Effect of Amiodarone on Clinical Status and Left Ventricular Function in Patients With Congestive Heart Failure
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.
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.
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 β-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.
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.
Differences between treatment groups in categorical and continuous variables were detected with the χ2 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 α level of .05 was considered statistically significant; no adjustment was made for multiple comparisons. Data are presented as mean±1 SD.
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.
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.
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.
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.
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.
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).
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 β-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 β-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 β-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, β-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 β-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. β-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 β-blockers in these nonischemic patients occurs on end points related to progressive heart failure,18 20 including hospitalizations for CHF.
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
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.
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
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.
S. Singh, R. Fletcher, S. Gross Fisher, P. Deedwania, D. Lewis, B. Massie, B.N. Singh, C. Colling.
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).
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.
↵1 See “Appendix.”
- Received September 18, 1995.
- Revision received November 29, 1995.
- Accepted December 10, 1995.
- Copyright © 1996 by American Heart Association
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