(Circulation. 1996;93:2128-2134.)
© 1996 American Heart Association, Inc.
Articles |
Effect of Amiodarone on Clinical Status and Left Ventricular Function in Patients With Congestive Heart Failure
From the Department of Veterans Affairs Cooperative Studies Program (S.G.F.), Washington, DC, and Hines, Ill; Veterans Affairs Medical Center and University of California (San Francisco) (B.M.M.); Veterans Affairs Medical Center, Fresno, Calif, and the University of California (San Francisco) (P.C.D.); Wadsworth Veterans Affairs Medical Center and the University of California (Los Angeles) (B.N.S.); and Veterans Affairs Medical Center and Georgetown University Medical School, Washington, DC (R.D.F., S.N.S.).
Correspondence to Barry M. Massie, MD, Cardiology Division (111C), VA Medical Center, 4150 Clement St, San Francisco, CA 94121.
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Abstract |
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Background Although trials of amiodarone therapy in patients with congestive heart failure have produced discordant results with regard to effects on survival, most studies have reported a significant rise in left ventricular ejection fraction during long-term therapy. In the present study, we determined whether this increase in ejection fraction is associated with an improvement in the symptoms and/or physical findings of heart failure or a reduction in the number of hospitalizations for heart failure.
Methods and Results In the Department of Veterans Affairs
cooperative study of amiodarone in congestive heart failure,
674 patients with New York Heart Association class II through IV
symptoms and ejection fractions of 
40% were treated with
amiodarone or placebo for a median of 45 months in a
randomized, double-blind, placebo-controlled protocol. Clinical
assessments and radionuclide ejection fraction were performed at
baseline and after 6, 12, and 24 months. Compared with the placebo
group, ejection fraction increased more in the amiodarone group
at each time point (8.1±10.2% [mean±SD] versus 2.6±7.9% at 6
months, 8.0±10.9% versus 2.7±8.0% at 12 months, and 8.8±10.1%
versus 1.9±9.4% after 24 months, all P<.001). However,
this difference was not associated with greater clinical improvement,
lesser diuretic requirements, or fewer hospitalizations for
heart failure (11.1% for amiodarone and 13.6% for placebo
group; overall relative risk in the amiodarone group, 0.81
[95% CI, 0.56 to 1.10], P=.18). Of note is the trend
toward a reduction in the combined end point of hospitalizations and
cardiac deaths (relative risk, 0.82 [CI, 0.65 to 1.03],
P=.08), which was significant in patients with
nonischemic etiology (relative risk, 0.56 [CI, 0.36 to
0.87], P=.01) and absent in the ischemic group
(relative risk, 0.95).
Conclusions Although amiodarone therapy resulted in a substantial increase in left ventricular ejection fraction in patients with congestive heart failure, this was not associated with clinical benefit in the population as a whole. The substantial reduction in the combined end point of cardiac death plus hospitalizations for heart failure in the nonischemic group suggests possible benefit in these patients.
Key Words: amiodarone • cardiomyopathy • heart failure • prognosis • morbidity
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Introduction |
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As experience has grown with the use of amiodarone for the treatment of ventricular arrhythmias in patients with congestive heart failure (CHF), it has been noted that therapy with this agent produced concomitant improvement in measurements of left ventricular function1 2 and exercise tolerance.2 In a randomized, controlled trial of amiodarone in patients with severe CHF, there was both a survival benefit and a reduction in the number of hospitalizations for heart failure.3 These apparent benefits are in marked contrast to the negative inotropic and hemodynamic responses to other antiarrhythmic agents in this patient population4 5 and, with the relative infrequency of proarrhythmic events,6 have made amiodarone a logical antiarrhythmic agent of choice in the treatment of CHF patients.5 7
In contrast to these favorable results with amiodarone, in the recently completed randomized, double-blind, placebo-controlled trial of amiodarone in patients with CHF conducted by the Department of Veterans Affairs Cooperative Studies Program, no improvement was observed in all-cause or sudden death mortality.8 Nevertheless, as previously,2 a significant increase in left ventricular ejection fraction (EF) was noted in the group treated with active amiodarone compared with the placebo-treated group. The goal of the present study was to determine whether this improvement in left ventricular function was accompanied by improvement in symptoms and/or the physical findings of CHF or by a reduction in hospitalizations for heart failure.
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Methods |
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Patient Population
The design of this trial and the characteristics of the enrolled patients have been described previously.8 9 In brief, 674 patients with New York Heart Association (NYHA) functional class II, III, or IV CHF of at least 3 months' duration were enrolled and randomized in a total of 25 centers. They were required to have dyspnea on exertion or paroxysmal nocturnal dyspnea, a left ventricular EF of
40% as measured with radionuclide
angiography, and either a cardiothoracic ratio on chest
radiography of >0.50 or a left ventricular
end-diastolic dimension of 
5.5 cm. Patients were also
required to have frequent ventricular premature beats (10
per hour averaged over a 24-hour period) but no symptomatic
arrhythmias or sustained ventricular
tachycardia. In addition, patients were required to receive
vasodilator therapy with either an
angiotensin-converting enzyme inhibitor or
hydralazine and nonparenteral nitrates. Other medications for
heart failure, such as diuretics and digoxin, were given as
deemed appropriate by the responsible physician.
Exclusion criteria included women of childbearing age; myocardial
infarction or revascularization within 3 months;
heart failure due to uncorrected primary valvular disease or
restrictive or infiltrative cardiomyopathy; a
history of aborted sudden death, symptomatic
ventricular arrhythmia, or need for continuing
antiarrhythmic therapy; QRS duration of 180 milliseconds or
QTc of 500 milliseconds; active drug or alcohol abuse;
uncontrolled thyroid disease; noncardiac conditions or malignancy that
was likely to be fatal within 3 years; and symptomatic
hypotension or systolic blood pressure of <90 mm Hg.
Treatment with ß-blockers or investigational medications was not
permitted.
The protocol was approved by the institutional review board of each participating center and by the Human Rights Committee of the Hines Veterans Affairs Cooperative Studies Program Coordinating Center. The conduct of the study was monitored by the latter committee, as well as by an external data and safety monitoring board. All participants provided written informed consent before entering the study.
Study Design
Patient recruitment commenced in September 1989 and continued
for 3.5 years, with a subsequent minimal follow-up of 1 additional
year. There was an initial baseline phase, during which medical therapy
was optimized, compliance was monitored, and radionuclide EF
measurements and ambulatory ECGs were performed. At random, patients
were stratified with regard to etiology of CHF (ischemic or
nonischemic), left ventricular EF (30%
versus <30%), and participating hospital. Patients with a history or
ECG evidence of myocardial infarction, current or previous typical
angina pectoris, positive coronary angiograms, or a positive
stress test were classified as having an ischemic etiology, and
the remaining subjects were considered to have heart failure of a
nonischemic etiology.
Treatment with amiodarone or matching placebo began on an outpatient basis at a total daily dose of 800 mg for the first 2 weeks, 400 mg QD for the next 50 weeks, and 300 mg QD for the remainder of the 4.5-year trial. Dose reduction or temporary discontinuation was permitted if limiting side effects occurred, but reinstitution of the protocol-stipulated therapy was encouraged. Patients who permanently discontinued study drug were followed to the end of the trial and analyzed by the intention-to-treat principle. Clinic visits were scheduled after 2 weeks and monthly thereafter; these visits included an interim history and complete cardiovascular examination. Laboratory testing and ECGs were performed at appropriate intervals. The radionuclide EF determination was repeated at 6, 12, and 24 months.
The primary end point of the trial was all-cause mortality, and secondary end points included cardiac mortality and sudden cardiac death, as categorized by a blinded mortality committee based on all available data from investigators and family members. These data have been presented previously.8 For the present study, the hypothesis that amiodarone improves left ventricular function and/or clinical heart failure status was tested by evaluating changes in EF, NYHA functional class (with class II being subdivided into IIs and IIm for slightly and moderately symptomatic patients, respectively, to increase sensitivity to detect changes), symptoms, physical findings, and diuretic dosage during the course of the first 24 months of follow-up. In addition, differences were sought in hospitalization rates for heart failure and the combination of hospitalizations and cardiac mortality in the two treatment groups.
Statistical Analysis
Differences between treatment groups in categorical and
continuous variables were detected with the 
2 test
and the Student's t test, respectively. Changes in
parameter measurements between groups over time were
examined based on application of the Student's t test to
the difference in scores from baseline to the time point of interest.
Kaplan-Meier survival techniques were used to examine differences
between treatment groups in the time from randomization to a particular
event (ie, cardiac death, CHF hospitalization, and so on). Patients not
experiencing the event of interest were censored at the date of the
last follow-up visit or the date of death from another cause. In
all cases, a two-sided 
level of .05 was considered
statistically significant; no adjustment was made for multiple
comparisons. Data are presented as mean±1 SD.
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Results |
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Patient Characteristics and Dropouts
Table 1
displays the characteristics of the
treatment groups, confirming that they were well matched at baseline
with regard to demographic characteristics, clinical
presentation, and medications. As has been noted
previously,8 the study medication was discontinued in 90
patients in the amiodarone group (27%) and in 78 patients in
the placebo group (23%) because of side effects. The difference
between the two groups was not significant (P=.10), and the
characteristics of these patients were similar to those of the entire
study population.
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Effect of Amiodarone on Left Ventricular
EF
Fig 1 illustrates the changes in EF from baseline
to 6, 12, and 24 months. In the patients undergoing repeat assessments,
EF rose in both treatment groups. However, the increase in the
amiodarone group was significantly greater than the increase in
the placebo group: 8.1±10.2% versus 2.6±7.9% (absolute %)
(P<.001) at 6 months, 8.0±10.9% versus 2.7±8.3%
(P<.001) at 12 months, and 8.8±10.1% versus 1.9±9.4%
(P<.001) at 24 months. These changes represent a
33% relative increase over baseline at each time point in the
amiodarone group. An analysis limited to patients who
remained on randomized therapy yielded very similar results.
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To determine whether the EF changes were potentially explained by
changes in heart rate or blood pressure, the patients were divided into
subgroups based on whether the EF increased substantially (by 5%),
was unchanged (defined by a change <5%), or declined by 5% at 6
months. In the amiodarone group, the changes in heart rate were
inversely related to the EF changes. The heart rate declined
significantly more in patients experiencing a >5% improvement in EF
than in those with a 5% decrease in EF (-13.1±13.7 versus
-4.2±10.1 bpm, P=.037), and patients not showing a
substantial change in EF had an intermediate heart rate response
(-11.1±14.2 bpm). The heart rate changes did not differ between the
EF subgroups in the placebo-treated group. There was no difference
in blood pressure changes in the EF subgroups regardless of
treatment.
Effect of Amiodarone on Clinical Status and Physical
Findings
NYHA functional class did not change significantly over the first
12 months of follow-up, and there were no intergroup differences.
Fig 2 illustrates the proportions of patients exhibiting
an improvement or a worsening in NYHA functional class after 3, 6, 12,
and 24 months. There were no significant differences between the
treatment groups at any time point.
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To evaluate patients' subjective assessment of their clinical status, they were also asked to rate whether they were improved, unchanged, or worse. Again, there was no apparent difference between the treatment groups.
Table 2 lists the proportion of patients who were found
to have physical findings indicative of clinical heart failure. There
is an apparent trend toward a lower incidence of third heart sounds in
the amiodarone group during the first 12 months of
follow-up. However, these results were not corrected for multiple
comparisons, and the intergroup differences are relatively small and
variable from visit to visit. Jugular distension trended in the
opposite direction.
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Analyses of the subset of patients who remained "on treatment" did not alter the findings with regard to these indexes of clinical status and physical findings.
Clinical Evidence of Heart Failure Progression
During the course of follow-up, the dose of diuretics
was increased in 76 patients and reduced in 30. There were no
significant differences between the amiodarone and placebo
group in the proportions of patients experiencing upward and downward
adjustment of diuretic dose.
Hospitalizations for worsening CHF occurred in 167 of the 674 patients
(25%). There was no significant intergroup difference in the
proportion of patients hospitalized (13.6% on placebo and 11.1% on
amiodarone, P=.14). Fig 3 shows the
Kaplan-Meier curves for survival without hospitalization for heart
failure. By this analysis as well, there was no significant
reduction in the number of hospitalizations by amiodarone
therapy. An analysis limited to the patients who remained on
randomized therapy also showed no significant difference in the number
of hospitalizations between the amiodarone and placebo
groups.
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) and the placebo patients (
). The
numbers below indicate the numbers of patients remaining under
follow-up after each year.
Fig 4 shows Kaplan-Meier curves for survival without
cardiac death or hospitalization for CHF. There was a trend toward a
reduction in this end point with amiodarone (relative risk,
0.82 [95% CI, 0.65 to 1.03]; P=.08). Of note, as shown in
Fig 5, is that there was no between-treatment
difference in this outcome in patients with ischemic heart
disease (relative risk, 0.95 [95% CI, 0.73 to 1.24];
P=.69), but there was a substantial reduction in events in
the nonischemic group (relative risk, 0.56 [95% CI, 0.36
to 0.87]; P=.01).
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Discussion |
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This study provides two major, and apparently contradictory, findings. It is clear that amiodarone therapy was associated with a substantial and persistent increase in left ventricular EF. However, this improvement did not translate into a significant improvement in clinical symptoms, physical findings, or major outcomes related to CHF in the study population as a whole.
Possible Explanations for Unexpected Findings
The first question that arises from this apparent paradox is
whether the EF change reflects improved left ventricular
function. It is possible that the initial EF measurements were
inaccurate because of a high frequency of ventricular
ectopy and that they appeared to rise during amiodarone
treatment because ectopy was reduced (premature ventricular
contraction frequency declined from 254±370 to 44±145 per hour, and
the proportion of patients with ventricular
tachycardia decreased from 77% to 33% at 3
months).8 The use of beat rejection algorithms on most
computers makes this unlikely, however. EF is load dependent and
therefore may be affected by changes in left ventricular
afterload or preload. Although amiodarone has vasodilator
properties, it did not significantly reduce blood pressure, and there
was no relation between blood pressure and EF change. The fact that the
participants in this trial were already receiving more potent
vasodilators also makes this explanation less likely.
The changes in heart rate are more likely to have played a role in the EF responses. The decline in heart rate was significantly greater in the amiodarone group, but even more notable is the inverse relation between the magnitude of heart rate reduction and the increase in EF. There are several ways in which the heart rate and EF changes could be linked. When left ventricular preload is inadequate (preload mismatch), such as in the setting of tachycardia or mitral stenosis, EF may underestimate left ventricular function.10 However, preload mismatch is unlikely in a dilated cardiomyopathy population. Also, it is recognized that in both animals and humans, chronic, excessive tachycardia can depress left ventricular function and induce reversible heart failure in previously normal ventricles.11 12 In the setting of dilated or ischemic cardiomyopathy, a decrease in heart rate might therefore result in improved left ventricular performance.
Last, it is likely that the negative chronotropic action of amiodarone is explained in part by its noncompetitive ß-adrenoreceptor–blocking activity.13 14 The decrease in heart rate with amiodarone, particularly at high doses, may be substantial and may in the short term impair cardiac output15 but during chronic treatment appears to be compensated for by the increase in EF.
Relation to Previous Results With Amiodarone
A number of studies have demonstrated an improvement in left
ventricular EF or clinical heart failure end points with
amiodarone therapy.1 2 3 Cleland et al1
reported an improvement in central hemodynamics with
amiodarone therapy in patients with heart failure, but their
study was small and nonrandomized. Hamer et al2 found an
increase in both EF and exercise tolerance in a prospective, randomized
trial. However, both of these studies were small, and harder clinical
end points were not examined. Furthermore, unlike the present
study, background vasodilator therapy was not consistently
used.
The most important previous study of amiodarone in patients with CHF is the Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA) trial.3 In GESICA, in contrast to the Veterans Affairs trial, all-cause mortality was reduced by 28% (P<.03), and sudden death mortality was reduced by 27% (P=.056). For comparison with the present study, the most relevant findings from GESICA were the 23% reduction in deaths from progressive heart failure and the 31% decrease in the combined end point of death plus hospitalization for heart failure. In addition, a higher proportion of amiodarone-treated patients improved by at least one NYHA functional class. Serial measurements of EF and changes in other heart failure indexes were not reported.
Possible explanations for the divergent results of these two trials have been discussed previously.8 The most likely of these is the substantially lower proportion of GESICA patients with ischemic cardiomyopathy (39% versus 72%). In the present study, although amiodarone produced no significant differences in the number of hospitalizations for CHF or in survival in the entire population, in the nonischemic patients both the number of hospitalizations and the combination of number of hospitalizations and cardiac death were reduced by 44%. No differences were noted in the ischemic group. Thus, the present results are quite consistent with the 31% decrease in number of hospitalizations and death in GESICA, which included a population weighted toward nonischemic disease. There is growing evidence that nonischemic heart failure may respond better to a variety of therapeutic interventions, such as ß-blockers and calcium channel blockers.16 17 18 19 20 21
Other differences between the trials include the greater severity of illness in GESICA, as demonstrated by several indexes: 79% were in NYHA functional class III or IV versus 43% in the Veterans Affairs trial; mean EF was lower (20% versus 25%); and the 2-year placebo group mortality rate was higher (55% versus 30%). The dose of amiodarone was smaller in GESICA (300 mg/d versus 400 mg/d for the first year), and the drop-out rate was lower. Finally, because treatment was not blinded in GESICA, there was a potential for bias that may be more relevant for soft heart failure end points than for survival analyses.
Interpretation of EF Changes in Heart Failure Trials
The discordance between the EF results and clinical end points
during CHF therapy in the present trial and in previous studies has
important ramifications. Although intuitively improvement in indexes of
cardiac function in patients with CHF appears to be beneficial,
experience has often contradicted this assumption. Many agents that
produce substantial improvement in hemodynamic
measurements, such as ß-adrenoreceptor agonists,
phosphodiesterase inhibitors, and potent vasodilators, have
had adverse, rather than beneficial, effects on
prognosis.22 23 Changes in EF have had variable
prognostic value. Angiotensin-converting enzyme
inhibitors have relatively little effect on EF but a
significant beneficial effect on survival. In contrast, positive
inotropic agents, including digoxin, and vasodilator regimens, such as
the combination of hydralazine and isosorbide dinitrate,
increase EF but have an adverse, unknown, or at least less beneficial
effect on survival than angiotensin-converting enzyme
inhibitors.22 23 24 25
This variable relation between EF and prognosis has been thought to reflect the different mechanisms by which drugs may affect EF. Positive inotropic agents may increase contractility while exacerbating the imbalance between energy supply and demand of the failing heart. Vasodilators may improve EF by altering loading conditions, but they also have the potential to activate adverse neurohormonal systems. Angiotensin-converting enzyme inhibitors may accomplish the former without stimulating the latter response.
Of all of the medications investigated for the treatment of heart failure, ß-blockers have produced what may be the most consistent and surprising effects on EF.16 17 18 19 20 26 27 28 Despite their potential negative inotropic actions, during long-term therapy EF tends to rise, frequently substantially. This has been thought to reflect reversal of underlying cardiac dysfunction, perhaps by preventing catecholamine toxicity or restoring energetic balance.16 17 Because amiodarone also inhibits adrenergic excitation by a noncompetitive mechanism,13 14 by analogy this becomes a possible mechanism for its positive effect on EF. Several additional findings with amiodarone are analogous to the experience with ß-blocker. Amiodarone appeared to have a beneficial effect on clinical outcomes in the patients without evidence of ischemic heart disease, but no effect was seen in those with heart failure due to coronary disease. ß-Blockers also tend to produce greater improvements in EF and clinical status in the primary cardiomyopathy group.20 26 Furthermore, as in this study, the primary benefit of ß-blockers in these nonischemic patients occurs on end points related to progressive heart failure,18 20 including hospitalizations for CHF.
Potential Limitations
The occurrence of a type II error for some of the end points
examined in this study cannot be excluded. Although the lack of
difference from placebo for the study population as a whole was a
consistent finding across symptomatic, physical
examination and clinical end points, the 18% reduction in the combined
end point of cardiac death and hospitalization for heart failure
approached statistical significance. If this were the case, however, it
is likely that a benefit was present in only the
nonischemic group. The high withdrawal rate may have also
limited the power to detect positive end points, but analyses
of the subset of patients who remained on therapy showed similar
effects as the intention-to-treat analyses, so it is
unlikely that important drug effects were missed for this reason.
This study did not include measurements of exercise tolerance, which is a frequently used end point in heart failure studies and one that has been previously noted to improve during amiodarone therapy.2 Still, the clinical importance is questionable of a change in exercise capacity without any associated evidence of clinical benefit. Indeed, divergent effects between short-term changes in exercise tolerance and long-term clinical outcome have also been noted, most prominently with flosequinan.22 29
Implications
This trial highlights the potential discordance between
measurements of cardiac function and clinical assessments.
Amiodarone therapy was associated with a substantial rise in
left ventricular EF but no improvement in symptoms,
clinical signs of CHF, or overall outcome. It is tempting to make an
analogy with the arrhythmia suppression experience. Spontaneous
increases in EF probably indicate improved cardiac function and
amelioration of the underlying pathology, carrying with them a better
prognosis. Drugs that produce significant increases in EF do not
necessarily improve outcome with regard to heart failure status or
survival. With some agents and in heart failure of some etiologies,
there may be a closer link between EF changes and prognosis. Indeed,
this may be the case with amiodarone in the subset of patients
with nonischemic cardiomyopathy.
Without additional data, however, the present results do not
provide convincing evidence that amiodarone produces clinically
significant improvement in the symptoms, signs, or prognosis of most
patients with heart failure.
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Acknowledgments |
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This study was supported by the Department of Veterans Affairs Cooperative Studies Program, Washington, DC, and by supplementary grants from Sanofi Winthrop Recherche, Paris, France, and Wyeth-Ayerst Laboratories, Philadelphia, Pa.
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Footnotes |
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1 See "Appendix."
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Participating Veterans Affairs Medical Centers and Investigators
Bronx VAMC, Bronx, NY: P. Schwitzer, P. Patascil; Chicago West Side VAMC, Chicago, Ill: J. Cumming, T. Redmond; Dallas VAMC, Dallas, Tex: P. Grayburn, S. Dougherty; Fresno VAMC, Fresno, Calif: P.C. Deedwania, R. Kanefield; Jackson VAMC, Jackson, Miss: T.N. Srivastava, T. King; Kansas City VAMC, Kansas City, Mo: D. Lewis, R. Corbett; Loma Linda VAMC, Loma Linda, Calif: D.R. Ferry, K. Okubo; Long Beach VAMC, Long Beach, Calif: R. Wesley, S. Saniga; Louisville VAMC, Louisville, Ky: A. Joseph, N. Zettwoch; Madison VAMC, Madison, Wis: P. Kosolcharoen, K. Cox; Miami VAMC, Miami, Fla: C.S. Chakko, J. Johnson; Newington VAMC, Newington, Conn: M.J. Radford, D. Roth; North Chicago VAMC, Chicago, Ill: R. Singh, A. Skillman; Oklahoma VAMC, Oklahoma City: R. Lazzara, T. Deacon; Pittsburgh VAMC, Pittsburgh, Pa: M. Amici, J. Pullman; Providence VAMC, Providence, RI: S. Sharma, E. Cocci; Richmond VAMC, Richmond, Va: K.A. Ellenbogen, E. Early; Salem, Vir: D. Russell, M. Judd; Salt Lake City VAMC, Salt Lake City, Utah: R. Klein, L. Morrison; San Francisco VAMC, San Francisco, Calif: B. Massie, E. Der; Sepulveda VAMC, Sepulveda, Calif: V.N. Udhoji, P. Pekale; Syracuse VAMC, Syracuse, NY: R. Warner, P. Lilja; Washington VAMC, Washington, DC: R. Hall, D. Lazzeri; West Haven VAMC, West Haven, Conn: I. Cohen, L. Canestri.
Cochairmen's Office, Washington, DC
S.N. Singh, R.D. Fletcher, D. Lazzeri.
Cooperative Studies Program Central Research Pharmacy,
Albuquerque, NM
M. Sather (chief), C.L. Colling (study pharmacist).
Central Holter Monitor Laboratory, Washington,
DC
R.D. Fletcher.
Hines Cooperative Studies Program Coordinating Center
W.G. Henderson (chief), S. Gross Fisher (biostatistician), L.
Weber (study programmer), D. Cavello and M. Biondic (study
coordinators)
Data and Safety Monitoring Board
J.T. Bigger (chairman), J. Anderson, D. Echt, M. Packer, J.
Morganroth, G. Williams.
Executive Committee
S. Singh, R. Fletcher, S. Gross Fisher, P. Deedwania, D. Lewis,
B. Massie, B.N. Singh, C. Colling.
Mortality Committee
B.N. Singh (chairman), D. Lewis, S. Singh, S. Gross Fisher.
Department of Veterans Affairs Central Office
D. Deykin (chief of Cooperative Studies Program), J. Gold
(administrative officer), P. Huang (staff assistant).
Received September 18, 1995; revision received November 29, 1995; accepted December 10, 1995.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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1. Cleland JG, Dargie HJ, Findlay IN, Wilson JT. Clinical, haemodynamic, and antiarrhythmic effects of long term treatment with amiodarone of patients with heart failure. Br Heart J. 1987;57:436-445.
2. Hamer AW, Arkles LB, Johns JA. Beneficial effects of low dose amiodarone in patients with congestive cardiac failure: a placebo-controlled trial. J Am Coll Cardiol. 1989;14:1768-1774. [Abstract]
3. Doval HC, Nul DR, Grancelli HO, Perrone SV, Bortman GR, Curiel R. Randomised trial of low-dose amiodarone in severe congestive heart failure. Lancet. 1994;344:493-498. [Medline] [Order article via Infotrieve]
4. Pratt CM, Eaton CM, Francis M, Woolbert S, Mahmarian J, Roberts R, Young JB. The inverse relationship between baseline left ventricular ejection fraction and outcome of antiarrhythmic therapy: a dangerous imbalance in the risk-benefit ratio. Am Heart J. 1989;118:433-440. [Medline] [Order article via Infotrieve]
5. Stevenson WG. Mechanisms and management of arrhythmias in heart failure. Curr Opin Cardiol. 1995;10:274-281. [Medline] [Order article via Infotrieve]
6.
Hohnloser SH, Klingenheben T, Singh BN.
Amiodarone associated proarrhythmic effects: a review
with special reference to torsade de pointes
tachycardia. Ann Intern Med. 1994;121:529-535.
7. Chatterjee K. Amiodarone in chronic heart failure. J Am Coll Cardiol. 1989;14:1755-1756. Editorial.
8.
Singh SN, Fletcher RD, Fisher SG, Singh BN, Lewis HD,
Deedwania PC, Massie BM, Colling C, Lazzeri D.
Amiodarone in patients with congestive heart failure and
asymptomatic ventricular
arrhythmia. N Engl J Med. 1995;333:77-82.
9. Singh S, Fletcher RD, Fisher S, Deedwania P, Lewis D, Massie B, Singh B, Colling CL. Congestive heart failure: survival trial of antiarrhythmic therapy (CHF-STAT). Control Clin Trials. 1992;13:339-350. [Medline] [Order article via Infotrieve]
10. Ross J Jr. Afterload mismatch and preload reserve: a conceptual framework for the analysis of ventricular function. Prog Cardiovasc Dis. 1976;18:255-264. [Medline] [Order article via Infotrieve]
11. Grogan M, Smith HC, Gersh BT, Wood DL. Left ventricular dysfunction due to atrial fibrillation in patients initially believed to have idiopathic dilated cardiomyopathy. Am J Cardiol. 1992;69:1570-1573. [Medline] [Order article via Infotrieve]
12. Brignole M, Gianfranchi L, Menozzi C, Bottoni N, Bollini R, Lolli G, Oddone D, Gaggioli G. Influence of atrioventricular junction radiofrequency ablation in patients with chronic atrial fibrillation and flutter on quality of life and cardiac performance. Am J Cardiol. 1994;74:242-246. [Medline] [Order article via Infotrieve]
13. Freedman M, Somberg JC. Pharmacology and pharmacokinetics of amiodarone. J Clin Pharmacol. 1991;31:1061-1069. [Abstract]
14.
Podrid PJ. Amiodarone: reevaluation of
an old drug. Ann Intern Med. 1995;122:689-700.
15. Gottlieb SS, Riggio DW, Lauria S, Peters RW, Shorofsky SR, Cines M, Froman D, Gold MR. High dose oral amiodarone loading exerts important hemodynamic actions in patients with congestive heart failure. J Am Coll Cardiol. 1994;23:560-564. [Abstract]
16. Eichhorn EJ. The paradox of beta-adrenergic blockade for the management of congestive heart failure. Am J Med. 1992;92:527-538. [Medline] [Order article via Infotrieve]
17. Doughty RN, MacMahon S, Sharpe N. Beta-blockers in heart failure: promising or proved? J Am Coll Cardiol. 1994;23:814-821. [Abstract]
18. Waagstein F, Bristow MR, Swedberg K, Camerini F, Fowler MB, Silver MA, Gilbert EM, Johnson MR, Goss FG, Hjalmarson A. Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Lancet. 1993;342:1441-1446. [Medline] [Order article via Infotrieve]
19.
Bristow MR, O'Connell JB, Gilbert EM, French WJ,
Leatherman G, Kantrowitz NE, Orie J, Smucker ML, Marshall G, Kelly P,
Deitchman D, Anderson JL. Dose-response of chronic
ß-blocker treatment in heart failure from either idiopathic
dilated or ischemic cardiomyopathy.
Circulation. 1994;89:1632-1642.
20.
CIBIS Investigators. A randomized trial of
ß-blockade in heart failure: the Cardiac Insufficiency Bisoprolol
Study (CIBIS). Circulation. 1994;90:1765-1773.
21. Packer M. Results of the Prospective Randomized Amlodipine Survival Evaluation (PRAISE) trial. Presentation at American College of Cardiology Scientific Meeting, April 1995.
22. Packer M, Rouleau J, Swedberg K, Pitt B, Fisher L, Klepper M, and PROFILE Investigators and Coordinators. Effect of flosequinan on survival in chronic heart failure: preliminary results of the PROFILE study. Circulation. 1993;88(suppl I):I-301. Abstract.
23. Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, Hendrix GH, Bommer WJ, Elkayam U, Kukin ML, Mallis GI, Sollano JA, Shannon J, Tandon PK, DeMets DL. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med. 1991;325:1468-1475. [Abstract]
24.
Packer M, Gheorghiade M, Young JB, Costantini PJ, Adams
KF, Cody RJ, Smith LK, Van Voorhees L, Gourley LA, Jolly MK.
Withdrawal of digoxin from patients with chronic heart failure
treated with angiotensin-converting-enzyme
inhibitors: RADIANCE study. N Engl
J Med. 1993;329:1-7.
25. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R, Dunkman WB, Loeb H, Wong M, Bhat G, Goldman S, Fletcher RD, Doherty J, Hughes CV, Carson P, Cintron G, Shabetai R, Haakenson C. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med. 1991;325:303-310. [Abstract]
26.
Woodley SL, Gilbert EM, Anderson JL, O'Connell JB,
Deitchman D, Yanowitz FG, Mealey PC, Volkman K, Renlund DG, Menlove R,
Bristow MR. ß-Blockade with bucindolol in heart failure caused
by ischemic versus idiopathic dilated
cardiomyopathy.
Circulation. 1991;84:2426-2441.
27. Fisher ML, Gottlieb SS, Plotnick GD, Greenberg NL, Patten RD, Bennett SK, Hamilton BP. Beneficial effects of metoprolol in heart failure associated with coronary artery disease: a randomized trial. J Am Coll Cardiol. 1994;23:943-950.
28. Olsen SL, Gilbert EM, Renlund DG, Taylor DO, Yanowitz FD, Bristow MR. Carvedilol improves left ventricular function and symptoms in chronic heart failure: a double-blind, randomized study. J Am Coll Cardiol. 1995;25:1225-1231.
29.
Massie BM, Berk MR, Brozena SC, Elkayam U, Plehn JF,
Kukin ML, Packer M, Murphy BE, Neuberg GW, Steingart RM, Levine TB,
DeHaan H. Can further benefit be achieved by adding flosequinan
to patients with congestive heart failure who remain
symptomatic on diuretic, digoxin, and an
angiotensin converting enzyme inhibitor?
Results of the flosequinan-ACE inhibitor trial
(FACET). Circulation. 1993;88:492-501.
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|
|
|
|
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|
|
|
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|
|
|
|
|
|
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|
|
|
|
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|
|
|
|
|
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|
|
|
|
|
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|
|
|
|
 |
|
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|
|
|
|
 |
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|
|
|
|
 |
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
|
|
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|
|
|
|
 |
|
 Amiodarone Improves Ventricular Function Journal Watch Cardiology, September 1, 1996; 1996(901): 4 - 4. [Full Text]
|
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