Cardiac Electrophysiology Review 2003;7:452–456C© 2004 Kluwer Academic Publishers. Manufactured in The Netherlands.

Amiodarone versus Implantable Defibrillator (AMIOVIRT):Background, Rationale, Design, Methods, Resultsand Implications

Mevan Wijetunga and S. Adam StrickbergerDivision of Cardiology, Washington Hospital Center,Washington, DC, USA

Abstract. Non ischemic dilated cardiomyopathy(NIDCM) is a substrate for sudden cardiac death.Treatment with amiodarone may have a positive orneutral survival benefit. The role of ICD therapy inthe primary prevention of sudden cardiac death inasymptomatic NIDCM patients is not clear. The purposeof the Amiodarone versus Implantable Defibrillator(AMIOVIRT) study was to compare total mortality,arrhythmia-free survival, quality of life and costsof therapy in patients with NIDCM, asymptomaticnon-sustained ventricular tachycardia (NSVT) andleft ventricular ejection fraction ≤0.35 who wererandomized to therapy with amiodarone (52 patients)or an ICD (51 patients). At the first scheduled interimanalysis, the previously determined stopping rule forfutility was reached and the study was stopped. Therewas no statistically significant difference in the 1-and 3-year survival rates in the patients who receivedamiodarone compared with those who received an ICD(90% and 87% for amiodarone group versus 96% and88% for ICD group; p= 0.8). There was a trend towardsimproved arrhythmia-free survival rates (p = 0.1), andcost of medical care ($ 8,879 vs. $ 22,039, p = 0.1) inthe patients who were treated with amiodarone ascompared to the patients who were treated with anICD. At one year, the quality of life measures were notsignificantly different (p= 0.1).

Key Words. sudden cardiac death, primary prevention,amiodarone, implantable defibrillator, non ischemic di-lated cardiomyopathy

Background

Non ischemic dilated cardiomyopathy (NIDCM) is asubstrate for sudden cardiac death and treatmentwith amiodarone may have a positive or neutral sur-vival benefit [1,2]. In the subset of NIDCM patientswith syncope or cardiac arrest, implantable defibril-lator (ICD) therapy is thought to improve survival[3,4]. Although non-sustained ventricular tachycar-dia (NSVT) may be a risk factor for sudden death inpatients with NIDCM, it is unclear if patients withNIDCM and asymptomatic NSVT have a survivalbenefit with ICD therapy [5,6].

The purpose of the AMIOdarone Versus Implant-able Defibrillator Randomized Trial (AMIOVIRT)was to compare the total mortality rates of patientswith NIDCM and asymptomatic NSVT who were

randomized to therapy with amiodarone or an ICD[7].

Rationale and Design

AMIOVIRT was an unblinded, randomized trial thatcompared total mortality in patients with NIDCMand NSVT who were randomized to treatment witheither amiodarone or an ICD.

There are several design issues with AMIOVIRTthat need to be addressed. First, eletrophysiologictesting was not included in the study design becausein patients with NIDCM and asymptomatic NSVT,electrophysiologic testing has a low sensitivity, speci-ficity, and positive and negative predictive values forfatal ventricular arrhythmias [8–10].

Second, a third group treated only with standardmedical therapy was not included in the trial de-sign. A third group would have doubled the sam-ple size and the feasibility of completing the studywould have been greatly reduced. Furthermore, noprevious study has demonstrated a harmful effectof amiodarone or an ICD on the survival of pa-tients with ischemic or non-ischemic cardiomyopa-thy [1,2,11–17]. Consequently, it was reasonably as-sumed that any observed difference in survival be-tween the two groups would not be due to negativeeffects of either treatment, but due to a positive effectof the therapy. If mortality was equivalent betweenthe treatment groups, then the questions would bewhether both therapies were neutral or equally ef-fective. The investigators assumed they could dis-criminate between equally effective and ineffectivetherapies based upon the arrhythmia-free survivalrates.

Methods

AMIOVIRT was conducted from August 1996 to June2001 at 10 medical centers in the United States.Subjects were randomized to treatment with eitheramiodarone or an ICD. A sample size of 219 patients

Address correspondence to: S. Adam Strickberger, M.D., 110Irving Street, NW Washington, DC 20010-2975, USA. E-mail:strickberger@medstar.net

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in each group was calculated based on 80% powerto observe a reduction of mortality from 20% to 10%(p < 0.05, two-sided t test). Patients who declinedparticipation in the study were followed in a volun-tary registry. All patients carried the clinical diagno-sis of NIDCM, with a left ventricular ejection frac-tion ≤0.35, documented NSVT, and New York HeartAssociation functional Class I-III. Patients with syn-cope, pregnancy, a contraindication to amiodarone orICD treatment, ongoing therapy with a Class I an-tiarrhythmic drug, or a NIDCM diagnosed within 6months were excluded from study participation.

Amiodarone was initiated with 800 mg/day duringthe first week, followed by 400 mg/day for one year,and then 300 mg/day. Standard medical therapy withACE inhibitors, beta blockers and spironolactone wasencouraged. The outcome measures included death,cause of death, arrhythmia-free survival, quality oflife, and the cost of treatment. The events committeewas blinded to patient randomization, and evaluatedand determined the cause of each death. Arrhythmia-free survival was determined from the absence ofdeath, syncope, life-threatening ventricular arrhyth-mias or appropriate ICD therapies. Quality of lifewas measured using two standard questionnaires;the Quality of Well Being Schedule and the StateTrait Anxiety Inventory. To explore the cost of bothin- and out-patient management, data were collectedfrom 24 patients, all of whom were treated at 1 cen-ter. The analyses were based on an intention-to-treatbasis, i.e. the analysis was based on the initially as-signed treatment for each patient.

Results

At the first scheduled interim analysis of the first 10deaths, the previously determined stopping rule forfutility (mortality difference at a significance levelof <0.025 or >0.025, 90% power, assuming enroll-ment of 600 patients) was reached and the study wasstopped.

A total of 103 patients were randomized into thestudy. Of these, 51 were randomized to treatmentwith ICD and 52 were randomized to treatment withamiodarone. The dose of amiodarone in the patientswho were assigned to this medication was 303 ± 93mg/day.

The baseline characteristics did not differ betweenthe two treatment groups and are summarized inTable 1. The follow-up was 2.0 ± 1.3 years (range0.1 to 4.8 years).

There was no statistically significant differencein the 1- and 3-year survival rates in the patientswho received amiodarone compared with those whoreceived an ICD (90% and 87% for amiodaronegroup versus 96% and 88% for ICD group, P = 0.8;Figure 1). There was a trend towards improvedarrhythmia-free survival rates (p = 0.1; Figure 2),

Table 1. Baseline patient characteristics (all patients)

n (total) 103Age (years) 59 ± 11Female (%) 30LVEF 0.23 ± 0.09Duration of NIDCM (years) 3.2 ± 4.0 yNYHA Class II-III (%) 83NSVT (beats/min) 155 ± 24ACE inhibitors (%) 85Beta blockers (%) 52Potassium sparing diuretic (%) 20

None of the characteristics in the table reached a statistical signifi-cance of p < 0.05, between the two treatment groups. LVEF = left ven-tricular ejection fraction, NYHA = New York Heart Association, ACEinhibitors = angiotensin converting enzyme inhibitors.

and cost of medical care ($ 8,879 vs. $ 22,039, p = 0.1)in the patients who were treated with amiodaroneas compared to the patients who were treated withan ICD. The quality of life measures were not sig-nificantly different between the treatment groups(P = 0.1).

Clinical implicationsThe major finding of AMIOVIRT is that 1- and 3-yearmortality rates were not different in patients withNIDCM, left ventricular ejection fraction ≤0.35 andasymptomatic NSVT who were treated with amio-darone as compared to an ICD. There were trends to-wards improved arrhythmia-free survival and lowercosts of medical care in patients treated with amio-darone therapy, although the quality of life measure-ments were similar between the 2 treatment groups.

The results of AMIOVIRT are comparable to thosein the recently published Cardiomyopathy Trial(CAT) [18]. In CAT, 104 patients with newly diag-nosed idiopathic dilated cardiomyopathy and an ejec-tion fraction of ≤0.30 were randomized to treatmentwith an ICD or medical therapy. No difference in sur-vival was observed between the treatment groupsafter 2 or 4 years. The CAT trial included patientswith new onset NIDCM (<9 months) irrespective ofthe presence of NSVT, whereas AMIOVIRT only in-cluded patients with NSVT and a chronic diagnosisof NIDCM [7,18].

The 1-year mortality rate in AMIOVIRT was ap-proximately 10%, and was less than expected [7].The liberal use of angiotensin converting enzymeinhibitors, beta blockers and spironolactone may ex-plain the higher than expected survival rates ob-served in this trial [19–26].

The 1-year survival rate among the patients inAMIOVIRT who were treated with amiodarone werehigher than the 1-year survival rates among patientswith ischemic cardiomyopathy who were treatedwith amiodarone in other trials [11,12,27]. This ob-servation suggests that amiodarone may be more ef-fective in preventing arrhythmic death in patients

454 Wijetunga and Strickberger CEPR 2003; Vol. 7, No. 4

Fig. 1. Kaplan-Meier estimates of cumulative survival among patients treated with amiodarone (solid line) or an implantabledefibrillator (dotted line). (Reproduced with permission from Elsevier Inc.).

Fig. 2. Kaplan-Meier estimates of arrhythmia-free survival among patients treated with amiodarone (solid line) or an implantablecardioverter-defibrillator (dotted line). (Reproduced with permission from Elsevier Inc.).

with NIDCM as opposed to patients with ischemiccardiomyopathy. Furthermore, in asymptomatic pa-tients with ischemic cardiomyopathy, prophylacticimplantation of an ICD is superior to treatment withamiodarone [11,12,27]. This is in contrast to theobservation from AMIOVIRT, where patients withNIDCM, left ventricular dysfunction and asymp-tomatic NSVT, had comparable survival benefitswith an ICD or amiodarone. These findings sug-gest that patients with cardiomyopathy secondaryto coronary artery disease may respond differentlyto treatment than patients with NIDCM, highlight-ing the notion that ischemic and non-ischemic my-

ocardial arrhythmogenic substrates may be funda-mentally different. Future trials of patients with leftventricular dysfunction and heart failure should,perhaps, include patients only with ischemic or non-ischemic cardiomyopathy.

The use of ICD therapy has grown substantiallyin the United States because of the proven survivalbenefit of this therapy in patients with ischemic car-diomyopathy and left ventricular dysfunction [27].The findings of AMIOVIRT, however, suggest thatprophylactic ICD therapy may not offer similar sur-vival benefit in asymptomatic patients with NIDCM.The implication of AMIOVIRT is that treatment with

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amiodarone may be reasonable as an initial approachto improve survival in patients with NIDCM andNSVT.

Implications for future trialsAMIOVIRT did not include a standard medical treat-ment group, in addition to the amiodarone and ICDgroups. Without a control group, the present studycannot exclude the possibility that neither amio-darone nor an ICD affects mortality or improvesclinical outcomes. However, the arrhythmia-free sur-vival rates from AMIOVIRT support the hypothe-sis that amiodarone lowers the risk of sudden deathby decreasing the frequency of ventricular tachycar-dia and ventricular fibrillation. The Sudden CardiacDeath in Heart Failure Trial (SCD-HeFT), now inprogress, does not have this limitation. The SCD-HeFT design includes medical, amiodarone and ICDtreatment groups [28].

The relatively small sample size in AMIOVIRTpermits a mortality difference observed with a powerof only 3%. The study was stopped due to theprospective rule used to identify inability to dif-ferentiate between ICD and amiodarone therapy.Based on the present results, if the study were con-tinued to achieve a statistical power of 80%, it isestimated that approximately 12,000 randomizedpatients would be required. If the mortality rates ob-served in AMIOVIRT are applicable to SCD-HeFT,then the latter trial may be underpowered to observesignificant mortality differences among the treat-ment groups.

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