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CLINICAL STUDIES

Beta-blocker use and survival in patients with ventricular fibrillation or symptomatic ventricular tachycardia: the antiarrhythmics versus implantable defibrillators (AVID) trial

Derek V. Exner, MD, MPH^*, James A. Reiffel, MD, FACC, Andrew E. Epstein, MD, FACC, Robert Ledingham, MS, Michael J. Reiter, MD, PhD, FACC, Qing Yao, PhD, Henry J. Duff, MD, Dean Follmann, PhD^*, Eleanor Schron, RN^*, H. Leon Greene, MD, FACC, Mark D. Carlson, MD, FACC, Michael A. Brodsky, MD, FACC, Toshio Akiyama, MD, FACC, Christina Baessler, MSN, Jeffrey L. Anderson, MD, FACC the AVID Investigators^,1

^* National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA
University of Washington, Seattle, Washington, USA
Antiarrythmics Versus Implantable Defribillators (AVID) clinical sites, USA

Manuscript received October 5, 1998; revised manuscript received February 23, 1999, accepted April 30, 1999.

Reprint requests and correspondence: Dr. Derek V. Exner, National Heart, Lung, and Blood Institute, 6701 Rockledge Drive, Room 8146, Bethesda, Maryland 20892.
Derek_Exner{at}nih.gov

	Abstract

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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.

Abbreviations and Acronyms   ACE = angiotensin-converting enzyme   AVID = Antiarrhythmics Versus Implantable Defibrillators   CAMIAT = Canadian Amiodarone Myocardial Infarction Arrhythmia Trial   EMIAT = European Myocardial Infarct Amiodarone Trial   CI = confidence interval   ICD = implantable cardioverter defibrillator   LV = left ventricular   MI = myocardial infarction   NYHA = New York Heart Association   RR = relative risk   VF = ventricular fibrillation   VT = ventricular tachycardia

Post hoc analyses from two high-risk, post-MI trials have indicated that patients receiving amiodarone and a beta-blocker are at a substantially (30% to 72%) lower risk of death compared with patients treated with amiodarone alone (10–14). Whether beta-blockers alter the survival of patients with VF or VT treated with amiodarone is uncertain. Likewise, the capacity of beta-blockers to alter the mortality of patients with these arrhythmias, who have already received an implantable cardioverter defibrillator (ICD), has not been fully investigated.

The Antiarrhythmics Versus Implantable Defibrillators (AVID) trial evaluated the mortality difference of antiarrhythmic drugs versus ICD therapy in patients with VF or symptomatic VT. The AVID trial was terminated early due to improved survival in patients randomized to ICD therapy (15). Although these results are compelling, the more frequent use of beta-blockers in ICD-treated patients has led some authors to question the superiority of ICD therapy (16).

This analysis evaluated the association of beta-blocker use, alone and in combination with amiodarone or an ICD, with survival in AVID patients with VF or symptomatic VT.

	Methods

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Definitions.   For the purpose of this analysis, symptomatic VT was defined as VT with syncope or VT with hemodynamic compromise and a left ventricular (LV) ejection fraction 0.40. Patients presenting with VF or symptomatic VT were eligible for randomization, whereas those already receiving amiodarone, with ventricular arrhythmias secondary to a correctable cause, a limited life expectancy, New York Heart Association (NYHA) class IV symptoms or contraindications to amiodarone or ICD therapy were not eligible for randomization (17–19).

Study population (Fig. 1).   The AVID registry included patients enrolled in the randomized trial (15) and patients screened, but not randomized (17–19). There were 3,117 registry patients with VF or symptomatic VT as their index arrhythmia, 2,901 (93%) of whom were discharged from hospital with aminodarone alone, an ICD alone or neither of these therapies. Survival of the 970 randomized and 1,931 eligible, nonrandomized patients with VF or symptomatic VT who received one of these three treatment strategies, and thus were included in the present analysis, was determined using the National Death Index, as of December 31, 1996.

View larger version (38K): [in this window] [in a new window]   Figure 1 The 2,901 persons in the present analysis included 970 randomized and 1,931 eligible, nonrandomized patients discharged from hospital with amiodarone alone, an ICD alone or neither of these therapies. Numbers of patients within each treatment strategy are shown in parentheses.

Statistical analysis.   Continuous baseline characteristics are presented as mean ± SD. Univariate comparisons were made using analysis of variance or the chi-square test. Pair-wise comparisons were made using a Student t test or chi-square test. All-cause mortality was the primary end point of this analysis. Deaths in randomized patients were further classified as cardiac or noncardiac (20), and cause-specific mortality rates were compared using the log-rank test statistic. The composite end point of death or recurrent arrhythmia (21,22) was also evaluated in randomized patients. Stratification by history of MI (23) and index arrhythmia (23) was performed in the combined groups of amiodarone-treated and ICD-treated patients. Amiodarone-treated patients were stratified by heart rate (<70 vs. 70 beats/min) at the time of hospital discharge (12–14). Cox proportional hazards models were used to evaluate the univariate (unadjusted) and multivariate (adjusted) association of beta-blockers with survival. The prespecified multivariate model included beta-blocker use, age, gender, race, index arrhythmia, history of heart failure, ejection fraction, heart rate at hospital discharge and any relevant baseline differences between patients receiving, versus those not receiving, beta-blockers. The Cox models were used to determine relative risk (RR) estimates and 95% confidence intervals (CI). Analyses were performed using SIR (Scientific Information Retrieval Inc., New South Wales, Australia), SPSS 6.1 (SPSS Inc., Chicago, Illinois) and Stata Release 5.0 (Stata Corporation, College Park, Texas) statistical software.

	Results

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Characteristics and beta-blocker use, randomized patients.   Patients discharged receiving beta-blockers had fewer symptoms of heart failure and were less likely to be prescribed a diuretic or angiotensin-converting enzyme (ACE) inhibitor compared with those not receiving beta-blockers (Table 1). Patients receiving an ICD and beta-blocker had less LV dysfunction, slower mean heart rates at hospital discharge and were less likely to be prescribed digoxin or a calcium channel blocker, but more likely to be prescribed aspirin compared with those receiving an ICD alone.

Reasons for use of beta-blockers, agents and doses, randomized patients.   Beta-blockers were most commonly prescribed after the index arrhythmia for the ventricular arrhythmia itself or the presence of coronary artery disease. A greater proportion of ICD-treated patients received beta-blockers for supraventricular arrhythmias or sinus tachycardia, whereas a greater proportion of amiodarone-treated patients received beta-blockers for hypertension (Table 2).

Characteristics and beta-blocker use, eligible, nonrandomized patients.   Among the three treatment groups, those receiving amiodarone were older and had slower mean heart rates at the time of hospital discharge (Table 3). Amiodarone-treated patients were also less likely to have had VF as their index arrhythmia, more likely to have a history of heart failure and more likely to be prescribed warfarin or a diuretic. The ICD-treated patients were more often white and less likely to have a history of hypertension, compared with the other two groups. Otherwise untreated patients had less LV dysfunction and were less likely to have a history of MI compared with those treated with amiodarone or an ICD. Untreated patients were also less likely to be prescribed an ACE inhibitor, but more likely to receive sotalol or another antiarrhythmic drug, and more likely to have undergone a coronary artery bypass or coronary artery angioplasty procedure after their index arrhythmia, compared with patients treated with amiodarone or an ICD.

Eligible, nonrandomized patients receiving beta-blockers had less LV dysfunction, were less likely to have a history of heart failure and were less likely to be prescribed a diuretic, but more likely to be prescribed aspirin compared with those not receiving beta-blockers (Table 4). Patients receiving amiodarone and a beta-blocker were younger on average, and more often white compared with those receiving amiodarone alone. Patients receiving amiodarone and a beta-blocker had slower mean heart rates, were more likely to have VF or a history of hypertension but less likely to be prescribed an ACE inhibitor compared with those receiving amiodarone alone. Patients receiving an ICD and beta-blocker had slower mean heart rates and were more likely to have a history of hypertension, but were less likely to receive digoxin, warfarin or sotalol compared with those receiving an ICD alone. Patients receiving an ICD and beta-blocker were also more likely to have undergone a revascularization procedure after their index arrhythmia compared with those receiving an ICD alone. Untreated patients receiving beta-blockers were more likely to have VF, but less likely to be prescribed an ACE inhibitor, digoxin or sotalol compared with patients not receiving amiodarone, an ICD or beta-blocker. Untreated patients receiving beta-blockers were also more likely to have undergone a revascularization procedure after their index arrhythmia compared with patients not receiving beta-blockers (Table 4).

Modes of death, randomized patients (table 5).  

Adjusted survival, randomized patients.   The use of beta-blockers at the time of hospital discharge was not independently associated with survival in randomized patients (Table 6). Furthermore, the survival of patients receiving beta-blockers at the time of their index arrhythmia who continued to receive these agents was similar to that of patients in whom beta-blockers were initiated after their index arrhythmia (RR = 0.81; 95% CI 0.45 to 1.46; p = 0.49). Patients receiving amiodarone and a beta-blocker, or an ICD and a beta-blocker, had a survival similar to patients receiving amiodarone alone, or an ICD alone.

Adjusted survival, eligible, nonrandomized patients.   Overall, beta-blocker use was associated with improved survival in eligible, nonrandomized patients (Table 6). However, beta-blockade was not associated with an independent, survival benefit in patients treated with amiodarone alone or an ICD alone. In contrast, beta-blocker use remained associated with a significant, independent survival benefit in otherwise untreated patients. Furthermore, because 49 (12%) of these 412 otherwise untreated patients received sotalol (Table 3), the association of beta-blocker use with survival was evaluated in patients discharged without amiodarone, an ICD or sotalol. In these 363 patients, beta-blocker use remained independently associated with improved survival (RR = 0.46; 95% CI 0.24 to 0.87; p = 0.012), with a point estimate similar to that observed for the entire group of 412 patients (Table 6).

For amiodarone-treated patients, age (RR = 1.66 per decade increase), ejection fraction (RR = 0.80 per 0.10 increase), discharge heart rate (RR = 1.16 per 10 beats/min increase), history of heart failure (RR = 1.56) and use of other antiarrhythmic drugs (RR = 2.28) were significantly associated with survival in the multivariate model. For ICD-treated patients, age (RR = 1.49 per decade increase), ejection fraction (RR = 0.78 per 0.10 increase) and history of heart failure (RR = 2.89) were significantly associated with survival in the multivariate model. In addition to beta-blockade, age (RR = 1.48 per decade increase) was significantly associated with survival in the otherwise untreated patient multivariate model.

Death or recurrent arrhythmia, randomized patients.   Beta-blockade was not associated with a reduction in the composite end point of death or recurrent arrhythmia in amiodarone and ICD-treated patients separately, or combined (adjusted RR = 0.97, 95% CI 0.73 to 1.30, p = 0.86).

Discharge heart rate, amiodarone-treated patients.   In the combined group of 1,142 amiodarone-treated patients, a heart rate 70 beats/min at the time of hospital discharge was associated with an increased risk of death compared with a heart rate of <70 beats/min (adjusted RR = 1.30; 95% CI 1.00 to 1.69; p = 0.047). However, no significant association between survival and beta-blockade was observed in patients within either heart rate strata (p > 0.4 for each).

Influence of index arrhythmia and MI history.   In the combined group of 1,142 amiodarone-treated patients, beta-blockade was not associated with survival in the 655 (57%) patients with symptomatic VT (RR = 0.81; 95% CI 0.47 to 1.41; p = 0.45) or the 487 (43%) patients with VF (RR = 1.14; 95% CI 0.61–2.16; p = 0.67). Similarly, in the combined group of 1,347 ICD-treated patients, beta-blockade was not associated with survival in the 649 (48%) patients with symptomatic VT (RR = 0.69; 95% CI 0.33 to 1.43; p = 0.30) or the 698 (52%) with VF (RR = 1.03; 95% CI 0.54 to 2.00; p = 0.91).

In the combined group of amiodarone-treated patients, beta-blocker use was not associated with improved survival in the 450 (39%) patients with no history of MI (RR = 0.80; 95% CI 0.41 to 1.59; p = 0.52) or the 692 (61%) with a history of prior MI (RR = 1.07; 95% CI 0.64 to 1.82; p = 0.78). However, in the combined group of ICD-treated patients, beta-blocker use was associated with a trend toward improved survival in the 529 (39%) patients without a history of MI (RR = 0.43; 95% CI 0.16 to 1.17; p = 0.08). Beta-blocker use was not significantly associated with survival in the combined group of 818 (61%) ICD-treated patients with a history of MI (RR = 0.99; 95% CI 0.55 to 1.76; p = 0.97).

	Discussion

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The present analysis demonstrates that beta-blocker use at the time of hospital discharge was not associated with improved survival in patients with VF or symptomatic VT treated with amiodarone alone or an ICD alone. However, beta-blocker use was associated with an independent mortality reduction in eligible, nonrandomized patients who were not treated with amiodarone or ICD therapy.

Amiodarone-treated patients.   Amiodarone has a variety of electrophysiologic effects, including a weak nonselective, noncompetitive beta-blocking property (24). Because amiodarone and beta-blockers may exert their antiarrhythmic effects by reducing sympathetic tone (25,26), their combination might be expected to be superior to the effect of either alone. Whereas combining these agents is often avoided because of concern over side effects, excess rates of adverse cardiovascular and noncardiovascular effects have not been observed compared with therapy with a beta-blocker alone (27) or amiodarone alone (10,11).

The European Myocardial Infarct Amiodarone Trial (EMIAT) and Canadian Amiodarone Myocardial Infarction Arrhythmia Trial (CAMIAT) were randomized, placebo-controlled studies that evaluated the capacity of amiodarone to reduce overall mortality and arrhythmic death in high-risk post-MI patients, respectively (10,11). Whereas neither study found a significant reduction in overall mortality, post hoc analyses from both trials indicated that patients receiving amiodarone and a beta-blocker had a lower risk of death compared with patients receiving amiodarone alone (12–14). In EMIAT and CAMIAT, unadjusted all-cause mortality reductions of 30% (12) and 60% to 72% (14), respectively, were observed. Furthermore, in both analyses, the beneficial effect of combining amiodarone with a beta-blocker was most prominent in patients with more rapid baseline heart rates. In contrast with EMIAT and CAMIAT, the combination of amiodarone and a beta-blocker in AVID patients was not associated with improved survival. This result may reflect differences between the amiodarone-treated patients in AVID versus those in EMIAT and CAMIAT. Although the age and gender distribution of patients in the three trials was similar, patients in AVID had life-threatening ventricular arrhythmias, more advanced LV dysfunction and a greater use of heart failure medications. Finally, although the analyses from EMIAT and CAMIAT demonstrated that patients with more rapid heart rates had the greatest benefit from the combination of amiodarone and a beta-blocker (12–14), the present analysis did not corroborate this. However, amiodarone-treated patients in AVID with heart rates 70 beats/min were at a higher risk of death. This result may reflect differences in the timing of the baseline heart rate measurements in AVID (at hospital discharge) versus EMIAT and CAMIAT (before initiation of amiodarone) or differences in the study populations.

Patients treated with an implantable cardioverter defibrillator.   Because beta-blockers reduce mortality in persons with heart failure (3–5), they would be expected to be beneficial in ICD-treated patients, most of whom have LV dysfunction. Furthermore, although beta-blockers may be used in conjunction with ICD therapy to reduce the incidence of recurrent arrhythmias (21,22), this was not a common reason cited for the use of beta-blockers in randomized AVID patients. Furthermore, beta-blockade was not associated with a significant reduction in the composite end point of death or recurrent arrhythmia in randomized AVID patients.

Beta-blockers have been shown to reduce mortality when initiated in the early phase of an acute MI, particularly in patients with LV dysfunction (1,2), yet the ability of beta-blockers to reduce mortality when administered beyond the immediate post-MI period appears less certain (28,29). However, recent randomized trials in patients with heart failure which have included persons with ischemic heart disease have demonstrated significant mortality reductions in patients treated with beta-blockers, mostly the result of a reduced risk of sudden death (4,5).

Otherwise untreated patients.   In the same clinical practice setting, patients with VF or symptomatic VT who receive amiodarone or ICD therapy are likely to differ from patients who are otherwise untreated. In the present analysis, these otherwise untreated patients had less LV dysfunction, fewer symptoms of heart failure and less frequent ACE inhibitor or diuretic use compared with eligible, nonrandomized patients treated with amiodarone or an ICD.

Because beta-blockers appear to decrease mortality by reducing the incidence of sudden death in patients with ischemic heart disease (30) and heart failure (4,5), it is probable that the survival benefit observed with beta-blockade in the otherwise untreated AVID patients was due to a decline in sudden death. Because amiodarone and ICD therapy are primarily used to reduce sudden, arrhythmic death in patients with VF or VT, it is not surprising that beta-blocker use was not associated with a prominent, additive survival benefit in AVID. Finally, the rate of revascularization after the index arrhythmia was also greatest in the otherwise untreated patients. This discrepancy may also have been an important factor in the results observed (31). However, the results of the present analysis are consistent with previous work by Brodsky and colleagues, who reported that concomitant beta-blockade was most efficacious in VT/VF patients who were younger, had less LV dysfunction and no history of coronary artery disease (23).

Study limitations.   This analysis was not a randomized comparison of outcome in patients receiving, versus those not receiving, beta-blockers. Although adjustments were made for known relevant differences, it is possible that the groups differed in other important respects. In addition, the present analysis lacked sufficient power to detect a small, but perhaps clinically relevant, effect from beta-blockade. However, the present analysis had reasonable (>80%) power to detect a prominent (35%) mortality reduction associated with beta-blocker use (12,14). Finally, although the doses of beta-blockers prescribed in randomized patients are lower than what have been used in post-MI (1,2,29) and heart failure trials (4,5), these doses are similar to what have been reported in studies of similar patients with VT and VF (6,32).

Conclusions.   Although eligible, nonrandomized patients who did not receive amiodarone or an ICD had a significant survival benefit associated with beta-blockade, the role of beta-blockers as monotherapy in patients with VT or VF is limited because the ICD is more efficacious (33).

The AVID patients treated with amiodarone or an ICD had no significant additional mortality reduction associated with concurrent beta-blockade. However, because beta-blockers confer additional benefits in the management of patients with heart disease, it remains appropriate to prescribe beta-blockers to patients with VF and symptomatic VT in whom they are clinically indicated for other reasons. Moreover, differences in the use of beta-blockers in randomized AVID patients do not explain the increased survival observed with ICD therapy.

	Acknowledgments

 
We thank Myron Waclawiw, PhD, Division of Biostatistics, and Jeffrey Cutler, MD, Division of Epidemiology and Clinical Applications, at the National Heart, Lung, and Blood Institute, for their expert advice and assistance.

	Footnotes

 
This study was supported by a contract (N01 HC-25117) with the National Heart, Lung, and Blood Institute. Dr. Exner is a Clinician-Scientist (phase I) of the Medical Research Council of Canada and Research Fellow of the Alberta Heritage Foundation for Medical Research.

¹ See reference 15 for a listing of AVID investigators and sites.

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