Heart 1996;75:23-28

Induction of ventricular fibrillation predictssudden death in patients treated with amiodaronebecause of ventricular tachyarrhythmias after amyocardial infarction

Luz-Maria Rodriguez, Eduardo B Stemick, Joep L R M Smeets, Carl Timmermans,Karel den Dulk, Giuseppe Oreto, Hein J J Wellens

AbstractObjective-To examine the value of pro-granmmed electrical stimulation of theheart in predicting sudden death inpatients receiving amiodarone to treatventricular tachyarrhythmias after myo-cardial infarction.Design-Consecutive patients; retrospec-tive study.Setting-Referral centre for cardiology,academic hospital.Patients-106 patients with ventriculartachycardia (n = 77) or ventricular fibril-lation (n = 29) late after myocardialinfarction.Interventions-Programmed electricalstimulation was performed while onamiodarone treatment for at least onemonth.Measurements and main results-In80/106 patients either ventricular fibrilla-tion (n = 15) or sustained monomorphicventricular tachycardia (n = 65) wasinduced. After a mean follow up of 50 (SD40) months (1-144), 11 patients died sud-denly and two used their implantable car-dioverter defibrillator. By multivariateanalysis two predictors for sudden deathwere found: (1) inducibility of ventricularfibrillation under amiodarone treatment(P << 0.001), and (2) a left ventricularejection fraction of < 40% (P < 0.05). Thesurvival rate at one, two, three, and fiveyears was 70%, 62%, 62%, and 40%respectively for patients in whom ventric-ular fibrillation was induced, and 98%,96%, 94%, 94% for patients with inducedsustained monomorphic ventriculartachycardia. Where there was no sus-tained arrhythmia, five year survival was100%.Conclusions-In patients receiving amio-darone because of life threatening ven-tricular arrhythmias after myocardialinfarction, inducibility of ventricular fib-rillation, but not of sustained monomor-phic ventricular tachycardia, indicates ahigh risk of sudden death.

(Heart 1996;75:23-28)

Keywords: ventricular arrhythmias; programmed elec-trical stimulation; sudden death; myocardial infarction

Studies in the early eighties suggested thatprogrammed electrical stimulation cannotaccurately predict recurrences of ventriculartachycardia/ventricular fibrillation duringamiodarone treatment.L"This resulted in thesuggestion that high risk patients should betreated with amiodarone empirically withoutthe aid of invasive testing.4 More recently, theprognostic value of programmed electricalstimulation in the evaluation of amiodaronetreatment for ventricular tachyarrhythmias hasagain been analysed.5-12 Variables helpful inpredicting ventricular tachycardia recurrenceand sudden death in those studies included:persistent ability to induce the clinical arrhyth-mia, a change in the mode of induction, andmodifications of the index arrhythmia whilethe patient was on amiodarone.The purpose of our study was to re-examine

the value ofprogrammed electrical stimulationof the heart in predicting sudden death inpatients receiving amiodarone because of ven-tricular tachyarrhythmias after myocardialinfarction.

MethodsPATIENTSThe study population consisted of 106 consec-utive patients, 92 males and 14 females, withmyocardial infarction and sustained ventricu-lar tachyarrhythmias treated with amiodarone,in whom a programmed electrical stimulationstudy was performed while on amiodarone.Clinical and angiographic data are listed intable 1.

Evaluation of these patients on admissionincluded clinical history, physical examina-tion, 12-lead electrocardiogram, long termelectrocardiographic monitoring, exercise test-ing, left ventricular ejection fraction measure-ment, and programmed electrical stimulationwhile off antiarrhythmic drugs (14 patients)and while on amiodarone in 106 patients.Antiarrhythmic drugs given previously hadbeen empirically selected (not by serial drugtesting).

AMIODARONE THERAPYAmiodarone was given after previous antiar-rhythmic drug treatment had failed in all but14 patients. In 86 patients failure was due torecurrent spontaneous ventricular arrhythmiasand in six because of side effects of the antiar-

Department ofCardiology, Universityof Limburg, AcademicHospital, Maastricht,The NetherlandsL-M RodriguezE B SternickJ L RM SmeetsC TimmermansK den DulkG OretoH J J WellensCorrespondence to:Dr L-M Rodriguez,Department of Cardiology,University of Limberg,Academic Hospital,6202 AZ Maastricht,The Netherlands.Accepted for publication13 July 1995

23

Rodriguez, Sternick, Smeets, Timmermans, den Dulk, Oreto, et al

Table 1 Clinical datafrom the 106 patients studied

Age (years) (SD, range)Sex (male/female)Type of arrhythmia

Sustained monomorphic VTVentricular fibrillation

Symptoms during arrhythmiaDizzinessSyncopeCardiac arrest

Number of previous antiarrhythmic drugs12> 3

Myocardial infarction locationAnteriorInferiorMultiple

No of involved coronary arteries> 50% in diameter

123

Left ventricular ejection fraction (mean %) (SD, range)Left ventricular ejection fraction (%)<40%> 40%

Left ventricular aneurysm

VT, ventricular tachycardia.

60 (9) (38-84)92/14

7729

432835

39458

543418

34353433 (10) (15-61)

792755

rhythmic agent. Before amiodarone treatment,39 patients received a single antiarrhythmicdrug, 45 patients received two, seven patientsreceived three, and the remaining patientreceived four. In 14 patients amiodarone was

given as first choice because of the concomi-tant presence of atrial fibrillation.

Oral amiodarone loading dose consisted of1 g/d during one week. Thereafter a mainte-nance dose of 200 mg/d was given.

ELECTROPHYSIOLOGICAL EXAMINATIONAt the time of the electrophysiological study,all patients had been on oral amiodarone for atleast one month (1 to 48, median 1 month).The end points of programmed ventricular

stimulation were: induction of sustainedmonomorphic ventricular tachycardia, ventric-ular fibrillation, or completion of the protocol.The ventricular pacing protocol used for

ventricular tachycardia induction has beendescribed in detail elsewhere.13

FOLLOW UPThe patients were followed up at our outpa-tient clinic at regular intervals. The end pointsof the follow up were: recurrence of sympto-matic sustained ventricular tachycardia ordeath (either sudden or due to other causes).

STATISTICAL ANALYSISAnalysis was conducted according to "theintention to treat" principle.'4 Statistical analy-sis was performed using the SAS statisticalsoftware package.'5 Clinical, haemodynamic,and electrophysiological variables consideredrelevant to the long term outcome (asdescribed in table 1) were studied by univari-ate and multivariate analysis using the Coxhazard model.'6 Age was analysed as a continu-ous variable. To compare outcome based onthe findings at electrophysiological study, lifetables were constructed for sudden death andnon-sudden cardiac death and comparedbetween groups using the Wilcoxon and logrank statistic. Quantitative variables weretested by Student's t test and nominal findingsby the X2 test. Continuous variables are

expressed as the mean (SD). P values of< 0 05 were considered as significant.

ResultsELECTROPHYSIOLOGICAL STUDY ONAMIODARONESustained ventricular arrhythmias wereinduced in 80 out of 106 patients (75%).Sustained monomorphic ventricular tachycar-dia was induced in 65 patients and ventricularfibrillation in 15. The remaining 26 patientshad no sustained ventricular arrhythmiainduced.

Type of arrhythmiaThe clinical ventricular arrhythmia (ventricu-lar tachycardia or ventricular fibrillation) wasreproduced during the electrophysiologicalstudy in 41 patients. A single type of sustainedmonomorphic ventricular tachycardia, notclinically documented, was induced in 19patients. More than one type of sustainedmonomorphic ventricular tachycardia, alsonot clinically documented, was induced in theremaining 20 patients.

Mode of inductionSustained monomorphic ventricular tachycar-dia and ventricular fibrillation was induced byone ventricular premature beat in nine andtwo patients respectively. Forty eight patientshad monomorphic ventricular tachycardia andeight had ventricular fibrillation induced bytwo ventricular premature beats. Eightpatients with sustained monomorphic ventricu-lar tachycardia and five patients with ventricu-lar fibrillation required three ventricularpremature beats for initiation of the arrhyth-mia.

FOLLOW UPArrhythmic eventsDuring a mean follow up of 50 (40) months(range 1-144), 29 patients died (27%). Elevenof the deaths were sudden (10%). Twopatients in whom a defibrillator was implantedand who received appropriate shocks forhaemodynamically poorly tolerated ventriculararrhythmias, as documented by ventricularinterval measurements (ventricular rates of200 to 230/min), were added to the suddendeath group. Therefore the total sudden deathgroup consisted of 13 patients (11 with sud-den death, two needing a defibrillator shock).

Sudden death occurred in (1) nine patientsin whom ventricular fibrillation was induced(six with sustained monomorphic ventriculartachycardia and three with ventricular fibrilla-tion as their index arrhythmia); (2) in threepatients of the induced sustained monomor-phic ventricular tachycardia group; and (3) inone patient in whom no sustained arrhythmiawas induced. The last four patients had sus-tained monomorphic ventricular tachycardiaas their index arrhythmia. Twelve patients hadcardiac death (12%), pump failure occurred innine patients, and a new myocardial infarctionin three. Six patients had a non-cardiac death(6%).

24

Sudden death in patients using amiodarone because of ventricular tachyarrhythmias

Table 2 Relation between the clinical presentation during the index arrhythmia and outcome

Clinical presentation

Dizziness (n = 43) Syncope (n = 28) Cardiac arrest (n = 6)

Index arrhythmia SD CD NCD SD CD NCD SD CD NCD

SMVT 3 5 3 3 1 1 1 4 0

NS P = 0-0001

P = 00007

VF - 6 2 2

No statistic significance for sudden death between groups.CD, cardiac death; NCD, non-cardiac death; SD, sudden death; SMVT, sustained monomorphic ventricular tachycardia; VF,ventricular fibrillation.

Twenty eight patients had syncope duringtheir clinical episode of sustained monomor-phic ventricular tachycardia. Three of thesepatients died from sudden death, one fromnon-sudden cardiac death, and one from non-cardiac death.

Comparison between the clinical presenta-tion (dizziness, syncope, or cardiac arrest)during the index arrhythmia (sustained mono-morphic ventricular tachycardia/ventricularfibrillation) and outcome is shown in table 2.The occurrence of sudden death in patients

with sustained monomorphic ventriculartachycardia was not related to the clinical pre-sentation. Overall, cardiac death occurredmore often in patients with a sustainedmonomorphic ventricular tachycardia whopresented with cardiac arrest than in thosepresenting with only dizziness or syncope, andsudden death was seen more often in patientswith ventricular fibrillation than in patientssuffering from sustained monomorphic ven-tricular tachycardia (20% v 9%).The variables shown in table 3 were first

screened by univariate analysis for differencesbetween patients with and without suddendeath. Thereafter the same variables werestudied in a multivariate model. Inducibility ofventricular fibrillation while on amiodaronetreatment for at least one month was the onlyvariable in the univariate model with statisticalsignificance.

In patients with sustained monomorphicventricular tachycardia as the presentingarrhythmia less ventricular fibrillation wasinduced and there was a lower incidence ofsudden death (P < 0-001). Six out of 11patients (54%) in whom ventricular fibrillationwas induced on amiodarone treatment andin whom the same ventricular arrhythmiawas the index arrhythmia died suddenly.

Table 3 Results of univariate and multivariate analysis: correlation with sudden death

Univariate MultivariateAge 0-70 075Index arrhythmia SMVT/VF 0-20 0 09Time interval, myocardial infarction to

first arrhythnic event < 2 months 0 77 0 33Cardiac arrest during the index arrhythmia 0 44 0-07Myocardial infarction location (anterior

v inferior) 0-76 0 70Multiple myocardial infarctions 0-80 0 75Left ventricular ejection fraction < 40% 0-21 0 05Left ventricular aneurysm 0-48 0-80Multivessel disease 0.19 0-25Inducibility ofVF v SMVT on amiodarone

treatment < 0-001 < 0 0001

VF, ventricular fibrillation; SMVT, sustained monomorphic ventricular tachycardia.

Stepwise logistic regression analysis of theclinical, haemodynamic, and electrophysiologi-cal data showed that inducibility of ventricularfibrillation (P < 0-001) and a low left ventricu-lar ejection fraction (< 40%) (P < 0 05) wereindependent predictors for sudden death.Syncope or cardiac arrest during the indexarrhythmia, and ventricular fibrillation as theclinical arrhythmia were found to be of border-line statistical significance (P = 0 07 and 009respectively). Of importance was the findingthat inducibility of sustained monomorphicventricular tachycardia while on amiodaronewas not a predictor for sudden death.The outcome of the population according

to their index arrhythmia is shown in table 4.Actuarial curves for sudden death for

patients with induced ventricular fibrillation,sustained monomorphic ventricular tachycar-dia, and no sustained arrhythmias were con-structed. The survival rate at one, two, three,and five years was 70%, 62%, 62%, and 40% inthe induced ventricular fibrillation patientsgroup, and 98%, 96%, 94%, and 94% in theinduced sustained monomorphic ventriculartachycardia patients group respectively. Fiveyear survival was 100% in the group with nosustained arrhythmia (Wilcoxon, P << 0o001;Log rank P << 0-001) (fig 1). The positivepredictive value, specificity, and sensitivity

100*****

80 - VF-+SMVTSR60 - --NSVA

2 40C,)

20VF 9 6 5 4 3 2 1 0 0 0 0 0

SMVT 52 42 30 23 17 13 12 8 5 2 1 0NSVe 2,1 210 1,9 1,6 1,5 1,1 1,o

0 12 24 36 48 60 72 84 96 108120132 144Months follow up

Figure 1 Survival curves (sudden cardiac death) inrelation to the arrhythmia induced during amiodaronetreatment. NSVA, no sustained ventricular arrhythmias;SMVT, sustained monomorphic ventricular tachycardia;VF, ventricularfibrillation. The numbers at the bottom ofthe graph are the numbers ofpatients who remainedavailable for analysis at each year during the follow upperiod.

25

Rodriguez, Sternick, Smeets, Timmermans, den Dulk, Oreto, et al

Table 4 Outcome of 106 patients with SMVTIVF after myocardial infarction treated with amiodarone. Values arenumbers ofpatients

Index arrhythmia

SMVT (n =77) VF(n=29)

Induced arrhythmia: SMVT (n = 53) VF (n = 4) NI (n = 20) SMVT (n = 12) VF (n =11) NI (n = 6)

OutcomeSudden death 3 3 1 0 6 0Cardiac death 7 1 2 0 2 0Non-cardiac death 0 0 2 2 2 0Alive 43 0 15 10 1 6

MI, myocardial infarction; NI, non-inducible; SMVT, sustained monomorphic ventricular tachycardia; VF, ventricular fibrilla-tion.

Figure 2 Survival curves(non-sudden cardiac death)in relation to thearrhythmia induced duringamiodarone treatment.NSVA, no sustainedventricular arrhythmias;SMVTI sustainedmonomorphic ventriculartachycardia; VF,ventricularfibrillation. Thenumbers at the bottom ofthe graph are the numbersofpatients who remainedavailable for analysis ateach year during the followup period.

80

60~g21nE

40

2(

SMNS'

-VFSMVTNSVA

VF 9 7 6 5 3 2 1 0IVT 52 42 30 22 17 14 13 8VA 22 20 19 16 15 11 11 90 12 24 36 48 60 72 84 96 '

Months follow up

0 0 0 05 2 1 08 4 21108 120 132 144

patients], and no sustained ventriculararrhythmias [two out of 26 patients]). Thesurvival rate from non-sudden cardiac death atone, three, and five years was 85%, 71%, and71% in the induced ventricular fibrillationgroup, 95%, 93%, and 83% in the sustainedmonomorphic ventricular tachycardia group,and 96%, 96%, and 96% in the group with nosustained ventricular arrhythmias, respectively(fig 2).

Non-fatal recurrent ventricular tachycardiawas observed in 49 patients (46%). Forty twopatients had sustained monomorphic ventricu-lar tachycardia and seven had ventricular fib-rillation as their index arrhythmia.

for the inducibility of ventricular fibrillation onamiodarone treatment for at least one monthwere 60%, 94%, and 69% respectively. Bothventricular fibrillation as index arrhythmia andthe left ventricular ejection fraction of < 40%had a low positive predictive value (six out of29 [21%] and 12 out of 79 [15%], respec-tively).When non-sudden cardiac death was used

as the end point, no significant differenceswere found between the three groups (inducedventricular fibrillation [three out of 15patients], induced sustained monomorphicventricular tachycardia [seven out of 65

106 Patients

Dead 31 Alive 75/I

13 12 6SCD CD NCD

2 1 1

DEF SCD

AAD Surgery DEF No AADIlI

56 9 8 2

45 6 5 1 8 1 1 6Amio Amio Other Amio No Sotalol Amio No

+ AAD AAD AADother AAD

Figure 3 Flow chart showing the follow up of the patients and their current treatment.AAD, antiarrhythmic drug; Amio, amiodarone; CD, non-sudden cardiac death; DEF,defibrillator; NCD, non-cardiac death; SCD, sudden cardiac death.

SurgeryDuring follow up, 18 patients underwent coro-nary artery bypass surgery because of newischaemia (13 patients from the sustainedmonomorphic ventricular tachycardia and fivefrom the ventricular fibrillation index arrhyth-mia group). Twelve patients had arrhythmiasurgery because of ventricular tachycardiarecurrences (all were from the sustainedmonomorphic ventricular tachycardia indexarrhythmia group). Three underwent aneurys-mectomy alone (one patient died duringsurgery), five had endocardial resection andaneurysmectomy, and four underwent cryoab-lation and aneurysmectomy (two patientsdied, one from chronic lung disease and theother one from pump failure after surgery).One patient who underwent arrhythmiasurgery is still on amiodarone.

Side effectsSide effects were observed in seven out of 106patients (7%). Severe peripheral neuropathyrequiring drug discontinuation occurred inone patient. Moderate toxicity was observed insix patients and included visual disturbancesin one and hypothyroidism in one. Bothpatients were continued on amiodarone on adose of 100 mg daily. Symptomatic AV blockeither in the AV node (n = 2) or distal to theAV node (n = 2) necessitated permanent car-diac pacing in four patients.

Current treatment (fig 3)At the time of writing, 56 of the 75 patientswho were still alive were receiving antiarrhyth-mic drugs. Forty five patients were on amio-darone alone. Six patients were takingamiodarone in combination with anotherantiarrhythmic drug (amiodarone and fle-

26

n k

Sudden death in patients using amiodarone because of ventricular tachyarrhythmias

cainide, n = 1; amiodarone and propafenone,n = 4; amiodarone and mexitil, n = 1).Antiarrhythmic drugs other than amiodaronewere being used by five patients. This includedd-sotalol (n = 1), sotalol (n = 1), and /3 block-ers (n = 3). Two patients were without anti-arrhythmic drug treatment.A programmable cardioverter defibrillator

was implanted in nine patients because ofspontaneously recurring, haemodynamicallypoorly tolerated ventricular tachyarrhythmiasin spite of amiodarone treatment (five patientsfrom the sustained monomorphic ventriculartachycardia and four from the ventricular fib-rillation group). One of these patients diedpostoperatively from sepsis. Two patients hadused their defibrillator (Medtronic 7217B)because of ventricular fibrillation in one andfast, haemodynamically poorly tolerated ven-tricular tachycardia in the other. One patienthad documentation of slow ventricular tachy-cardias not requiring use of the device. In theremaining five patients no spontaneous ven-tricular tachyarrhythmias requiring electricaltreatment had occurred. Two of eight livingpatients were on antiarrhythmic drugs, one onamiodarone and one on d-sotalol.

DiscussionOur study suggests that programmed electricalstimulation of the heart in patients treatedwith amiodarone because of sustainedmonomorphic ventricular tachycardia or ven-tricular fibrillation after a myocardial infarc-tion allows identification of those patients whoare at high risk of dying suddenly.

Inducibility of ventricular fibrillation underamiodarone treatment for at least one monthwas the strongest predictor of sudden death byunivariate and multivariate analysis. A low leftventricular ejection fraction (< 40%) was alsoan independent predictor of sudden death.Syncope or cardiac arrest during the indexarrhythmia and the index arrhythmia itself(sustained monomorphic ventricular tachycar-dia/ventricular fibrillation) showed a trend inthe multivariate analysis.

Sudden death occurred in 60% of patientsin whom ventricular fibrillation was inducedon amiodarone treatment and in 21% ofpatients in whom ventricular fibrillation wasthe index arrhythmia.

In patients with sustained monomorphicventricular tachycardia as their index arrhyth-mia ventricular fibrillation was less ofteninduced (5%) and there was a lower incidenceof sudden death (9%). Induction of a sus-tained monomorphic ventricular tachycardiaor failure to induce a sustained ventriculararrhythmia did not identify patients prone todevelop sudden death.The positive predictive value of induced

ventricular fibrillation was better (60%) thanthe positive predictive value of either clinicalventricular fibrillation (21 %) or a left ventricu-lar ejection fraction of < 40% (15%).

There were no significant differences in theincidence of non-sudden cardiac deathbetween the three groups.

REVIEW OF PUBLISHED REPORTSThe value of programmed electrical stimula-tion in assessing the efficacy of amiodaronetreatment in patients with life threateningarrhythmias is still controversial. Some investi-gatorslA have reported a poor predictive valueof programmed electrical stimulation inpatients taking amiodarone, whereas others5-7consider it predictive.McGovern et a16 found two significant inde-

pendent predictors of recurrent arrhythmias:persistence of inducibility of ventricular tachy-cardia during electrophysiological testing, and alowered left ventricular ejection fraction. Intheir study the type of induced ventriculartachycardia (non-sustained or sustained) wasnot mentioned. Also, fatal (sudden death) andnon-fatal events (recurrent ventricular tachy-cardia) were analysed together.

Klein et a18 found that easier induction ofventricular tachycardia during amiodaronetreatment versus control was highly predictiveof arrhythmia recurrence. In their paper sud-den death and recurrent ventricular tachycar-dia were also not differentiated.

Kadish et a19 looked for predictors of recur-rent ventricular tachycardia and sudden death.No predictor of recurrent ventricular tachycar-dia was found. However, they did find predic-tors of cardiac arrest or sudden death. Theseincluded haemodynamic instability of thearrhythmia induced on electrophysiologicaltesting during amiodarone treatment, youngerage, low left ventricular ejection fraction, thepresence of a left ventricular aneurysm, and apoorly tolerated rhythm at clinical presenta-tion. Survival at one and three years ofpatients with poorly tolerated arrhythmiasinduced at electrophysiological study duringamiodarone treatment were similar to ourresults (75% v 70%, and 70% v 62% respec-tively).

LIMITATIONS OF OUR STUDYThe optimal time to assess the role of the elec-trophysiological study in patients treated withamiodarone because of life threateningarrhythmias with coronary artery disease is stillcontroversial. The pharmacokinetic profile ofamiodarone is unusual and not fully under-stood, making it difficult to determine whensteady state is achieved with this agent.'7 18The value of early electrophysiological

studies in patients taking amiodarone for 10to 14 days in predicting outcome from ventric-ular tachyarrhythmias in coronary artery dis-ease has been reported by Manolis et al."1However, since clinical practice suggests thatit may take several weeks of amiodarone load-ing before full clinical efficacy can be estab-lished,'7 18 we selected a period of one monthof amiodarone treatment to evaluate the roleof the electrophysiological study in predictingoutcome.Our study is a retrospective one, from a ter-

tiary referral centre with a limited number ofpatients. To be admitted to the study thepatient had to be on amiodarone for at leastone month, thereby excluding patients dyingearly after the onset of their arrhythmia. This

27

Rodriguez, Sternick, Smeets, Timmertnans, den Dulk, Oreto, et al

may explain why, in contrast to previous stud-ies,1920 we did not find that clinical variablessuch as (1) a time interval of < 2 monthsbetween myocardial infarction and the firstepisode of sustained ventricular arrhythmia,(2) syncope during the presenting arrhythmia,(3) presence of multiple myocardial infarc-tions, or (4) location of myocardial infarction(anterior v inferior) were of value in predictingrisk of sudden death during follow up.

Another limitation of our study was thatonly 14 patients underwent baseline electro-physiological examination. This feature isexplained by the fact that the majority of ourpatients were already on amiodarone treat-ment when referred to our hospital.

CONCLUSIONSOur retrospective study suggests that inpatients receiving amiodarone because of lifethreatening ventricular arrhythmias aftermyocardial infarction, the inducibility of ven-tricular fibrillation, but not of a sustainedmonomorphic ventricular tachycardia, indi-cates a high risk of dying suddenly. We believethat this finding should now be evaluatedprospectively. It might be of help in selectingpatients for non-pharmacological treatment.

1 Heger JJ, Prystowsky EN, Jackman WM, Nacarelli GV,Warfel KA, Rinkenberger RL, et al. Amiodarone: clinicalefficacy and electrophysiology during long-term therapyfor recurrent ventricular tachycardia or ventricular fibril-lation. NEnglJMed 1981;305:539-45.

2 Hamer AW, Finerman WB, Peter T, Mandel WJ. Disparitybetween the clinical and electrophysiologic effects ofamiodarone in the treatment of recurrent ventriculartachyarrhythmias. Am HeartJ 1981;102:992-1000.

3 Waxman HI, Groh WC, Marchlinski FE, Buxton AE,Sadowski LM, Horowitz LN, et al. Amiodarone for con-trol of sustained ventricular tachyarrhythmias. Clinicaland electrophysiologic effects in 51 patients. Am J Cardiol1982;50: 1066-74.

4 Nademanee K, Hendrickson JA, Jannan R, Singh BH.Antiarrhythmic efficacy and electrophysiologic actions ofamiodarone in patients with life-threatening ventriculararrhythmias: potent suppression of spontaneously occur-ring tachyarrhythmias versus inconsistent abolition ofinduced ventricular tachycardia. Am Heart J 1982;103:950-9.

5 Horowitz LN, Greenspan AM, Spielman SR, Webb CR,Morganroth J, Rotmensch H, et al. Usefulness of electro-physiologic testing in evaluation of amiodarone therapyfor sustained ventricular tachyarrhythmias associatedwith coronary artery disease. Am J Cardiol 1985;55:367-71.

6 McGovern B, Garan H, Malacoff RF, DiMarco JP, GarantG, Sellers D, et al. Long-term clinical outcome of ventric-ular tachycardia or fibrillation treated with amiodarone.Am ICardiol 1984;53:1558-63.

7 Nacarelli GV, Fineberg NS, Zipes DP, Heger Jf, DuncanG, Prystowsky EN. Amiodarone: risk factors for recur-rences of symptomatic ventricular tachycardia identifiedat electrophysiologic study. Jf Am Coil Cardiol 1985;68:814-21.

8 Klein LS, Fineberg N, Heger JJ, Miles WM, KammerlingJM, Chang M-S, et al. Prospective evaluation of adescriminant function for prediction of recurrent ventric-ular tachycardia or ventricular fibrillation in coronaryartery disease patients receiving amiodarone and havinginducible ventricular tachycardia at electrophysiologicstudy. Am J Cardiol 1988;61:1024-30.

9 Kadish AH, Buxton AE, Waxman HL, Flores B, JosephsonME, Marchlinsli FE. Usefulness of electrophysiologicstudy to determine the clinical tolerance of arrhythmiarecurrences during amiodarone therapy. Jf Am CollCardiol 1987;10:90-6.

10 Zhu J, Haines DE, Lerman BB, DiMarco JP. Predictors ofefficacy of amiodarone and characteristics of recurrenceof arrhythmia in patients with sustained ventriculartachycardia and coronary artery disease. Circulation 1987;76:802-9.

11 Manolis AS, Urichio F, Estes ME. Prognostic value of earlyelectrophysiologic studies for ventricular tachycardiarecurrence in patients with coronary artery diseasetreated with amiodarone. Am J Cardiol 1989;63:1052-7.

12 Kim SG, Felder SD, Figura I, Johnston DR, Mercado AD,Fisher JD. Prognostic value of changes in the mode ofventricular tachycardia induction during therapy withamiodarone and class 1A antiarrhythmic agent. Am JCardiol 1987;59:1314-8.

13 Brugada P, Wellens HJJ. Programmed electrical stimula-tion of the human heart. In: Josephson ME, Wellens HJJ,eds. Tachycardias; mechanism, diagnosis and treatment.Philadelphia: Lea and Febiger, 1984;61-89.

14 Yusuf S, Garg R, Zucker D. Analysis by intention-to-treatprinciple in randomized trials and databases. PACE1991;14:2078-82.

15 The SAS software. In: PHREG procedure, 1990:435-79..16 Cox DR. Regression models and life tables. J7 Stat Soc (b)

1972;34:187-220.17 Holt DW, Tucker GT, Jacson PR, Storey GCA.

Amiodarone pharmacokinetics. Am Heart J 1983;106:840.

18 Haffajee CI, Love JC, Canada AT, Lesko U, Askourian G,Alpert JS. Clinical pharmacokinetics and efficacy ofamiodarone for refractory tachyarrhythmias. Circulation1983;67: 1347-55.

19 Brugada P, Talajic M, Smeets J, Mullenders R, WellensHJJ. Risk stratification of patients with ventricular tachy-cardia or ventricular fibrillation after myocardial infarc-tion. The value of the clinical history. Eur Heart J7 1989;10:747-52.

20 Willems AR, Tijssen JGP, Van Capelle FJL, et al. Deter-minants of prognosis in symptomatic ventricular tachy-cardia or ventricular fibrillation late after myocardialinfarction. IAm Coll Cardiol 1990;16:521-30.

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