

First order

kinetics

Metabalites

I

(acute)

renal excretion

Hepotic ond intestinal

half-life

Total body clearance

Therapeutic

h)

Dosage

and of Ventricular

Regimen

of Intravenous

Amiodarone

currently with warfarin may cause prothrombin times to-triple. Concomitant &e of am~odarone and any of these drugs requires lower doses and close monitoring.

ANTIARRHYTHMIC AND ANTIFIBRIUATORY EFFECTS OF AMIODARONE:ESTABLISHED AND POTENTIALEXPANDING INDICATIONS The role of arniodarone as an antiarrhythmic drug needs to be viewed in the context of its profile as a complex molecule with unique electropharmacologic and pharmacodynamic properties that differ from those of all other antiarrhythmic agents. In this article, the role of the drug in the acute and chronic control of VT/VF (approved by the FDA in 1985) will be discussed. The potential indications for reducing mortality in other subsets of patients at high risk for sudden arrhythmia deaths, such as postmyocardial infarction patients and those with heart failure, will also be mentioned. There is a growing trend to use amiodarone to maintain sinus rhythm in patients with atrial fibrillation and flutter. The administration of the intravenous formulation of the drug was approved for the control of refractory destabilizing VT/VF in 1995. The relevant clinical data will therefore be summarized briefly here. The clinical role of amiodarone in controlling cardiac arrhythmias is becoming increasingly well defined from experiential data as well as from controlled clinical trials. The drug’s spectrum of activity following oral therapy differs from that following for the Suppression

of Recurrent

Destabilizing

Ventricular

Fibrillation

loading infusion Rapid infusion

1.5 mg/ml

Follawed

1.8 mL (900

by slaw infusion

Maintenance infusion

I

(150

mg in 100 mL D5W)

mg in 500

ml D5W)

1mq/mL

For breakthrough arrhythmias, supplemental infusions[1.5 mg/ml;

15 mg/min 1 mg/min,

in 10 min 33.3

Reduce ta 0.5

ml/hour

over the next 6 haurs

mg/min,, 16.6

mL/hour

over the remoining

18 hours

150 mg in 100 mL DsW) may be given at a rate of 15 mg/min in 100 ml over 10 minutes

Alternatively, the rate of the infusionmaybe increased.

A SYMPOSIUM:

PHARMACOTHERAPY

OF

CARDIAC

ARRHYTHMIAS

45

120

Class

Ia

Class

Ib

Class

Ic

Class

11

Class

111

1

FIGURE 3. Comparative effects ofvariouselectrophysioiagic classes ofantiarrhythmic drugsonthesuppression of nonsustained VTdurin treatment of cardiac ar mias,# esemean dataorebaP on meta-anaiysis of studies inwhichdatawereacquired onthenumbers of patients takin ihe testdruginwhomallepisodes o! nansustained VTwereeliminated duringrepeatI+ohur monitoring. (Adapted fromAmHeartJ,”)

?? I--L L

Quinidine I Dlsopyrtunide I Tocainide I PrOpafenOne I Propmnolol Mexiletine Procainamlde Flacalnlde Amiodarot?e PureClass111 Encainide

intravenous administration. The reason for these dif- tively, and the cumulative incidence of arrhythmia ferences are not well understood. recurrence was 19Y0,26Y0,and 28%, respectively. Ventricular arrhythmias: The wide spectrum of ac- The authors concluded that despite the side-effect tions of amiodarone in controlling ventricular ar- profile of the drug, amiodarone was an effective and rhythmias may be related to the drug’s unusual phar- reasonably well-tolerated antiarrhythmic compound. macodynarnic and electrophysiologic properties. Its Of interest, only a small number of patients who had unique qualities include its long elimination half-life, inducible sustained VT at control electrophysiologic iodinated nature, and anti-ischemic and antiadre- study became noninducible during amiodarone thernergic actions, as well as its divergent effects on sys- apy. Clearly, these data have bearing on the contintolic and diastolic function, increasing the former uing debate on the issue whether success of longand decreasing the latter.21The drug is unique in term therapy can be predicted more accurately by the terms of its low propensity to induce proarrhythmic effects of the drug on the suppression of spontanereactions compared with class I agents as well as ously occurring arrhythmias on Helter recordings or other class III agents.18’23 Arniodarone differs from on the basis of whether inducible tachycardia is elicother class 111agents in the following ways: ( 1) it ited by programmed electrical stimulation of the does not exhibit reverse use and reverse rate de- heart. The data from Weinberg et a130provide further pendency of action on depolarization,~ (2) it con- support for the belief that the failure of arniodarone sistently reduces dispersion of repchrization, 12’17to prevent ventricular arrhythmia induction does not and (3) it attenuates the generation of early after- necessarily preclude excellent clinical outcome. The depolarizations in isolated myocardial tissues.25As role of programmed electrical stimulation in selectan unusually potent antiectopic agent,zbarniodarone ing patients for long-term antiarrhythmic therapy approduces a near-complete su pression of nonsus- pears doubtful, and most clinicians use the drug emtained ventricular tachycardia ~ (Figure 3); it is also pirically. It is unlikely that further controlled clinical exceedingly potent in reducing simple and complex trials will be carried out to settle the issue.23In a recent study involving 121 patients with inducible premature ventricular complexes.zo Ventricular tochycardia andfibrillation andsurvivors VT, the results of early (2 weeks) and late (6 weeks) ofsuddendeafh:Two large studies have demonstrated programmed electrical stimulation testing after that when amiodarone is administered in a loading amiodm-one loading and maintenance dosing redose followed by a maintenance regimen of 200– vealed no difference in long-term prognosis among 400 mg/day, it is effective in controlling malignant responders, nonresponders, and partial responders. arrhythmias, including those associated with cardiac There was also no difference in long-term prognosis arrest, in 60–75% of patients in whom conventional between those in whom rapid hemodynamically unagents (especially class I compounds) have been in- stable VT was induced during treatment and those effective.27,28The results from these studies appear in whom the VT rate was slow and well tolerated representative and consistent. Herre et a129treated during treatment.31 The empiric use of amiodarone in VT/VF is furseveral hundred patients with VT/VF and cardiac arrest with amiodarone after each patient had been ther supported by the results of the Cardiac Arrest in unsuccessfully treated with an average of 2.9 drugs. Seattle: Conventional versus Amiodarone Drug At the end of 5 years of follow-up, there was a 21% Evaluation (CASCADE) study. This study was unincidence of sudden death, that is, an average of 470 dertaken to compare the efficacy of guided therapy a year, with a 790 incidence in the first year. In the using conventional drugs (quinidine, procainarnide, study conducted by Weinberg et al,30469 patients flecainide, or combination) with the efficacy of emwere treated with amiodarone and followed for 5 piric therapy using amiodarone.32There were 228 years. The cumulative incidence of sudden death at patients— 113 in the amiodarone group and 115 in 1, 2, and 5 years was 9%, 13910,and 22Y0,respec- the guided therapy group. Survival was significantly 46

THE

AMERICAN

JOURNAL

OF

Cardiology@

VOL.

78

(4A)

AUGUST

29{

1996

greater in the amiodarone group than in the group in CURRENTSTATUSOF THE ROLEOF which guided therapy with conventional drugs was INTRAVENOUSAMIODARONE IN THE use&32Equal numbers of patients from both groups ACUTECONTROLOF VT/VF had an ICD. Patients treated with amiodarone were There have been numerous uncontrolled studies less likely to receive a shock from an implanted de- that suggested the potential of amiodarone for confibrillator, and syncope followed by defibrillator trolling refractory VT/VF without evidence of QT shock occurred less often in the amiodarone treated prolongation. A number of smrdl uncontrolled studpatients than in the patients treated with conventional ies on the use of intravenous arniodarone in patients undergoing cardiopulmonary resuscitation have also drug therapy. A number of conclusions can be reached. Clearly, yielded promising results. Recently, the results of 3 empiric amiodarone therapy is an effective means of controlled, blinded studies have been reportedg’loon therapy for survivors of cardiac arrest and is superior the effects of intravenous amiodarone in refractory to therapy with class I agents. Sotalol was also found VT/VF. Two of the studies were dose-ranging trials, to be superior to class I agents in the Electrophys- in which patients with VT/VF refractory to lidocaine iologic Study Versus Electrocardiographic Monitor- and procainamide were randomized into 3-limb pating (ESVEM) trial involving patients with VT/VF.33 allel studies.gIn 1 of these, 1 of 3 doses—500 mg, It is reasonable to presume that therapy with amio- 1,000 mg, or 2,000 mg—was infused over 24 hours. darone or sotalol represents the best medical therapy There was a clear trend toward a better response in for VT/VF, and it is not unethical to conduct clinical the higher-dose groups in terms of event rate, but trials comparing the efficacy of these drugs with that total and cardiac mortality were not statistically difof an ICD. However, no controlled trials have been ferent among the groups. The study was not statisperformed to examine”the precise comparative effi- tically powered to examine this issue. A greater decacy of amiodarone and sotalol in patients with VT/ gree of hypotension occumed at the highest dose VF and in survivors of cardiac arrest. Such a trial is used. In the second dose-ranging study, the 3 doses likely to be of much practical and theoretical importance in the control of ,life-threatening ventricular were 125 mg, 500 mg, and 1,000 mg over 24 hours. In this study, there were more events per hour and a tachyarrhythmias. A number of critical editorials and reviews have shorter time to first event in the low-dose group. The emphasized that effectiveness of amiodarone34-3G differences among the groups were significant. The and sotalo137therapy might be comparable to that of provision for the use of supplemental doses of the implantable devices in terms of impact on total mor- drug was permitted, and it allowed the quantitation tality. Whether drug therapy for VT/VF is superior, of the additional therapy as an endpoint. The largest numbers of supplemental doses were used in the inferior, or comparable to therapy with an ICD re- group treated with the lowest dose of the drug. mains unresolved and is the subject of 3 ongoing The third study was a double-blind comparison randomized trials. In the Cardiac Arrest Survival in of 2 doses of amiodarone10( 125 mg and 1,000 mg) Hamburg (CASH). study, out-of-hospital cardiac ar- with intravenous bretylium (2,500 mg/24 hours) in rest survivors are being randomized to an ICD, amio- patients refractory to procainamide and lidocaine. darone, or metoprolol.38Propafenone was the fourth The group treated with the higher-dose regimen of limb of the trial but was discontinued because it was amiodarone had a comparable response to the group associated with excess mortality compared with the given bretylium, and both regimens were superior to ICD after 15 months of enrollment into the study.38 the low-dose amiodarone. Intolerable hypotension In the Canadian Implantable Device Study (CIDS), occurred twice as frequently with bretylium than patients with VT/VF are being randomized to em- with amiodarone, requiring cross-over to arniodapiric arniodarone or ICD.3’ In the Antiarrhythmic rone. Other adverse reactions were minor, and torVersus Implantable Device (AVID) trial, patients sades de pointes did not occur in any of the study with cardiac arrest or symptomatic VT are being ran- limbs. Hypotension occurred in 16% of the patients domized to best medical therapy (amiodarone or so- treated with amiodarone, but it was only severe talol) versus ICD.39The results of these comparative enough to require discontinuation of the drug in drug and device trials are likely to be of profound <29Z0.There was no significant difference in total or importance for the future management of patients cardiac mortality among the 3 groups. with VT/VF and of survivors of cardiac arrest. Thus, these results indicate that intravenous arnioIn the meantime, it appears reasonable to make a darone may play a significant role in the acute condecision on the presumption that device and drug trol of recurrent refractory VT/VF when lidocaine, therapy are equally effective in reducing total mor- procainamide, and bretylium have failed or have not tality in patients surviving cardiac arrest and in pa- been tolerated. The clinician may choose to initiate tients presenting with symptomatic sustained mono- concomitant oral loading immediately or during the morphic VT.40However, in choosing between drug course of the infusion for the long-term prophylaxis therapy and an ICD in an individual patient, it should against arrhythmia recurrence. It should be emphabe noted that a significant number of patients receiv- sized that while the intravenous drug is undoubtedly ing an ICD eventually ‘need drug therapy to reduce effective in acutely controlling VT/VF, it remains the number of symptomatic shocks from the device. unclear whether intravenous loading of amiodarone A SYMPOSIUM:

PHARMACOTHERAPY

OF

CARDIAC

ARRHYTHMIAS

47

shortens the period of loading by the oral route. However, the initial administration of the drug in patients who cannot take the oral drug is an important therapeutic use of intravenous amiodarone. Uncontrolled data have suggested that intravenous amiodarone may be effective in facilitating the resuscitation of patients with cardiac arrest, but whether amiodarone should be added to the drug regimens being used during cardiopulmonary resuscitation is unclear. The issue is under consideration.

AMIODARONE IN PATIENTSAT HIGH RISKFOR SUDDEN DEATH There are several subsets of patients with cardiac disease and accompanying electrical instability, which may form the substrate for reduced survival from arrhythmia death. Such patients may have hypertrophic cardiomyopathy, recent or remote myocardial infarction, and congestive cardiac failure. In all 3, there is increased frequency of occurrence of VT/VF. There are no controlled data in the case of hypertrophic cardiomyopathy, and the available data However, although it is Preli~are conflicting.A1,AZ nary, controlled data on postmyocardial infarction patients and patients with cardiac failure are becoming available. The potential role of amiodarone in these 2 settings will be discussed in light of the evolving data, with a particular emphasis on data from placebo-controlled clinical trials. Thepast-Mlpatienk Numerous clinical trials have established that ~ blockers, aspirin, angiotensin-converting enzyme (ACE) inhibitors, and thrombolytic therapy, when given prophylactically to the survivors of myocardial infarcts, do reduce mortality. Whether such an improvement might occur with arniodarone given prophylactically is a question that remains to be answered. There are theoretical reasons to suggest that the drug may have the potential to reduce mortality in survivors of myocardial infarction. Amiodarone is a coronary vasodilator and a powerful anti-ischemic agent; it has significant antiadrenergic actions while being antifibrillatory and having a potent suppressant effect on ambient arrhythmias, including nonsustained VT. Amiodarone also has a low proarrhythmic potential and, like ~ blockers, reduces heart rate. Numerous trials with amiodarone have indicated benefit on mortality.+-47 Two recent clinical studies are relevant to these indications. In the Base] Antiarrhythmic Study of Infarct Survival (BASIS) study, Burkart et ala randomized 312 survivors of acute infarction to 1 of 3 groups: the first was treated with low-dose amiodarone (n = 98), the second with no antiarrhythmic treatment (n = 100), and the third with individualized drug therapy (n = 114). The death rate was 13% in the no-treatment group, 1090in the individualized therapy group, and 5$%in the amiodarone-treated group (p <0.05 compared with no treatment group) at the end of the first year. Ceremuzynski et a145in .Poland conducted another randomized study in 305 patients given amiodarone and 308 patients given placebo. The patients were 48

THE

AMERICAN

JOURNAL

OF

Cardiology@’

VOL.

78

followed for 1 year. The postinfarct patients could not be given @blockers because of specific contraindications. Amiodarone reduced cardiac mortality (p <0.048); there were 21 deaths in the amiodarone group (6.9%) and 33 ( 10.7%) in the control group. The low-dose amiodarone was well tolerated, as there was only 1 patient with pulmonary toxicity out of the 305 patients followed for 12 months. No cases of torsades de pointes were encountered. In the follow-up observation of BASIS4Cpatients, amiodarone was stopped at the end of the first year. The patients were followed for a mean of 72 months (range 55-125 months). By actuarial life-table analysis, the probability of death after 84 months was 30% for the amiodarone-treated patients and 45% for control patients. Over the entire follow-up period, the mortality rate was lower in the amiodarone group than in the control group with respect to cardiac deaths (p = 0.047) as well as total deaths (p = 0.03). The sudden death and total cardiac death rates were low during the ‘follow-up, 1.290per year in the amiodarone group, and 4.570 per year in the control group for total mortality. These data raise the possibility that postmyocm-dial infarction patients need to be treated only for ‘the first year after an infarct. Confirmation of these results by a blinded trial is likely to have major implications for survivors of postmyocardial infarction. Preliminary dataframhe CAMIATandEMIATstudies:

Two recently completed double-blind studies have provided important preliminary results. The first is the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT) .47In the pilot phase of CAMIAT, 77 survivors of infarction who also had arrhythmias were randomized in a double-blind manner to amiodarone 300–400 mg/day or to placebo. One patient ( 1.2’%0)in the amiodarone group and 4 patients ( 13.8~o)in the placebo group died as a result of arrhythmias, resulting in an overall mortality of 10.4?ZO and 20.7Y0,respectively. There was a trend in favor of amiodarone for all the major endpoints—arrhythmia deaths, resuscitation from VF, and total mortality in the small pilot study. The definitive study, still to be reported in full, involved 1,250 patients with recent myocardial infarction and 10 premature ventricular complexes/hour. The primary hypothesis was that amiodarone will reduce arrhythmia mortality. The study was not powered to detect a significant change in total mortality. Arrhythmia mortality was reduced by 32.6% (p <0.001), cardiovascular mortality was reduced by 27.6% (p <0.01), and all-cause mortality was reduced by 21.0?70,which did not reach statistical significance. The European Myocardial Infarct Amiodarone Trial (EMIAT)48 focused on patients with left ventricular ejection fraction <4070 who were perceived as being at a higher risk for sudden death than all patients with infarction taken as a group. EMIAT was not a suppression trial, as its primary endpoint was total mortality. Preliminary data from EMIAT reported at the 1996 Annual Scientific Meeting of the American College of Cardiology in(4A]

AUGUST

29,

1996

dicated that amiodarone did not reduce all-cause mortality. However, there were 50?Z0fewer arrhythmia deaths (p <0.006) and significantly fewer arrhythmia deaths plus resuscitated cardiac arrests (p <0.002) in patients treated with amiodarone compared with those treated with placebo. It should be emphasized that these overall data from the CAMIAT and EMIAT studies are preliminary and are in need of detailed analysis and interpretation. When the full reports on these studies are published, the data will need to be interpreted in the context of the entire body of evidence relating to the drug’s effect on mortality in postinfarct patients as well as in other subsets of patients at increased risk for arrhythmia death. Such analyses may permit the delineation of the role of amiodarone in reducing mortality in the post-infarction patient further than is possible with the current standard prophylactic therapy. Amiodarone andthehigh-riskpatient withheartfailure:It is known that patients with congestive cardiac

failure and asymptomatic premature ventricular complexes and nonsustained VT are at particular risk for fatal cardiovascular events.49-51The annual mortality is about z 15%, and half the deaths are sudden and presumed arrhythmia in origin. Therefore, the hypothesis that amiodarone might reduce total mortality in patients with moderate-tosevere congestive heart failure and asymptomatic ventricular arrhythmias was tested.20’52 The Congestive Heart Failure Survival Trial with Antiarrhythmic Therapy (CHF STAT)20 study used a double-blind, placebo-controlled protocol sponsored by the Veterans Affairs Cooperative studies. In CHF STAT, 674 patients with congestive heart failure ,with 210 premature ventricular complexes/hour and left ventricular ejection fraction <40~0 were randomized to placebo (n = 338) or to amiodarone (n = 336). At the median follow-up of 45 (O–54) months in this study there was no significant difference (p = 0.60) in all-cause mortality between placebo and amiodarone. Among the placebo patients, the actuarial 2year survival was 70.8% (95% confidence interval ICI], 65.7-75.9% ); among the amiodarone patients the rate was 69.4% (95% CI, 64.2–74.6%). There was also no significant difference in incidence of death (p = 0.43) between amiodarone and placebo; corresponding 2-year sudden death-free survival was 81% for placebo and 85% for amiodarone. There was a trend in favor of amiodarone for reducing total mortality in patients with nonischemic cardiomyopathy (p = 0.07) but not in those with ischernic cardiomyopathy (Figures 4 and 5). Amiodarone was highly effective in suppressing premature ventricular complexes (280% suppression in 70% of patients) and in eliminating runs of VT (6790 free of VT runs at 2 weeks compared to 23~ofree of VT at baseline). The total mortality in the group in which the arrhythmias were suppressed (responders) and the total mortality in the group in which they were not suppressed (nonresponders), were not significantly different. The findings were similar for patients with

nonsustained ventricular tachycardia; that is, there was no difference between patients in whom the drugs eliminated nonsustained VT and those in whom it failed to do so. The data are thus in line with increasing observations that arrhythmia suppression and mortality can be divergent,23and suppression of either inducible or spontaneously occurring arrhythmias does not ensure reduction in sudden death and total mortality. A study from the Argentine, Grupo de Estudio de la Sobrevida en 1aInsuficiencia Cardiaca en Argentina (GESICA),52 in which 516 patients with New York Heart Association class III and IV heart failure were randomized to amiodarone (300 mg/ day) or to standardized medical therapy, revealed a significant reduction in mortality of the whole population. There was a 28% reduction in all-cause mortality, from 41.49?’0to 33.5Y0 (95~0 CI = 4– 45%; p = 0.024). GESICA and CHF STAT had markedly different numbers of patients with ischemic versus’nonischemic cardiomyopathy. In GESICA, 3990 of the patients had coronary artery disease compared to 70% in CHF STAT. It is tempting to speculate that this might account for the favorable trend in the patients treated with amiodarone who had cardiac failure of nonischemic origin (p = 0.07). This idea is supported by the recent data on long-term ~ blockade with bisoprolol in patients with congestive heart failure, which revealed no significant effect on total mortality5gin patients with history of myocardial infarction. However, there was a highly statistically significant decrease in total mortality (p <0.01) in patients with nonischemic cardiomyopathy. The data indicate the substrate specificityof drug responses in terms of total mortality. Amiodaroneand maintenance of sinusrhythmin atrialfibrillation: From the electrophysiologic stand-

point, long-term amiodarone administration is likely to exert a potent antifibrillatory action in the atria, in which it substantially prolongs the action potential durationojAIn numerous studies, albeit uncontrolled, it has been found to be the most effective drug in maintaining normal sinus rhythm.55-G0Middlekauff et alGlrecently reviewed the results from relatively large, nonrandomized studies in which doses lower than those generally used for ventricular arrhythmias were given. The investigators found that low doses of amiodarone successfully maintained sinus rhythm in 53–7990 of patients with paroxysmal or chronic atrial fibrillation during a mean follow-up of 15–27 months. Patients in these groups had refractory cases of atrial fibrillation and had not responded to multiple conventional antiarrhythmic compounds. In the largest of these studies,55amiodarone was administered at doses of 200–400 mg/day to 121 patients with atrial arrhythmias, including 95 with atrial fibrillation, and successfully suppressed atrial fibrillation in 78$Z0 during a mean follow-up of 27.3 months. More recently, Gosselink et albzstudied 89 patients undergoing electrical cardioversion. During loading, 15 patients ( 16%) converted to normal sinus rhythm

A SYMPOSIUM:

PHARMACOTHERAPY

OF

CARDIAC

ARRHYTHMIAS

49

BEzl

1.o -

O,o -

-

O,a co.7-

FIGURE 4, Kaplon-Meier tsstimates of withischemic carsurvival in tients r ;::d~~~;~yS:-

g ~O.e go,,. i

amiadarone andplacebo. No differences werefoundbetwwniheeffects aflhedrw andthatofthepiacaba onsurviva.[Reprintiwithpermis1 sionfromN EnglJMed.~

o.4-

$ ~o.3-

~-a.25 p=o.m

0.20.1mgm~olm 0,00

1

.9

12

24 29

07 @a

120 12!

n-184 “. i.M

1

1

18

24

30

?4

1

!

1

1

42

40

w

w

SurvivalTime (months)

1,0-

0,90,6-

z0,7-

b ~5 0.6-

FfGIJRE 5. Kapfan-Meier estimates of survival in patients withnanischemic cardiomyopathy. k wasa trend

~ 0.5-

:E!$%S%r%%%llityinduced by amiodarcme. (Reprinted withpermission fromN EnglJ Med.?

S ~ : Chi-.qmre.3.39 P=O.07

0.20.1$&mne 0.00

1 6

n. 76 n= 79 ( 12

1 18

Ss 57

18

%

1

1

24

24

30

I

1

,

42

4s

54

1

m

SurvivalTime (months)

within 4 weeks. and after cardioversion of the remainder, altog&her 90% were in normal sinus rhythm. Actuarially, 5370 of these patients were in normal sinus rhythm after 3 years. In the study by Chun et alG3of patients who had proven refractory to conventional therapy (mean number of 2.3 drug trials per patient), 91 study patients (chronic atrial fibrillation in 44, paroxysmal atrial fibrillation in 47, mean age 59 years) were given a loading dose followed by maintenance doses of amiodarone (mean dose 277 * 102 mg/day) over a 10-year period. During follow-up the probability of remaining in normal sinus rhythm was linear over 6 years. The actuarial rate of maintenance of sinus rhythm (after a month of loading) at 1, 2, and 5 years was 0.87, 0.80, and 0.57, respectively. In 21 patients arrhythmia recurrence necessitated arniodarone dose adju~tmentupward, after which 76$Z0 remained in sinus rhythm for a mean follow-up of 2.3 years. The 50

THE

AMERICAN

JOURNAL

OF

CARDIOLOGY@

VOL.

78

actuarial rate of drwz discontinuation for side effects at 1, 2, and 5 year; was 0.06, 0.12, and 0.27, respectively. The most common side effects were skin changes (5.5$ZO),altered thyroid state (3.3%), and pulmonary fibrosis (3.3~o), but there were no fatalities or cases of torsades de pointes during the period of drug administration. It appears reasonable to assume that the drug withdrawal rate on low-dose amiodarone (i.e., <400 mg/day) is likely to be no more than 10~0in the first year of therapy. Thus, it appears from these extensive studies that low-dose amiodarone maintains normal sinus rhythm in paroxysmal and chronic atrial fibrillation with a high success rate and an acceptable side-effect profile. Importantly, the efficacy of amiodarone is not influenced by the duration of the last atrial fibrillation episode, the type of underlying heart disease, the-K)atient’sa~e~ or left ventricular dysfunction. Injeed, left ~trial size does [4A)

AUGUST

29,

1996

not seem to be an important factor in the efficacy rate of amiodarone,ss However, despite these results, there has been no randomized controlled study comparing the precise efficacy of oral amiodarone with other antiarrhythmic agents in maintaining normal sinus rhythm. Disch et alw recently reported a Markov decision analysis comparing warfarin, quinidine, and lowdose amiodarone in managing chronic atrial fibrillation, They examined 5 randomized controlled trials of warfarin, 6 randomized controlled trials of quinidine, and 13 longitudinal studies of low-dose amiodarone. The decision analysis model wasused to assess outcomes in large, hypothetical cohorts of patients with atrial fibrillation followed from 65 to 70 years of age. Each patient was treated within 1 of 4 clinical strategies: ( 1) no treatment, (2) warfarin, (3) electrical conversion followed by quinidine, or (4) electrical cardioversion followed by low-dose amiodarone. In the hypothetical cohort, there were fewer patients who had disabling events on amiodarone (1.4%) than on quinidine ( 1.8%), warfarin (2.6%), or no treatment (7.4%). Also, amiodarone was associated with the lowest 5-year mortality ( 13.6%), compared with warfarin ( 14.4%), quinidine ( 15.2%), and no treatment ( 18.2%). The Disch study indicated that on warfarin the annual rate of stroke was 1.35% and of major bleed was 1.46%; the corresponding figures for amiodarone were O.1% and 0.0%. Clearly, the data supporting the effectiveness of amiodarone in patients with atrial fibrillation is compelling, but blinded and controlled studies are necessary to establish with confidence the role of the drug in the arrhythmia.

STAT trial in the United States.20’45 The precise incidence of hepatoxicity, thought to be about IYo,is not known, More common is the transient increase in liver enzymes, Numerous minor side effects of the drug have been reported. Troublesome but less serious side effects include mastalgia, epididymitis, and bluish skin pigmentation. The incidence of bluish pigmentation is unrelated to dose, but skin changes do become increasingly common and troublesome with the increasing duration of therapy. Proarrhythmic reactions andconduction disturbonees:

An unexplained feature of arniodarone treatment is the unexpectedly low incidence of torsades de pointes, which appears to be a reasonably specific proarrhythmic correlate of prolonged cardiac repolarization.la The fact that torsades de pointes rarely occurs during monotherapy with arniodarone over prolonged periods of time, despite the prolongation of the QT interval to >600 msec and the accompanying bradycardia of s50 beatslmin, is in direct contrast to the effects seen with other class III agents. When torsades de pointes occurs in the setting of amiodarone therapy, it usually, but not invariably, occurs when amiodarone is used in conjunction with therapy with other QT-prolonging drugs such as quinidine or procainamide, or it occurs in the context of severe electrolyte disturbances. It remains puzzling that even in heart failure the incidence of torsades de pointes during chronic amiodarone therapy is low. Occasionally, ventricular tachycardia maybe precipitated by amiodarone during the early loading phases of the drug, and incessant arrhythmia has been described. These events may be a result of the initial class I actions of the drug, which tend to resolve with continued drug administration, presumaSIDE-EFFECT PROFILEOF bly because the class III and antiadrenergic effects AMIODARONE The available data indicate that the observed ben- of the drug become dominant. Amiodarone may also eficial effects of the compound should be balanced produce significant and symptomatic bradycardia, against the well-known potentially serious deleteri- especially when it is used in combination with rateIowering calcium channel antagonists, ~ blockers, or ous actions. Adversereactions: Adverse events are common other agents that depress sinus-nodal function. In the during amiodarone therapy. Minor side effects in- last case pacemaker implantation may be required if clude corneal microdeposits and subjective gastro- drug therapy needs to be continued long term. intestinal side effects that seldom require drug discontinuation. Amiodarone-induced hypothyroidism CONCLUSIONS Amiodarone is a complex iodinated molecule occurs in about 5–8’ZOof patients and may require thyroid hormone replacement. Hyperthyroidism in- with a variegated pattern of electropharmacologic, duced by arniodarone occurs in about 2% of patients antiarrhythmic, antifibrillatory, and anti-ischemic and may require discontinuation of the drug. Nec- properties. Its pharmacokinetic and side-effect prorologic side effects include peripheral neuropathy files are equally complex, and the drug’s overall and myopathy. electropharmacologic properties differ from those of A particularly important adverse reaction caused nearly all other antiarrhythmic agents. The drug is by amiodarone is the development of pulmonary tox- potent in suppressing spontaneously occurring venicity. During the early years of amiodarone therapy, tricular arrhythmias. Its major indication is the conthe incidence of pulmonary toxicity was reported to trol of life-threatening ventricular arrhythmias. be in the rangeof5–15Y0. With much more stringent Arniodarone and sotalol are regarded as the best attention now being paid to dosage schedules, the medical therapy for cardiac arrest survivors as well incidence appears to have fallen to <3~o in many as for those with sustained monomorphic ventricular centers in the United States; overall, it might be as tachycardia. It is widely believed that the efficacy of low as l~o, as noted in the Polish postmyocardial arniodarone in these patients is comparable to that of infarction secondary prevention trial and the CHF an ICD in terms of impact on total mortality. A numA SYMPOSIUM:

PHARMACOTHERAPY

OF

CARDIAC

ARRHYTHMIAS

51

ber of controlled clinical trials are in progress to define the comparative clinical utility of the 2 forms of therapy in patients with VT/VF. The role of amiodarone in prolonging survival in high-risk postinfarct patients and in patients with cardiac failure is being explored in controlled and blinded trials. There ,are emerging data suggesting that the compound may be very effective in maintaining stability of sinus rhythm in patients with atrial fibrillation and flutter after DC cardioversion. This also is the subject of controlled clinical trials in which amiodarone is being compared with placebo and other antifibrillatory compounds such as sotalol.

21. AmmarA, WongM, SinghBN. Divergenteffectsof chronicamiodarone administrationon systoficand diastolicfunctionin patientswithheart disease. AmJ Cardiol 1995;75:465–469. 22. HamerAWF, ArklesLB, JohnsJA. Beneficialeffectsof low dose amiodaronein patientswithcongestivecardiacfailure:a placebo-controlledtrial, J Am Coil Cardiol 1989;14:1768-1774. 23. SinghBN, AhmedR. Class 111antiarrhythnricdrugs. Curr Opin Cardiol 1994;19:12–22. 24. SagerPT, UppalP, FolhnerC, AntimisiarisM, Pruitt C, Sin@ BN. Frequency-dependent electrophysiologic effectsof arniodiwone in humans.Circulation 1993;88:1063–1071. 25. Tr@nakaC, SinghBN. Barium-inducednondrivenactionpotentialsas a modelof triggeredpotentialsfrom early afterdepnlarizations:significanceof slowchannelactivityanddifferingeffectsof quinidineand amiodarone.JAm

Coil Cardiol 1990;15:213-221. 26. SalernoD, GillingharnKJ,BerryDA,HodgesM. A comparisonof antiar-

rhytfunicdrugs for the suppressionof ventricularectopicdepolarization.A meta-anafysis.AmHeart J 1990;120:340–353. 27. MasonJW. Arnindarone.NEngl JMed 1987;316:455-466. 28. NademrmeeK, SinghBN, HendricksonJ, IntarachotV, LopezB, Feld G, CarrnomDS, Weis JN. Amiodaronein refractorylife-threateningventricular 1. CharlierR, DeltourG, Bauti.neA. Pharmacologyof amiodarone,an antian- arrhythmias.AnnInternMed 1983;98:577–584. girraldrug with a new biologicalprofile.Arzrzeimittefjimw% 1968;18:1408– 29. HerreJM, SauveMJ,MaloneP, GriffinJC,HelmyI, LangbergJJ,Goldberg H, ScheinmanMM. Long-ternrresultsof amiodaronetherapyin patientswith 1421. 2. SinghBN, VaughanWilliamsEM. The effectof arrriodarnne,a new anti- recurrentsustainedventriculartachycardiaor ventricuhufibrillation.JAm CO1l Cardiol 1989;13:442-449. anginaldrug,on cardiacmuscle.Br J Pharrrracol 1970;39:657–667. 3. RosenbaumMB, ChialePA, RybaD, EfizariMV. Controlof tachyarrhyth- 30. WeinbergBA,MilesWM.KleinLS, ZipesDP. Fiveyearfollow-upof 589 rniasasswiatedwith Wolff-Parkinson-White syndromeby arniodaronehydro- patientstreatedwithamiodarone.Arn Heari J 1993;125:109–120. 31. Nasir N, SwarnaUS, BoeheneKA, Doyle TK, PacificoA. Therapyof chloride.AmJ Cardiol 1974;34:215–222. predictionof efficacywith 4. RosenbamnMB, ChialePA, HrdpemMS, Nau GJ, PrzybylskiJ, Levi RJ, sustainedventriculararrhytfrrniaswith“irniodarone: LazzariJO, Elizari M. Clinicafefficacyof arnindamneas an arrti-arrhytbmic seriafelectrophysiologicstudies. J Cardiovasc PharrrracolTtrer 1996;l:123– 132. agent.Am J Cardiol 1976;38:934-942. drugtherapyin 5. SinghBN. The cmningof age of the classIff antiarrhythmicprinciple:ret- 32. The CASCADEinvestigators.Randomizedarrtiarrhythrrric survivorsofcardiacarrest(the CASCADEStudy).AmJCardiol 1993;72:280– rospwtiveand futuretrends.AmJ Cardiol 19%;78(suppI4A):17–27. 287. 6. SinghBN. Arnindarnne:historicaldevelopmentand pharmacologicprofile. 33. MasonJW, for the ElectrnphysiologicStudyversusElectrocardiographic Am Heart J 1983;106:788-797. test7. SinghBN. Advantagesof B blcwkersversusantiarrhythnricagentsand cal- Monitoring(ESVEM) investigators.A comparisonof electrophysiologic efficacyfor verrtriccium antagonistsin secondazypreventionafter myncardialinfarction.Am J ing withHeltermonitoringto predictantiarrhythnric-drng ulartachyarrhythrnias. N Engl J Med 1993;329:445–451. Cardiol 1990;66(suPP1):9C-20C. not the ultimategold 8. IkedaN, NademaneeK, KannarrR, SinghBN.Electrnpbysiologic effectsof 34. Singh BN, Implantablecardioverter-defibrillators: amindarone:experimentalandclinicalobservationsrelativeto serumandtissue standardfor gaugingtherapyof VT/tibrillation?AmJ Cardiol 1994;73:12111213. concentmtions.AmHeart J 1984;108:890–899. 35. Zipes DP. Are implantablecardioverter-defibrillators better than conven9. ScheirunarrMM,LevineJH, CannomDS, FriehlingT, KopelmmrHA,Chil- tional antiarrhvtfnrricdrum for survivors of cardiac arrest? Circulation son DA, Platia EV, WilbcrDJ, KoweyPR, for the IntravenousAmiodarone 1995;91:2115-”2117. MnkicenterInvestigatorsGrnup.Dose-rangingstudy of intravenousanrioda- 36. KimSG.Impkrntabledefibrillatortherapy:doesit reallyprolonglife?How rone in patientswith life-threateningventriculartachyarrhythmias.Circulation can we rrroveit?AmJ Cardiol 1993:71:1213–1218. 1995;92:3264-3272. 37. Ku~karnpV, Mermi J, Mewis C, BrarmU, Seipel L. Does pragmrnrmed 10. KoweyPR, LevineJH, Herre JM, PacificoA, LindsayBD, Plumb VJ, electrical stimulationpredict long term efficacy of dl-sotafol?Circulation JanosikDL, KopelrnanHA, ScheirrmanMM, for the IntravenousArnindarone 1994;90:1-545. MukicenterInvestigatorsGrnup.Randorrrized,double-blindcomparisonof in- 38. SiehelsJ, CappatoR, RuppelR, SchneiderMAE, Kuck KH, the CASH travenousamiodaroneandbretyliumin thetreatmentof patientswithrecurrent Investigators.PrcliminmyresultsofthecardiacarreststudyHarnbnrg(CASH). hemudynarnicallydestabilizingventriculartachycardiaand fibrillation.Circu- AmJ Cardiol 1993;72(suPP1):109F113F. lation 1995;92:3255–3263. 39. ComollySJ, GentM, RobertsRS, DorianP, GreenMS, KleinGJ,Mitchell 11. PritchardDA, Singh BN, HurleyPJ. Effects of arniodaroneon thyrnid LB, SheldonRS, Roy D, on behrdfof the CIDS Co-Investigators.Canadian functionin patientswithiachenricheartdisease.BrHeart J 1975;37:856–860. implantabledefibrillatorstudy (CIDS): studydesign and organization.Am J 12. AntirnisiraisM, SarrnaJSM, SchoenbaumMP, SharrnaPP, Venkrrtaramarr Cardiol 1993;72(suPP1):103F– 1O8F. K, SinghBN.Effectsofamiodaroneon thecircadianrhytfmrandpowerspectral 40. Kim SG. Evaluationof the managementof malignantventriculartachyarchangesof heart rate and QT interval.Significancefor the contrnlof sudden rhythmias:the rolesof drugtherapyandimplantabledefibnllatnrs.AmHeart J cardiacdeath.AmHeart J 1994;128:884–891. 1995;130:1144-1150, 13. WellensHJJ, BrugadaP, AbdolMrH, DassenWR. A comparisonof the 41. McKerrnaWJ, AdamsKM, PolonieckiJD, Dickie S, Oakfey CM, Krikfer electmphysiologiceffectsof intravenousand oraJmniodaronein the samepa- DM, GoodwinJF. Longterm smvivalwithanrindaronein patientswithhypertient. Circulation1984;69:120–124. tzuphiccardiomyopathyandventriculartachycardia.Circulation1989;80:11-7. 14. MoradyF, DiCarloLA, KrolRB, BaermarrJM, de BuitleirM. Acuteand 42. MaronBJ, FananapazirL. Suddencardiacdeath in hypertr6phiccardiochroniceffectsof arniodaroneon ventricrdarrefractonness, intraventricularcon- myopathy.Circrdation1992;85(suppl1):157–163. ductionand ventriculartachycardiainduction.JArn COUCardiol1986;7:148– 43. NademrmeeK, SinghBN,StevensonWG,WeissJN.Amiodaroneandpnst157. MI patients.Circulation. 1993;88:76+774. 15. ShenasaM, DenkerS, MahmudR, LehnrannM, EstradaA, AkhtarM. 44. BurkartF, PfistererM, KiowskiW, Follath F, BurckhardtD. Effect of Effectof amindaroneon conductionandretlactorinessof theHis-Pnrkinjesys- antiarrhythmictherapyon mortalityin survivorsof myncardialinfarctionwith tem in the humanheart. JAm COZ1Cardiol 1984;4:105–110. asymptomaticcomplexventriculararrhythmias:BaselAntiarrhythmicStudyof 16.SinghBN.Electrophanrracology of anriodarone.In: VaughanWilfiarnsEM, InfarctSurvivaf(BASIS). JAm Coil Cardiof 1990;16:1711-1718. CampbellTJ, eds.Arzti-arrhythmia Drugs. Berlin:Springer-Verlag,1988:335– 45. CeremuzynskiL, fGeczarE, Krzenrirrska-PaJmla M, KuchJ, NartowiczE, 364. Smielak-KommbelJ, DyduszynskiA, MaciejewiczJ, ZaleskaT, Lazarczyk17. Cui G, Sen L, SagerP, UppaiP, SinghBN. Effectsof arniodarone, sema- KedziaE, MotykaJ, PaczkowskaB, SczanieckaO, YnsufS. Effect of arrriotilide,and sotalolon QT dispersion.AmJ Cardirrl1994;74:896–900. daroneon mortalityafter myocardiafinfarction:a double-blind,placebo-con18. HolrdoserSH, fGingenhebenT, SinghBN. Arnindamne-associated prnar- trolled,pilotstudy. JAm COUCardiol 1992;20:1056-1062. rhythmiceffects:a reviewwith specialreferenceto torsadede pnintestachy- 46. PfistererME, KiowskiW, BmnnerH, BurkhardtD, BurknrtF. Long-ternr cardia.AnnInternMed 1994;121:529–535. benefitof l-year anriodaronetreatmentfor persistentcomplexventricularar19. C.St& P, BonrassaMG, DelayeJ, JarrirrA, FromentR, DavidP. Effectsof rhytfrnriasatler myncardialinfarction.Circulatiorr 1993;87:309-311. arnindaroneon cardiacandcornnaryhemodynamicsandon myocardiafmetab- 47. Cairns JA, Comolly SJ, Gent M, RobertsR. Post-myccamlialinfarction olisminpatientswithcoromuyarterydisease.Circufatiorr1979;59:1165-1173. mortalifyin patients with ventricnfarprematuredepolarizations:Canadian 20. SinghSN, FletcherRD. GrossFisherS, SinghBN, LewisHO,Deedwania ArniodarmreMyocardiafInfarctionArrhytfrndaTriafPilot Study. Circulation PC,MassieBM,GolfingCC,LazzeriD,fortheSurvivalTrialofAntiarrhythmic 1991;84:550-557. Therapyin CongestiveHeartFailure.Amindaronein patientswith congestive 48. CanrnrAJ, JulianD, JanseG, MmrozA, SchwartzP, SimonP, FranginG. heart failure and aaymptomaticventricular arrhythmia. N Engl J Med FortheEuropeanMycardial InfarctAnriodaroneTrial(EMfAT)Investigators. AmJ Cardiol 1993;72(suPP1):95F-98F. 1995;333:77–82.

52

THE

AMERICAN

JOURNAL

OF

Cardiology@

VOL.

78

(4A)

AUGUST

29,

1996

andparoxysmalatrialfibrillationresistantto quinidinetherapy,JAm Coil Cardiol 1985;6:1402-1407. 58.BmdskyMA,AllenBJ, WalkerCJ III, CaseyTP, LuckettCR, HenryWL. Arniodaronefor maintenanceof sinusrhythmafter conversionof atrirdfibrillation in the aetdrrgof a dilated left atrium. Am J Cardiol 1987;60:572575. 59. BlevinsRD. KerirrNZ, BenaderetD, Fmmin H, Faitel K, JamrrdillaR, RuberrfireM. Amiedarorrein the managementof refractoryahial fibrillation, Arch Intern A4ed 1987;147:1401–1404. 1984;51:195–201. 52. DovalHC,Nul DR. GrancelliHO,PerroneSV,BortmrmGR,CnrielR, for 60. VitoloE, TrorwiM, LarovereMT, RmrroloR, MorabitoA. Amiodarone theGrrqmde Estudiode Ia Sobrevidaen Ia InsuficienciaCardiacaenArgentina veraus quirridirtein the prophylaxis of atrird fibrillation. Acta Cardiol (GESICA) Investigators.Randomisedtrial of low-doseamiodaronein severe 1981;36:431–444, 61. MiddlekrmffHR, WienerI, SaxonLA, StevensonWG. Low-doseamiocongestiveheartfailure.I.urrcet1994;344:493-498. 53. CIBISInvestigator andCommittees.A randomizedtrialof (~-blockadein darone for atrial fibrillation:time for a prospectivestudy? Ann hriem &fed heartfailure.The CardiacInsufficiencyBisoprololStudy(CIBIS). Circulation 1992;116:1017-1020. 62. GosselirrkATM,CrijnsHJGM,VsrrGelderIC, HilfigeH, WiesfeldACP, 1994;90:1765-1773. S4. OlssonSB,BrnrsonL, VamanskaaE. Class3 antiarrhythmicactionin man. Lie RI. Lc.w-doaeamiodaronefor maintenanceof sinus~hythmaftercardiovObservationsfrom monophasicaction potentialrecordingsand arrriodamrre emionof atrialfibrillationor flutter. JAMA 1992;267:3289-3293. 63.ChunSH,SagerPT.StevensonWG,NademrmeeK,MiddlelrauffHR,Sirrgh treatment.Br Heart J 1973;35:1255–1259. 55. Graboys TB, Podrid PJ, I-ownB. Efficacyof amiodaronefor refractory BN. Long-termefficacyof amiodrrronefor the maintenanceof normalsinus rhythmin patierrtawith atrirrlfibrillationor flutter.Am J Cardiol 1995;76:47– supraverrtdculartachyarrhythmiaa. Am Heart J 1983;106:870-875. 56. GoldRL,HaffajeeCI, CharosG, SloanK, BakerS, AIwrt JS. Amiodarone 50. 64. DiachDL, GreenbergML, HolzbergerPT. MrdenkaDJ, BirkmeyerJD. for refractoryatrirdfibrillation.AmJ Cardiol 1986;57:124-127. 57. HorowitzLN, SpiehmmSR, GreensparrAM, MirrtzGS, MorgarrrntfrJ, Managingatrial fibrillation:a Markovdecisionanalysiscomparingwarfarin, Arm hrtem Med 1994;120:449-457. BrnwnR, BradyPM, KayHR.Useof amiodaronein thetreatmentofperaisterrt quinidirre,and low-dosearniodrirone. 49. HolmesJ, Kubo S, Cody R , fGigfieldP. Arrhythmia in ischemiaand rrmrischemicdilated cardiomyopathy:predictionof mortalityby ‘arnbtdatoty Am J Cardiol 1985;55:146–151. elecmomrdiography. 50. MeinertzTM, HofmamrT, KasperW, TreeseN, BechtoldH, .%ienenU, Pop T, LeitrrerEV, AndresenD, MeyerJ. Significanceof ventriculararrhythmiasin idiopathicdilatedcardiomyopathy. AmJ Cardiol 1984;53:902-907. 51. Von OlshrmsenK, SchaferA, MehmelHC, SchwarzF, SengesJ, Kfibl.x W. Ventriculararrhythmiasin idiopathicdilatedcardiomyopathy.Br Heart J

A SYMPOSIUM:

PHARMACOTHERAPY

OF

CARDIAC

ARRHYTHMIAS

53