(Circulation. 1995;92:1499-1506.)
© 1995 American Heart Association, Inc.
Articles |
Double-Blind, Placebo-Controlled Study of the Long-term Efficacy of Carvedilol in Patients With Severe Chronic Heart Failure
From the Division of Circulatory Physiology and Center for Heart Failure Research, Columbia University, College of Physicians and Surgeons, and the Division of Cardiology, Mount Sinai School of Medicine, New York, NY.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion References |
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Background Clinical trials have shown that ß-adrenergic blocking drugs are effective and well tolerated in patients with mild to moderate heart failure, but the utility and safety of these drugs in patients with advanced disease have not been evaluated.
Methods and Results We enrolled 56 patients with severe chronic heart failure into a double-blind, placebo-controlled study of the vasodilating ß-blocker carvedilol. All patients had advanced heart failure, as evidenced by a mean left ventricular ejection fraction of 0.16±0.01 and a mean maximal oxygen consumption of 13.6±0.6 mL · kg-1 · min-1 despite digitalis, diuretics, and an angiotensin-converting enzyme inhibitor (if tolerated). After a 3-week, open-label, up-titration period, 49 of the 56 patients were assigned (in a double-blind fashion using a 2:1 randomization) to receive either carvedilol (25 mg BID, n=33) or matching placebo (n=16) for 14 weeks, while background therapy remained constant. Hemodynamic and functional variables were measured at the start and end of the study. Compared with the placebo group, patients in the carvedilol group showed improved cardiac performance, as reflected by an increase in left ventricular ejection fraction (P=.005) and stroke volume index (P=.010) and a decrease in pulmonary wedge pressure, mean right atrial pressure, and systemic vascular resistance (P=.003, .002, and .017, respectively). In addition, compared with placebo, patients treated with carvedilol benefited clinically, as shown by an improvement in symptom scores (P=.002), functional class (P=.013), and submaximal exercise tolerance (P=.006). The combined risk of death, worsening heart failure, and life-threatening ventricular tachyarrhythmia was lower in the carvedilol group than in the placebo group (P=.028), but carvedilol-treated patients had more dizziness and advanced heart block.
Conclusions Carvedilol produces clinical and hemodynamic improvement in patients who have severe heart failure despite treatment with angiotensin-converting enzyme inhibitors.
Key Words: heart failure • carvedilol • receptors, adrenergic, beta
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Introduction |
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TopAbstractIntroductionMethods Results Discussion References |
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Both experimental and clinical evidence suggests that activation of the sympathetic nervous system contributes importantly to the progression of left ventricular dysfunction to end-stage heart failure.1 This belief has led to the evaluation of ß-adrenergic blocking drugs in patients with heart failure in an attempt to interfere with the deleterious effects of prolonged sympathetic stimulation.2 Controlled clinical trials have shown that the long-term administration of metoprolol, bucindolol, nebivolol, bisoprolol, and carvedilol can improve ventricular function and clinical status in selected patients with an idiopathic dilated cardiomyopathy.3 4 5 6 7 8 9 In addition, long-term therapy with propranolol can reduce mortality in patients with left ventricular dysfunction after a myocardial infarction.10
Despite these encouraging results, physicians remain concerned that ß-blockers may be detrimental to patients with established heart failure. Such fears may be particularly warranted in patients with the most advanced disease, in whom the sympathetic nervous system may play a supportive (rather than deleterious) role to support cardiac contractility.11 In this regard, it is noteworthy that previous studies of ß-blockade in heart failure generally evaluated only patients with mild to moderate symptoms3 4 5 6 7 8 12 13 14 or mild to moderate hemodynamic abnormalities (ejection fraction >0.20 to 0.25 and pulmonary wedge pressure <14 to 18 mm Hg),3 4 5 6 7 8 9 10 12 13 14 and in most cases, these patients were not resistant to treatment with angiotensin-converting enzyme (ACE) inhibitors. In the few reports in which ß-blockers were given to patients with severe hemodynamic and clinical abnormalities, treated patients commonly failed to show improvement, and many tolerated the drugs poorly.15 16 These observations raised questions about the utility of ß-blockers in heart failure, since these drugs would be difficult to use if they were valuable only when patients had few symptoms but exacerbated the severity of heart failure in patients with progressive disease.
The objective of the present study was to evaluate the long-term
efficacy and safety of ß-blockade in patients who had severe chronic
heart failure despite the use of ACE inhibitors. The ß-blocker used
in this study was carvedilol, which, in addition to having mildly
selective effects on ß1-receptors, exerts peripheral
vasodilator effects by blocking
1-receptors.17 18 These vasodilator
properties may enhance the efficacy and safety of ß-blockade in
patients with advanced disease.
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Methods |
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TopAbstractIntroductionMethods Results Discussion References |
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Patient Population
Patients with chronic heart failure who remained symptomatic despite conventional therapy were eligible for the study. Heart failure was defined as the presence of dyspnea or fatigue at rest or on exertion for >2 months in association with a left ventricular ejection fraction
0.35 as assessed by
radionuclide ventriculography. All patients had one or more of the
following characteristics indicative of advanced disease: (1) New York
Heart Association functional class III or IV symptoms; (2) maximal
oxygen consumption <14
mL · kg-1 · min-1; or (3)
pulmonary wedge pressure 
18 mm Hg. These clinical and
physiological abnormalities were present
despite 2 months of treatment with digoxin, diuretics (in
sufficient doses to maintain patients free of edema), and an ACE
inhibitor (except for five patients who could not tolerate
captopril or enalapril). The doses of these drugs were kept constant
for at least 2 weeks before entry into the study. Patients were excluded from participation in the study if they had uncorrected primary valvular disease, active myocarditis, or an obstructive, hypertrophic, or restrictive cardiomyopathy. Patients were also excluded if they had active angina, a myocardial infarction or stroke within the past 3 months, significant hepatic or renal disease, high-degree atrioventricular block, or chronic obstructive pulmonary disease. Patients receiving calcium channel blockers, ß-adrenergic agonist or antagonist drugs, or antidepressant agents were not enrolled. The protocol was approved by the institutional review boards of the two participating institutions, and informed consent was obtained from all study patients.
Study Protocol
During a 5-day period before entry into the
study, all patients
underwent the following functional, hemodynamic, and
physiological evaluations.
Clinical status was investigated by two methods: (1) Functional capacity was assessed by the physician according to the New York Heart Association classification and (2) symptom severity was quantified by the patient in a questionnaire that inquired about the severity of seven specific symptoms of heart failure in a manner that closely mimicked the usual patient-physician dialogue. The responses to these questions were summed to produce a symptom score ranging from 0 (least symptoms) to 21 (worst symptoms).
Effort tolerance was evaluated in two ways: (1) Maximal exercise capacity was assessed by the measurement of peak oxygen consumption during graded bicycle exercise accompanied by gas exchange measurements19 and (2) submaximal exercise tolerance was determined by the measurement of the distance traversed during a 6-minute walk.20
Ventricular function was investigated by both invasive and noninvasive approaches: (1) Right heart catheterization was performed to measure thermodilution cardiac output, intracardiac and pulmonary pressures, and derived hemodynamic variables with procedures and formulas that have been published in detail elsewhere21 ; and (2) left ventricular ejection fraction was quantified by radionuclide ventriculography.
Blood was collected for the measurement of (1) serum electrolytes and renal function, (2) plasma norepinephrine and epinephrine (by high-performance liquid chromatography22 ), and (3) serum aldosterone (by radioimmunoassay23 ) from an indwelling catheter after the patient had rested in the supine position for at least 1 hour.
After completion of these baseline measurements, all patients entered an open-label run-in phase during which they received carvedilol 3.125 mg orally twice daily for 1 week, 6.25 mg orally twice daily for 1 week, and 12.5 mg orally twice daily for 1 week. If carvedilol was well tolerated during this run-in period, patients were randomly assigned in a double-blind fashion (2:1 allocation) to continue to receive carvedilol or to be switched to placebo. During the double-blind treatment period, patients received 12.5 mg (carvedilol or placebo) orally twice daily for 1 week and then 25 mg (carvedilol or placebo) orally twice daily for a total of 14 weeks of blinded therapy. Background therapy with digoxin, diuretics, and ACE inhibitors was kept constant during this period, although transient changes (generally <1 week in duration) in the doses of these medications could be made if clinically indicated. Open-label therapy with carvedilol (or any other ß-blocker) was not allowed. At the end of the double-blind phase, all functional, hemodynamic, and physiological evaluations that were performed at the start of the study were repeated with identical procedures and methods.
Statistical Analysis
The primary objective of the study was
to evaluate the effect of
carvedilol (compared with placebo) on clinical and functional
variables (functional class symptoms and exercise tolerance) in
patients with advanced heart failure. The secondary objectives of the
study were to evaluate the effects of carvedilol (compared with
placebo) on hemodynamic, neurohormonal, and
physiological variables.
All analyses were carried out using statistical methods specified before the blind was broken. The baseline characteristics of the two treatment groups were compared by the Mann-Whitney U test for continuous variables and the Fisher exact test for categorical variables. Treatment effects were assessed by performing between-group comparisons, and analyses were carried out according to the patients' original randomized assignments (intention-to-treat principle). For these primary analyses, an ANOVA procedure was used for normally distributed data, and the Mann-Whitney U test was used for non–normally distributed data. Differences in the cumulative risk of cardiovascular events in the two treatment groups were evaluated for significance by the Mantel-Cox log-rank test.
After these prespecified analyses were completed, two additional analyses were performed. First, changes in measured variables within each treatment group during the study were evaluated for significance by ANOVA and the Wilcoxon signed rank test. Second, changes in measured variables between the two treatment groups were adjusted for baseline differences in mean arterial pressure by an ANCOVA procedure on ranked means using the baseline mean arterial pressure as the covariate.
All analyses were two-sided, and differences with P<.05 were considered statistically significant.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Open-Label Phase of the Study
We enrolled 56 patients (45 men and 11 women, 25 to 79 years old) with chronic heart failure into the study. The cause of heart failure was idiopathic dilated cardiomyopathy in 33 patients, ischemic heart disease in 17 patients, and primary valvular regurgitation in 5 patients (all had undergone mitral and/or aortic valve replacement). Seventy-three percent of the patients had class III or IV symptoms (class III in 35 patients and class IV in 6 patients); 64% had a peak oxygen consumption (
O2max) of
<14
mL · kg-1 · min-1; and 80% had
a
pulmonary wedge pressure 18 mm Hg. Values for left
ventricular ejection fraction ranged from 0.05 to 0.35
(mean, 0.16). Of these 56 patients, 7 entered but failed to complete the open-label run-in phase of the study. One patient died suddenly (while receiving 6.25 mg of carvedilol twice daily), 2 patients died of progressive heart failure (1 while receiving 6.25 mg twice daily and the other while receiving 12.5 mg twice daily), and 1 patient died of digitalis toxicity (while receiving 3.125 mg twice daily). Two patients withdrew because of nonfatal adverse reactions: wheezing in 1 (while receiving 12.5 mg twice daily) and dehydration, renal insufficiency, hyperkalemia, digitalis toxicity, and junctional rhythm in another (while receiving 3.125 mg twice daily). The seventh patient withdrew because of noncompliance with appointments and medications. The patients who withdrew from the open-label phase did not differ in their pretreatment characteristics from the patients who completed this phase of the study.
Of the 49 patients (88%) who completed the open-label run-in period, 18 (37%) developed increased dyspnea or fluid retention during this phase of the study. This symptom was managed by a transient increase in the dose of diuretics (in all 18 patients) and a delay in the schedule of weekly dosage increments of carvedilol (in 11 of the 18 patients). In addition, 11 of the 49 patients (22%) experienced dizziness during the open-label run-in period. This symptom was managed by decreasing the dose of the ACE inhibitor in 1 patient and transiently decreasing the dose of diuretic in 2. Dizziness disappeared inthe remaining 8 patients without any additional intervention.
The 49 patients were randomly assigned (2:1)
to long-term therapy with
carvedilol (33 patients) or placebo (16 patients). The baseline
characteristics of these patients are summarized in Table 1
.
The two groups were similar with respect to all 28
pretreatment clinical, functional, and
physiological characteristics except for mean
arterial pressure and the derived variable, systemic
vascular resistance, which (by chance) were higher in the patients
randomly assigned to carvedilol than in those assigned to placebo.
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Efficacy of Carvedilol During the Double-Blind Phase of the
Study
Of the 49 patients who entered the double-blind phase, 6 failed
to
complete the study (4 on carvedilol [12%] and 2 on placebo
[12%])
and thus did not undergo repeat measurements of efficacy. The effects
of placebo and carvedilol on the primary and secondary end points of
the study in the remaining 43 patients are summarized in Table
2.
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Clinical Effects
Patients treated with
carvedilol showed a marked improvement in
symptom scores (11.4 to 5.4, P=.0003) and functional class
(2.8 to 1.9, P<.0001), whereas these variables did not
change in patients receiving placebo (P<.001 and
P=.008, respectively, for the differences between the two
groups) (Fig 1). These clinical benefits were
accompanied by an increase in the distance traversed during a 6-minute
walk in the carvedilol group (+53 m on carvedilol versus -51 m on
placebo, P=.006 for the difference between the groups) (Fig
2), but the drug did not enhance maximal oxygen
consumption (Table 2
).
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Hemodynamic Effects
The clinical improvement produced by carvedilol was associated
with a significant improvement in cardiac performance. Compared
with the patients treated with placebo, patients treated with
carvedilol showed significant increases in stroke volume index (+10.4
versus -0.3 mL/m2, P=.015) and left
ventricular ejection fraction (+6.5 versus -0.4 units,
P=.005) and significant decreases in mean
arterial pressure (-11.4 versus +5.3 mm Hg,
P<.001), mean pulmonary artery pressure (-7.6
versus +3.3 mm Hg, P=.009), pulmonary wedge
pressure (-7.8 versus +2.6 mm Hg, P=.004), mean
right
atrial pressure (-4.1 versus +4.0 mm Hg, P=.001),
and
systemic vascular resistance (-17% versus +11%,
P=.017).
Despite the marked rise in stroke volume index, the cardiac index did
not increase with carvedilol, since the heart rate decreased
substantially during long-term treatment with the drug (-25 versus
-1
beats per minute, P<.001).
Physiological
Effects
In association with these favorable hemodynamic
and clinical responses, plasma epinephrine decreased in
patients treated with carvedilol (compared with placebo)
(P=.014), and this was accompanied by a decline in serum
aldosterone (P=.065) despite background therapy
with ACE inhibitors. Plasma norepinephrine also
tended to decline in patients treated with carvedilol, although this
effect was not significantly different from the change seen in patients
treated with placebo.
Secondary Analyses
The
magnitude and significance of these clinical,
hemodynamic, and physiological
effects produced by carvedilol were not altered when these changes were
adjusted with the baseline mean arterial pressure as a
covariate (to account for the higher mean arterial pressure
in patients randomized to carvedilol). In addition, the magnitude of
the clinical, hemodynamic, and
physiological effects produced by carvedilol
(corrected for the changes seen in the placebo group) was not different
in patients with (n=13) or without (n=36) coronary artery
disease as the cause of their heart failure.
Safety of Carvedilol During the Double-Blind Phase of the
Study
The adverse effects seen during the double-blind phase of the
study are shown in Table 3. Patients in the carvedilol
group tended to have a higher incidence of first-degree and advanced
heart block, but there were no significant differences between the
groups with respect to symptomatic
bradyarrhythmias. Patients receiving carvedilol tended to
experience more dizziness, but this symptom could be managed by
temporary adjustment of the doses of diuretics and ACE
inhibitor and did not require withdrawal of any patient
from the study. Worsening heart failure requiring
intravenous diuretic therapy or discontinuation of
the study medication was significantly more common in patients
randomized to placebo (P=.030). Clinically significant
tachyarrhythmias (two episodes of resuscitated
ventricular tachycardia/fibrillation) tended to be
more common in the placebo group but were treated without the
discontinuation of double-blind medication.
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Adverse reactions severe
enough to cause withdrawal from the study were
seen in a similar proportion of patients in the two groups (Table
3).
Of the 33 patients in the carvedilol group, 4 (12%) were withdrawn: 2
because of sudden death, 1 because of multi–organ system failure
eventually leading to death (cause unknown), and 1 because of renal
failure that reversed upon cessation of study medication. Of the 16
patients in the placebo group, 2 (12%) were withdrawn from the study:
1 died suddenly and 1 was the victim of a homicide. By intention to
treat, 2 of 16 patients (12%) in the placebo group and 3 of 33
patients (9%) in the carvedilol group died. Yet, the combined risk of
major cardiovascular events (defined as death,
worsening heart failure [requiring intravenous
diuretic therapy or discontinuation of the study medication],
and hemodynamically destabilizing
ventricular tachycardia or ventricular
fibrillation) was significantly lower in the carvedilol group than in
the placebo group (18% versus 44%, P=.028), Fig
3.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The present study demonstrates that, in those who tolerate low doses of the drug, ß-blockade with carvedilol produces clinical and hemodynamic benefits in patients with severe chronic heart failure. The addition of carvedilol to conventional therapy (including ACE inhibitors) led to an improvement in symptoms, functional capacity, and submaximal exercise tolerance. These beneficial clinical effects were accompanied by a significant enhancement of left ventricular performance, as evidenced by an increase in stroke volume index and left ventricular ejection fraction and a decrease in right and left ventricular filling pressures and systemic vascular resistance. The responses to carvedilol were similar in patients with or without coronary artery disease. Moreover, in the double-blind phase of the study, carvedilol was well tolerated and produced few serious adverse reactions. The major side effect of the drug was dizziness, which could generally be controlled by alterations in the doses of diuretics and ACE inhibitors. The results of this controlled trial indicate that ß-blockade with carvedilol may be useful in the management of advanced heart failure, regardless of the cause of cardiac dysfunction.
The findings of the present study are similar to the results of
previous placebo-controlled studies with ß-adrenergic blocking drugs
in patients with dilated cardiomyopathy. Earlier
studies with metoprolol, bucindolol, nebivolol, bisoprolol, and
carvedilol3 4 5 6 7 8 9
showed that long-term (>3 months) treatment
improved symptoms (as assessed by the patient and the physician) and
enhanced left ventricular performance (as assessed
by invasive and noninvasive measures of cardiac function). The
treatment effect reported in these previous trials is strikingly
similar in its direction and magnitude to the therapeutic effect seen
in the present study. However, as a whole, the patients enrolled in
the present study had more advanced disease than the patients
evaluated in any previous trial of ß-blockade in heart failure.
Whereas patients in earlier
studies3 4 5 6 7 8 12 13 14
generally had
mild to moderate symptoms of heart failure associated with a mean left
ventricular ejection fraction >0.20 to 0.25 and a mean
pulmonary wedge pressure <14 to 18 mm Hg, patients in the
present study had severe impairment of their functional capacity
(mean O2max=13.5
mL ·kg-1 · min-1) and had
advanced
cardiac dysfunction (mean left ventricular ejection
fraction of 0.16 and mean pulmonary wedge pressure of 24
mm Hg), despite the use of ACE inhibitors. One third of
our patients had systolic blood pressures <100 mm Hg and thus would
have been excluded from previous trials.9 These findings
are noteworthy in view of previous experience that has suggested that
patients with advanced disease fail to respond favorably to
ß-adrenergic blockade.15 However, these earlier studies
were uncontrolled, and thus the poor results may have reflected the
natural history of heart failure rather than a lack of response to
treatment. This possibility is supported by the results of the
present controlled trial, in which patients with advanced disease
experienced hemodynamic and clinical benefits from
ß-blockade in a manner similar to that reported in patients with mild
to moderate symptoms.
An important finding of the present study was that long-term treatment with carvedilol improved submaximal exercise tolerance (as assessed by the distance traversed during a 6-minute corridor walk) but did not enhance maximal exercise capacity (as assessed by gas exchange measurements). The lack of improvement in peak exercise performance is not surprising, in view of the ability of ß-blockers to attenuate exercise-induced increases in heart rate, an important determinant of maximal cardiac output and thereby of maximal oxygen delivery and consumption.24 Previous placebo-controlled studies with bucindolol, nebivolol, and carvedilol have also noted a lack of improvement in maximal exercise capacity4 5 6 7 ; the few studies that have reported a favorable effect on peak exercise performance with a ß-blocker either were uncontrolled or estimated exercise tolerance by indirect methods.3 25 Despite their ability to ameliorate symptoms, the inability of ß-blockers to improve maximal exercise tolerance in previous studies has raised doubts about the efficacy of these drugs, since the objective assessment of exercise tolerance is one of the key end points used in demonstrating the utility of a new therapeutic agent,26 and such measures generally parallel the symptomatic response to drug therapy.27 To address this issue, we added an evaluation of submaximal exercise performance to the conventional assessment of peak exercise capacity when we designed the present study, in the hope that this measure would provide an assessment of functional capacity that would not be influenced by the effect of ß-blockers on maximal heart rate. Our observation that carvedilol improved submaximal (but not maximal) exercise performance is consistent with recent observations7 and has important implications for the design of future clinical trials.
In addition to addressing concerns about efficacy, the present trial provides an opportunity to evaluate the safety of ß-blockade in patients with advanced heart failure. Previous investigators have questioned the use of ß-blockers in such patients because of reports indicating that these individuals are at high risk of serious adverse reactions, including worsening heart failure and death. In these reports, metoprolol was poorly tolerated in 5% to 15% of patients with mild to moderate heart failure,3 12 13 but this risk increased to nearly 50% in patients with severe disease.15 16 In the present study of patients with advanced disease, the frequency of adverse reactions during initiation of therapy with carvedilol was high; the majority of patients experienced an important cardiovascular event, which in some cases (4 of 56 patients, 7%) was fatal. Since this phase was not randomized, the relation of these events to therapy with carvedilol cannot be determined. Yet, it is noteworthy that in 83% of the patients who experienced side effects, these could be managed by adjustment of the dose of concomitant medications and did not prohibit continued treatment with the ß-blocker. More importantly, in patients who could tolerate the drug, the combined risk of death, worsening heart failure, and life-threatening ventricular arrhythmias was significantly lower in patients treated with carvedilol than in those treated with placebo. These observations suggest that even in patients at highest risk of side effects from therapy, the long-term benefits of ß-blockade may outweigh the short-term risks that accompany the initiation of treatment.
The mechanisms by which ß-adrenergic blockade may exert beneficial effects in patients with heart failure have not been elucidated, but two hypotheses have been proposed.28 On the one hand, the favorable responses to ß-blockade may be related to its ability to attenuate the adverse effects of prolonged sympathetic stimulation on the failing heart.1 High concentrations of catecholamines can exert toxic effects on the myocardium,29 30 and the withdrawal of this deleterious influence for long periods can restore cardiac performance toward normal levels.14 31 On the other hand, the favorable responses to ß-blockers may be related to their ability to reverse the ß-receptor downregulation that is characteristic of patients with heart failure13 ; the resulting increase in ß-receptor density may provide hemodynamic benefits by sensitizing the heart to the inotropic and lusitropic effects of endogenous catecholamines. However, this hypothesis is difficult to support, since the cardiac ß-receptors (although increased in density) remain blocked in the presence of a ß-blocker (at least at rest), and yet, cardiac performance at rest improves markedly during treatment with these drugs.28 Furthermore, this mechanism cannot explain the benefits of carvedilol in heart failure, since this ß-blocker does not increase the density of cardiac ß-receptors because of the unique binding properties of the drug.32 33 Taken together, these observations suggest that ß-receptor upregulation is not the primary mechanism responsible for the benefits of ß-blockers in heart failure.
Nevertheless, the benefits of carvedilol in the present study may
not be explained solely by its ß-blocking properties. Unlike other
ß-blockers that have been used in heart failure, carvedilol also
blocks -adrenergic receptors; the resulting vasodilator effect could
enhance the efficacy and safety of the drug. In fact, some of the
effects of carvedilol in the present study can be explained by its
vasodilator actions; systemic vascular resistance decreased modestly
but significantly, and dizziness was a prominent side effect of
treatment, as it is with other -adrenergic blockers. Yet, it should
be noted that ß-blockers without vasodilating effects may also
decrease systemic vascular resistance (because of the withdrawal of
peripheral vasoconstriction as the heart failure state
improves),15 and long-term -blockade has not proved to
be an effective therapeutic intervention in chronic heart
failure.34 35 36 Hence, it is unclear
whether the benefits of
carvedilol can be explained by its actions on peripheral
-adrenergic receptors. Nevertheless, it is noteworthy that
carvedilol possesses other pharmacological properties that might be
useful in heart failure. The drug exerts antioxidant effects and acts
to reduce the proliferation of vascular smooth muscle in
vitro.37 38 Such effects are potentially of
therapeutic
value, since heart failure is characterized both by the heightened
formation of oxygen free radicals in the failing heart39
and by peripheral vascular
remodeling.40 41
In conclusion, the findings of the present study indicate that long-term treatment with the ß-blocker carvedilol provides hemodynamic and clinical benefits in patients with severe chronic heart failure. This study confirms previous observations of therapeutic efficacy with ß-blockade in mildly impaired patients and extends those observations to patients with more advanced disease, most of whom were still symptomatic despite treatment with ACE inhibitors. The finding that ß-blockers may be useful when added to ACE inhibitors in patients with severe disease complements the recent finding that ACE inhibitors may be useful when added to ß-blockers in patients with mild disease.42 The combined use of drugs that inhibit two different neurohormonal systems is particularly rational given the deleterious effects and interactions that both the sympathetic nervous system and the renin-angiotensin system have in patients with chronic heart failure.1 The finding that carvedilol may be beneficial in patients with advanced heart failure opens the way for conducting large-scale trials to evaluate the effect of long-term ß-blockade on the survival of patients with this disease.
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Acknowledgments |
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This study was supported by grant RR-00645 from the NIH, Division of Research Resources, Bethesda, Md, and by SmithKline Beecham Pharmaceuticals, King of Prussia, Pa.
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Footnotes |
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Reprint requests to Milton Packer, MD, Division of Circulatory Physiology, Columbia-Presbyterian Medical Center, 630 W 168th St, New York, NY 10032.
Received January 10, 1995; accepted March 29, 1995.
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L. Demopoulos, M. Yeh, M. Gentilucci, M. Testa, R. Bijou, S. D. Katz, D. Mancini, M. Jones, and T. H. LeJemtel Nonselective ß-Adrenergic Blockade With Carvedilol Does Not Hinder the Benefits of Exercise Training in Patients With Congestive Heart Failure Circulation, April 1, 1997; 95(7): 1764 - 1767. [Abstract] [Full Text]
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K. Ogunyankin and B. N. Singh Reflections on Recent Clinical Trials in Patients With Heart Failure and Those With Reduced Ventricular Function Journal of Cardiovascular Pharmacology and Therapeutics, January 1, 1997; 2(3): 147 - 152. [PDF]
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K. Chatterjee Heart Failure Therapy in Evolution Circulation, December 1, 1996; 94(11): 2689 - 2693. [Full Text]
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M. Packer, W. S. Colucci, J. D. Sackner-Bernstein, C.-s. Liang, D. A. Goldscher, I. Freeman, M. L. Kukin, V. Kinhal, J. E. Udelson, M. Klapholz, et al. Double-Blind, Placebo-Controlled Study of the Effects of Carvedilol in Patients With Moderate to Severe Heart Failure: The PRECISE Trial Circulation, December 1, 1996; 94(11): 2793 - 2799. [Abstract] [Full Text]
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W. S. Colucci, M. Packer, M. R. Bristow, E. M. Gilbert, J. N. Cohn, M. B. Fowler, S. K. Krueger, R. Hershberger, B. F. Uretsky, J. A. Bowers, et al. Carvedilol Inhibits Clinical Progression in Patients With Mild Symptoms of Heart Failure Circulation, December 1, 1996; 94(11): 2800 - 2806. [Abstract] [Full Text]
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M. R. Bristow, E. M. Gilbert, W. T. Abraham, K. F. Adams, M. B. Fowler, R. E. Hershberger, S. H. Kubo, K. A. Narahara, H. Ingersoll, S. Krueger, et al. Carvedilol Produces Dose-Related Improvements in Left Ventricular Function and Survival in Subjects With Chronic Heart Failure Circulation, December 1, 1996; 94(11): 2807 - 2816. [Abstract] [Full Text]
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E. M. Gilbert, W. T. Abraham, S. Olsen, B. Hattler, M. White, P. Mealy, P. Larrabee, and M. R. Bristow Comparative Hemodynamic, Left Ventricular Functional, and Antiadrenergic Effects of Chronic Treatment With Metoprolol Versus Carvedilol in the Failing Heart Circulation, December 1, 1996; 94(11): 2817 - 2825. [Abstract] [Full Text]
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M. Packer, M. R. Bristow, J. N. Cohn, W. S. Colucci, M. B. Fowler, E. M. Gilbert, N. H. Shusterman, and The U.S. Carvedilol Heart Failure Study Group The Effect of Carvedilol on Morbidity and Mortality in Patients with Chronic Heart Failure N. Engl. J. Med., May 23, 1996; 334(21): 1349 - 1355. [Abstract] [Full Text] [PDF]
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M. A. Pfeffer and L. W. Stevenson {beta}-Adrenergic Blockers and Survival in Heart Failure N. Engl. J. Med., May 23, 1996; 334(21): 1396 - 1397. [Full Text]
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COMMITTEE MEMBERS, J. F. WILLIAMS Jr, M. R. BRISTOW, M. B. FOWLER, G. S. FRANCIS, A. GARSON Jr, B. J. GERSH, D. F. HAMMER, M. A. HLATKY, C. V. LEIER, et al. Guidelines for the Evaluation and Management of Heart Failure : Report of the American College of Cardiology/ American Heart Association Task Force on Practice Guidelines (Committee on Evaluation and Management of Heart Failure) Circulation, November 1, 1995; 92(9): 2764 - 2784. [Full Text]
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