amiodarone and post-mi patients

K Nademanee, BN Singh, WG Stevenson and JN WeissAmiodarone and post-MI patients

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764

Amiodarone and Post-MI Patients

Koonlawee Nademanee, MD; Bramah N. Singh, MD, DPhil;William G. Stevenson, MD; James N. Weiss, MD

Survivors of acute myocardial infarction (MI) re-main at risk of sudden cardiac death after beingdischarged from the hospital. In these patients,

frequent premature ventricular contractions (PVCs)and depressed ventricular function herald sudden car-diac death.1-3 These observations triggered the idea thatif PVCs were suppressed by antiarrhythmic agents, thensudden cardiac death could be averted.3,4 That belief ledto an explosion in the use of antiarrhythmic drugs 20years ago, and the pharmaceutical industry mounted amassive development campaign to find more effectiveantiarrhythmic agents for ventricular arrhythmia sup-pression, which, it was hoped, would prevent suddencardiac death. To this end, throughout the 1980s, abouttwo new antiarrhythmic compounds were developedevery year.5As the number of antiarrhythmic drug prescriptions

rose dramatically,6 soon came troubling reports thatclass 1 antiarrhythmic agents failed to reduce the sud-den cardiac death rate: Indeed, many class I compoundshad proarrhythmic and negative inotropic effects.7-9CAST I and II dealt what many considered the fatalblow to the use of class lc antiarrhythmic drugs inpost-MI patients10"'1: Encainide and flecainide in-creased the mortality rate of these patients, whereasmoricizine, a class la agent, significantly increased therisk of sudden cardiac death during the first 2 weeks oftherapy and was not effective over the long term.'1Given the results of CAST and other studies, manyphysicians were skeptical about whether antiarrhythmicagents played any role in sudden cardiac death prophy-laxis. By the 1990s, physicians were in a quandary: Howshould one treat potentially life-threatening ventriculartachyarrhythmias in MI survivors?As many antiarrhythmic agents were falling from

favor, amiodarone -an antiarrhythmic compound thathad been viewed since its approval in 1984 by the Foodand Drug Administration as a "last resort" drug-wasgaining hard-won acceptance on the basis of severalstudies showing that the drug effectively controlledlife-threatening ventricular tachyarrhythmias.12-19 Datafrom several trials20-24 suggesting that amiodaronemight effectively control and prevent arrhythmias in MIsurvivors also called for a reevaluation of the "last-resort" status of the drug.

From the Department of Cardiology, Denver (Colo) GeneralHospital; the Department of Medicine, University of ColoradoSchool of Medicine, Denver; and the Department of Medicine,University of California Los Angeles School of Medicine.

Reprint requests to Dr Nademanee, Denver General Hospital,Cardiology Department, 777 Bannock St, Denver, CO 80204.

We plan to review the current knowledge of theelectrophysiological actions of amiodarone (specificallyhow the drug works in ischemia-related ventriculararrhythmias), to review the current clinical trials study-ing the effectiveness of amiodarone in post-MI patients,and to appraise the drug's value and limitations in thesepatients.

Antiarrhythmic ActionsThe pharmacodynamics and pharmacokinetics of

amiodarone are still poorly understood.25,26 The drugwas developed in Belgium (Labaz Inc) as an antianginalagent in 196227; only later was it found to possessantiarrhythmic and electrophysiological effects.27-29Amiodarone relaxes vascular smooth muscle, acts as acoronary and peripheral vasodilator,30 and significantlyslows the heart rate and cardiac metabolism28'29: That is,it increases coronary blood supply but decreases oxygendemand. These effects formed the basis of the pharma-cological rationale for the original indication of thecompound to treat angina pectoris.The initial observations in dogs that chronic oral

amiodarone administration produced progressivebradycardia led to studies of its electrophysiologicaleffects. Singh and Vaughan Williams31 discovered thatchronic amiodarone therapy uniformly lengthened theaction potential duration (APD) of isolated rabbit atrialand ventricular muscle (Fig 1). This observation sug-gested that amiodarone belonged to the class 3 antiar-rhythmic category: Its defining property- lengtheningboth the APD of a given tissue and the refractoryperiod-was responsible for the antiarrhythmic effect.However, the drug has other antiarrhythmic propertiesas well: Amiodarone depresses the fast sodium chan-nel,32 inhibits sympathetic activity,2829 and blocks theL-type calcium channel.33 The relative contributions ofeach electrophysiological effect to the overall antiar-rhythmic activity and efficacy of amiodarone are still notfully understood.

Effects on the Fast Sodium Channeland Conduction

Amiodarone blocks predominantly the inactivatedstate (but not the open state) of the sodium channels ina use-dependent manner.3234 At room temperature,recovery time constants for Na' current activation arein the order of 1 millisecond at plateau potentials inventricular myocytes35 and Purkinje cells.34 Follmer etal34 demonstrated that amiodarone causes tonic block ofthe sodium channel. Tonic block is composed of both a"true" resting state block and an inactivated channelblock. The magnitude of an amiodarone-induced tonic



Nademanee et al Amiodarone and Post-MI Patients 765

CONTROL0

100mV[ ~ 200MC

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AMIODARONE [

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block suggests that this action may contribute to theantiarrhythmic efficacy of amiodarone, particularly indepolarized tissues (ie, ischemic myocardium).

Similar to its effect on INa, amiodarone depresses theVma, in a use-dependent manner in different types ofcardiac tissues.32 The effect of amiodarone on Vm,, ischaracterized by fast onset and offset kinetics.32,34 Theeffect of amiodarone on the Vmu, is enhanced at thedepolarized potential. Thus, amiodarone blocks theVm.. and conduction at faster heart rates, at the shortpremature interval, and more so in diseased (eg, isch-emic) than in healthy tissue at a normal heart rate.34

Effects on the Slow Inward Calcium Channels(L-Ca2' Channels)

The effects of amiodarone on Ica parallel its effects onINa. The drug blocks Ica predominantly during the inac-tivated state and, to a lesser degree, the resting state.33Nattel et aP25 reported use-dependent blocking effects ofamiodarone on the atrioventricular (AV) nodal conduc-tion time. Amiodarone also decreases phase 4 depolar-ization in the sinoatrial (SA) node and the amplitude ofthe APD of the SA node.36 Nishimura et a133 demon-strated that amiodarone blocks the calcium channel inguinea pig ventricular myocytes. The drug more effec-tively blocks depolarized rather than well-polarizedcells, which may be pertinent in terms of the antiar-rhythmic efficacy of amiodarone.

Effects on Potassium Channels and RepolarizationThe most profound effect of amiodarone is its length-

ening of the APD and refractoriness, especially whenthe drug is administered over a long period oftime.252636 The drug blocks the delay rectifier current(Ik), causing an increase in the APD37; there is evidencesuggesting that it may also block the inward rectifiercurrent (Ikl).38 Amiodarone also inhibits the ATP-sen-sitive potassium channel,39 which may play a major rolein preventing ventricular arrhythmias during ischemia.Unlike other class 3 antiarrhythmic compounds (sotalol,sematilide) and class 1A compounds (quinidine)40 thatshow a reverse use-dependent effect on the APD pro-longation, amiodarone uniformly lengthens the APD atnormal and faster heart rates.41 The effect of amio-

dV/dt

300 V/ISe

FIG 1. Traces show effects of chronic ami-odarone administration on the characteristicsof transmembrane potentials in rabbit ven-tricular myocardium. Upper panel shows atypical recordingfrom the ventricular muscleof a control rabbit; lower panel is from onetreated with 20 mg/kg amiodarone (29.4 molIkg) daily for 6 weeks. In each panel, the toptrace represents zero potential; middle trace,the transmembrane potentials at slow andfast sweep speeds; bottom trace, contractions.On the right upper trace is shown the extra-cellular electrogram showing the rate of riseof intracellular potential. Note that the majoreffect of the drug was to increase the timecourse ofrepolarization with a minimal effecton the upstroke velocity ofphase 0. Repro-duced with permission.31

darone on repolarization is evident within the first weekof drug treatment and continues to increase in a step-wise fashion over a 6-week period when given at aconstant dose. These effects on repolarization havebeen demonstrated in most cardiac tissues.36

Clinical Electrophysiological EffectsThe clinical electrophysiological effects of ami-

odarone are generally congruent with those found in theexperimental laboratory. Amiodarone-induced prolon-gation of the APD in cardiac muscle was confirmed inhuman monophasic action potential recordings.42 Theelectrophysiological effects of amiodarone administeredintravenously differ strikingly from those that developwhen the drug is administered chronically. Chronic oralamiodarone therapy produces a marked increase in therefractory periods of all cardiac tissues, whereas acuteintravenous amiodarone therapy has no effects on therefractory periods except on the AV node43 (Fig 2). Thedrug when administered chronically has little effect onthe QRS duration and His-Purkinje conduction atslower heart rates, but that effect increases significantlyat faster heart rates.44 However, these marked use-dependent effects on conduction were not observedwhen amiodarone was administered intravenously. Theacute effect of intravenous amiodarone on the AV nodeis similar to the finding of Gloor et al45 that amiodaronedepressed sinus node automaticity and intranodal AVconduction when injected into the SA and AV nodalarteries of anesthetized dogs. These changes were notaffected when propranolol or atropine was given butwere sensitive to alterations in the level of calcium inthe perfusate, suggesting that the primary acute elec-trophysiological effect of intravenous amiodarone maybe due to its ability to block ICa.

Latency of the Onset of Antiarrhythmic Actionand the Role of Desethylamiodarone,

an Amiodarone MetaboliteThere is extensive evidence showing that amiodarone

has a delayed onset of antiarrhythmic action and effi-cacy.43 Although the mechanism responsible for thisdelay is unclear, it is clear that this delayed onset ofaction varies among individuals. The lag could be due



766 Circulation Vol 88, No 2 August 1993

50%-

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node ERP ERP ERP ERPERP antegrade retrograde

FIG 2. Bar graph ofcomparative electrophysiological effectsofintravenously vs orally administered amiodarone in patientswith cardiac arrhythmias. Acute intravenous effects weredetermined 2 to 10 minutes after 5 mg/kg amiodarone wasinfused over 2 minutes; the chronic effects were determinedafter a loading dose of 1200 to 1600 mg followed with amaintenance dose of 200 to 600 mg/d. Note that intravenous(IV) amiodarone does not lengthen QTc interval nor does itaffect the effective refractory period (ERP) of myocardialtissues except at the level ofthe atrioventricular (AV) node. Incontrast, chronic oral amiodarone administration prolongsthe QTc interval and the ERP of all tissues. Reproduced withpermission.43

(in whole or in part) to the drug's unusual pharmaco-kinetics and long variable half-life.4'47 Other factorsmay be responsible for the stepwise increase in thedrug's action (eg, the amiodarone metabolite deseth-ylamiodarone [DAM] and the effect of amiodarone onthyroid function).

Several studies have demonstrated that DAM has thesame pharmacological profile as that of the parentcompound.48 Both acute and chronic administration ofDAM reduces the number of P-receptors,49 alters thy-roid metabolism, and blocks INa and Ic .50 However,DAM appears to have a greater effect on sodiumchannels than does the parent compound.50 Kato et al51demonstrated that both amiodarone and DAM signifi-cantly prolonged the APD and effective refractoryperiod in rabbit atrial and ventricular tissues after theanimals had been chronically treated with both com-pounds. They also noted the delayed-onset action ofDAM on the APD of atrium and ventricle and on sinuscycle length. Both compounds decreased phase 4 depo-larization in the sinus pacemaker potentials. All of thissuggests that whereas the activity of the metabolite isundoubtedly additive to that of the parent compoundduring chronic administration, the delayed onset ofaction by amiodarone cannot be attributed solely to theeffects of DAM.The molecular structural similarity of amiodarone

and DAM to the thyroid hormone and the similarelectrophysiological effects of both compounds to thoseof hypothyroidism have led to the speculation thatamiodarone exerts its action on the heart by inhibitingthe T3 nuclear receptor to produce a condition mimick-ing intracellular hypothyroidism.47'52 If this hypothesis iscorrect, it would explain the delayed onset of action byamiodarone because the dynamic changes in thyroidfunction are time dependent. Latham et al53 studied thecapacity of increasing concentrations of amiodaroneand DAM nuclear extracts on blocking the receptor

TABLE 1. Factors Contributing to ElectrophysiologicalAbnormalities During Acute Ischemia

Elevated extracellular [K']Intracellular acidosisLactate accumulationCatecholamine releaseElevated intracellular cyclic adenosine monophosphateLysophospholipid accumulationFatty acid ester accumulationFree fatty acid accumulationFree radicals

binding of radioactive-labeled triiodothyronine (T3).They found that there was only minimal receptor bind-ing to amiodarone. However, all receptor preparationshad substantial affinities (Kd) to the DAM analog. Theyconcluded that amiodarone may exert some of its elec-trophysiological effects by metabolic conversion toDAM, which may then competitively prevent the thy-roid hormone from binding to the nuclear receptor siteswithin the myocardium. The precise link between theeffects of amiodarone on the heart and thyroid functionremain uncertain.Whatever the mechanisms governing the delayed

onset of action by amiodarone, such a delay and thevariability of this delay among individuals makes regu-lating amiodarone dosing difficult. Indeed, the manydisparate views of the efficacy of amiodarone and itstoxicity can be attributed at least in part to this delayedonset of action.

Evidence of Antiarrhythmic Efficacy in IschemicVentricular Arrhythmias

MI induces a myriad of metabolic and electrophysio-logical changes that can cause arrhythmias (Table1).54'55 During ischemia there is a rapid loss of cellularK+, resulting in an extracellular accumulation of K' thatpartially depolarizes the membrane.56 Other factorssuch as hypoxia and changes in intracellular calciummay also cause membrane depolarization.57 Tissues thatare partially depolarized are potentially arrhyth-mogenic; ischemia-induced partial depolarization couldcause abnormal automaticity or reentry. Since the cel-lular K+ loss during ischemia is largely due to increasedK' conductance by the activation of ATP-sensitive K+channels (KATp), the ability of amiodarone to block KATPmay help prevent ischemia-induced arrhythmias. Thedepolarized tissues also allow amiodarone to bind to theinactivated sodium channels more readily. This wouldhave a greater effect on the conduction and excitabilityof the tissues. Mason et a132 demonstrated that amio-darone abolished depolarization-automaticity that hadbeen caused by a decreased membrane potential.

Intracellular free [Ca21] increases early during isch-emia; the elevated intracellular [Ca 2+] may activate thedepolarizing inward current through nonspecific Ca 2+_activated channels or electrogenic Na+-Ca2' exchange,resulting in afterdepolarization and triggered activity.57Since amiodarone blocks the inactivated Ca21 channels,it should suppress Ca2+-mediated triggered activitycaused by delayed afterdepolarization (DAD). Ohta etal58 found that this was indeed the case: They studied inisolated rabbit ventricle delayed triggered activity




caused by DAD resulting from hypokalemia. Theyfound that chronic amiodarone treatment reduced theamplitude of DAD and the subsequent induction oftriggered activity. Amiodarone superfusion depressedthe DAD, although much less so than when adminis-tered chronically. These observations may explain whyamiodarone has a low arrhythmogenic potential despiteits ability to markedly increase the QT interval andrepolarization.

Elevation of intracellular free [Ca+] caused by isch-emia may also activate intracellular proteases and phos-pholipases that degrade phospholipid-producing lyso-phosphoglycerides. These compounds then accumulatein the sarcolemmal membrane, causing membrane de-polarization and changes in the APD.59 The products offatty acid metabolism decrease the resting membranepotential and Vm., especially when the tissues areacidotic. Since amiodarone inhibits the phospholipaseenzyme,60,61 it prevents the breakdown of membranephospholipids produced by phospholipase. As a phos-pholipase inhibitor, amiodarone could prevent the ac-cumulation of lysophosphoglycerides and other am-

phiphiles, thus preventing arrhythmogenesis caused bythese products during ischemia.The data briefly reviewed stress that the electrophar-

macological and metabolic actions of amiodarone are

complex, as are the chain of electrophysiological eventsoccurring during myocardial ischemia. It is tempting tospeculate that the multiple pharmacological actions ofamiodarone work together to nullify the deleteriouselectrophysiological consequences of ischemia and pre-vent arrhythmogenesis after acute coronary occlusion.However, the relative importance of the individualcomponents of the multifaceted actions of amiodaroneremains a matter of conjecture.

Antiadrenergic Effects of AmiodaroneCharlier and his colleagues28,29 were the first to show

in vivo that amiodarone blunted the various cardiovas-cular effects of catecholamines. When Polster andBroekhuysen62 studied the inhibitory effects of ami-odarone on the heart rate response during incrementaldoses of isoproterenol infusion and on the norepineph-rine-induced contraction of isolated rat aortic strips,they found that amiodarone behaved as a nonspecificsympathetic inhibitor. Using direct ligand binding assayson rat myocardial 13-receptors, Nokin et a163 concludedthat both propranolol and amiodarone prevented theincreases in 13-receptor density induced by myocardialischemia after coronary ligation. Venkatesh et a149showed that in rabbits that had received chronic ami-odarone therapy there was a gradual decrease of 13-re-ceptors and a parallel, progressive decrease in the heartrate. Gagnol et al64 showed that in rat heart membranepreparations, amiodarone noncompetitively antago-nized the activation of adenylate cyclase by isoprotere-nol, glucagon, and secretin (but not sodium fluoride).They postulated that amiodarone could either inhibitthe coupling of 13-receptors with the regulatory unit ofthe adenylate cyclase complex through different recep-tors or decrease the number of functional 13-receptorson the surface of the myocardium. Either way, the netresult is that amiodarone attenuates the positive chro-notropic actions of catecholamines, a property that is

crucial in warding off arrhythmias precipitated by myo-cardial ischemia.The sympathetic-blocking property of amiodarone,

similar to that of 3-blockers,65 may improve the mortal-ity rate of post-MI patients. That action may also inhibitischemia-induced ventricular fibrillation (VF). Lom-bardi et al6 demonstrated that after 2 minutes of leftcoronary occlusion, preganglionic sympathetic outputincreased concomitantly with a fall in the VF threshold.13-Adrenergic blockade prevented the decrease in VFthreshold induced by myocardial ischemia. 13-Blockadealso reduces the incidence of VF during ischemia.13-Adrenergic stimulation during ischemia shortens ven-tricular refractoriness, increases ventricular excitability,and enhances the temporal dispersion of ventricularrepolarization that increases susceptibility to ventricu-lar fibrillation. 13-Adrenergic stimulation also provokesafterdepolarization, causing arrhythmias resulting fromtriggered activity. The antisympathetic property of ami-odarone is an important addition to the drug's otherantiarrhythmic properties in preventing ischemia-in-duced VF.

Antifibrillatory Effects in ExperimentalInfarct Models

The data from studies of isolated tissues are conso-nant with those from studies of hearts and from in vivoexperimental models, as follows. Using the Langendorfltechnique on isolated perfused rat hearts, Lubbe et a167showed that amiodarone caused a dose-related de-crease in heart rate and an increase in the VF thresholdbefore and after coronary ligation. In rats that had beenpretreated with amiodarone (range, 2 minutes to 3weeks), the VF threshold increased in a dose-depen-dent manner. After coronary ligation was performed onrats that had been pretreated with amiodarone, theincidence of spontaneous arrhythmias decreased, as didthe ischemia-induced VF threshold. When the rats thathad been pretreated with a sufficiently high dose ofamiodarone underwent coronary ligation, the VFthreshold exceeded the baseline level in control rats.This study also showed that amiodarone appeared toremain active at the myocardial receptor sites even afterit was no longer present in the perfusing myocardium.When Lubbe et al studied the effects of amiodarone on

metabolic changes in rat hearts during ischemia, theyfound that the antifibrillatory effect of amiodarone wasindependent of amiodarone-induced heart rate changes.Amiodarone had no effect on the tissue content ofadenosine triphosphate or creatine phosphate in eithernormal or ischemic myocardium. From this they con-cluded that it was unlikely that the protective effects ofamiodarone were due to its ability to attenuate ischemia-induced metabolic damage. Amiodarone prevented theischemia-induced increase in the tissue cyclic adenosinemonophosphate (cAMP) concentration after coronaryligation. The effect of amiodarone on cAMP was dosedependent: After pretreatment for 2 minutes, the cAMPlevel in ischemic tissue increased only about 18% (com-pared with a 40% increase in hearts not pretreated withamiodarone). After pretreatment for 1 week, the cAMPlevel in ischemic myocardium was equivalent to that inthe normal myocardium. In line with these findings, thestudy of Gagnol et al,64 in which amiodarone was admin-istered incrementally to rat heart membranes, showed




that the drug progressively inhibited adenylcyclase activ-ity stimulated by isoproterenol.

All of these observations suggest that amiodarone, byinhibiting the arrhythmogenic catecholamine responseduring ischemia, prevents a fall in the VF thresholdinduced by myocardial ischemia. In the same study,Lubbe's group also determined the effects of ami-odarone on spontaneous ventricular tachyarrhythmias(ventricular extrasystole, ventricular tachycardia, andVF) after coronary artery occlusion and reperfusionexperiments. Rats that had been pretreated with ami-odarone had a substantial decrease in the incidence ofventricular tachyarrhythmias during ischemia. However,the effects of amiodarone pretreatment on the inci-dence of ventricular premature extrasystoles, ventricu-lar tachycardia, and VF after reperfusion are even morestriking: The incidence of ventricular tachycardia andVF in the control group was 100% when the ischemicmyocardium was reperfused. In contrast, a dose-relateddecrease in the incidence of these arrhythmias occurredafter pretreatment with amiodarone. Ventricular tachy-cardia and VF did not occur after intravenous pretreat-ment at dosages of 42, 49, and 56 ,umol/kg. Riva andHearse68 confirmed the findings of Lubbe's group whenthey studied the antiarrhythmic effects of amiodaroneand DAM versus control on ventricular tachyarrhyth-mias caused by ischemia and reperfusion in anesthe-tized rats. A 5.0 mg* kg` dose of amiodarone and DAMbefore ischemia reduced the incidence of ventriculartachycardia during the ischemic period from 67% to20% (P<.02) and 47%, respectively. During reperfu-sion, mortality was reduced from 53% to 7% and 7%(P<.02), respectively, and reperfusion-induced ventric-ular fibrillation was reduced from 73% to 20% (P<.01)and 47%, respectively. The antiarrhythmic effects ofamiodarone and DAM on reperfusion-induced arrhyth-mias differ from those of conventional 8-blockingagents; ,-blockade, although effective on ischemia-in-duced VF, is ineffective in reperfusion-induced VF.66This study stressed that DAM, like its parent com-pound, protects the heart against malignant ventriculararrhythmias as a consequence of myocardial ischemiaand reperfusion.Other studies using different experimental models of

ischemic ventricular arrhythmias have confirmed thestriking antiarrhythmic efficacy of amiodarone.13,69-71Rosenbaum et a113 showed that chronic pretreatmentwith amiodarone prevented VF in dogs after coronaryligation. Chew et a169 studied the antiarrhythmic effectsof amiodarone on ischemic ventricular arrhythmias inconscious dogs. Control dogs that had large myocardialinfarcts developed early bimodal ventricular arrhyth-mias peaking at 3 to 5 minutes and at 12 to 125 minutes.(VF occurred equally frequently during each peak.)Chronic amiodarone treatment (30 mg/kg daily) for 3 to4 weeks markedly suppressed spontaneous ventriculararrhythmias. The incidence ofVF was 9% in the treatedanimals compared with 29% in the control animals.Patterson et a170 conducted a study that used consciousdogs in the attempt to mimic the sudden coronary deaththat occurs in humans. The investigators randomizedtheir animals on the fourth day after anterior wallmyocardial infarction to receive either short-term intra-venous amiodarone (10 mg/kg per hour) or long-term

days). Both short-term and long-term treatment re-duced the incidence of VF provoked by occlusion of theleft circumflex artery in the presence of previous ante-rior MI. The study of short-term intravenous ami-odarone revealed an incidence of VF at the rate of 60%and 100% in the amiodarone-treated and controlgroups, respectively (P<.05); the chronic amiodaronetreatment group showed only a 20% incidence of VFcompared with 91% in the control group (P<.002).

Their data corroborated other findings that bothlong-term and short-term amiodarone therapy pre-vented ischemia-induced VF in animals that had sur-vived MI. Chronic amiodarone treatment appeared tobe more effective than acute amiodarone treatment.The difference between the effects of acutely and chron-ically administered amiodarone could not be accountedfor on the basis of differences between the plasma andtissue levels.Taken together, these data show that chronic ami-

odarone therapy effectively treats sudden death in theinfarcted animal model, one that closely resembles thatof MI survivors. Against this experimental back-ground-which provides a cogent argument for thepotent antifibrillatory potential of chronically adminis-tered amiodarone - recent clinical trial data will now bediscussed to determine the role of amiodarone inpost-MI survivors.

Prevention of Sudden Cardiac Death inPost-MI Patients

There is no disagreement that survivors of MI con-tinue to face a significant risk of lethal ventriculararrhythmias and sudden cardiac death even though theincidence of VF declines dramatically 24 hours or moreafter the episode. Marcus et a1l analyzed the data from867 post-MI patients enrolled in the Multicenter Post-infarction Program (MPIP); they found that of the 867patients, 108 patients suffered cardiac death during the48-month follow-up period. Nearly three times as manyof these cardiac deaths were classified as arrhythmicdeaths (n=80) rather than myocardial failure (n=28).However, 54 (68%) of the arrhythmic deaths occurredin patients with heart failure, either nondisabling (26cases, 32.5%) or disabling (28 cases, 35%). Only 26patients (32.5%) who suffered arrhythmic deaths didnot have congestive heart failure. Also, a majority ofcardiac deaths (76%) were associated with congestiveheart failure. They also found that 60% of the patientshad myocardial ischemia preceding the terminal event.Their data also showed that the actuarial survival ratedropped relatively sharply during the first 6 monthsafter the patients were discharged from the coronarycare unit and then declined at a constant hazard rate;the first-6-months hazard rate was about three timesgreater than the corresponding "late" hazard rate.Stevenson et a172 determined the causes of death afterMI in 172 victims who had evidence of old MI atautopsy. The majority of these patients died because ofthe MI (117 [81%] in-hospital deaths and 19 [68%]out-of-hospital deaths). In this study, the mechanism ofdeath after recurrent infarction was due largely to pumpfailure and arrhythmias. These observations suggestthat therapy with antiarrhythmic agents aiming to pre-vent cardiac and sudden arrhythmic death in post-MIpatients must consider not only the effects of the drugoral amiodarone treatment (10 mg/kg per day for 24




on electrophysiological parameters in the normal heartbut also its effects on electrophysiological abnormalitiesassociated with congestive heart failure and recurrentmyocardial ischemia. That is, a therapeutic drug regi-men should not worsen heart failure or ischemic ven-tricular arrhythmias. To significantly reduce the mortal-ity rate of ischemia-related deaths, the regimen mustdecrease either the incidence of recurrent MI or theassociated fatal ventricular arrhythmias. An effectiveregimen should significantly improve the mortality ratewithin the first 6 months of therapy, which is when therisk of death is highest.

Class 1 agents tend to have a negative inotropiceffect,9 and some have the potential to increase theincidence of VF during ischemia.73 If a patient who hasventricular dysfunction takes a drug that has negativeinotropic effects (eg, class 1 agents), the patient mayrespond to the drug as far as PVC suppression isconcerned only to succumb to lethal heart failure orischemic VF.73-75 This was the case in the CAST IIstudy: Patients who were treated with moricizine had ahigher incidence of congestive heart failure than thosewho were given placebo.1" Class lc agents also reduceheart rate variability, a marker for an increase in thesympathetic-parasympathetic ratio. As a result, class lcagents may decrease the VF threshold. In contrast,amiodarone does not affect heart rate variability,76 andit has a sympathetic-blocking property. All class 1 drugshave inherent proarrhythmic effects; they may suppressnonischemic PVCs but may provoke VF during ischemiaor heart failure.

Findings such as these account for why treating post-infarction arrhythmias with antiarrhythmic agents hasbeen virtually abandoned; yet, amiodarone has little orno negative inotropic effects77 and a very low incidence ofproarrhythmic effects compared with other antiarrhyth-mic drugs.78'79 Despite its reputed noncardiac side ef-fects, it may be the safe and effective drug therapy thathigh-risk post-MI patients need. Recent clinical studiesuniformly show that amiodarone effectively reduces therate of early postinfarction mortality.20-24 80 A review ofclinical studies on the role of amiodarone in treatingpostinfarction arrhythmias follows.

Clinical StudiesCeremuzynski et a120 conducted a randomized, dou-

ble-blind study to evaluate the effect of 1-year treatmentwith amiodarone (n=305) or placebo (n=308) on mor-tality, ventricular arrhythmias, and clinical complicationsin high-risk postinfarction patients who were not eligibleto receive 13-blockers and who did not necessarily mani-fest high-density ventricular arrhythmias. In this trial,amiodarone therapy significantly reduced cardiac mortal-ity and ventricular arrhythmias (21 deaths in the amio-darone group [6.9%] versus 33 [10.7%] in the placebogroup). Most deaths were cardiac deaths (all 33 deathswere cardiac in the placebo group; 19 of the 21 deathswere cardiac deaths [6.2%] in the amiodarone group).The odds ratio was 0.55 in favor of the amiodarone group(95% confidence interval, 0.32 to 0.99). The difference incardiac death was statistically significant (P=.048; Fig 3).Most deaths were sudden in both groups-within 1 hourof the onset of symptoms (20 placebo-treated patientsand 10 amiodarone-treated patients). However, unlikethe findings of the p-blocker trials, in this study amio-

98%*

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4 8 12 16 20 24 28 32 36 40 44 48 52WEEKS FROM RANDOMISATON

FIG 3. Survival curves in patients randomly allocated totreatment with amiodarone and placebo who did not suffer acardiac death. Reproduced with permission.20

darone did not prevent reinfarction: Fourteen and 10patients developed reinfarction in the amiodarone groupand the placebo group, respectively. Other findings arenoteworthy. Most deaths occurred in the first 6 months ofthe trial. The incidence of serious ventricular arrhyth-mias (Lown grade 4) was also significantly lower in theamiodarone group than in the placebo group (7.5%versus 19.5%). Bearing in mind these data and theefficacy of amiodarone, it is likely that the primarymechanism whereby amiodarone reduces the incidenceof sudden cardiac death is its antifibrillatory and antiar-rhythmic properties rather than by lowering the inci-dence of ischemia-related VF episodes that are due tothe decrease in the number of ischemic events caused bythe drug.

Burkhart et a123 in the Basel Antiarrhythmic Study ofInfarct Size (BASIS) studied 312 survivors of MI whohad Lown class 3 or 4B arrhythmias on 24-hour ECGmonitoring. Patients were randomized to either individ-ualized antiarrhythmic treatment (n= 100), 200 mg/damiodarone therapy (n=98), or control (n=114). Dur-ing the 1-year follow-up period, the cumulative mortal-ity rates were 13% in the control group, 10% in theindividualized antiarrhythmic treated group, and 5% inthe amiodarone group. Amiodarone reduced the totalmortality rate by 61% from that in the control group(P<.05) and reduced the incidence of arrhythmic events(P<.01).These investigators continued to study patients in the

BASIS trial in a long-term study80 to determine if thebeneficial effect of amiodarone persisted even thoughthe drug was discontinued 1 year later (mean follow-up,72 months; range, 55 to 125 months).

Fig 4 shows that the probability of death after 84months according to actuarial life-table analysis (Kap-lan Meier) was 30% for amiodarone-treated patientsand 45% for control patients. For the total follow-upperiod, the mortality rate was much lower in the ami-odarone group than in the control group with respect toall deaths (P=.03) and to cardiac deaths (P=.047). Thismortality reduction was due entirely to the first-yearamiodarone effect, since there was no difference be-tween the amiodarone and control groups only whenconsidering survival after discontinuation of ami-

i )* ~~~Placbo x Asslodarone|

._ i;

_X

*'"

Al-1= 3J99M

0.6 1 3-.

l UU%.' 'I

non %., .,.. I, .; ... 71,1 I,, ,,I,,,,,,,............... .1-11

kg ai




Probabilityof survival

(%)

1.0

.8 BASIS-amiodaronegroup

.6

.4 BASIS-control

.2groupv

0 12 24 36 48 60 72 84 96 108

Patients at risk Time (months)BASIS-control group 114 94 87 82 78 72 48 44 26

BASiS-amiodarone group 98 89 84 80 76 66 51 37

FIG 4. Graph compares probability of survival from theonset of myocardial infarction with the last follow-up inpatients treated with amiodarone for 1 year and the controlgroup. The duration in the shaded area signifies the ami-odarone treatment period during the first year. BASIS, BaselAntiarrhythmic Study of Infarct Survival. Reproduced withpermission.80

odarone. They concluded that the beneficial effect ofamiodarone on the survival rate persists for years, whilestressing the importance of early postinfarction treat-ment with amiodarone. Since the rate of sudden deathand all cardiac deaths was low during late follow-up(1.2% per year in the amiodarone group and 4.6% per

year in the control group), patients may not warrantamiodarone therapy after the first year after infarction.

Pfisterer et a12P cautioned that the beneficial effects ofamiodarone reported in their study were tempered byits lack of efficacy in those patients who had poor leftventricular function (ejection fraction <40%). Even so,this caution itself is tempered by other factors: Thenumber of patients in the amiodarone group was quitesmall; the data were analyzed as a substudy without aplanned randomization schema to ensure the equalityof number and confounding variables in each controland amiodarone group. Regardless, the value of ami-odarone in MI survivors who have poor left ventricularfunction requires further study in larger randomizedtrials.

In the Canadian Amiodarone Myocardial InfarctionArrhythmia Trial (CAMIAT) Pilot Study, Cairns et a124randomized 77 postinfarction patients who had arrhyth-mias in a double-blind fashion to either 300 to 400 mg/damiodarone or placebo. One patient (2.1%) in theamiodarone group and four (13.8%) in the placebogroup died as a result of arrhythmias; overall mortalityrates were 10.4% and 20.7%, respectively. More than

Decrease inMortality

Total

Cardiac Death

Sudden Death, -4

Hockings AMI

Burkart AMI _---

Cairns AMI

Ceremuz. AMI 8- *l

.. .1

Increase inMortality

0.2 0.4 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8 3.0 3.2 3.4 3.6 3.8 4.0

Odds Ratio (amiodarone: placebo)

FIG 5. Plot of overall effects of amiodarone (AMI) on total

cardiac, and sudden cardiac death mortality rates (see Table 2).

one third of the patients in both groups discontinuedtherapy because of side effects, the most commonreasons being elevation of thyroid-stimulating hormoneand skin reactions. The authors concluded that moder-ate loading and maintenance doses of amiodaroneeffectively suppress ventricular premature depolariza-tions (VPDs) and does so with acceptable levels oftoxicity. There were strong trends favoring amiodaronefor the principal outcomes, arrhythmic death and resus-citated VF, as well as for all causes of mortality.

Trials in ProgressCairns et al are continuing the full-scale phase of

CAMIAT using the same study population and inter-vention as those used in the pilot study. A VeteransAdministration trial will assess the value of amiodaronein patients with class III and IV congestive heart failureand VPDs. The European Myocardial Infarction Ar-rhythmia Trial will evaluate the effect of amiodarone inearly postinfarction patients who have low ejectionfractions (without regard to the frequency of theirVPDs). These trials will involve more than 3400 patientsand thus increase the available data fourfold.

Comparing Amiodarone and Other Modalities asSecondary Prevention Treatment in MI SurvivorsTable 2 and Fig 5 summarize the overall effects of

amiodarone from the three randomized prospectivetrials discussed above and from the study of Hockings etal.81 The effects of a combined outcome from these

TABLE 2. Effects of Amiodarone on Mortality Rates in Post-MI Patients

No. of Total Cardiacsubjects mortality death Sudden death

Study Ami Placebo Ami Placebo OR 95% CI P Ami Placebo OR 95% CI P Ami Placebo OR 95% CI P

Burkart 98 114 5 15 0.35 0.10-1.08 .04 5 13 0.42 0.11-1.31 .09 4 10 0.44 0.10-1.60 .16

Ceremuz. 305 308 21 33 0.62 0.33-1.13 .09 19 33 0.55 0.29-1.03 .045 10 20 0.49 0.20-1.12 .06Hockings 100 100 16 11 1.54 0.63-3.89 .30Cairns 48 29 5 6 0.45 0.10-1.99 .31 5 5 0.56 0.12-2.71 .39 1 4 0.13 0.00-1.48 .064 Groupscombined 551 551 47 65 0.70 0.46-1.05 .073 Groupscombined 451 451 29 51 0.54 0.32-0.89 .01 15 34 0.42 0.21-0.81 .005

MI, myocardial infarction; OR, odds ratio; CI, confidence intervals; Ami, amiodarone.

m

Ei ml




Decrease inMortality

CLASS

IA

IB

IC

11

Amiodarone

IV

Increase inMortality

-0

a-

i-0.0 0.2 0.4 \0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4

Odds Ratio (active: Control)

FIG 6. Plot shows effects of antiarrhythmic therapy on totalmortality after myocardial infarction. Modified from Teo etal.82 The effects of amiodarone on mortality were calculatedbased on the studies from References 20, 23, 24, and 80. Seetext for discussion. IV, intravenous.

trials suggest that amiodarone effectively reduces themortality rate of post-MI patients (30% reduction in 1year, P=.07). When comparing these combined data onamiodarone with the overview by Teo et al of 53randomized trials that treated more than 20 000 pa-tients with various classes of antiarrhythmic agents82(Fig 6), amiodarone and /-blockers are the only twoclasses of drugs that improved the survival rate; class 1agents showed no overall beneficial effect on all causesof mortality and actually increased the mortality rate.The effects of amiodarone on cardiac death and suddendeath in MI survivors are even more impressive: Within1 year of amiodarone treatment, the drug reducedcardiac mortality rate by 46% (P=.01) and suddendeath rate by 58% (P=.005). If these findings areconfirmed by the larger trials (including the VA coop-erative trial in heart failure patients), amiodaronewould be considered the compound that best reducescardiac mortality in MI survivors during the first year ofthe follow-up period. But this remains to be seen.Many other questions about amiodarone still need to

be answered. Why does amiodarone succeed whereother antiarrhythmic drugs have failed? How does itwork? Although proponents of class 3 agents may inferfrom these data that amiodarone works by prolongingrepolarization, the inference that all class 3 agents havethe same effect is too simplistic because amiodarone hasother antiarrhythmic properties. Similarly, proponentsof /3-blockers may infer that amiodarone is effectivebecause of its sympathetic-blocking properties. How-ever, /-blockade -while essential -may not be the onlyfactor contributing to the success of amiodarone.To reiterate, amiodarone is the only antiarrhythmic

agent shown thus far to prevent sudden cardiac deathduring the first year in post-MI patients. Sotalol, a drugthat closely resembles amiodarone, has gained recogni-tion recently83-85 and has its own proponents. A compar-ison of the two drugs, both of which have class 3antiarrhythmic, antisympathetic, and anti-ischemic prop-erties, would help to illustrate the unique pharmacolog-ical status of amiodarone.

Bearing in mind that a study by Julian et a186 did notfind that sotalol reduced mortality (although there wasa trend suggesting this), the mortality rate in this studywas 18% lower in the sotalol than in the placebo group.Sotalol did not prevent sudden death (2.9% in thesotalol group compared with 2.4% in the placebogroup), but sotalol did significantly reduce the incidenceof MI. This would mean that if the prolongation of theAPD and 3-blockade were the principal mechanism ofaction responsible for preventing sudden cardiac deathin post-MI patients, then one would expect sotalol to beas effective as amiodarone in this study-or more so.

Sotalol was not shown to be more effective than ami-odarone: Therefore, the effectiveness of amiodarone can-not be due solely to its class 3 effect. Having said this, onecannot rule out the possibility that the class 3 action playsa role in the efficacy of amiodarone. The difference maybe because sotalol has more proarrhythmic effects thatcause fatal arrhythmias.87 This would naturally offset thebeneficial effects of sotalol. Unlike sotalol, amiodaronehas negligible proarrhythmic effects, perhaps because ofits calcium-channel blocking properties, which may pre-vent early afterdepolarization,m a mechanism believed tocause torsade de pointes and polymorphic ventriculartachycardia in patients who have abnormal prolongationof the repolarization.

Amiodarone ToxicityAlthough amiodarone appears to reduce the mortal-

ity rate of MI survivors, many physicians are leery of thedrug's reputed toxicity. The toxicity of amiodaronecannot be denied8990: The drug affects virtually everyorgan in the body, especially when it is taken at highdoses for a long period of time. However, several factsabout amiodarone toxicities deserve emphasis. There isa sharp contrast between the incidence of side effectsreported by the European studies91 and the Americanstudies8990 (which used a higher dose and found ahigher incidence of side effects). The findings of Cere-muzynski20 and Cairns24 confirmed the European obser-vation that low-dose amiodarone treatment is associ-ated with few short-term side effects; these observationswere also the most systematic assessment of amiodaronebecause they were the result of a double-blind placebo-controlled study. Ceremuzynski et al found that 55 ofthe 305 amiodarone-treated patients were withdrawnfrom the drug because they developed "adverse effects"(as opposed to 19 from the 308 placebo-treated group).However, if one were to exclude inconsequential sideeffects (eg, first-degree AV block, bundle branch block,etc), the number of serious side effects falls from 55 toapproximately 25, which is much closer to the placebofigure. This is an emphatic indication that amiodarone isa very well-tolerated drug in short term.

SummaryAmiodarone is a viable drug for preventing sudden

cardiac death, particularly during the first year after MI.If larger trials confirm the aforementioned prospectivetrials of Ceremuzynski et al, Cairns et al, and the BASIStrial, the efficacy of amiodarone would outweigh the riskof its side effects during the first year after MI. Based onthe long-term observation from the BASIS trial, theduration of amiodarone therapy need not be more than1 year-which, as we have learned, is when these




post-MI patients would benefit most from the drug. It isalso likely that the effects of amiodarone would com-plement those of aspirin and angiotensin convertingenzyme inhibitors. The SAVE,92 CONSENSUS II,93and SOLVD94 trials demonstrated that captopril andenalapril did not reduce the mortality rate during thefirst year after MI, nor did they reduce the suddencardiac death rate. Their beneficial effects becameevident only during the second year and thereafter.

Unlike other antiarrhythmic agents of various classes,amiodarone possesses antiarrhythmic properties butdoes not exert deleterious effects on ventricular func-tion. More studies are needed to determine if thebenefit of amiodarone could be enhanced by combina-tion therapy95 (eg, angiotensin converting enzyme inhib-itors, aspirin, or pl-blockers). Whether amiodarone willprovide the same protection for patients who have poorleft ventricular function or congestive heart failure isnot known. The European and VA cooperative studiesshould help answer this question. If it turns out thatamiodarone is beneficial, one must then determinewhether higher doses of the drug will offer more pro-tection, and, if so, if that greater protection would beoffset by increased toxicity. How much amiodaroneshould be given to offer the most protection with theleast risk? Another intriguing research question is this:If we treat patients with amiodarone for more than 1year, would the drug continue to improve the mortalityrate in subsequent years? Other studies are needed inpatients at very high risk of sudden cardiac death (ie,those who have a low ejection fraction and high-densityVPDs). A study comparing amiodarone and sotalol in

high-risk patients for sudden cardiac death is alsoneeded. These clinical studies should be carried outwith basic science research investigating the actions ofamiodarone at the molecular and cellular level in orderto give us a better understanding of how the drug works.

AcknowledgmentThe authors thank Mary Kolb, BA, for editorial assistance.

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KEY WORDS * aminodarone * myocardial infarction * suddendeath * antiarrhythmic agents



amiodarone and post-mi patients

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