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(Circulation. 1996;94:2817-2825.)
© 1996 American Heart Association, Inc.

Articles

Comparative Hemodynamic, Left Ventricular Functional, and Antiadrenergic Effects of Chronic Treatment With Metoprolol Versus Carvedilol in the Failing Heart

Edward M. Gilbert, MD; William T. Abraham, MD; Stephanie Olsen, MD; Brack Hattler, MD; Michel White, MD; Patrice Mealy, RN; Patti Larrabee, BS; Michael R. Bristow, MD, PhD

the University of Utah School of Medicine (E.M.G., S.O., P.M., P.L.), Salt Lake City, and the University of Colorado Health Sciences Center (W.T.A., B.H., M.W., M.R.B.), Denver.

Correspondence to Michael Bristow, Division of Cardiology, Campus Box B-139, University of Colorado Health Sciences Center, 4200 E 9th Ave, Denver, CO 80262. E-mail Michael.Bristow@UCHSC.edu.

	Abstract

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Background The basic pharmacology of the third-generation ß-blocking agent carvedilol differs considerably from second-generation compounds such as metoprolol. Moreover, carvedilol may produce different, ie, more favorable, clinical effects in chronic heart failure. For these reasons, we compared the effects of carvedilol and metoprolol on adrenergic activity, receptor expression, degree of clinical ß-blockade, hemodynamics, and left ventricular function in patients with mild or moderate chronic heart failure.

Methods and Results The effects of carvedilol versus metoprolol were compared in two concurrent placebo-controlled trials with carvedilol or metoprolol that had common substudies focused on adrenergic, hemodynamic, and left ventricular functional measurements. All subjects in the substudies had chronic heart failure resulting from idiopathic dilated cardiomyopathy. Carvedilol at 50 to 100 mg/d produced reductions in exercise heart rate that were similar to metoprolol at 125 to 150 mg/d, indicating comparable degrees of ß-blockade. Compared with metoprolol, carvedilol was associated with greater improvement in New York Heart Association functional class. Although there were no significant differences in hemodynamic effects between the carvedilol and metoprolol active-treatment groups, carvedilol tended to produce relatively greater improvements in left ventricular ejection fraction, stroke volume, and stroke work compared with changes in the respective placebo groups. Carvedilol selectively lowered coronary sinus norepinephrine levels, an index of cardiac adrenergic activity, whereas metoprolol did not lower coronary sinus norepinephrine and actually increased central venous norepinephrine levels. Finally, metoprolol was associated with an increase in cardiac ß-receptor density, whereas carvedilol did not change cardiac ß-receptor expression.

Conclusions The third-generation ß-blocking agent carvedilol has substantially different effects on left ventricular function, hemodynamics, adrenergic activity, and ß-receptor expression than does the second-generation compound metoprolol. Some or all of these differences may explain the apparent differences in clinical results between the two compounds.

Key Words: heart failure • receptors, adrenergic, beta • nervous system, autonomic

	Introduction

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The basic pharmacology of the third-generation ß-blocking agent carvedilol differs considerably from second-generation compounds such as metoprolol. Compared with metoprolol, carvedilol is relatively nonselective for blockade of ß₁- versus ß₂-receptors,^{1 2} blocks ₁-receptors^{1 3 4 5} (which accounts for its vasodilator properties^{6 7} ), has "atypical" effects on ß-receptors mediated by an interaction with G proteins that leads to downregulation of receptors in model systems,^{1 4 5} and has potentially important antioxidant⁸ and antiproliferative⁹ properties. Although second- and third-generation compounds share the property of blocking ß₁-adrenergic receptors, the multiple differences in other pharmacological properties provide the basis for quantitatively or qualitatively different clinical effects in chronic heart failure.

In IDC, all ß-adrenergic blocking agents that can be administered to subjects with chronic heart failure appear to inhibit myocardial disease progression^{2 7 10 11 12 13 14 15 16} and improve myocardial function,^{2 10} and at least the third-generation nonselective agents can improve LV function in ischemic cardiomyopathy.^{12 15 16} Additionally, data from larger clinical trials indicate that at least some ß-blockers can reduce hospitalizations^{11 17 18 19} and improve symptoms^{11 12 13 16} in mild or moderate heart failure. Although the effects of ß-blocking agents on LV function in the failing heart suggest that mortality should be favorably affected,¹⁰ the survival effects of ß-blocking agents appear to vary.^{11 17 20 21} For example, the second-generation, selective ß₁-compounds metoprolol¹¹ and bisoprolol²¹ appear to reduce mortality only slightly²¹ or not at all¹¹ in nonischemic dilated cardiomyopathy and have little effect in ischemic cardiomyopathy.²¹ On the other hand, the third-generation, nonselective ß-blocking agent carvedilol appears to have a substantial effect on mortality in both ischemic and nonischemic cardiomyopathy and, unlike the two second-generation compounds, reduces the incidence of sudden death.^{17 20}

In the current investigation, we report that carvedilol and metoprolol have both qualitatively and quantitatively different effects on hemodynamics, LV function, and cardiac adrenergic mechanisms in the intact failing human heart. These differences could potentially explain why carvedilol appears to produce a more marked survival benefit than metoprolol or bisoprolol in subjects with chronic heart failure.

	Methods

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General Description of Clinical Trial Substudies
The data were generated from two concurrently performed substudies of two placebo-controlled clinical trials that enrolled subjects with symptomatic heart failure resulting from a dilated cardiomyopathy. The first clinical trial was the MDC trial, which was conducted between 1987 and 1992.¹¹ The MDC trial¹¹ randomized patients with exclusively IDC to receive metoprolol or placebo on a 1:1 basis for 12 to 18 months of follow-up, and the substudy reported here had a duration of 6 months. The second trial was a phase II trial of carvedilol versus placebo conducted between 1989 and 1992.¹² The carvedilol study was a 4-month, randomized, double-blind, placebo-controlled trial of patients with chronic heart failure resulting from IDC or ischemic cardiomyopathy,¹² with only IDC patients included in the substudy; patients were randomized to receive carvedilol or placebo on a 3:2 basis. The substudy of MDC enrolled 48 of a total of 51 eligible subjects, whereas the carvedilol substudy enrolled all 41 patients with IDC from a total of 60 patients that also included patients with ischemic cardiomyopathy. Each study consisted of a baseline stabilization period (1 to 2 weeks in MDC, 4 to 6 weeks in the carvedilol study), a 1-week open-label challenge with a low dose of drug (5 mg BID for metoprolol, 3.125 mg BID for carvedilol), an up-titration period, and a double-blind treatment phase. The target doses of metoprolol and carvedilol were 50 mg two or three times daily and 25 to 50 mg twice daily, respectively. All subjects gave written informed consent approved by the Human Subjects Committee at the University of Utah.

Catheterization and Endomyocardial Biopsy Techniques
Patients underwent catheterization of the right heart and endomyocardial biopsy at baseline and at the 6-month follow-up in the MDC trial and at baseline and after 4 months of follow-up in the carvedilol trial. Catheterization of the right heart was performed after an overnight fast and several hours after administration of the last ß-blocker dose. Cardiovascular medications with the exception of antiarrhythmic agents were withheld immediately before the procedure. Right atrial, pulmonary arterial, and pulmonary capillary wedge pressures were measured. Cardiac output was determined by the Fick method. Systemic arterial pressures were measured by an arterial line placed in either a radial or femoral arterial catheter, and heart rate was determined by ECG telemetry monitoring during the procedure. Blood samples were obtained from the right atrium, the CS, and a systemic artery for determination of norepinephrine concentrations. Endomyocardial biopsy specimens for determinations of ß-adrenergic receptor density were obtained from the RV septum via the right internal jugular vein approach with the use of a 7F Stanford bioptome under fluoroscopic guidance. Three to five biopsy specimens were obtained from each patient at baseline and at follow-up evaluation.

Exercise Protocols and Assessment of Heart Rate and LV Function
Each protocol included assessment of peak oxygen consumption during symptom-limited exercise. The exercise protocol used for patients enrolled in the MDC trial was the modified Naughton protocol. Those patients enrolled in the carvedilol trial underwent graded maximal bicycle ergometric exercise tolerance testing using a ramped workload at either 5 or 10 W per minute so that the total duration of exercise would be between 8 and 15 minutes. Expired gas analysis was performed by mass spectrometry. Peak oxygen consumption was defined as the average oxygen consumption during the last minute of maximal exercise. For study entry, it was required that the two consecutive values for total exercise duration or peak oxygen consumption not vary by >30%. The values of the two tests were then averaged to obtain the baseline maximal exercise values. These protocols were repeated at the 6-month follow-up in the MDC trial and 4-month follow-up in the carvedilol study.

Heart rate was assessed during 24-hour ambulatory ECG monitoring. Holter monitoring was analyzed to determine the highest and lowest rates achieved as well as the average heart rate during the 24-hour period of monitoring at baseline and at follow-up. In addition, heart rate was assessed at the time of the exercise study to determine both resting and peak heart rates during symptom-limited exercise.

LV function was assessed by radionuclide ventriculography with the use of standard techniques for equilibrium imaging of ^99mTc-labeled red blood cells to measure LVEF. LVEF data are reported in EF units, defined as EF x100. LV dimensions were measured by M-mode echocardiography with the use of standard techniques.

ß-Adrenergic Receptor and Catecholamine Measurements
ß-Adrenergic receptors were measured in high-yield²² crude membrane fractions of RV endomyocardium and lymphocytes by previously described methods^{23 24} with endomyocardium obtained by multiple biopsies of the distal RV septum used as the starting material. In the metoprolol study, total ß-receptor density and K_d were estimated from ICYP saturation curves, with six to seven increasing concentrations of ICYP between 6.25 and 200 pmol/L and 1 µmol/L (±) propranolol used to determine nonspecific binding. In the carvedilol study, six to seven concentrations of ICYP between 6.25 and 300 pmol/L were used, because the lipophilic compound carvedilol is more difficult to wash out of membrane fractions than is metoprolol (unpublished data, 1996). Additionally, in the carvedilol study, ß-receptor subtypes were determined by calculation of the displacement of 50 pmol/L ICYP by .5 µmol/L CGP 20712A, a ß₁-selective compound that is 1000- to 3000-fold selective for human ß₁- versus ß₂-receptors.^{1 25} The displacement of ICYP by CGP 20712A divided by the propranolol displacement was used to estimate the ß₁-subtype fraction.

Plasma norepinephrine and epinephrine levels were measured from right atrial, systemic arterial, and CS sampling sites by radioenzymatic methodology with the use of previously described methods.²⁴

Statistical Methods
Three forms of statistical analysis were routinely used to assess potential differences in treatment efficacy. In each substudy, changes from baseline (end-of-study value minus baseline value) were compared between the ß-blocker and placebo groups by use of an unpaired t test. Changes from baseline between the two ß-blocker groups were similarly compared with each other by use of an unpaired t test. Finally, within each of the four treatment groups, the change from baseline was compared by use of a paired t statistic. A Mann-Whitney test was used to assess changes in NYHA functional class, and an ANOVA with a Scheffe's test was used to assess differences in baseline values among the four groups. In all analyses, a value of P<.05 in a two-tailed distribution was considered statistically significant, and all data are expressed as mean±SD.

	Results

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Subject Demographics
Subject demographics are shown in Table 1. The relatively young (50 years of age) IDC population in both substudies exhibited moderate to severe impairment in LV function (average LVEF of 20% to 24%), with mild to moderate impairment of exercise tolerance (average peak O₂ of 16.7 to 19.8 mL·min^-1·kg^-1). There were no differences in demographic descriptors between the two substudies and, with the exception that the metoprolol-treated group had a slightly lower LVEDD than the placebo-treated group of the carvedilol substudy, there were no differences in baseline cardiac functional data across the four subgroups.

View this table: [in this window] [in a new window]   Table 1. Subject Demographics and Other Baseline Data (Mean±1 SD)

Maintenance Doses Achieved
The average maintenance doses achieved in the four groups are given in Table 1. There were no differences between placebo and ß-blocker in either substudy, and the average dose of metoprolol or metoprolol placebo exceeded the carvedilol study doses (P<.05), as expected from the protocol-dictated difference in target doses and the fact that carvedilol is a higher-affinity ß-blocker than metoprolol.¹

Degree of ß-Blockade
Resting and Maximal Exercise Heart Rate
The degree of ß-blockade as assessed by resting heart rates recorded just before maximal exercise tests were performed and the maximal heart rate achieved during exercise was comparable in the metoprolol- and carvedilol-treated groups (Table 2). Metoprolol lowered the maximal exercise heart rate by 23±18 bpm, whereas carvedilol reduced heart rate by 26±15 bpm (P=NS).

View this table: [in this window] [in a new window]   Table 2. Heart Rate (bpm; Mean±1 SD) and NYHA Data*

Holter Heart Rates
Table 2 gives 24-hour Holter heart rate data for the highest, lowest, and average rates achieved. Metoprolol and carvedilol lowered all three rates to a comparable degree, indicating equivalent degrees of ß-blockade.

Effects on NYHA Functional Class
Table 2 gives NYHA functional class data. The only group demonstrating an improvement in functional class was the carvedilol treatment group, which had a significant shift toward lower classes compared with baseline values and with the change in its placebo group, as well as compared with changes in the metoprolol group.

Effects on LV Function
LVEF and LV Size
EF data are given in Table 3. Both metoprolol and carvedilol were associated with a significant increase in LVEF compared with the baseline values. Carvedilol increased LVEF by 11.6 EF units, whereas the carvedilol placebo group experienced an increase of 0.6 EF units (P=.0001). On the other hand, metoprolol did not significantly increase LVEF compared with placebo (P=.08), primarily because of a large placebo effect observed in the control group. When the changes from baseline were compared between the carvedilol- and metoprolol-treated groups, there was no statistically significant difference detected (respective changes in metoprolol and carvedilol groups of 10.9 and 11.6 EF units, Table 3 and Fig 1).

View this table: [in this window] [in a new window]   Table 3. Hemodynamics, LVEF, Exercise, and Echocardiographically Derived LVEDD Data (Mean±SD)

View larger version (24K): [in this window] [in a new window]   Figure 1. Effect of metoprolol, carvedilol, or placebo on LVEF (mean±SD). BSL indicates baseline values; EOS, end-of-study values.

LVEDD data are given in Table 3. Metoprolol was associated with a reduction in diastolic dimension over the 6-month course of the study, with a trend (P=.09) for a reduction compared with the change in the placebo group. In the carvedilol study, small, statistically insignificant reductions in LV size were observed in both the placebo- and carvedilol-treated patients during the 4 months of the study.

Hemodynamics
Hemodynamic changes are given in Table 3. Compared with baseline values, there were significant increases in stroke volume and LV stroke work index in the metoprolol-treated group. However, these changes were not significantly different from the changes observed in the placebo group. In the carvedilol-treated group, there were significant increases in stroke volume and LV stroke work index and a decline in pulmonary wedge pressure compared with baseline values, and the improvements in LV stroke work and stroke volume indexes were statistically different from the changes observed in the placebo group. Although the magnitude of the increase in the LV stroke work index tended to be higher in the carvedilol group than in the metoprolol group (P=.20), there were no statistically significant differences in the changes from baseline between the two ß-blocker groups. There were no changes in SVR noted for either ß-blocker.

Maximal Exercise Results
Table 3 gives maximal exercise data in terms of peak O₂ and total exercise. Neither ß-blocker produced a statistically significant increase in maximal exercise compared with changes in the placebo groups.

Effects on Adrenergic Activity
Table 4 and Fig 2 give data on adrenergic indexes. Metoprolol tended to increase norepinephrine levels in all sampled sites, and in the right atrial site, the changes were statistically significant compared with baseline. The increase in right atrial norepinephrine level in the metoprolol group was also significantly (P=.01) greater than the change in the carvedilol group. Carvedilol had no effect on arterial or central venous norepinephrine levels but was associated with a reduction in CS norepinephrine compared with baseline values or with changes in the placebo group (both P<.05). Compared with its placebo group, carvedilol treatment was also associated with a significant reduction in transmyocardial norepinephrine balance (CS minus arterial levels, P=.007). Additionally, compared with changes in the metoprolol group, carvedilol was associated with a strong trend toward reduction of CS norepinephrine levels (carvedilol, –155±219 pg/mL; metoprolol, +77±488 pg/mL; P=.07).

View this table: [in this window] [in a new window]   Table 4. Norepinephrine and Epinephrine Data (pg/mL; Mean±SD)

View larger version (21K): [in this window] [in a new window]   Figure 2. Changes in norepinephrine (NE) associated with ß-blocker or placebo (mean±SEM). CS-ART indicates CS minus arterial levels.

Epinephrine levels, presented in Table 4, ranged from 62 to 181 pg/mL. There were no changes in plasma epinephrine levels in any group compared with baseline values, changes in the placebo groups, or changes between the metoprolol and carvedilol groups. There were no differences in epinephrine levels among the three sample sites, whereas CS norepinephrine levels were consistently higher than arterial norepinephrine levels (for 67 baseline studies, arterial norepinephrine=386±236 pg/mL, CS norepinephrine=573±388 pg/mL, P=.0001; arterial epinephrine=89±88 pg/mL, CS epinephrine=88±98 pg/mL, P=NS). In the 67 subjects with serial arterial and CS catecholamine levels, the average norepinephrine balance value (CS-arterial) was +189±319 pg/mL (P=.0001 versus no change across the heart). In contrast, there was no significant production or extraction of epinephrine for these same subjects (transmyocardial balance=-3±65 pg/mL, P=NS).

As shown in Table 4, there was significant production of norepinephrine at baseline in the carvedilol-treated group that was no longer present at the end of the study. In contrast, in the carvedilol study placebo group, significant cardiac production of norepinephrine persisted throughout the 4-month treatment period. In the metoprolol study, nonsignificant trends toward production were present in both the placebo- and metoprolol-treated groups, at both baseline and the end of the study (probability values ranging from .07 to .34).

Effects on ß-Adrenergic Receptors
Table 5 and Fig 3 give ß-adrenergic receptor data in RV endomyocardial and lymphocytic membranes. Metoprolol was associated with an increase in total ß-receptor density in the heart (P=.03 versus baseline and versus change from baseline in the placebo group). In contrast, there was no change in cardiac ß-receptor density in the carvedilol-treated group compared with baseline or the placebo group. The upregulation in ß-receptors in the metoprolol group was statistically significantly greater than the change from baseline in the carvedilol group (P=.02). There were no significant changes in lymphocyte ß-receptor density. K_d values were higher in the carvedilol study because of the higher saturating concentration of ICYP used.

View this table: [in this window] [in a new window]   Table 5. ß-Adrenergic Receptor Data (Mean±SD)

View larger version (26K): [in this window] [in a new window]   Figure 3. CS norepinephrine (CS NE) and cardiac ß-receptor density: comparison of the effect of metoprolol vs carvedilol (mean±SEM). BSL indicates baseline values; EOS, end-of-study values.

Cardiac ß-receptor subtypes were measured in the carvedilol study, and neither receptor changed in either the placebo- or carvedilol-treated group (ß₁: placebo baseline=38.5±26.8 fmol/mg, end of study=38.8±21.3 fmol/mg; carvedilol baseline=22.8±17.8 fmol/mg, end of study=19.2±16.5 fmol/mg; ß₂: placebo baseline=26.0±26.1 fmol/mg, end of study=34.5±29.7 fmol/mg; carvedilol baseline=14.4±9.2 fmol/mg, end of study=14.2±11.4 fmol/mg).

	Discussion

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Our data indicate that the third-generation ß-blocking agent carvedilol differs from the second-generation compound metoprolol in several important respects. The first difference is that the two ß-blockers differed qualitatively in their effects on adrenergic activity. Carvedilol substantially and statistically significantly (compared with placebo) reduced two indexes of cardiac adrenergic activity, CS norepinephrine and transmyocardial norepinephrine balance, without affecting systemic norepinephrine levels. On the other hand, metoprolol increased central venous norepinephrine levels and had no apparent effect on transmyocardial balance. Moreover, the effects of carvedilol and metoprolol on CS norepinephrine levels were statistically different when changes in the two ß-blocker groups were compared directly. Neither agent affected epinephrine levels.

Second, the effects of carvedilol and metoprolol on cardiac ß-adrenergic receptors were clearly different. Metoprolol treatment was associated with upregulation of the total ß-receptor population, presumably due to upregulation of the ß₁-subtype, which is downregulated in the failing human heart.^{26 27} On the other hand, carvedilol had no effect on ß-adrenergic receptors despite the fact that it was associated with a marked improvement in myocardial function and a reduction in cardiac adrenergic activity. The results with metoprolol agree with previous open-label studies from our laboratory²⁸ and others,²⁹ and the behavior of cardiac ß-receptors in the two studies is consistent with the direct effects of the two compounds on ß₁-like receptors in cultured chick heart cells.¹ That is, because carvedilol downregulates chick heart cell ß₁-like receptors,¹ this "atypical" action may explain the lack of upregulation of ß-receptors in failing hearts treated with this non–intrinsic sympathomimetic activity^{1 2 3 4 5 6 7} third-generation compound.

Despite the fact that metoprolol restored ß-receptor density toward the normal range and increased (systemic markers) or did not change (cardiac markers) adrenergic drive compared with reduction of the latter by carvedilol, the effects of carvedilol on hemodynamics, LV function, and heart failure symptoms were at least as favorable as those produced by metoprolol. For example, compared with the net (active drug minus placebo) effect of metoprolol, carvedilol tended to improve LV function to a relatively greater extent (by respective amounts of 6 versus 11 EF units), and the carvedilol but not the metoprolol effect was statistically significant compared with the placebo change. However, there were no statistically significant differences between the degrees of improvement in the metoprolol and carvedilol treatment groups, because the difference in net effect was due to a greater placebo effect on LVEF in the metoprolol group. This in turn may have been due to the shorter stabilization period in the MDC protocol (1 to 2 weeks versus 4 to 6 weeks in the carvedilol protocol). Additionally, although there were no statistically significant differences between the improvements in stroke work and stroke volume indexes between the two ß-blocker groups, carvedilol tended to improve hemodynamics to a greater extent than did metoprolol, with trends toward larger increases in both stroke work and stroke volume indexes. Although the treatment periods varied in the two studies, the effect of ß-blockade on LV function improves over time (References 11, 30, and 31 and E.M.G. and M.R.B., unpublished data with carvedilol, 1996), and therefore the 4 months of carvedilol versus 6 months of metoprolol treatment biases the results for metoprolol and against carvedilol. Finally, patients treated with carvedilol did experience a greater degree of symptomatic improvement as judged by NYHA functional class criteria. The tendency for better LV function and symptom improvement with carvedilol could not be explained by differences in study subject demographics, because the two ß-blocker–treated populations were nearly identical in all important baseline characteristics. Interestingly, although carvedilol has vasodilator activity and metoprolol does not, no evidence of vasodilation could be observed for carvedilol at the end of the study, because SVR values did not differ significantly from baseline and the statistically insignificant net effect was similar to that of metoprolol. Because carvedilol does lower SVR when administered acutely,^{6 7} the lack of an SVR reduction by carvedilol when administered on a continuing basis may represent tolerance to this hemodynamic effect.

Recently, it has been demonstrated that ß-adrenergic receptors have intrinsic activity^{32 33} and that in murine left ventricles, overexpression of the human ß₂-receptor will increase contractility to levels equivalent to maximal ß-agonist stimulation.³³ The fact that only metoprolol upregulated ß-adrenergic receptors while producing effects on LV function that were generally not as favorable as carvedilol is further evidence that in the failing human heart, the regulation of cardiac ß-adrenergic receptors does not contribute to either diminished intrinsic myocardial function or restoration of function by ß-blocking agents. Rather, downregulation of ß-adrenergic receptors in the failing human heart appears to contribute to the loss of maximal exercise responses,³⁴ which would be an expected consequence of compromised ß-adrenergic signal transduction.³⁵ In that regard, it is interesting that metoprolol treatment for 12 months has been associated with an improved maximal exercise response,¹¹ whereas carvedilol treatment for 4 months has not.^{12 16} However, in the current study, neither metoprolol nor carvedilol improved maximal exercise compared with placebo during 6 or 4 months of treatment, respectively. It is possible that the longer treatment period, the slightly lower ß-blocking dose, or the larger sample size of MDC¹¹ explains the discrepancy between the current data and these formerly reported¹¹ metoprolol exercise data.

The pharmacological properties of metoprolol create the potential for adverse adrenergically mediated effects. The upregulation of cardiac ß-adrenergic receptors could resensitize this powerful³⁵ signal transduction pathway, potentially predisposing the heart to withdrawal phenomena³⁶ when blood levels reach trough or if a dose is missed. Additionally, ß₁-selective blocking agents recouple uncoupled cardiac ß₂-adrenergic receptors³⁷ through a cross-regulatory effect, further predisposing ß-adrenergic signal transduction pathways to withdrawal phenomena. Because metoprolol tends to increase systemic norepinephrine levels through effects on norepinephrine clearance,³⁸ may increase cardiac norepinephrine spillover in chronic heart failure in the short term,³⁹ and does not reduce cardiac adrenergic activity with this agent, there is obvious potential for drug-related increases in adrenergic activity to produce adverse events in the failing heart. On the other hand, because carvedilol lowers cardiac adrenergic activity, blocks ß₁-, ß₂-, and ₁-adrenergic receptors at high doses, and does not upregulate downregulated ß₁-receptors, its antiadrenergic properties greatly exceed those of metoprolol. This could be the general explanation for the different clinical results observed with these two agents in this and other studies,^{11 17 20} but other unique pharmacological properties possessed by carvedilol^{8 9} could also be involved.

The hemodynamic results observed for metoprolol in the current study are quite similar to 6-month data reported by two previous placebo-controlled trials of this agent in IDC,^{11 40} and the hemodynamic results with carvedilol are similar to previous reports in IDC⁷ or a mixed population of cardiomyopathy.^{12 16} Additionally, the tendency of the third-generation, nonselective ß-blocker carvedilol to improve hemodynamics to a somewhat greater extent than the second-generation, ß₁-selective compound metoprolol is similar to data presented in a previous study comparing metoprolol to the third-generation, nonselective compound bucindolol, in which the authors concluded that "bucindolol may have a slight hemodynamic advantage over metoprolol . . .".⁴¹ Although transmyocardial norepinephrine measurements have not been reported previously for metoprolol (or any other ß-blocker) in a placebo-controlled study, an earlier uncontrolled study⁴² reported no statistically significant effect of metoprolol on transmyocardial norepinephrine values. There are only two previous reports^{40 43} of the effects of metoprolol versus placebo on systemic norepinephrine levels in subjects with LV dysfunction and elevated baseline norepinephrine levels. One of these⁴⁰ measured only CS values and noted no change compared with baseline (although there was a significant change compared with placebo because these values increased during a 6-month period), and the other⁴³ described an increase in mixed venous norepinephrine levels after the short-term administration of metoprolol.

The present study had several potential weaknesses that could have influenced the results. The design was a comparison of two concurrently performed placebo-controlled trials as opposed to a single trial with a three-way randomization between placebo, metoprolol, and carvedilol. However, because the subject material and entry criteria were quite similar, it is unlikely that this "dual-trial" design influenced the outcome. The one major difference between the two clinical trials from which the substudies were derived was the duration of follow-up: 6 months for metoprolol and 4 months for carvedilol. As discussed above, this difference could not have accounted for the relatively greater effects of carvedilol on LV function, and it is unlikely to explain the qualitative differences of the two agents on adrenergic activity and receptor behavior, because there were no differences in the respective placebo groups. Another potential problem is that coronary blood flow was not measured, and drug-induced changes in coronary blood flow could affect CS norepinephrine levels. In the current study, this would seem unlikely in view of the fact that SVR was not altered by either drug, the heart rate–lowering effects (a major determinant of coronary blood flow) were similar, and epinephrine values (an internal control for changes in norepinephrine) did not change in any group and did not indicate baseline production as for the neurotransmitter norepinephrine. This is because epinephrine is not a neurotransmitter in human heart, and CS minus arterial values are either neutral or negative. Additionally, in a previous study, chronic metoprolol therapy was shown not to affect coronary blood flow in subjects with IDC,⁴² and in isolated coronary arteries, pharmacological doses of carvedilol do not change vascular tone.⁴⁴ Therefore, it is unlikely that a differential change in coronary blood flow produced by the two ß-blockers accounted for the different effects of metoprolol and carvedilol on transmyocardial norepinephrine levels.

In summary, in the intact human heart failing as the result of IDC, the third-generation ß-blocking agent carvedilol differs from the second-generation compound metoprolol by producing more comprehensive antiadrenergic effects. These data suggest that compared with second-generation ß-blocking agents, carvedilol has the potential to produce greater cardioprotection from harmful adrenergic stimuli by blocking all three (ß₁, ß₂, and ₁) adrenergic receptors, lowering cardiac adrenergic activity, and not sensitizing the adaptively downregulated ß₁-adrenergic pathway to adrenergic stimulation.

	Selected Abbreviations and Acronyms

 

CS = coronary sinus EF = ejection fraction ICYP = (125I)iodocyanopindolol IDC = idiopathic dilated cardiomyopathy Kd = radioligand dissociation constant LV = left ventricular LVEDD = left ventricular end-diastolic dimension LVEF = left ventricular ejection fraction MDC = Metoprolol in Dilated Cardiomyopathy RV = right ventricular SVR = systemic vascular resistance

	Acknowledgments

 
This work was supported by NHLBI grant No. RO1 HL-48013 (Drs Bristow and Gilbert); Public Health and Safety Research grant No. M01-RR00064 from the National Center for Research Resources, National Institutes of Health (Dr Gilbert); the Bayer Fund for Cardiovascular Research (Dr Gilbert); and grants from SmithKline Beecham Pharmaceuticals, King of Prussia, Pa, CIBA-GEIGY, Summit, NJ, and AB Hassle, Molndal, Sweden (Dr Bristow).

Received March 27, 1996; revision received June 28, 1996; accepted July 11, 1996.

	References

Top Abstract Introduction Methods Results Discussion References

 

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