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Randomised trial of effect of amiodarone on mortality in patientswith left-ventricular dysfunction after recent myocardialinfarction: EMIAT D G Julian, A J Camm, G Frangin, M J Janse, A Munoz, P J Schwartz, P Simon, for the European Myocardial Infarct Background Ventricular arrhythmias are a major cause of Ventricular arrhythmias are one of the main causes of death after myocardial infarction, especially in patients death in survivors of acute myocardial infarction. The w it h poor left -v ent ric ular func t ion. P rev ious at t empt s European Myocardial Infarct Amiodarone Trial (EMIAT) t o i d e n t i f y a n d su p p r e ss a r r h y t h m i a s w i t h v a r i o u s was conceived at the end of 1988, after many studies of antiarrhythmic drugs failed to reduce or actually increase antiarrhythmic drugs that block the sodium-channel (classI) showed no efficacy in the suppression of arrhythmias mortality. A miodarone is a pow erful antiarrhythmic drug and prevention of death in survivors of myocardial with several potentially beneficial actions, and has shown infarction.1–3 Later, the Cardiac Arrhythmia Suppression benefit in several small-scale studies. We postulated that Trials proved that in survivors of myocardial infarction this drug might reduce mortality in patients at high risk of at low risk of death, the suppression of ventricular deat h aft er my oc ardial infarc t ion bec ause of impaired extrasystoles with the sodium-channel-blocking drugs v ent ric ular func t ion, irrespec t ive of w het her t hey had flecainide and encainide, and possibly moricizine, was associated with excess mortality.4,5 Apart from ␤- Methods The European Myocardial Infarct Amiodarone Trial adrenergic blocking agents, the only antiarrhythmic drug (EMIAT) was a randomised double-blind placebo-controlled that showed any promise in the late 1980s was t rial t o assess w het her amiodarone reduc ed all-c ause amiodarone, although the number of patients studied was mort alit y ( primary endpoint ) and c ardiac mort alit y and too small to allow definite conclusions about the drug’s arrhy t hmic deat h ( sec ondary endpoint s) in survivors of effect on all-cause mortality.6–8 We, therefore, decided to my oc ardial infarc t ion w it h a left -v ent ric ular ej ec t ion conduct a large trial of amiodarone in survivors of fraction ( LVEF) of 40% or less. Intention-to-treat and on- myocardial infarction at increased risk of death.9,10 Although the presence of frequent or complex ventricular arrhythmias is an independent risk factor for Findings E M I A T enr ol l ed 1486 pat i ent s ( 743 i n t he mortality after myocardial infarction,11–13 and most trials amiodarone g roup, 743 in t he plac ebo g roup) . M edian of antiarrhythmic drugs have used such ventricular follow-up was 21 months. All-cause mortality (103 deaths arrhythmias as an entry criterion, there is no evidence in the amiodarone group, 102 in the placebo group) and that suppression of ventricular arrhythmias leads to a cardiac mortality did not differ betw een the tw o groups.
reduction in overall mortality. Moreover, the single However, in the amiodarone group, there was a 35% risk most powerful independent predictor of mortality, reduction (95% CI 0–58, p=0·05) in arrhythmic deaths.
including sudden death, is left-ventricular dysfunction.13,14 Interpretation Our findings do not support the systematic Thus, we decided to adopt a different approach from the pr ophy l ac t i c use of ami odar one i n al l pat i ent s w i t h other trials by taking no account of the presence of depr essed l eft - v ent r i c ul ar func t i on aft er my oc ar di al symptomless arrhythmias and by choosing depressed left- infarc t ion. How ever, t he lac k of proarrhy t hmia and t he ventricular ejection fraction (LVEF) as the main entry r e d u c t i o n i n a r r h y t h m i c d e a t h su p p o r t t h e u se o f criterion. We expected that most patients with left- amiodarone in patients for whom antiarrhythmic therapy is ventricular dysfunction would subsequently suffer from lethal arrhythmias, even if ventricular arrhythmias werenot initially present. In addition to its antiarrhythmic properties, amiodarone has anti-ischaemic actions and does not aggravate heart failure, properties that may havean additional beneficial effect on survivors of myocardial *Investigators listed at end of paper
Netherhall Gardens, London (Prof D G Julian MD); Cardiological The aim of this randomised placebo-controlled double- Sciences, St George’s Hospital Medical School, blind trial was to assess the effect of amiodarone on all- London SW17 0RE, UK (Prof A J Camm MD); Sanofi Recherche, cause mortality, cardiac mortality, and arrhythmic death Montpellier, France (G Frangin MD, A Munoz MD, Prof P Simon MD); in survivors of myocardial infarction with depressed left- Department of Clinical and Experimental Cardiology,Academic Medical Centre, Amsterdam, Netherlands (Prof M J Janse MD); and Department of Cardiology, University of EMIAT was a joint venture between the Working Group on Arrhythmias of the European Society of centre. The lower limit of the normal range was 40% or more forall centres.
We recruited patients for this randomised double-blind placebo- Patients were then randomly assigned amiodarone or placebo.
controlled trial from the coronary-care units of participating The daily regimen was 800 mg for 14 days, 400 mg for 14 weeks, European hospitals between Nov 30, 1990, and Oct 30, 1995. A and then 200 mg until the end of the study follow-up. The log-book was kept of all patients with documented myocardial maximum follow-up was 2 years and the minimum follow-up infarction surviving 5 days. Eligible patients were those aged 1 year, according to the time of enrolment.
18–75 years who had a LVEF on multiple-gated nuclear Patients were assessed at baseline, 2 weeks, 2 months, and angiography (MUGA) of 40% or less. MUGA was done 5–21 then every 4 months up to 2 years. 24 h ambulatory days after admission to the coronary-care unit.
electrocardiographic (Holter) monitoring was done at baseline, We excluded women of childbearing age who were not using 2 weeks, and 4 months. Chest radiography was done at baseline, reliable contraception and individuals who had: treatment with 2 months, and annually. Laboratory data, including amiodarone in the previous 6 months; documented bradycardia measurement of serum concentrations of potassium creatine (under 50 beats per min); second-degree or third-degree kinase, aspartate aminotransferase, alanine aminotansferase, and atrioventricular block; sinus pauses of more than 2·5 s unless thyrotropin, were collected at baseline, 2 weeks, and at months 2, controlled by a pacemaker; clinically significant hepatic disease; a history of documented thyroid dysfunction, long QT syndrome, The investigators notified the Coordinating Centre about any severe angina or congestive heart failure refractory to deaths and major adverse side-effects by fax within 24 h of the conventional therapy; a need for antiarrhythmic therapy other event. The Coordinating Centre forwarded these data to the than ␤-blockers or digoxin; a likelihood of imminent cardiac surgery; and other contraindications for amiodarone.
The Validation Committee reviewed deaths under masked Computer-generated randomisation was done in balanced conditions. We used the following criteria to classify the cause of blocks of four patients, and lists were prepared and kept at the Independent Statistical Centre (Clinical Pharmacology Unit, Cardiac deaths were grouped into three categories: “sudden”, Claude Bernard University, Lyon). This centre was also “non-sudden”, or “unwitnessed” presumed cardiac. Sudden responsible for conducting the interim analyses of efficacy and cardiac deaths occurred within 1 h of new symptoms, or in a safety, and for packaging the study treatments. Stratification was patient with no symptoms or stable symptoms, and with no left- based on clinical centre and ejection fraction. Treatment ventricular failure. Non-sudden cardiac deaths occurred more allocation was assigned under masked conditions by the EMIAT than 1 h after the onset of symptoms. Unwitnessed, presumed Coordinating Centre (Sanofi, Montpellier), and sent by fax to cardiac deaths were unexpected and not witnessed, within 24 h the investigators. The Coordinating Centre had no access to the of the patient’s being known to be well and with no symptoms or Before randomisation, patients from each centre were Sudden and non-sudden cardiac deaths were grouped into stratified according to their ejection fraction—31–40% and 30% documented, non-documented arrhythmic deaths, or non- or less. The accuracy of the MUGA equipment in each centre arrhythmic deaths, such as rupture and electromechanical was validated by the Ejection Fraction Committee. The normal dissociation. Unwitnessed deaths were presumed to be cardiac if range for ejection fraction was determined individually for each there was no alternative diagnosis. We defined sudden deathfrom myocardial infarction as a cardiac death, but not as an The Validation Committee also reviewed, under masked conditions, all arrhythmic events, suspected cases of pulmonary toxicity, biochemical alterations of thyroid hormones and liverenzymes, as well as evidence of clinical dysthyroidism andhepatic disorders.
The ambulatory electrocardiographic records were analysed centrally at the Holter Reading Centre.
The study protocol was approved by an ethics committee in each country or centre, and all patients had to give informedconsent to take part in the trial.
Study medication was stopped in patients with sustained ventricular tachycardia (୑30 s), symptomatic unsustainedventricular tachycardia, pulmonary infiltrate with no specificclinical cause, or intolerable side-effects. However, all patients were followed up and included in the intention-to-treat analysis.
Compliance was assessed by follow-up visits and tablet counts.
Data on mortality was sought for all patients at the end of theplanned follow-up.
The sample size calculations were based on a 15% 2-year mortality rate in the placebo group and a 35% reduction of riskin the amiodarone group, with type I and type II erorr rates of 0·05 and 0·20, respectively. These calulations indicated that1500 patients should be enrolled.
The primary analyses were by intention to treat, but we also did an on-treatment (efficacy) analysis of outcome events in eligible patients while on study medicaton or within 3 months ofearly permanent discontinuation. The primary endpoint was all-cause mortality and the secondary endpoints were cardiac mortality, arrhythmic death, and arrhythmic death plus At baseline (day of enrolment) continuous and categorical variables were compared by the t test and ␹2 test, respectively.
Survival curves of the proportion of patients who remained event-free, according to treatment group and ejection-fraction Mean (SD) creatine kinase activity (IU/L) Mean (SD) systolic blood pressure (mm Hg) VPB=ventricular premature beats. ACE=angiotensin-converting enzyme.
Table 1: Baseline characteristics of patients stratum, were calculated by the Kaplan-Meier method15 and compared by the log-rank test stratified by ejection fraction. We calculated the risk ratio and 95% CI values by Cox’sproportional hazards model,16 stratified by ejection fraction.
Cox’s proportional hazards model was also used to adjust for baseline imbalances in prognostic variables between groups.
Rules for censoring of data were defined before the Figure 2: Kaplan-Meier estimates of all-cause mortality by randomisation code was broken. For the intention-to-treat analysis, the follow-up was censored on the date of the last treatment within the previous 6 months (142), essential planned visit for complete follow-up, the end of the trial, or thedate of death. For the on-treatment analysis, data were censored antiarrhythmic treatment (142), and other contra- at 3 months after permanent discontinuation of study indications (406). Thus, 1486 patients were considered medication, or at the end of the follow-up as defined above.
eligible, gave informed consent to participate, and were Formal interim analyses were planned by the Safety Committee and done after the occurrence of every 60 deaths,with total mortality as the endpoint. The stopping guidelines for mortality were based on asymmetrical boundaries for benefit andharm.17 We followed the Peto18 approach with statistical guidelines for efficacy fixed at p<0·001. For safety monitoring, a report was produced every 4 months, and a fixed type-I error rate of 0·01 (one sided) was chosen as a statistical guideline. The committee also reviewed other adverse side-effects.
The Safety Committee did three interim analyses and recommended continuation of the study on each occasion.
However, one analysis showed higher mortality among patients in the amiodarone group who were receiving digoxin or digitoxinthan among those who were not; this difference in mortality was Intention-to-treat analysis by EFS and history of MINumber in analysis not significant. The Steering Committee was informed and advised investigators to adhere more strictly to the protocol, which stated that the dosage of digoxin or digitoxin should be halved on enrolment. This adverse trend did not continue.
We recruited 26 493 patients from 75 centres in 15 European countries. 7565 of the patients underwent a MUGA scan, and in 3255 (43%) the LVEF was 40% or less. We excluded 1769 patients with ejection fractions in the acceptable range because of lack of consent (409), EFS=ejection-fraction stratum; MI=myocardial infarction.
imminent cardiac surgery (286), other serious illness *Total patient-year ex posure: placebo=1206; amiodarone=1065.
(205), congestive cardiac failure (179), amiodarone LVF=left-venticular failure; CS=cardiogenic shock; EMD=electromechanical Table 3: Non-arrhythmic cardiac deaths and non-cardiac deaths p=0·67). By contrast, there was a 35% risk reduction(95% CI 0–58, p=0·05) in arrhythmic deaths among amiodarone-treated patients. A similar risk reduction was observed after the addition of resuscitated cardiac arrest(table 2, figure 3). There were more deaths from non- arrhythmic cardiac and non-cardiac causes in amiodarone- group patients than in placebo-group patients (table 3).
A history of myocardial infarction significantly increased the risk of death (24% vs 10%, p<0·0001). We, therefore,did a further analysis to adjust for this variable and the baseline imbalances in prognostic variables. The adjusted differences in all-cause and cardiac mortality between the treatment groups were not significant (table 2).
Baseline ambulatory electrocardiograms were evaluable in 1367 patients, of whom 191 died. The mortality rate was higher in those with frequent or complex arrhythmias than in those without arrhythmias (112/548 [20%] vs 79/819 [10%]. However, the group without arrhythmias was larger and comprised 60% of the trial population.
Of the 191 deaths, 79 (41%) occurred in the group Figure 3: Kaplan-Meier estimates of arrhythmic deaths and without baseline arrhythmias, and among these deaths 36 resuscitated cardiac arrest by group and ejection fraction (45%) were classified as arrhythmic. In intention-to-treatanalysis of the subgroup of 548 patients with arrhythmias enrolled in the trial, with a mean time of 15 days (Ϯ3·9) at baseline (40% of the trial population), the difference after the index myocardial infarction. There were 743 between the amiodarone and placebo groups in patients in the placebo group and 743 patients in the arrhythmic deaths did not achieve significance, but there amiodarone group. Subsequently, we found that four was a significant reduction in the combined endpoint patients (two in the amiodarone group, two in the placebo of arrhythmic deaths and resuscitated cardiac deaths group) did not fulfil all the eligibility criteria, but they (p=0·048) in amiodarone-treated patients compared with were retained in the trial. The trial profile shows overall patient numbers during the study (figure 1).
During the trial, 284 (38·5%) amiodarone-group The baseline characteristics of patients in the two patients discontinued their study medication compared groups were broadly similar, but there were some with 158 (21·4%) placebo-group patients (figure 4). The between-group differences that may have affected main causes of discontinuation of study medication are outcome—eg, ejection fraction, New York Heart shown in table 5. There was no significant difference in Association functional class, peak concentrations ofcreatine kinase, and a history of myocardial infarction (table 1). Of especial interest was the difference in previous myocardial infarction: 191 (26%) placebo-group patients versus 233 (32%) amiodarone-treated patients.
Two patients were lost to follow-up and 1484 patients were followed up to the end of the trial. 205 patients died.
The Validation Committee classified 31 of these deaths as non-cardiac and 174 as cardiac. Of the 174 cardiac deaths, 83 (48%) were arrhythmic (figure 1). In addition, there were 20 survivors of resuscitated cardiac arrest.
All-cause mortality did not differ between the treatment groups (risk ratio 0·99, p=0·96), even after patients were grouped by ejection fraction (figure 2). Similarly, there was no difference in total cardiac mortality (risk ratio 0·94, Table 4: Causes of early discontinuation of study medication thyroid disorders were common, but in the amiodaronegroup, clinical hypothyroidism and hyperthyroidism were observed in only 11 (1·5%) and 12 (1·6%) patients, respectively. No torsade de pointes was documented in As expected in survivors of myocardial infarction, several other drugs were used concomitantly throughout the trial (table 1). After the reports of the benefits of inhibitors of angiotensin-converting enzyme (ACE) were published, in 1992, the proportion of patients receiving these agents increased. Concomitant treatment with ACE inhibitors, diuretics, calcium antagonists, digoxin, ordigitoxin had no effect on differential treatment group mortalities. However, we found a strong tendency towards favourable interaction between use of ␤-blockers and cardiac mortality (figure 5), independently of left- Figure 4: Percentage of patients continuing study medication EMIAT showed that amiodarone was associated witha significant reduction in arrhythmic deaths and resuscitated cardiac arrests among patients discharged from hospital with depressed left-ventricular function afterrecent myocardial infarction. However, neither asignificant nor corresponding reduction in all-cause or total cardiac mortality was seen because of increasednon-cardiac, or cardiac but not arrhythmic, mortality.
Thus, EMIAT does not support the systemic prophylacticuse of this regimen of amiodarone in survivors of myocardial infarction. Nevertheless, amiodarone therapydoes lead to a reduction in arrhythmic death with no proarrhythmic effect, only a few minor side-effects, and aneutral effect on total mortality.
Our findings warrant a discussion of the rationale and background of this trial, the factors that might explain its 0·2 0·4 0·6 0·8 1·0 1·2 1·4 1·6 1·8 2·0 2·2 outcome, and our interpretation of the findings.
Patients recovering from myocardial infarction are at substantial risk of sudden arrhythmic death and Figure 5: Intention-to-treat analysis of 2-year total cardiac symptomatic arrhythmic events.1,2 There is a sound mortality by concomitant medication at baseline rationale for the use of antiarrhythmic drugs in suchpatients. However, the results of trials of antiarrhythmic the major risk factors for mortality and arrhythmic events drugs have mostly been adverse:4,5,19,20 antiarrhythmic drug between those patients who continued amiodarone therapy was associated with increased deaths, in most cases sudden and presumably arrhythmic, that were The on-treatment analysis showed a more striking risk attributed to a proarrhythmic effect. Yusuf and colleagues’ reduction than was shown in the intention-to-treat meta-analysis21 of trials of antiarrhythmic drugs after analysis in arrhythmic deaths among the patients taking myocardial infarction showed that sodium-channel amiodarone compared with those taking placebo (table 2).
blockers were harmful and that calcium-channel Adverse side-effects are shown in table 7. There were antagonists had no beneficial effects; by contrast, a three deaths in the amiodarone group from pulmonary favourable effect was observed with the use of amiodarone fibrosis, which was confirmed on necropsy; however, two in a small population. Similarly, Teo and colleagues’ of these patients had pre-existing pulmonary disease and meta-analysis22 of placebo-controlled trials of amiodarone should not have been included in the trial. Biochemical after myocardial infarction or in patients with heart failuresuggested that survival substantially improved with the use of amiodarone. The lack of efficacy of sodium-channel blockers has been variously ascribed to proarrhythmic and negative inotropic effects.23 An interaction with ischaemia has also been proposed.24 On the other hand, although amiodarone is predominantly thought of as an antiarrhythmic drug, it is also an anti-ischaemic agent.25,26 Importantly, amiodarone seems to have little or no proarrhythmic potential. Thus, we decided that it was appropriate to design and conduct a mortality trial with amiodarone among survivors of myocardial infarction at *Cases assessed by Validation Committee. †Central and peripheral.
Unlike the antiarrhythmic drugs used in previous trials, mainly sodium-channel and potassium-channel blockers, endpoint analyses, a conventional two-sided test of amiodarone has several actions.27 Amiodarone has a significance was judged to be essential, since previous blocking effect on sodium, calcium, and potassium studies of antiarrhythmic drugs had clearly shown the channels, and also has antiadrenergic and anti-ischaemic possibility of an adverse outcome associated with the effects. Lethal arrhythmias in postinfarction patients are active agent. Thus, we calculated that 1500 patients were likely to be the result of re-entry.28 In our study, the needed. In fact, we recruited 1486 patients, and our prolongation of the ventricular refractory period combined a-priori assumptions proved to be correct: mortality in the with adrenergic blockade might have contributed to the placebo group was 14% (102 of 743), and the arrhythmic reduction in arrhythmic deaths in the amiodarone-treated deaths constituted half (49%) of the placebo-group mortality (50 of 102). Thus, EMIAT had sufficient power EMIAT showed that amiodarone therapy had no effect to detect a 35% reduction in mortality in the amiodarone on the primary endpoint of 2-year all-cause mortality, group. However, a much larger trial would have been irrespective of the stratum of left-ventricular function.
necessary to detect the small apparent reduction in all- However, amiodarone was associated with a reduction in arrhythmic deaths among high-risk patients after We assessed left-ventricular function accurately by myocardial infarction. Our finding of a significant MUGA scanning, which was well validated and approved reduction in arrhythmic deaths and resuscitated cardiac centrally. Unlike some previous studies of antiarrhythmic arrests in the amiodarone group suggests that any possible drugs such as the Cardiac Arrhythmias Suppression Trial,4 proarrhythmic effects of amiodarone do not outweigh its in which mortality among placebo-group patients was antiarrhythmic benefit. But this reduction in arrhythmic lower than expected, the selection process in EMIAT deaths was balanced by an excess of five non-cardiac resulted in the anticipated number of trial endpoints.
deaths and 13 cardiac but non-arrhythmic deaths. This EMIAT showed that many arrhythmic deaths occurred in excess may have resulted from chance or from the patients who did not have frequent or complex ventricular imbalance in significant prognostic factors between the ectopic activity at baseline. Thus, if we had used such groups, but may also have been partly attributable to the ectopic activity as the only entry criterion, the power of the adverse side-effects of amiodarone, such as, the three trial would have been reduced. Other stratification deaths caused by pulmonary fibrosis.29 In our study, fatal criteria, such as heart rate variability31,32 or baroreceptor reinfarction contributed to the non-arrhythmic mortality sensitivity,33 which are more likely to predict the associated with amiodarone treatment. This finding is, occurrence of arrhythmic events could have been used but at first, difficult to explain because amiodarone is an were not fully appreciated when EMIAT was planned.
But since there was a significant reduction in arrhythmic reinfarctions (11 of 13) occurred in patients who had a events with amiodarone, it seems unnecessary to speculate history of myocardial infarction before the index whether better selection for arrhythmic risk would have infarction, a group that was over-represented in the changed the results of the trial. Nonetheless, it might have amiodarone group. Another explanation for the failure of been appropriate to exclude patients at risk of early death amiodarone to reduce non-arrhythmic death is that, by because of pump failure (very low ejection fraction) or preventing arrhythmic death, amiodarone treatment reinfarction (adverse coronary anatomy). Such exclusion did not preclude death from other non-arrhythmic criteria may have reduced the cardiac but non-arrhythmic mechanisms. The results of EMIAT underline the mortality associated with amiodarone therapy.
importance of using all-cause mortality, rather than an In some previous trials of postinfarction antiarrhythmic antiarrhythmic effect, as the primary endpoint in a survival drugs, patients were recruited up to 1 year after the index infarction. However, most patients die within the first few After adjustment for the imbalance in covariates months after infarction. Thus, in EMIAT patients were between the groups, there was some evidence of a enrolled and randomly allocated treatment before reduction in all-cause and total cardiac mortalities. Is this discharge from hospital. Furthermore, the loading dose of reduction real and would it have been statistically study medication was administered quickly to ensure drug significant if the trial had been larger? The original power activity before discharge. Early recruitment plus high calculations were based on the pilot study of the Canadian dosing may have accounted for the increased early Arrhythmia Myocardial Infarction Amiodarone Trial,8 the mortality in patients with very poor ventricular function Basel Antiarrhythmia Study of Infarct Survival,6 and the (figure 2), which contrasted with the antiarrhythmic partially completed Polish Amiodarone Trial7 which advantages associated with amiodarone.
showed that an all-cause mortality reduction of 35–50% Many of the adverse side-effects associated with might be achieved with amiodarone. We also knew, at the amiodarone are sufficiently troublesome to force time when EMIAT was planned, that poor ventricular discontinuation of the drug.34 In our study clinically function was a more powerful predictor of mortality than relevant pulmonary,29 hepatic,35 and thyroid disorders36,37 was the frequency of ventricular ectopic activity. Two occurred in a small proportion of amiodarone-treated studies showed that patients with an LVEF below 40% patients, and were much as we had anticipated, for would have a 2-year mortality of 15%, of which the example, there was no torsade de pointes.38 However, arrhythmic component would be about half.13,14 However, many biochemical abnormalities and minor side-effects there were only limited and inconsistent data on the effect occurred, which accounted for the high rate of of amiodarone on the mortality of patients with poor left- discontinuation of study medication.
ventricular function. We, therefore, elected to recruit This high rate of discontinuation suggests that although patients on the basis of poor ventricular function alone the primary analysis should be by intention to treat, a and, assuming a 2-year mortality of 15% in the placebo second on-treatment (efficacy) analysis should also be group, designed the study to detect a 35% reduction in done. The effect of amiodarone continues after all-cause mortality in the amiodarone group. For the discontinuation of the drug. We, therefore, decided to conduct the on-treatment analysis by censoring patients (B Brechenmacher, J B Caillard), Tours (B Charbonnier, G Pacouret), from further analysis for 3 months after permanent early Vandoeuvre (B Brembilla Perrot, N Danchin); Germany: Berlin(D Andresen), Cottbus (U Kreutzer, J Kolditz), Düren (H Simon, discontinution of study medication. But these analyses B Zentgraf), Hamburg (T Meinertz, M Volkmer, K Kuck, M Antz), may be of limited value because such a large proportion of Hannover (H Klein, G Claus), Heidelberg (J Brachmann, K Freigang), patients (amiodarone 38·5%, placebo 21·4%) Lübeck (J Potratz, G Taubert), Magdeburg (H Klein, S Grund), Mainz(N Treese, A Liebrich), München (L Goedel-Meinen, M Hofmann, discontinued study medication. In any event, both F G Nowak, K Coppenrath), Münster (M Borggrefe, J Brunn); Greece: Athens (S Moulopoulos, A Antoniou), Pireus (D V Cikkinos, Analyses of the interaction between use of concomitant G Athanassopoulos); Italy: Bari (P Rizzon, M Di Biase), Bologna(D Bracchetti, F Naccarella, B Magnani, A Capucci), Mestre (E Piccolo, medications at baseline and the mortality endpoints A Raviele), Milano (A Lotto, A Finzi), Varese (G Binaghi, A M Giorgio); suggested that there was an important interaction with Netherlands: Amsterdam (A Vermeulen), Capelle Aan Den Yssel ␤-blockers. There were fewer cardiac deaths among (W M Muijs van der Moer, S L Nio), Deventer (D J A Lok,M J C Osinga-Meek), Dordrecht (J B L ten Kate), Dordrecht (P Breuls), amiodarone-treated patients who were receiving Heerlen (J A Kragten, J H M de Warrimont-Henquet), Rotterdam concomitant ␤-blockers than among those who were not, (D C A Von Hoogenhuyze), Tilburg (N J Holwerda); Norway: Bergen probably because ␤-blockers were not prescribed to (O Johm, K Breivik); Poland: Warsaw (L Ceremuzynski, T Chamiec); patients at high risk of cardiac death. However, of those Portugal: Coimbra ( LProvidência, G Alves), Lisboa (C Ribeiro,A Bordalo); Spain: Barcelona (J Cinca, A Moya, A Bayes de Luna, patients who receive ␤-blockers, there was a substantial X Viñolas), Madrid (C Moro Serrano, A Hernandez-Madrid), Valencia reduction in cardiac and arrhythmic mortality among (J Cosin, M J Sancho-Tello, A Salvador, M Amela); Sweden: Lund those who were also given amiodarone. This finding (B Olsson, E Pantev); Switzerland: Basel (F Burkart, M Pfisterer), Bern(M Gertsch, T Chatterjee); Geneva (W Rütishauser, M Zimmermann), indicates that ␤-blockers confer additional benefit to the Lausanne (L Kappenberger, M Framer), Sion (P Vogt, D Fellay), Zurich efficacy of amiodarone, a finding also reported for the (F W Amann, E Schuiki); UK: Derby (M W Millar-Craig, A V Joy), treatment of sustained ventricular tachyarrhythmias.39 We Glasgow (R J Northcote), Gwent (J Davies, W Covell), Kent (B Gould,A Brian), Isleworth (T W Greenwood, E Ramhamadany), Leicester did not anticipate this interaction before the start of the (J Skehan, Y Haider), London (A J Camm, H A Staunton, J Cleland, trial, and its implications must be interpreted with Steering Committee—D G Julian (chairman), A J Camm, G Frangin, Our findings do not support the systematic prophylactic M J Janse, A Munoz, P J Schwartz, P Simon.
use of amiodarone in patients with poor left-ventricular Safety Committee—L Wilhelmsen (chairman), J P Boissel, S Pocock, function after myocardial infarction, irrespective of the presence of symptomless ventricular ectopic activity.
Validation Committee—F Burkart (chairman), R W Campbell However, the 35% risk reduction of fatal and resuscitated (co-chairman), S Levy, N Rehnqvist, G Frangin (secretary non-voting).
arrhythmic events associated with amiodarone shows that this drug affords protection from arrhythmic death in this Ex ecutive Committee—H Klein (chairman), G Frangin (co-chairman), high-risk population. In addition, no proarrhythmia was associated with amiodarone treatment. Thus, it may be Electrocardiography Monitoring Committee—G Breithardt, R Brion, possible to identify groups of patients at high risk of arrhythmia for whom amiodarone will offer a substantial Ejection Fraction Committee—M M Pfisterer (chairman), D Dymond.
survival benefit. Since we found such a substantial Coordinating Centre—Sanofi Recherche, Montpellier, France: G Frangin antiarrhythmic effect, balanced by non-arrhythmic (study director), E Bienvenu (administration), C Dechamp (international mortality, it may also be possible to achieve a significant CRA), A d’Halliun-Sulzer (event monitoring), J Galleyrand (statistician),R Mercier (data manager), A Pelizza (international CRA).
reduction in all-cause mortality among infarct survivors athigh risk of sudden arrhythmic death with a different drug Independent Statistical Centre—J P Boissel, A Leizorovicz, F Boutitie.
regimen, such as a lower loading dose, and a shorter Holter Reading Centre—R Brion, G Gonnot, M Brion.
Decoding Centre—J Descotes, J M Sapori.
Our findings contrast with the disappointing results of Signal Average Electrocardiography Analysis—G Breithardt, T Fetsch.
most previous trials of antiarrhythmic drugs aftermyocardial infarction. Thus, the clinician may be Heart Rate Variability Analysis—A J Camm, M Malik.
encouraged to consider amiodarone for patients with Country Monitor Group—Clinical Research Unit Sanofi: M Brunet, I symptomatic or sustained and potentially dangerous Carbarns, K Handelberg, P Montanari, A Müller, G Munoz, N Nikkitas,L Orö, E Ribiero, I Tjong-A-Hung, F Wider; Clinical Research arrhythmias, even after myocardial infarction, Although subgroup analysis suggests that amiodarone Drug Supply—Sanofi Recherche, Montpellier, France.
may be useful in some patients, definitive indications willrequire further clinical trials. Our results must be interpreted together with those of other placebo- We thank the study patients for their cooperation; Genevieve Fauris,Heather Switzman, and the study personnel for their assistance; controlled amiodarone survival studies. Review of the Lars Wilhelmsen and Florent Boutitie for their expert help with the pooled data may suggest new or prophylactic indications preparation of the manuscript; Jacques Galleyrand for the statistical for the use of amiodarone, but such conclusions must analysis; and Caroline Smeeden for secretarial assistnce.
This study was supported by a grant from Sanofi Recherche, await formal meta-analysis or further clinical trials.
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