European Myocardial Infarct Amiodarone Trial Research Articles

Risk stratifiers for arrhythmic and non-arrhythmic mortality after acute myocardial infarction

The effective discrimination between patients at risk of Arrhythmic Mortality (AM) and Non-Arrhythmic Mortality (NAM) constitutes one of the important unmet clinical needs. Successful risk assessment based on Electrocardiography (ECG) records is greatly improved by the combination of different indices reflecting not only the pathological substrate but also the autonomic regulation of cardiac electrophysiology. This study assesses the cardiac risk stratification capacity of two new Heart Rate Variability (HRV) parameters, Breath Concurrence 6 (BC6) -sinusoidal RR variability of 6 heart beats per breath cycle- and Primary Ectopia (PE) -presence of early ventricular contractions of any etiology- together with the Deceleration Capacity (DC). While BC6 characterizes the response to physiological and pathophysiological stimuli, PE qualifies autonomic cardiac electrophysiology. The analysis of the European Myocardial Infarct Amiodarone Trial (EMIAT) database indicates that BC6 is related with the risk of Arrhythmic Mortality (AM) and PE with the risk of Non-Arrhythmic Mortality. BC6 is the only single parameter that significantly discriminates between AM and NAM. While the combination of BC6 and DC contributes to the identification of AM risk, PE together with DC improves the prediction of NAM in patients with severe ischemic heart disease.

Risk prediction by heart rate turbulence and deceleration capacity in postinfarction patients with preserved left ventricular function retrospective analysis of 4 independent trials

Background and aim In the Improved Stratification of Autonomic Regulation–Risk trial, postinfarction patients with severe autonomic failure (SAF)—defined as abnormal heart rate turbulence in the presence of abnormal deceleration capacity (DC)—were at high risk of subsequent death, even if left ventricular function was not particularly compromised. The aim of this study was to investigate SAF as a risk predictor in independent postinfarction cohorts. Methods and results The data of 3 postinfarction trials (ie, St George's Hospital Medical School Postinfarction Survey, Holter substudy of the European Myocardial Infarction Amiodarone Trial with both the placebo and the amiodarone arms, and Multiple Risk Factor Analysis Trial) were reanalyzed in a blinded fashion. The populations included a total of 2534 postinfarction patients. Heart rate turbulence and DC were obtained from 24-hour Holter recordings. Patients with both abnormal heart rate turbulence (slope ≤2.5 ms/R-R and onset ≥0%) and abnormal DC (≤4.5 milliseconds) were considered suffering from SAF and prospectively classified as high risk. Primary end point was all-cause mortality. During follow-up, 291 of 2534 patients died. In all populations, SAF was a highly significant predictor of death in the subgroups of patients with preserved left ventricular ejection fraction (LVEF; >30%). The mortality risk of these patients was not statistically different from that of patients with impaired LVEF (≤30%). The combined use of the criteria, LVEF of 30% or less and LVEF of more than 30% as well as SAF lead to a significant increase of sensitivity in all populations, whereas the positive predictive accuracies were preserved. Conclusion In postinfarction patients with preserved left ventricular function, SAF identifies a subgroup with increased mortality risk equivalent to patients with LVEF of 30% or less.

HRV Scaling Exponent Identifies Postinfarction Patients Who Might Benefit From Prophylactic Treatment With Amiodarone

Analysing the Holter recordings collected at baseline during the European Myocardial Infarction Amiodarone Trial (EMIAT), we evaluate the possibility of using alpha, the slope of the power spectrum of heart rate variability signals (HRV) in the vicinity of f = 0, for postinfarction risk stratification. We found no relevant difference in the values of alpha for the placebo population. On the contrary, in the amiodarone arm, the distinction in the survival rates of those with high or low alpha-values was highly significant. Moreover, high risk patients with respect to alpha (higher values) did not seem to benefit from amiodarone. The results suggest that alpha might convey physiologic information that is different than what is expressed by other HRV characteristics, such as the triangular index. When combining high risk patients in term of triangular index (<20) and low risk patients with respect to alpha (<median), the difference in survival on placebo and amiodarone became very substantial (24.2% mortality on placebo, 8.7% on amiodarone, p = 0.017). This might offer a possibility of selecting patients likely to benefit from a prophylactic antiarrhythmic treatment after acute myocardial infarction.

Turbulence dynamics: An independent predictor of late mortality after acute myocardial infarction

Introduction The prognostic value of heart rate turbulence for predicting mortality after acute myocardial infarction is well established. This study investigates a new measure of heart rate turbulence, termed turbulence dynamics, which quantifies the relationship between turbulence slope and underlying heart rate (HR VPC). Methods Six hundred eight patients participating in the European Myocardial Infarction Amiodarone Trial had ≥ 25 ventricular premature complexes/24 h. During a follow-up period of 21 months (median), 120 patients died. Turbulence dynamics was assessed as the slope of the regression line between turbulence slope and HR VPC. Survival analyses included age, history of previous myocardial infarction, presence of diabetes mellitus, mean normal-to-normal interval, heart rate variability index, presence of non-sustained ventricular tachycardia, left ventricular ejection fraction, turbulence onset and turbulence slope. All risk predictors were dichotomized at pre-defined cut-off points, turbulence dynamics was dichotomized at the median. Primary endpoint of the study was death of any cause. Results In most patients, turbulence slope was inversely correlated to HR VPC. Univariately, turbulence dynamics was the second strongest risk predictor of mortality (relative risk 2.4 (95% confidence interval 1.6–3.6), p < 0.001). Multivariately, turbulence dynamics was the third strongest risk predictor (1.7 (1.1–2.7, p < 0.01)). Conclusion In the patient population studied, turbulence dynamics was an independent predictor of mortality. The results indicate that in addition to the overall level of autonomic function the loss of autonomic adaptability contributes to prognosis.

Letter Regarding Article by Wichterle et al, “Prevalent Low-Frequency Oscillation of Heart Rate: Novel Predictor of Mortality After Myocardial Infarction”

To the Editor: Wichterle et al recently presented in this journal a novel parameter of heart rate variability called prevalent low-frequency oscillation of heart rate (PLF).1 Using 2 groups of postinfarction patients derived from the EMIAT (European Myocardial Infarction Amiodarone Trial) and ATRAMI (Autonomic Tone and Reflexes After Myocardial Infarction) studies, they specifically compared and showed a predictive value for PLF that was stronger than that for heart rate turbulence (HRT) parameters using univariate analysis. They further showed that with Cox’s multivariate regression model, the relative risk for PLF remained high (4.6 and 3.6 in EMIAT and ATRAMI, respectively), whereas HRT parameters turbulence slope and turbulence onset lost their independence. Their study is noteworthy because in previous comparisons of measures of HRT and heart rate variability in large studies, HRT has consistently outperformed heart rate variability.2–4 We would like to point out that the prognostic ability of risk factors is changing significantly with declining mortality from acute ischemic events as a …

Usefulness of ventricular repolarization dynamicity in predicting arrhythmic deaths in patients with ischemic cardiomyopathy (from the European Myocardial Infarct Amiodarone Trial)

The European Myocardial Infarct Amiodarone Trial (EMIAT) investigated the effects of amiodarone versus placebo in patients after myocardial infarction who had left ventricular ejection fraction </=40% and were </=75 years of age. The present substudy examined whether ventricular repolarization (VR) dynamicity could differentiate patients who died from cardiac death from their matched survivors in this EMIAT population. In addition, we assessed whether VR dynamicity could differentiate patients who died from arrhythmic cardiac death (ACD) and from non-ACD. VR dynamicity (determined from Holter's recordings at baseline) was compared before antiarrhythmic therapy in 118 patients who had cardiac death and 118 matched survivors according to age, gender, left ventricular ejection fraction, and subsequent administration or nonadministration of amiodarone. VR dynamicity was compared within the cardiac death group between the 59 patients who died from ACD and the 59 who died from non-ACD. VR dynamicity was expressed as the slope of the linear regression between QTo (measured automatically) and stable RR intervals. Patients who died were found to have a significant steeper rate dependence of QTo intervals during the 3 periods than their matched survivors. In multivariate analysis, the QTo/RR nocturnal interval appeared to be the best independent predictor of cardiac death. In addition, patients who died from ACD were found to have a significant steeper rate dependence of QTo intervals during the morning period than those who died from non-ACD. In the multivariate analysis, the QTo/RR morning interval remained the best independent predictor of ACD. Thus, in the EMIAT trial, evaluation of QT dynamicity is a strong predictor of cardiac death. In addition, QT dynamicity could predict the occurrence of ACD in cases of cardiac death.

Optimising the Use of ??-Adrenoceptor Antagonists in Coronary Artery Disease

beta-Adrenoceptor antagonists (beta-blockers) provide multiple benefits to patients with coronary artery disease. The 2001 American Heart Association and American College of Cardiology (AHA/ACC) guidelines for secondary prevention of myocardial infarction (MI) recommend initiating beta-adrenoceptor blockade in all post-MI patients and continuing therapy indefinitely. Atenolol and metoprolol have been shown to decrease vascular mortality in the acute-MI period. In the post-MI period timolol provided a 39% reduction in mortality in the Norwegian Multicenter Study group and propranolol was associated with a 26% reduction in mortality in BHAT (Beta-blocker Heart Attack Trial). beta-Adrenoceptor antagonist therapy results in reduction of myocardial oxygen demand and is therefore also effective for the treatment of angina pectoris. In CAST (Cardiac Arrhythmia Suppression Trial) beta-adrenoceptor antagonist therapy was associated with a significant reduction in arrhythmic death or cardiac arrest. In the post-MI amiodarone trials EMIAT (European Myocardial Infarct Amiodarone Trial) and CAMIAT (Canadian Amiodarone Myocardial Infarction Trial) there was a mortality benefit and decreased arrhythmic death in patients who received both amiodarone and beta-adrenoceptor antagonist therapy, compared with patients receiving amiodarone therapy alone. In the post-MI defibrillator (implantable cardioverter defibrillator [ICD]) trials, AVID (Antiarrhythmic Versus Implantable Defibrillator) and MUSTT (Multicenter Unsustained Tachycardia Trial), beta-adrenoceptor antagonist therapy was independently associated with improved overall survival. The exception was the ICD patients in MUSTT, and the benefit was attenuated in the amiodarone and ICD patients in AVID.AHA/ACC guidelines recommend the use of beta-adrenoceptor antagonists in all patients with symptomatic left ventricular dysfunction, based on several large, controlled heart failure trials. Extended-release metoprolol succinate reduced all-cause mortality by 34% in MERIT-HF (Metoprolol Controlled-Release/Extended-Release Randomized Intervention Trial in Heart Failure). Bisoprolol was associated with a 34% mortality benefit in CIBIS-II (Cardiac Insufficiency Bisoprolol Study II) and carvedilol was associated with a 35% mortality reduction in the COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival) trial. beta-Adrenoceptor antagonists reduce perioperative mortality in patients undergoing cardiac as well as non-cardiac surgery; however, they remain underutilised. Contraindications to beta-adrenoceptor antagonist therapy include severe bradycardia, high-grade atrioventricular block, marked sinus node dysfunction and acute exacerbations of heart failure. Many of the perceived adverse effects of beta-adrenoceptor antagonists have not been substantiated by large clinical trials.beta-Adrenoceptor antagonists differ with regard to receptor selectivity, receptor affinity, lipophilicity and intrinsic sympathomimetic activity. Beneficial properties of beta-adrenoceptor antagonists may not always be extrapolated as a class effect, and patient selection and drug preparations should follow trial guidelines. The beneficial effects of beta-adrenoceptor antagonists are clearly proven in cardiac patients and those at risk for cardiac disease. They are indicated for heart failure and proven beneficial in patients undergoing cardiac and non-cardiac surgery. These benefits appear to be consistent across most patient subgroups. beta-Adrenoceptor antagonists are generally well tolerated, yet significant morbidity and mortality result from their continued underutilisation.

Turbulence Slope After Atrial Premature Complexes Is an Independent Predictor of Mortality in Survivors of Acute Myocardial Infarction

Heart rate turbulence is a potent postinfarction risk predictor that originally was investigated when it was triggered by ventricular premature complexes. Similar heart rate response is present after atrial premature complexes. "Atrial" turbulence slope (TSA) moderately correlates with "ventricular" turbulence slope (TSV). This study investigated the value of TSA assessed in 24-hour Holter recordings for postinfarction risk stratification. Predictive power of TSA was investigated in the placebo arm of the European Myocardial Infarction Amiodarone Trial, which enrolled patients surviving acute myocardial infarction with left ventricular ejection fraction (LVEF) < or =40%. Of 633 patients with available 24-hour Holter recordings, 87 died during the follow-up period of 662 +/- 105 days. The same methodology was used to calculate TSA and TSV. TSA was significantly lower in nonsurvivors compared to survivors (2.0 +/- 2.7 vs 3.0 +/- 3.3 msec/RR, P = 0.014). TSA< or =0.8 msec/RR was associated with relative risk all-cause mortality of 2.5 (95% confidence interval 1.6-3.9, P = 0.000046). In a multivariate Cox regression model including age, LVEF, QRS duration, mean RR interval, heart rate variability index, presence of nonsustained ventricular tachycardia, and TSV, TSA remained a significant predictor of total mortality with relative risk of 2.0 (95% confidence interval 1.2-3.4, P = 0.014). TSA is a significant and independent predictor of all-cause mortality in postinfarction patients with left ventricular dysfunction.

Implantable defibrillators and sudden cardiac death.

Sudden cardiac death (SCD) is among the most common causes of death in developed countries throughout the world. It is estimated that more than 3 million people die yearly from SCD, with a survival rate of less than 1%. In the United States, the Center for Disease Control recently estimated an annual incidence of 450 000 sudden deaths,1 with a survival rate of approximately 5%, although this probably is an overestimation. Although there has been a reduction in total cardiac mortality from 728 115 in 1989 to 719 456 in 1999, the percentage of deaths that are sudden has actually increased from 38% to 47%. The increase was greatest in women older than 65 years of age, from 56.3% to 63.9%. This has resulted primarily from an increase in out-of-hospital sudden deaths. There is a comparable incidence of SCD and survival rate in Western Europe.2 The magnitude of this problem can be understood by noting that SCD accounts for more deaths each year than the total number of deaths from AIDS, breast cancer, lung cancer, and stroke (Figure 1). Unfortunately, it is the first presentation of cardiac disease in 33% to 50% of patients and is 3 times as common in men than in women. Figure 1. Magnitude of the problem of sudden cardiac arrest. Coronary artery disease, with or without myocardial infarction, is by far the most common underlying disease for SCD in the western world, being responsible for approximately 75% of all SCDs.3,4 Cardiomyopathies (dilated and hypertrophic) and primary electrical heart disease account for most of the remainder. The two most important risk factors for SCD (ie, those with highest predictive value) are left ventricular ejection fraction (LVEF) less than 40% and clinical congestive heart failure.3,4 These are followed by significant ventricular arrhythmias (particularly …

Implantable Cardioverter Defibrillator in Arrhythmogenic Right Ventricular Cardiomyopathies

In the present issue of Circulation , Wichter et al1 report the largest single-center experience demonstrating the benefit of implantable cardiac defibrillators (ICDs) in the treatment of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). The patients seem well defined, and they meet the task force criteria. In addition, 50 of 60 patients have had the diagnosis confirmed by endocardial biopsy. Advances in molecular biology and genetics, however, suggest that the term ARVC encompasses a large spectrum of diseases with similar clinical presentations and histological features. This was discussed in part in a previous editorial in Circulation .2 Recent information suggests that there is an overlap in the different forms of diseases included under the general term ARVC . See p 1503 The term right ventricular cardiomyopathy , which was introduced by the World Heart Federation and World Health Organization in 1996 in the new classification of cardiomyopathies, was selected to encompass arrhythmogenic right ventricular dysplasia (ARVD) and several other clinical entities, some of them known by a different name. In the classical article by Marcus et al,3 the term right ventricular dysplasia was taken from a book chapter on reentrant arrhythmias published in 1977.4 This work reported the results of antiarrhythmic surgery in young male patients with good left ventricular function who had ventricular tachycardia (VT) originating in the right ventricle. The term dysplasia was chosen because the right ventricle of 3 operated patients was covered by fat. The remaining myocardium was present only in the subendocardium. This striking feature, which suggested the replacement of myocardium by fat, was strengthened by microscopic examination that showed strands of cardiomyocytes bordered by or sometimes embedded in fibrosis or adipose tissue. It was suspected that myocardial replacement by fat and fibrous tissue started early in life, possibly in the …

Primary Prevention of Sudden Cardiac Death

The trouble with sudden cardiac death (SCD) is just that—it is sudden and individually unpredictable. Recent data from the Centers for Disease Control showed that SCD accounted for >460 000 deaths, or about 63% of deaths due to cardiac disease, in 1999.1 Typically, a cardiac arrest results from sustained ventricular tachycardia (VT) or ventricular fibrillation that progresses to death if effective resuscitative efforts are not started within several minutes of the arrest.2 It is not surprising that the overall survival rate of patients with out-of-hospital cardiac arrest in the United States is low, estimated to be <5%.3 Although more widespread use of automated external defibrillators could lead to a reduction in SCD,3 it is unrealistic to expect too much from this technology, especially because most cardiac arrests either are unwitnessed or occur in a location without ready access to an automated external defibrillator. The epidemic proportions of SCD have led to decades of research and randomized clinical trials designed to predict which individuals are at risk of SCD and to determine what methods prevent it. See p 1082 Coronary artery disease (CAD) causes ≈70% of SCD,1 and most clinical trials have evaluated this patient population. The emphasis of this Focused Perspective is on antiarrhythmic drug and device trials, but the reader should remember that selective use of β-adrenergic–blockers and angiotensin-converting enzyme inhibitors has reduced SCD.2,4,5 It has been known for decades that patients at highest risk for SCD after myocardial infarction (MI) have substantial left ventricular dysfunction, frequent premature ventricular complexes (PVCs) or nonsustained VT, or both conditions.2 Early efforts to prevent SCD employed the PVC suppression method. The Cardiac Arrhythmia Suppression Trial (CAST) was a randomized, placebo-controlled study that tested the hypothesis that PVC suppression after MI would reduce arrhythmic death.6 …

Depressed heart rate variability identifies postinfarction patients who might benefit from prophylactic treatment with amiodarone: A substudy of EMIAT (the European Myocardial Infarct Amiodarone Trial)

OBJECTIVESThis substudy tested a prospective hypothesis that European Myocardial Infarct Amiodarone Trial (EMIAT) patients with depressed heart rate variability (HRV) benefit from amiodarone treatment.BACKGROUNDThe EMIAT randomized 1,486 survivors of acute myocardial infarction (MI) aged ≤75 years with left ventricular ejection fraction (LVEF) ≤40% to amiodarone or placebo. Despite a reduction of arrhythmic mortality on amiodarone, all-cause mortality was not changed.METHODSHeart rate variability was assessed from prerandomization 24-h Holter tapes in 1,216 patients (606 on amiodarone). Two definitions of depressed HRV were used: standard deviation of normal to normal intervals (SDNN) ≤50 ms and HRV index ≤20 units. The survival of patients with depressed HRV was compared in the placebo and amiodarone arms. A retrospective analysis investigated the prospective dichotomy limits. All tests were repeated in five subpopulations: patients with first MI, patients on beta-adrenergic blocking agents, patients with LVEF ≤30%, patients with Holter arrhythmia and patients with baseline heart rate ≥75 beats/min.RESULTSCentralized Holter processing produced artificially high SDNN but accurate HRV index values. Heart rate variability index was ≤20 U in 363 (29.9%) patients (183 on amiodarone) with all-cause mortality 22.8% on placebo and 17.5% on amiodarone (23.2% reduction, p = 0.24) and cardiac arrhythmic mortality 12.8% on placebo and 4.4% on amiodarone (66% reduction, p = 0.0054). Among patients with prospectively defined depressed HRV, the largest reduction of all-cause mortality was in patients with first MI (placebo 17.9%, amiodarone 10.3%, 42.5% reduction, p = 0.079) and in patients with heart rate ≥75 beats/min (placebo 29.0%, amiodarone 19.3%, 33.7% reduction, p = 0.075). Among patients with first MI and depressed HRV, amiodarone treatment was an independent predictor of survival in a multivariate Cox analysis. The retrospective analysis found a larger reduction of mortality on amiodarone in 313 (25.7%) patients with HRV index ≤19 U: 23.9% on placebo and 17.1% on amiodarone (28.4% reduction, p = 0.15). This was more expressed in patients with first MI: 49.4% mortality reduction on amiodarone (p = 0.046), on beta-blockers: 69.0% reduction (p = 0.047) and with heart rate ≥75 beats/min: 37.9% reduction (p = 0.054).CONCLUSIONMeasurement of HRV in a large set of centrally processed Holter recordings is feasible with robust methods of assessment. Patients with LVEF ≤40% and depressed HRV benefit from prophylactic antiarrhythmic treatment with amiodarone. However, this finding needs confirmation in an independent data set before clinical practice is changed.

Arrhythmic risk stratification of post-myocardial infarction patients.

Post-myocardial infarction risk stratification, especially arrhythmic risk stratification, is an issue that has still not been wholly addressed in modern clinical cardiology. In the past 10 years, arrhythmic risk stratification has been approached mainly by evaluating frequency and complexity of premature ventricular contractions, detected on Holter monitoring, often in association with determination of percent ejection fraction. This methodology has been proven to be limited and fallacious according to the Cardiac Arrhythmia Suppression Trial I and II (CAST I,II) results, in which suppression of premature ventricular contractions or premature ventricular beats throughout by antiarrhythmic drugs resulted in an increase in both cardiac and arrhythmic mortality. Only amiodarone as an antiarrhythmic drug, as proven in the recent European Myocardial Infarct Amiodarone Trial (EMIAT) and Canadian Amiodarone Myocardial Infarction Trial (CAMIAT), was effective in reducing arrhythmic mortality without affecting cardiac mortality, in patients selected mainly because of a reduced ejection fraction, with and without premature ventricular contractions. Conversely, it is well known that beta-blockers are effective in preventing sudden death in post-acute myocardial infarction (AMI) patients, thus reducing cardiac and arrhythmic mortality. Conversely, in other institutions, risk stratification in post-AMI patients has been performed by electrophysiologic study obtained, without any previous noninvasive arrhythmic risk stratification, in all post-AMI patients. In recent years, many other noninvasive electrocardiology parameters, such as late potentials (signal-averaged electrocardiography), heart rate variability, baroreflex sensitivity, and, more recently, T-wave alternance, have been shown to be useful, but they are associated with a low specificity in the noninvasive identification of patients at high risk for arrhythmic mortality. Conversely, in the Multicenter Automatic Defibrillation Implantation Trial (MADIT), electrophysiology confirmed that inducibility of ventricular tachycardia shows high specificity and a high predictive value for arrhythmic events. Nevertheless, the MADIT study population is not comparable to a cohort of consecutive patients who have recently had a myocardial infarction. In this setting, the highest risk of arrhythmic events can be observed in patients with depressed percent ejection fraction (< 35%) and in the first 6 months after AMI. Today, the most convincing approach seems to be the one combining both noninvasive risk stratification parameters (e.g., premature ventricular beats > 10/h or reduced heart rate variability < 70 ms or a positive signal-averaged electrocardiogram) followed by a further arrhythmic risk stratification, obtained through electrophysiologic study. Several published and ongoing trials that utilize various arrhythmic risk stratification techniques as part of their protocol are reviewed.

Amiodarone: clinical trials.

Amiodarone is an antiarrhythmic agent commonly used in the treatment of supraventricular and ventricular tachyarrhythmias. This article reviews the results and clinical implications of primary and secondary prevention trials in which amiodarone was used in one of the treatment arms. Key post-myocardial infarction primary prevention trials include the European Myocardial Infarct Amiodarone Trial (EMIAT) and the Canadian Amiodarone Myocardial Infarction Trial (CAMIAT), both of which demonstrated that amiodarone reduced arrhythmic but not overall mortality. In congestive heart failure patients, amiodarone was studied as a primary prevention strategy in two pivotal trials: Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiac en Argentina (GESICA) and Amiodarone in Patients With Congestive Heart Failure and Asymptomatic Ventricular Arrhythmia (CHF-STAT). Amiodarone was associated with a neutral overall survival and a trend toward improved survival in nonischemic cardiomyopathy patients in CHF/STAT and improved survival in GESICA. In post-myocardial infarction patients with nonsustained ventricular tachycardia and a depressed ejection fraction, the Multicenter Automatic Defibrillator Implantation Trial (MADIT) demonstrated that implantable cardioverter-defibrillators (ICD) statistically improved survival compared to the antiarrhythmic drug arm, most of whose patients were taking amiodarone. In patients with histories of sustained ventricular tachycardia or ventricular fibrillation, the Cardiac Arrest Study in Seattle: Conventional Versus Amiodarone Drug Evaluation (CASCADE) trial demonstrated that empiric amiodarone lowered arrhythmic recurrence rates compared to other drugs guided by serial Holter or electrophysiologic studies. However, arrhythmic death rates were high in both treatment arms of the study. Several secondary prevention trials, including the Antiarrhythmics Versus Implantable Defibrillators Study (AVID), the Canadian Implantable Defibrillator Study (CIDS), and the Cardiac Arrest Study Hamburg (CASH), have demonstrated the superiority of ICD therapy compared to empiric amiodarone in improving overall survival. Based on the above findings, amiodarone is safe to use in post-myocardial infarction and congestive heart failure patients that need antiarrhythmic therapy. Although amiodarone is effective in treating malignant arrhythmias, high-risk patients should be considered for an ICD as frontline therapy.

Lessons from antiarrhythmic trials involving class III antiarrhythmic drugs

Beta-adrenergic blockers reduce mortality and sudden death in patients convalescing from myocardial infarction, and probably in patients with heart failure. However, the notion that class I antiarrhythmic drugs might save lives by suppressing the triggers of life-threatening ventricular arrhythmias was proved incorrect when the Cardiac Arrhythmia Suppression Trial (CAST) demonstrated that patients, whose ventricular ectopics were successfully suppressed by a number of class I antiarrhythmic drugs, died more readily than similar patients when treated with drugs rather than the placebo. Attention was diverted to class III antiarrhythmic drugs for patients with a poor ejection fraction who survived myocardial infarction and those with heart failure. A preliminary metaanalysis of 3 trials (Basel Antiarrhythmic Study of Infarct Survival [BASIS], Polish Amiodarone Trial [PAT], and the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial [CAMIAT]) suggested that amiodarone might reduce arrhythmic and all-cause mortality in high-risk post–myocardial-infarction (MI) patients. BASIS suggested that this was only true for patients with preserved ventricular function. Nevertheless, 2 major trials were instituted: the European Myocardial Infarct Amiodarone Trial (EMIAT) and the CAMIAT. Both reported similar results except that patients recruited because of high-density ventricular ectopy seemed to benefit a little more from amiodarone than did patients with poor ventricular function. Detailed analysis of these trials revealed important insights into the value of amiodarone.

Angina and its treatment.

Angina and its treatment.

The Azimilide Post-Infarct Survival Evaluation (ALIVE) Trial

The AzimiLide post-Infarct surVival Evaluation (ALIVE) trial is a new clinical trial using an innovative design to examine the potential of azimilide, a novel type of antiarrhythmic, for improving survival in post myocardial infarction (MI) patients at high risk of sudden cardiac death. Azimilide is the first of a unique class of antiarrhythmic drugs that blocks both slow and rapid components of the delayed rectifier potassium currents in human myocardium. Preclinical studies have shown the drug to be effective in reducing cardiac tachyarrhythmias, even under ischemic conditions. Currently, azimilide is in Phase III trials for the treatment of supraventricular arrhythmias. The ALIVE study design is based on lessons learned from the Cardiac Arrhythmia Suppression Trials (CAST), the Survival With Oral d-Sotalol (SWORD) trial, and the European Myocardial Infarction Amiodarone Trial (EMIAT) and identifies recent post-MI patients at high risk of sudden cardiac death. The hypothesis underlying this trial is that azimilide will improve survival in this patient population. The ALIVE trial is designed as a double-blind, placebo-controlled, multinational trial that will overcome the shortcomings of previous antiarrhythmic trials by using left ventricular ejection fraction and heart rate variability as predictors to target a post-MI patient population at high risk of sudden death. The major inclusion criteria for the study are adult patients of either gender with a left ventricular ejection fraction of 15–35% who have had a recent MI (within 6–21 days). Additional stratification will be based on patients with heart rate variability ≤20 U (heart rate variability index). Exclusion criteria include factors that may predispose a patient to nonarrhythmia-induced death or to low risk of sudden cardiac death caused by arrhythmia. Sample size is based on the assumption that the all-cause mortality rate (the primary endpoint) for 1 year in placebo patients at high risk for sudden cardiac death (heart rate variability ≤20 U) is 15% and that azimilide will decrease all-cause mortality by at least 45% in these patients. The trial consists of 3 groups—patients receiving 75 mg azimilide orally each day, patients receiving 100 mg azimilide orally each day, and patients receiving placebo. No dose adjustments for age, gender, renal or hepatic failure, or concomitant use of warfarin or digoxin are thought necessary with azimilide. Enrollment for the trial is expected to continue for 24 months, and treatment is scheduled to be administered for a 1-year follow-up period.

Identification of post acute myocardial infarction patients with potential benefit from prophylactic treatment with amiodarone. A substudy of EMIAT (the European Myocardial Infarct Amiodarone Trial).

To perform a retrospective analysis of subgroups of patients enrolled into the European Myocardial Infarct Amiodarone Trial (EMIAT) in order to identify patients who might benefit from prophylactic amiodarone treatment and patients in whom amiodarone might be harmful. Baseline characteristics of the 1486 patients enrolled in EMIAT were used to investigate the all-cause mortality effect of amiodarone (intention-to-treat) in patients with a left ventricular ejection fraction 30-40% and < 30%, in patients with and without arrhythmia signs on Holter recordings, in patients with high and low baseline resting heart rate, in patients on and off beta-blocker treatment, and in a combination of these groups. A univariate analysis suggested that all-cause mortality is reduced on amiodarone in patients with an ejection fraction < 30%, with arrhythmia on the initial Holter, on beta-blocker treatment, and with an increased initial heart rate. A trend towards an increase of all-cause mortality was noted in patients with an ejection fraction 30-40%, without arrhythmia on Holter, off beta-blockers, and with a low baseline heart rate. A multivariate analysis suggested that the univariate observations are mutually additive. The study might serve as a basis for future prospective trials where amiodarone could be tested in patients with a recent myocardial infarction, having a reduced left ventricular ejection fraction, a high initial heart rate, and taking beta-blockers.

Clinical Implications of the European Myocardial Infarct Amiodarone Trial (EMIAT)

Clinical Implications of the European Myocardial Infarct Amiodarone Trial (EMIAT)

Amiodarone reduced arrhythmic death but not cardiac death in patients with MI and depressed left ventricular function

Source Citation Julian DG, Camm AJ, Frangin G, et al., for the European Myocardial Infarct Amiodarone Trial Investigators. Randomised trial of effect of amiodarone on mortality in patients with lef...