Author + information
- Received October 23, 1998
- Revision received January 22, 1999
- Accepted February 12, 1999
- Published online October 1, 1999.
- Michael J Domanski, MD, FACC∗,*,
- Sanjeev Sakseena, MD, FACC, FESC†,1,
- Andrew E Epstein, MD, FACC‡,
- Alfred P Hallstrom, PhD‡,
- Michael A Brodsky, MD, FACC∥,
- Soo Kim, MD, FACC∗,
- Scott Lancaster, MS§,
- Eleanor Schron, RN, MS∗,
- for the AVID Investigators
- ↵*Reprint requests and correspondence: Dr. Michael J. Domanski, National Heart, Lung, and Blood Institute, 6701 Rockledge Drive, Room 8146, Bethesda, Maryland 20892-79936
We sought to assess the effect of baseline ejection fraction on survival difference between patients with life-threatening ventricular arrhythmias who were treated with an antiarrhythmic drug (AAD) or implantable cardioverter-defibrillator (ICD).
The Antiarrhythmics Versus Implantable Defibrillators (AVID) study demonstrated improved survival in patients with ventricular fibrillation or ventricular tachycardia with a left ventricular ejection fraction (LVEF) ≤0.40 or hemodynamic compromise.
Survival differences between AAD-treated and ICD-treated patients entered into the AVID study (patients presenting with sustained ventricular arrhythmia associated with an LVEF ≤0.40 or hemodynamic compromise) were compared at different levels of ejection fraction.
In patients with an LVEF ≥0.35, there was no difference in survival between AAD-treated and ICD-treated patients. A test for interaction was not significant, but had low power to detect an interaction. For patients with an LVEF 0.20 to 0.34, there was a significantly improved survival with ICD as compared with AAD therapy. In the smaller subgroup with an LVEF <0.20, the same magnitude of survival difference was seen as that in the 0.20 to 0.34 LVEF subgroup, but the difference did not reach statistical significance.
These data suggest that patients with relatively well-preserved LVEF (≥0.35) may not have better survival when treated with the ICD as compared with AADs. At a lower LVEF, the ICD appears to offer improved survival as compared with AADs. Prospective studies with larger patient numbers are needed to assess the effect of relatively well-preserved ejection fraction (≥0.35) on the relative treatment effect of AADs and the ICDs.
Patients surviving life-threatening ventricular tachyarrhythmias are at high risk for a fatal recurrent arrhythmia (1,2). The Antiarrhythmics Versus Implantable Defibrillators (AVID) study showed that treatment with an implantable cardioverter-defibrillator (ICD) is more effective in preventing death in these patients than empiric antiarrhythmic drug (AAD) therapy (almost all drug-treated patients in AVID received amiodarone) (3).
Although the results of AVID apply, in principle, to the entire trial population, there was a substantial variation in the left ventricular function of these patients. Specifically, the difference in treatment effect might be less in patients with a lower ejection fraction. Although mortality generally increases with increasing New York Heart Association (NYHA) functional class, the proportion of deaths that are sudden declines from 50% to 80% in functional class II to 5% to 30% in functional class IV (4). In other words, the “sicker” patients are more likely to die of progressive heart failure rather than suddenly, presumably due to a fatal arrhythmia. Because the competing risks for mechanism of death have different likelihoods of occurring depending on heart failure severity, we reasoned that the relative effectiveness of the ICD and AAD might be different in patients with different left ventricular ejection fractions (LVEFs). Observational studies have suggested that the efficacy of amiodarone may vary with the extent of left ventricular dysfunction (5).
The purposes of this study were 1) to examine the effect of LVEF at randomization on the survival difference between patients treated with AAD and ICD therapy; and 2) to present survival data on patients with a spectrum of left ventricular function after a sustained ventricular tachyarrhythmia who are treated with an AAD (essentially amiodarone) or the ICD for use in planning future intervention trials.
The AVID study was a multicenter, randomized comparison of two treatment strategies for patients who had survived a life-threatening sustained ventricular tachyarrhythmia. The study design and results have been presented elsewhere (3,6). Briefly, patients resuscitated from ventricular fibrillation (VF), sustained ventricular tachycardia (VT) with syncope or sustained VT with an LVEF ≤0.40 and symptoms suggesting severe hemodynamic compromise due to the arrhythmia (near-syncope, congestive heart failure and angina) were randomized to receive an ICD or pharmacologic therapy. The primary end point was mortality from any cause.
The relative effects of ICD and AAD therapy to prevent death were evaluated for prospectively defined subgroups of LVEF ≥0.35 and <0.35. The test for an interaction between treatments in these two subgroups was not significant, although the point estimate of the hazard ratio in the higher LVEF group was closer to 1 as compared with the study-wide hazard ratio of 0.62 (3). The confidence interval for the point estimate in the higher ejection fraction group does not permit distinction between chance fluctuation and low power. We speculated that a LVEF of 0.35 might not be low enough to select a group with substantial competing causes of death. The patients were subgrouped post hoc according to whether the LVEF was <0.20, 0.20 to 0.34 or >0.34. Within each subgroup, survival functions were estimated by the methods of Kaplan-Meier and compared between drug and device by the log-rank statistic. A simple proportional hazards regression model (Cox) involving only the left ventricular subgroup category and treatment arm was used to test for an interaction between the LVEF level and treatment. The LVEF subgrouping was treated as a categoric variable rather than an ordered variable because the published data suggested that the relative benefit of the ICD would be diminished in the very low ejection fraction group and the previously described analysis suggested that the effect was diminished in the high LVEF subgroup. To improve the efficiency of the test, comparisons were made within the ejection fraction strata, adjusting for baseline factors known to be related to survival. These include age, index arrhythmia, gender, NYHA functional class, history of diabetes, history of myocardial infarction, coronary artery disease and therapy at discharge with beta-adrenergic blocking agents or an angiotensin-converting enzyme (ACE) inhibitor.
Baseline characteristics of study group
Baseline characteristics of the study group are shown in Table 1, grouped according to LVEF (Group 1 <0.20; Group 2 0.20 to 0.34; Group 3 >0.34). Significant relations (p ≤ 0.05) were found between ejection fraction and histories of myocardial infarction and congestive heart failure, and ejection fraction at hospital discharge (Table 2)when coronary artery bypass graft surgery, amiodarone, beta-blockers, calcium blockers, digitalis or ACE inhibitors had been used. There was no relation between LVEF and a history of VT or VF.
Adverse cardiovascular outcomes
Most patients assigned to AAD treatment received amiodarone (97%). Crossover rates were modest (18% at two years) in both arms of group 3 and increased to 24% and 31% for the middle and lowest LVEF groups, respectively (Table 3). Overall, survival at one and two years was 89.3 ± 2.9% and 81.6 ± 4.1%, respectively, in the ICD-treated patients, and 82.3 ± 3.5% and 74.7 ± 4.4% in AAD-treated patients. For patients with an LVEF <0.20, the survival rate was 82.4 ± 10.4% and 71.6 ± 14.6% at one and two years in the ICD-treated patients, respectively, and 73.0 ± 10.0% and 63.8 ± 11.6% in the AAD-treated patients (Fig. 1). In patients with an LVEF between 0.20 and 0.34, the overall survival rate was 89.2 ± 4.1% and 82.5 ± 5.7% at one and two years, respectively, in the ICD-treated patients and 79.8 ± 5.5% and 71.8 ± 6.7% in the AAD-treated patients. In patients with an LVEF >0.34, there was no difference in survival between AAD-treated and ICD-treated patients. The formal test for an interaction did not reach statistical significance, but the test had low power. For patients with an LVEF between 0.20 and 0.34, there was a significantly improved survival with ICD as compared with AAD therapy (p < 0.05). In the smaller subgroup with an LVEF <0.20, the same magnitude of survival difference was seen as in the 0.20 to 0.34 LVEF group, but the difference did not reach statistical significance.
The survival differences in each of the left ventricular function strata were relatively unchanged when adjusted for the covariates listed already, including the use of beta-blockers. The relative hazard estimates (and associated p values) for AAD as compared with ICD therapy obtained from the proportional hazard model were 1.70 (p = 0.13), 1.46 (p = 0.08) and 1.21 (p = 0.52) for the lower, intermediate and higher LVEF groups, respectively, after adjustment for other clinical characteristics, including history of atrial fibrillation, which, in the LVEF <0.20 group, was greater in the AAD-treated patients.
In the AVID trial, treatment with an ICD was found to result in improved survival as compared with treatment with an AAD. The present study suggests that the difference may be modulated by the degree of left ventricular dysfunction. Patients with moderate to severe left ventricular dysfunction (group 2) appeared to have improved survival with ICD as compared with AAD therapy. The magnitude of the difference persisted in group 1 (patients with profoundly depressed ejection fraction), although statistical significance was not reached, probably because of the small number of patients (n = 140). For patients with relatively well-preserved left ventricular function (LVEF ≥0.35), the data suggest that survival of ICD-treated patients is no better than that of AAD-treated patients.
The reason for the absence of improved survival in ICD-treated as compared with AAD-treated patients with higher ejection fractions and the presence of improved survival in the ICD-treated patients with low and very low ejection fractions cannot be explained with certainty. Given the wide confidence intervals, the simple play of chance cannot be excluded. However, a weak protective effect of amiodarone in preventing arrhythmic death has been demonstrated in patients who have had a myocardial infarction (7,8), and observational studies suggest that the benefit of AAD therapy may be greater in patients with a higher LVEF (5), whereas the ICD is highly effective in converting malignant ventricular arrhythmias regardless of ejection fraction. It is possible that in ventricles with better left ventricular function, amiodarone is relatively more effective in preventing malignant ventricular arrhythmias than in the “sicker” ventricles of patients with moderately and severely reduced ejection fraction. If this were the case, amiodarone in the group 3 patients may have reduced the mortality and done so with enough effectiveness to reduce the mortality differences between the treatment modalities. That this may, indeed, be the case is supported by evidence from several studies. Goldstein et al. (9)studied post–myocardial infarction patients followed in the Cardiac Arrhythmia Suppression Trial (CAST). These investigators showed that the ease of suppressing ventricular ectopy correlated with improved survival. Spielman et al. (10)studied predictors of success in suppressing recurrent sustained VT in 84 patients with this arrhythmia. They found that higher ejection fraction and the absence of aneurysm and hypokinesia correlated with suppressibility. Meissner et al. (11)studied the relation between ejection fraction and antiarrhythmic drug efficacy in suppressing inducibility at electrophysiologic study of VT in 201 patients with a history of VT or VF. In this study, ejection fraction was the only factor that correlated significantly with drug success or failure in suppressing inducibility. High crossover rates can obscure differences. However, crossover rates were low in group 3, where no difference was observed, and higher in groups 1 and 2, where differences were observed. Also, patients with a better LVEF may die of causes not correctable with an ICD.
Patients resuscitated from a life-threatening ventricular tachyarrhythmia have a particularly poor long-term prognosis (12). Also, LVEF is a strong prognostic indicator for survival (12). Apart from beta-blockers, aspirin and perhaps ACE inhibitors, only two modalities—amiodarone and the ICD—have been demonstrated to have efficacy in the prevention of arrhythmic death. The data presented here provide information on the survival of patients presenting with ventricular tachyarrhythmias and varying degrees of left ventricular dysfunction who are treated with either an AAD or ICD. The data presented involve patients from the current era who were treated with conventional ancillary therapy. The two-year survival rate for these contemporary ICD recipients was 83% in group 3, 83% in group 2 and 72% in group 1. For contemporary AAD-treated patients, the two-year survival was 83% in group 3, 72% in group 2 and 64% in group 1. These data should prove useful in designing future clinical trials, particularly in sample size calculations.
Comparison to previous studies
The survival rate of patients in AVID is comparable to that observed in a number of other studies that have been published during the last five years. Fogoros et al. (13)reported a two-year survival rate of 76% in ICD-treated patients who had drug-refractory VT or VF and an LVEF <0.30. Powell et al. (14)reported a two-year survival rate of ∼86% in post–cardiac arrest ICD-treated patients. Wever et al. (15)reported 29 patients with a mean LVEF of 0.30 who had ICD placement after cardiac arrest. The survival rate at a median follow up of two years was 86%. In the Cardiac Arrest Study Hamburg (16), post–cardiac arrest patients randomized to receive amiodarone who had an LVEF <0.25 had a 60% two-year survival rate, which is similar to the findings in AVID. In the Cardiac Arrest in Seattle: Conventional vs Amiodarone Drug Evaluation (CASCADE) study (17), post–cardiac arrest patients randomized to receive amiodarone with an LVEF <0.30 had a two-year survival rate of 60%, which is comparable to the AVID results for patients with an LVEF <0.20. For the CASCADE patients, the survival rate of patients with an LVEF 0.25 to 0.34 was 74%, almost precisely the same as the 72% survival rate reported for AVID patients with similar left ventricular function (17).
Comparison with other recent studies suggests that the mortality rates for AVID patients undergoing treatment in the current era are similar to those for patients in studies reported during the last five years. These data also emphasize the importance of considering ejection fraction in planning clinical trials of patients similar to those in the AVID population.
This study was a retrospective subgroup analysis. Furthermore, the relatively small numbers of patients at risk after two years limit the value of comparison beyond two years. Also, the test of an interaction between ejection fraction and mortality did not reach statistical significance. However, the power of the test to detect an interaction was limited.
The overall AVID trial demonstrated improved survival of ICD-treated as compared with AAD-treated patients after resuscitation from a sustained ventricular tachyarrhythmia. These subgroup data suggest that the benefit of ICD over AAD occurred mainly in patients with a moderately severe reduction in left ventricular function (LVEF 0.20 to 0.35) who survive a sustained, life-threatening ventricular tachyarrhythmia. This recommendation should also be made for patients with profound left ventricular dysfunction (LVEF <0.20). The results raise the question of whether AADs may result in similar survival outcome as with ICD treatment in patients with relatively well-preserved left ventricular function. Only a suitably powered, randomized trial can answer this question.
These data suggest that patients with relatively well-preserved LVEF (≥0.35) may not have better survival when treated with an ICD as compared with an AAD. At lower LVEFs, the ICD appears to offer improved survival as compared with AAD. Prospective studies with larger patient numbers are needed to assess the effect of relatively well-preserved ejection fraction (≥0.35) on the relative treatment effect of AAD and ICD.
↵1 Dr. Sakseena is or has been a consultant and/or investigator for Medtronic, Inc. (Minneapolis, Minnesota), Cardiac Pacemakers, Inc. (St. Paul, Minnesota), Intermedics, Inc. (Angleton, Texas) and Angetion, Inc. (Minneapolis, Minnesota).
- antiarrhythmic drug
- angiotensin converting enzyme
- Antiarrhythmics Versus Implantable Defibrillators study
- implantable cardioverter-defibrillator
- left ventricular ejection fraction
- New York Heart Association
- ventricular fibrillation
- ventricular tachycardia
- Received October 23, 1998.
- Revision received January 22, 1999.
- Accepted February 12, 1999.
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