Comparison of dilated cardiomyopathy and coronary artery disease in patients with life-threatening ventricular arrhythmias: Differences in presentation and outcome in the AVID registry.

BACKGROUND: The etiology of structural heart disease in patients with life-threatening arrhythmias (ventricular tachycardia [VT]/ventricular fibrillation [VF]) may define clinical characteristics at presentation, may require that different therapies be administered, and may cause different mortality outcomes. METHODS: In the Antiarrhythmics Versus Implantable Defibrillators (AVID) registry, baseline clinical characteristics, treatments instituted, and ultimate mortality outcomes from the National Death Index were obtained on 3117 patients seen at participating institutions with VT/VF, irrespective of participation in the randomized trial. By use of these data, 2268 patients with coronary artery disease (CAD) were compared with 334 patients with dilated nonischemic cardiomyopathy (DCM). RESULTS: The CAD group was 7 years older and had a higher percentage of males. DCM patients were more likely to be African American, have severely compromised left ventricular function (52% vs 39%), and have a history of congestive heart failure symptoms (62% vs 44%). Patients with CAD were more likely to be treated with b-blockers and calcium channel blockers and less likely to be treated with angiotensin-converting enzyme inhibitors. Patients with DCM were more likely to be treated with diuretics, warfarin, and an implantable cardioverter defibrillator for VT/VF (54% vs 48% for CAD); the use of other antiarrhythmic therapies did not differ between the 2 groups. Two-year survival was not significantly different between the groups (76.6% [95% CI 74.6%-78.7%] vs 78.2% [95% CI 73.6%-82.9%]). CONCLUSIONS: In AVID registry patients with VT/VF, demographic and clinical characteristics were different between patients with CAD and those with DCM. Despite these differences, overall survival was similar in these 2 groups.

Relationship between rehospitalization and future death in patients treated for potentially lethal arrhythmia.

INTRODUCTION: It is generally considered that death is the only appropriate endpoint to evaluate interventions for preventing death; however, this belief may be based on the previous use of inappropriate or inadequate surrogates for death. The aim of this study was to evaluate whether rehospitalization following implementation of an intervention is a reasonable surrogate for death. METHODS AND RESULTS: The time from discharge following intervention to rehospitalization was evaluated for 997 patients discharged after baseline hospitalization in the Antiarrhythmics Versus Implantable Defibrillators Trial. The relationship between rehospitalization for various reasons and subsequent death was compared in the two treatment arms to assess the adequacy of rehospitalization as a surrogate for death. Included were rehospitalization for: any reason, a cardiac problem, a noncardiac problem, new or worsened congestive heart failure (CHF), an acute coronary syndrome, and a cardiac procedure. For all of the reasons except cardiac procedure, rehospitalization was associated with a substantially increased hazard for subsequent death. Rehospitalization for new or worsened CHF was most closely (that is, temporally) related to subsequent death and was the only reason for rehospitalization, which fully explained the treatment effect of implantable cardiac defibrillators compared with antiarrhythmic drugs on death. CONCLUSION: Rehospitalization is a significant risk factor for subsequent death. However, only rehospitalization for new or worsened CHF appears to be a potential surrogate for death in the setting of antiarrhythmic interventions.

Beta-blocker use and survival in patients with ventricular fibrillation or symptomatic ventricular tachycardia: the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial.

OBJECTIVES: To evaluate whether use of beta-adrenergic blocking agents, alone or in combination with specific antiarrhythmic therapy, is associated with improved survival in persons with ventricular fibrillation (VF) or symptomatic ventricular tachycardia (VT). BACKGROUND: The ability of beta-blockers to alter the mortality of patients with VF or VT receiving contemporary medical management is not well defined. METHODS: Survival of 1,016 randomized and 2,101 eligible, nonrandomized patients with VF or symptomatic VT followed in the Antiarrhythmics Versus Implantable Defibrillators (AVID) trial through December 31, 1996 was assessed using Cox proportional hazards analysis. RESULTS: The 817 (28%) patients discharged from hospital receiving beta-blockers had less ventricular dysfunction, fewer symptoms of heart failure and a different pattern of medication use compared with patients not receiving beta-blockers. Before adjustment for important prognostic variables, beta-blockade was not significantly associated with survival in randomized or in eligible, nonrandomized patients treated with specific antiarrhythmic therapy. After adjustment, beta-blockade remained unrelated to survival in randomized or in eligible, nonrandomized patients treated with amiodarone alone (n = 1142; adjusted relative risk [RR] = 0.96; 95% confidence interval [CI] 0.64-1.45; p = 0.85) or a defibrillator alone (n = 1347; adjusted RR = 0.88; 95% CI 0.55 to 1.40; p = 0.58). In contrast, beta-blockade was independently associated with improved survival in eligible, nonrandomized patients who were not treated with specific antiarrhythmic therapy (n = 412; adjusted RR = 0.47; 95% CI 0.25 to 0.88; p = 0.018). CONCLUSIONS: Beta-blocker use was independently associated with improved survival in patients with VF or symptomatic VT who were not treated with specific antiarrhythmic therapy, but a protective effect was not prominent in patients already receiving amiodarone or a defibrillator.

Predictive value for future arrhythmic events of fractal dimension, a measure of time clustering of ventricular premature complexes, after myocardial infarction. CAST Investigators. Cardia Arrhythmia Suppression Trial.

OBJECTIVES: Our objective was to test fractal dimension (D), a measure of clustering of ventricular premature complexes (VPCs), on entry Holter recording as a predictor of future arrhythmic death and other-cause mortality in postinfarction patients in the Cardiac Arrhythmic Suppression Trial (CAST). BACKGROUND: Nonlinear dynamic methods of signal processing are being applied in medicine to provide new insights into apparently "chaotic" biologic events, including cardiac arrhythmias. One such application is the derivation of a fractal D to describe the clustering of VPCs in time. METHODS: Baseline Holter recordings were analyzed in blinded manner for 484 patients: 237 died or had a resuscitated cardiac arrest during follow-up, and 247 matched patients had no events. Fractal D, measured in four ways, was assessed as a predictor using Cox regression. RESULTS: One measure of D (high resolution D) was a significant univariate (relative hazard ratio 0.79 per SD change, p = 0.011) and multivariate (hazard ratio 0.75, p = 0.046) predictor of arrhythmic death but not other death (univariate p = 0.95, relative hazard 0.95, p = 0.66). Fractal D was greater (VPCs less clustered) in those patients free of arrhythmic events. On subgroup analysis, the predictive value of D resided in the randomized patient group (i.e., those who showed VPC suppression during initial antiarrhythmic drug titration and were randomized to blinded therapy with active drug or placebo) (multivariate hazard ratio 0.57, p = 0.001). CONCLUSIONS: A high resolution fractal D was predictive of arrhythmic (but not nonarrhythmic) death in a large postinfarction cohort. Further study of this new signal processing approach to ambulatory electrocardiographic recording will be of interest.

Association between ease of suppression of ventricular arrhythmia and survival.

BACKGROUND: We tested the hypothesis that patients whose ventricular arrhythmias are easy to suppress have a lower rate of arrhythmic death, defined as arrhythmic death and nonfatal cardiac arrest, the primary end point in the Cardiac Arrhythmia Suppression Trials (CAST-I and CAST-II), than patients whose ventricular arrhythmias are hard to suppress. In addition, we evaluated the association between ease of suppression of ventricular arrhythmias and mortality of all causes. METHODS AND RESULTS: CAST-I investigated the effect on arrhythmic death of ventricular premature depolarization (VPD) suppression achieved by three drugs, encainide, flecainide, and moricizine, at two different dose levels; CAST-II investigated the same effect, using moricizine alone at three dose levels. If suppression was achieved, patients were randomized to the effective active drug or corresponding placebo. To examine the independence of easily suppressed ventricular arrhythmias as a predictor of arrhythmic death, we adjusted statistically for other variables that were related both to ease of suppression and arrhythmic death. Patients with ventricular arrhythmias (n = 1778) that were easy to suppress had fewer arrhythmic deaths during follow-up than those with ventricular arrhythmias that were hard to suppress (n = 1173) (relative risk, .59; P = .003). Patients whose VPDs were easily suppressed were older and had a lower frequency of prior history of heart failure and myocardial infarction. They also had a higher incidence of anterior myocardial infarction, VPD frequency, and average ejection fraction. After adjusting for these variables, we found that easily suppressed ventricular arrhythmias were still significant predictors of arrhythmic death (relative risk, .66; P = .013). CONCLUSIONS: This study shows that the ease of VPD suppression identifies a subgroup of postmyocardial infarction patients who have low risk of arrhythmic death.

Moricizine and quality of life in the Cardiac Arrhythmia Suppression Trial II (CAST II).

The Cardiac Arrhythmia Suppression Trial II (CAST II) was a double-masked placebo-controlled randomized trial that compared the survival effects of moricizine to placebo in postmyocardial infarction arrhythmia patients. The quality-of-life outcome measures were designed prospectively for CAST and were previously shown to have high reliability and clinical discriminative validity. The CAST quality-of-life instrument detected significant differences between moricizine and placebo. In particular, moricizine was most strongly associated with inferior social activity and satisfaction scores (p = .014) and lower scores for overall contentment with life (p = .007). Moreover, the quality-of-life measures improved significantly for both the moricizine and placebo treatment groups after entry into the clinical trial. These results indicate that the CAST quality-of-life instrument is sensitive for assessing pharmacological therapies in the treatment of heart disease.

Prognostic significance of signal-averaged electrocardiogram after thrombolytic therapy and/or angioplasty during acute myocardial infarction (CAST substudy). Cardiac Arrhythmia Suppression Trial (CAST) SAECG Substudy Investigators.

Thrombolytic therapy and angioplasty during the early phase of an acute myocardial infarction (AMI) have been shown to improve prognosis. Time-domain analysis of the signal-averaged electrocardiogram (SAECG) provides strong, independent prediction of arrhythmic events (arrhythmic death/resuscitated cardiac arrest) after AMI. To determine whether the prognostic significance of an abnormal SAECG (QRS duration > or = 120 ms) measured after AMI is influenced by thrombolytic therapy/angioplasty given in the AMI period, the predictive value of SAECG was compared in patients with and without prior thrombolysis/angioplasty in a substudy of the Cardiac Arrhythmia Suppression Trial. Information was available in 787 patients. The average follow-up was 10 +/- 3 months and arrhythmic events occurred in 33 patients (4.2%). The prevalence of abnormal SAECG in patients with and without thrombolytic therapy/angioplasty was 9.4% (34 of 363 patients) and 14.9% (63 of 424 patients), respectively (p < 0.02). The arrhythmic event rate for patients with abnormal SAECG with and without thrombolytic therapy/angioplasty was 20.6% (7 of 34 patients) and 20.6% (13 of 63 patients), respectively. The arrhythmic event rate for patients with normal SAECG with and without thrombolytic therapy/angioplasty was 0.9% (3 of 329 patients) and 2.8% (10 of 361 patients), respectively. It is concluded that in patients with an AMI (1) the use of thrombolytic therapy/angioplasty is associated with a significantly decreased prevalence of abnormal SAECG, (2) thrombolytic therapy/angioplasty associated with a normal SAECG portends an excellent prognosis, and (3) an abnormal SAECG is predictive of an increased incidence of arrhythmic events in all patients regardless of prior thrombolytic therapy/angioplasty.(ABSTRACT TRUNCATED AT 250 WORDS)

New insights into the definition and meaning of proarrhythmia during initiation of antiarrhythmic drug therapy from the Cardiac Arrhythmia Suppression Trial and its pilot study. The CAST and CAPS Investigators.

OBJECTIVES: This study was undertaken to determine the characteristics of worsening ventricular arrhythmia during antiarrhythmic drug titration. BACKGROUND: Proarrhythmia is an evolving concept in cardiology. Its definition, incidence and clinical significance in various patient settings require refinement. METHODS: The impact of early proarrhythmia was analyzed in 3,840 patients in the Cardiac Arrhythmia Suppression Trial (CAST). RESULTS: Drug therapy did not affect the incidence of new, sustained but nonfatal ventricular tachycardia (placebo 0.5%, active drug 0.4%). Nevertheless, there was a threefold increase in arrhythmic death (placebo 0.5% vs. active drug 1.6%). The incidence of increased ventricular premature depolarizations was equivalent (3% to 5%) for the three study drugs and indistinguishable from that seen with placebo. Patients with increased ventricular premature depolarizations on the first drug tested had fewer at baseline (65 +/- 94 vs. 137 +/- 260 per hour; mean +/- SD) (p < 0.01). When increased ventricular premature depolarizations occurred with the first drug, they were much more likely also to be present with the second drug (for example, 42% vs. 5%, p < 0.001). Increased ventricular premature depolarizations during initiation of therapy independently predicted increased risk of subsequent arrhythmic death (independent relative risk 2.34, p = 0.0053) in the absence of continued antiarrhythmic drug therapy. CONCLUSIONS: The overall incidence of early worsening of arrhythmia in the present study was low. In the absence of placebo control, the incidence of proarrhythmia will be overestimated. Increased ventricular premature depolarizations had characteristics that suggest they often represent spontaneous variability rather than proarrhythmia. The main finding is that markedly increased ventricular premature depolarizations during drug titration predict long-term increased risk of arrhythmic death in this patient population despite absence of long-term antiarrhythmic drug therapy.

Relation of baseline characteristics to suppression of ventricular arrhythmias during placebo and active antiarrhythmic therapy in patients after myocardial infarction.

In the Cardiac Arrhythmia Pilot Study (CAPS), patients early (6-60 days) after acute myocardial infarction (MI) with ventricular premature complexes (VPCs) of over 10 per hour were randomized to receive, unaware, therapy with one of four antiarrhythmic drugs (n = 402) or placebo (n = 100). Treatment success was defined as 70% or more decrease in VPC rate and 90% or more decrease in VPC runs. If the first active drug was ineffective, a second drug was given. If placebo was ineffective, a second placebo was given. To determine whether or not baseline clinical characteristics predict the response to antiarrhythmic therapy, 10 baseline variables were selected for investigation: age, prior MI, time from CAPS MI to randomization, ejection fraction, baseline VPC frequency, presence of runs (greater than or equal to 3 consecutive VPCs, greater than or equal to 100 beats/min), beta-blocker therapy, digitalis therapy, MI transmurality, and MI location. At the end of the first drug treatment, apparent treatment success in patients receiving placebo was associated on univariate analysis with absence of prior MI, with trends for younger age and Q wave MI, whereas in patients receiving active therapies, higher ejection fraction and younger age were associated with better suppression. In the encainide and flecainide treatments, where the greatest response was observed, absence of prior MI, higher ejection fraction, and younger age were associated with more successful treatment. In a multivariate analysis with these variables, ejection fraction and age remained significant for all active therapies, absence of prior MI and ejection fraction remained significant in the encainide and flecainide treatments, and absence of prior MI in the placebo treatment. Few variables except ejection fraction were associated with VPC suppression during the 1-year follow-up, and only lower ejection fraction and older age related to loss of long-term suppression. Thus, there are only a few independent baseline clinical variables (notably, ejection fraction) that substantially affect antiarrhythmic drug efficacy in suppressing VPCs in patients early after MI. Some variables, however, may be associated with spontaneous arrhythmia variability, leading to an apparent (placebo) response. These findings will be helpful in designing and interpreting treatment studies in patients after MI.