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.     

Analysis of implantable cardioverter defibrillator therapy in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial

INTRODUCTION: The implantable cardioverter defibrillator (ICD) is commonly used to treat patients with documented sustained ventricular tachycardia (VT) or ventricular fibrillation (VF). Arrhythmia recurrence rates in these patients are high, but which patients will receive a therapy and the forms of arrhythmia recurrence (VT or VF) are poorly understood. METHODS AND RESULTS: The therapy delivered by the ICD was examined in 449 patients randomized to ICD therapy in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Trial. Events triggering ICD shocks or antitachycardia pacing (ATP) were reviewed for arrhythmia diagnosis, clinical symptoms, activity at the onset of the arrhythmia, and appropriateness and results of therapy. Both shock and ATP therapies were frequent by 2 years, with 68% of patients receiving some therapy or having an arrhythmic death. An appropriate shock was delivered in 53% of patients, and ATP was delivered in 68% of patients who had ATP activated. The first arrhythmia treated in follow-up was diagnosed as VT (63%), VF (13%), supraventricular tachycardia (18%), unknown arrhythmia (3%), or due to ICD malfunction or inappropriate sensing (3%). Acceleration of an arrhythmia by the ICD occurred in 8% of patients who received any therapy. No physical activity consistently preceded arrhythmias, nor did any single clinical factor predict the symptoms of the arrhythmia. CONCLUSION: Delivery of ICD therapy in AVID patients was common, primarily due to VT. Inappropriate ICD therapy occurred frequently. Use of ICD therapy as a surrogate endpoint for death in clinical trials should be avoided.     

Seasonal variation of mortality in the Antiarrhythmics Versus Implantable Defibrillators (AVID) study registry.

OBJECTIVES: We postulated that the pattern of death would be nonrandom with respect to temporal variables. BACKGROUND: Previous studies have demonstrated increased sudden death is associated with periods of relative stress, and overall mortality is associated with temporal variables. METHODS: In the Antiarrhythmics Versus Implantable Defibrillators (AVID) registry, vital status was obtained for 4,450 patients (who had a recent episode of sustained ventricular arrhythmias or unexplained syncope and inducible ventricular tachycardia) through the National Death Index Service as of December 31, 1997 (follow-up 25.5 +/- 13.7 months). RESULTS: Mortality was not associated with the day of the week or with holidays but was associated with season (P = .033). Seasonal variation was present both in northern and southern sites. Mortality was higher during the winter months compared to the remaining months (111.2% in winter vs 96.5% in other months, P = .036). In addition, increased mortality was associated with a high-risk season variable defined (prior to evaluation of treatment arm associations) as spring in the north and winter in the south (P < .001). The hazard ratio for death associated with this "high-risk season" measured 1.25 (P = .001) compared to the other seasons in each region. A test of interaction between "high-risk" season and implantable cardioverter-defibrillator (ICD) status suggested that the group with ICDs experienced reduced mortality during the "high-risk season" compared to the group without ICDs (P = .047). CONCLUSIONS: Mortality was higher in the winter months and in the respective regional "high-risk" seasons. Furthermore, seasonal variation in mortality may have been due to variation in sudden arrhythmic death, and associated increases in mortality were reduced by ICD therapy.     

Antiarrhythmic drug use in the implantable defibrillator arm of the Antiarrhythmics Versus Implantable Defibrillators (AVID) Study

BACKGROUND: Previous retrospective or observational series suggest that many patients with an implantable cardioverter-defibrillator (ICD) will be treated with antiarrhythmic drugs (AADs) to modify the frequency or manifestation of recurrent ventricular arrhythmias. The relative clinical benefit, however, is uncertain, and deleterious interactions can occur. The objective of this clinical investigation was to study the need for, and effects of, concomitant AAD use with the ICD in a prospectively defined cohort. METHODS: All patients randomly assigned to the ICD arm of the Antiarrhythmics Versus Implantable Defibrillators (AVID) study were followed for the addition of class I or III AADs ("crossover") after hospital discharge. Addition of AADs was strictly regulated by AVID protocol. The timing and reasons for crossover and the effects on ventricular arrhythmia recurrence were analyzed. Patients were excluded if they required AADs before hospital discharge after index arrhythmias or if they had no ventricular arrhythmia before initiation of AADs. RESULTS: After a median follow-up of 135 days, 81 (18%) of the 461 eligible patients required AADs and formed the crossover group. The primary reason for crossover was frequent ICD shocks in 64% of patients. The most common AAD selected was amiodarone (in 42%). Independent predictors of crossover were lower ejection fraction, absence of ventricular fibrillation, or presence of nonsyncopal ventricular tachycardia at presentation, prior unexplained syncope, female sex, and history of cigarette smoking. Before AAD use, the 1-year arrhythmia event rate was 90%; after AAD, the event rate was only 64% (P =.0001). The time to first event was extended from 3.9 +/- 0.7 months to 11.2 +/- 1.8 months. There were 1.4 +/- 3.7 fewer ICD therapy events (P =.005) after crossover, predominantly accounted for by reduction in shocks rather than antitachycardia pacing therapies. CONCLUSIONS: The majority of patients who receive ICDs for sustained ventricular tachycardia or ventricular fibrillation can be treated without AADs. Most commonly, AADs are added to combat frequent ICD shocks, which are successfully reduced by AAD therapy.     

Follow-up of patients with unexplained syncope and inducible ventricular tachyarrhythmias: analysis of the AVID registry and an AVID substudy. Antiarrhythmics Versus Implantable Defibrillators

INTRODUCTION: A prospective registry and substudy were conducted in the Antiarrhythmics Versus Implantable Defibrillators (AVID) Study to clarify the prognosis and recurrent event rate, risk factors, and impact of implantable cardioverter defibrillator (ICD) therapy in patients with unexplained syncope, structural heart disease, and inducible ventricular tachyarrhythmias. METHODS AND RESULTS: Included in the AVID registry were patients from all participating sites who had "out of hospital syncope with structural heart disease and EP-inducible VT/VF with symptoms." In addition, 13 collaborating sites provided more in-depth clinical and electrophysiologic data as part of a formal prospective substudy. Patients in the substudy were followed by local investigators for recurrent arrhythmic events and mortality. Registry patients were tracked for fatal outcomes by the National Death Index. A total of 429 patients with syncope were entered in the AVID registry, of whom 80 participated in the substudy. Of the substudy patients, 21 patients (26%) had inducible polymorphic ventricular tachycardia/ventricular fibrillation (VT/VF), 11 patients (14%) had sustained monomorphic VT <200 beats/min, and 48 patients (60%) had sustained monomorphic VT > or = 200 beats/min. The ICD was used as sole therapy in 75% of the syncope substudy patients (and with antiarrhythmic drug in an additional 9%) and in 59% of the syncope registry patients. Survival rates at 1 and 3 years were 93% and 74% for the substudy patients and 90% and 74% for the registry patients, respectively. Survival of the syncope substudy patients (predominantly treated by ICD) was similar to the VT patients treated by ICD and superior to the VT patients treated by an antiarrhythmic drug (P = 0.05) in the randomized main trial. Mortality events in the substudy were marginally predicted by ejection fraction (P = 0.06) but not by electrophysiologic study-induced arrhythmia. The significant predictor of increased mortality in the registry was age (P = 0.003) and of reduced mortality was treatment with ICD (P = 0.006). CONCLUSION: The results of these analyses support the role of the ICD as primary antiarrhythmic therapy in patients with unexplained syncope, structural heart disease, and inducible VT/VF at electrophysiologic study.     

In-hospital versus out-of-hospital presentation of life-threatening ventricular arrhythmias predicts survival: results from the AVID Registry. Antiarrhythmics Versus Implantable Defibrillators.

OBJECTIVES: This study describes the outcomes of patients from the Antiarrhythmics Versus Implantable Defibrillators (AVID) Study Registry to determine how the location of ventricular arrhythmia presentation influences survival. BACKGROUND: Most studies of cardiac arrest report outcome following out-of-hospital resuscitation. In contrast, there are minimal data on long-term outcome following in-hospital cardiac arrest. METHODS: The AVID Study was a multicenter, randomized comparison of drug and defibrillator strategies to treat life-threatening ventricular arrhythmias. A Registry was maintained of all patients with sustained ventricular arrhythmias at each study site. The present study includes patients who had AVID-eligible arrhythmias, both randomized and not randomized. Patients with in-hospital and out-of-hospital presentations are compared. Data on long-term mortality were obtained through the National Death Index. RESULTS: The unadjusted mortality rates at one- and two-year follow-ups were 23% and 31.1% for patients with in-hospital presentations, and 10.5% and 16.8% for those with out-of-hospital presentations (p < 0.001), respectively. The adjusted mortality rates at one- and two-year follow-ups were 14.8% and 20.9% for patients with in-hospital presentations, and 8.4% and 14.1% for those with out-of-hospital presentations (p < 0.001), respectively. The adjusted long-term relative risk for in-hospital versus out-of-hospital presentation was 1.6 (95% confidence interval [CI] 1.3-1.9). CONCLUSIONS: Compared with patients with out-of-hospital presentations of life-threatening ventricular arrhythmias not due to a reversible cause, patients with in-hospital presentations have a worse long-term prognosis. Because location of ventricular arrhythmia presentation is an independent predictor of long-term outcome, it should be considered as an element of risk stratification and when planning clinical trials.     

Patients at lower risk of arrhythmia recurrence: a subgroup in whom implantable defibrillators may not offer benefit. Antiarrhythmics Versus Implantable Defibrillator (AVID) Trial Investigators

OBJECTIVES: The goal of this study was to identify subgroups of arrhythmia patients who do not benefit from use of the implantable cardiac defibrillator (ICD). BACKGROUND: Treatment of serious ventricular arrhythmias has evolved toward more common use of the ICD. Since estimates of the cost per year of life saved by ICD therapy vary from $25,000 to perhaps $125,000, it is important to identify patient subgroups that do not benefit from the ICD. METHODS: Data for 491 ICD patients enrolled in the Antiarrhythmics Versus Implantable Defibrillators Study were used to create a hazards model relating baseline factors to time to first recurrent arrhythmia. The model was used to predict the hazard for recurrent arrhythmia among all trial patients. A priori cut points provided lower and higher recurrent arrhythmia risk strata. For each stratum the incremental years of life due to ICD versus antiarrhythmic drug therapy were calculated. RESULTS: Factors that predicted recurrent arrhythmia were: ventricular tachycardia as the index arrhythmia, history of cerebrovascular disease, lower left ventricular ejection fraction, a history of any tachyarrhythmia before the index event and the absence of revascularization after the index event. Survival times (over a follow-up of three years) were identical in each arm of the lowest risk sextile (survival advantage 0.03 +/- 0.12 [se] years), while the survival advantage for patients above the first sextile was 0.27 +/- 0.07 (se) years (two-sided p = 0.05). CONCLUSIONS: Patients presenting with an isolated episode of ventricular fibrillation in the absence of cerebrovascular disease or history of prior arrhythmia who have undergone revascularization or who have moderately preserved left ventricular function (left ventricular ejection fraction > 0.27) are not likely to benefit from ICD therapy compared with amiodarone therapy.     

Relative effectiveness of the implantable cardioverter-defibrillator and antiarrhythmic drugs in patients with varying degrees of left ventricular dysfunction who have survived malignant ventricular arrhythmias. AVID Investigators. Antiarrhythmics Versus Implantable Defibrillators.

OBJECTIVES: 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). BACKGROUND: 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) < or =0.40 or hemodynamic compromise. METHODS: Survival differences between AAD-treated and ICD-treated patients entered into the AVID study (patients presenting with sustained ventricular arrhythmia associated with an LVEF < or =0.40 or hemodynamic compromise) were compared at different levels of ejection fraction. RESULTS: In patients with an LVEF > or =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. CONCLUSIONS: These data suggest that patients with relatively well-preserved LVEF (> or =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 (> or =0.35) on the relative treatment effect of AADs and the ICDs.     

Clinical Significance of Device-Related Complications in Clinical Trials and Implications for Future Trials: Insights from the Antiarrhytmics versus Implantable Defibrillators (AVID) Trial

BACKGROUND: Implantation of transvenous implantable cardioverter-defibrillators (ICDs) utilizing a non-thoracotomy approach has become routine therapy for survivors of life-threatening tachyarrhythmias. In the Antiarrhythmics versus Implantable Defibrillator (AVID) Trial, we sought to identify and prospectively characterize the frequency of lead and ICD-related complications. Between June 1, 1993, and April 7, 1997, 539 patients received non-thoracotomy ICDs. A total of 62 first complications occurred. The subclavian route of insertion resulted in more complications than the cephalic vein route, 46 of 339 (14%) versus 6 of 135 (4%), p =.005 as did the abdominal versus pectoral generator site; 31 of 238 (13%) versus 17 of 291 (6%), p <.02. Most dislodgements and system infections tended to occur in the 3 months following implantation, whereas lead fractures continued to occur throughout follow-up. Failure to use peri-operative antibiotics was a predictor of system infection (p =.001).These data suggest that cephalic vein access and pectoral generator site may result in fewer complications. Although implantation techniques and generator technology continue to evolve, the continued occurrence of lead fractures and the need for premature system revision supports the practice of close routine ICD system surveillance.     

Effect of first ventricular tachycardia cycle length on rate of ventricular arrhythmia recurrence in patients with implantable cardioverter-defibrillator

Background

Some controversies exist regarding the proper treatment of hemodynamically tolerated and slow ventricular tachycardia (VT). We intended to assess the effect of cycle length of first VT episode on total ventricular arrhythmia burden in a cohort of patients with implantable cardioverter-defibrillator (ICD).

Method

Between March 2000 and March 2005, 195 patients underwent ICD implantation at our center. We included 158 patients (mean age, 58.3 ± 12.9 years) with follow-up of 3 months or more in this study. Clinical, electrocardiographic, and ICD-stored data and electrograms were collected and analyzed.

Results

During the follow-up of 16.7 ± 10.6 months, 45 (28.5%) and 20 (12.6%) patients received first appropriate ICD therapy for VT and ventricular fibrillation, respectively. We divided the 45 patients with VT (based on the median value of VT cycle length) into 2 groups. Although patients with VT cycle length of less than 350 had higher total mean number of appropriate ICD therapy (25 vs 6.3, P = .023), during multivariate regression analysis, only left ventricular ejection fraction (EF) of less than 25% (P = .020) was correlated with total number of appropriate ICD therapy. First VT cycle length (P = .341), QRS duration (P = .126), age (P = .405), underlying heart disease (P = .310), indication of ICD implantation (P = .113), and sex (P = .886) have failed to predict the total burden of ventricular arrhythmia during the follow-up period.

Conclusion

After adjustment for left ventricular EF, initial VT cycle length per se did not confer a lower risk for subsequent ventricular arrhythmia recurrence compared with those with faster VT. Left ventricular EF of less than 25% was correlated with higher ventricular arrhythmia burden in patients with ICD.     

Spontaneous sustained ventricular tachycardia in the Electrophysiologic Study Versus Electrocardiographic Monitoring (ESVEM) trial

Objectives. We compared the QRS waveforms of the initial and subsequent complexes of spontaneous sustained monomorphic ventricular tachycardia and the rhythm induced at electrophysiologic study to test the theory that premature ventricular complexes “trigger” spontaneous ventricular tachycardia and that a stable substrate exists such that the spontaneous arrhythmia can be reproduced at electrophysiologic study.Background. Failure rates have been high in several recent studies in which prevention of ventricular tachyarrhythmias was guided by suppression of premature ventricular complexes or induced ventricular tachycardias.Methods. Digital waveform analysis was used to distinguish events of ventricular tachycardia initiated by configurationally distinct, possibly triggering, complexes (type 1) from events in which the initial QRS waveforms were identical to subsequent complexes, suggesting no requirement for premature ventricular beats (type 2).Results. Of 1,102 episodes of spontaneous ventricular tachycardia, 73 (6.6%) were type 1; 1,012 were type 2 (91.8%); and 17 (1.5%) were uncertain. Of 59 patients only 14 (24%) had only type 1 episodes (group 1), whereas 37 patients (63%) had predominantly type 2 events (group 2) (p < 0.0001). Sustained ventricular tachycardia was inducible in all group 1 patients, and in most (57%) the induced rhythm was similar to the spontaneous rhythm. Ventricular tachycardia could not be induced in 7 patients from group 2 (19%), and in 18 patients (49%) the induced and spontaneous rhythms were dissimilar. Recurrence of arrhythmia rates differed according to the guidance method in group 2.Conclusions. Discrepancies between observed and predicted modes of initiation of ventricular tachycardia and between spontaneous and induced rhythms could result in inappropriate guidance and subsequent failure of antiarrhythmic treatment.     

Predictive value of ventricular arrhythmia inducibility for subsequent ventricular tachycardia or ventricular fibrillation in Multicenter Automatic Defibrillator Implantation Trial (MADIT) II patients.

In the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II, implantable cardioverter-defibrillator (ICD)-randomized patients underwent electrophysiologic testing. Both inducible and noninducible patients received an ICD. We correlated inducibility with the occurrence of subsequent ventricular tachycardia (VT) or ventricular fibrillation (VF). Intracardiac ICD electrograms for subsequent events were analyzed to categorize the spontaneous arrhythmia as VT or VF. The two-year Kaplan-Meier event rate for VT in inducible patients was 29.0% versus 19.3% in noninducible patients. However, ICD therapy for spontaneous VF was less common at two years in inducible patients (3.2%) than in noninducible patients (8.6%). In the MADIT II study, inducibility predicted an increased likelihood of VT but decreased VF. OBJECTIVES: We correlated electrophysiologic inducibility with spontaneous ventricular tachycardia (VT) or ventricular fibrillation (VF) in the Multicenter Automatic Defibrillator Implantation Trial (MADIT) II. BACKGROUND: In the MADIT II study, 593 (82%) of 720 implantable cardioverter-defibrillator (ICD) randomized patients underwent electrophysiologic testing. Patients received an ICD whether they were inducible or not. METHODS: A "standard" inducibility definition included sustained monomorphic or polymorphic VT induced with three or fewer extrastimuli or VF induced with two or fewer extrastimuli. We compared a narrow inducibility definition (only monomorphic VT) and a broad definition (standard definition plus VF with three extrastimuli). We used ICD-stored electrograms to categorize spontaneous VT or VF. RESULTS: Inducible patients (standard definition) had a greater likelihood of experiencing ICD therapy for VT than noninducible patients (p = 0.023). Unexpectedly, ICD therapy for spontaneous VF was less common (p = 0.021) in inducible patients than in noninducible patients. The two-year Kaplan-Meier event rate for VT or VF was 29.4% for inducible patients and 25.5% for noninducible patients. Standard inducibility did not predict the combined end point of VT or VF (p = 0.280, by log-rank analysis). The narrow inducibility definition outperformed the standard definition, whereas the broad definition appeared inferior to the standard definition. CONCLUSIONS: In the MADIT II study patients, inducibility was associated with an increased likelihood of VT. Noninducible MADIT II study subjects using this electrophysiologic protocol had a considerable VT event rate and a higher VF event rate than inducible patients. Induction of polymorphic VT or VF, even with double extrastimuli, appears less relevant than induction of monomorphic VT.     

Signal-averaged electrocardiographic late potentials in patients with ventricular fibrillation or ventricular tachycardia: correlation with clinical arrhythmia and electrophysiologic study

High-frequency potentials measured in the terminal 40 ms of the signal-averaged QRS complex during sinus rhythm are of abnormally low amplitude in most patients with ventricular tachycardia (VT). However, less is known about high-frequency late potentials in patients with ventricular fibrillation (VF), and the relation between late potentials and arrhythmia inducibility during electrophysiologic study has not been established. Signal-averaged electrocardiography was used to measure high-frequency (more than 25 Hz) late potentials in 24 patients with spontaneous VF, 27 patients with spontaneous sustained VT, and 19 normal subjects, none of whom were receiving antiarrhythmic drugs. Late-potential amplitude in patients with VT was significantly lower than that in patients with VF (p less than 0.02). Late-potential amplitude in patients with VF was not significantly different from that in normal subjects. Ventricular arrhythmia induction was attempted during electrophysiologic study in 46 of the patients with VF or VT. Late-potential amplitude was significantly lower in 26 patients with reproducibly inducible sustained ventricular arrhythmias than in 20 without (p less than 0.001). The correlation between late-potential amplitude and arrhythmia inducibility was independent of that between late-potential amplitude and clinical arrhythmia (VT vs VF).