25.Clinical effects of beta-adrenergic blockade in chronic heart failure
Boissel
Philippe Lechat, Milton Packer, Stephan Chalon, Michel Cucherat, Tarek Arab and Jean-Pierre
Double-Blind, Placebo-Controlled, Randomized Trials
-Adrenergic Blockade in Chronic Heart Failure: A Meta-Analysis of
βClinical Effects of Print ISSN: 0009-7322. Online ISSN: 1524-4539
Copyright ? 1998 American Heart Association, Inc. All rights reserved.
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Circulation doi: 10.1161/01.CIR.98.12.1184
1998;98:1184-1191Circulation.
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Clinical Effects of?-Adrenergic Blockade in
Chronic Heart Failure
A Meta-Analysis of Double-Blind,Placebo-Controlled,Randomized Trials
Philippe Lechat,MD,PhD;Milton Packer,MD;Stephan Chalon,MD;Michel Cucherat,MD;
Tarek Arab,MD;Jean-Pierre Boissel,MD,PhD
Background—?-Blockers have improved symptoms and reduced the risk of cardiovascular events in studies of patients with heart failure,but it is unclear which end points are most sensitive to the therapeutic effects of these drugs. Methods and Results—We combined the results of all18published double-blind,placebo-controlled,parallel-group trials of?-blockers in heart failure.From this combined database of3023patients,we evaluated the strength of evidence supporting an effect of treatment on left ventricular ejection fraction,NYHA functional class,hospitalizations for heart failure,and death.?-Blockers exerted their most persuasive effects on ejection fraction and on the combined risk of death and hospitalization for heart failure.?-Blockade increased the ejection fraction by29%(P?10?9)and reduced the combined risk of death or hospitalization for heart failure by37%(P?0.001).Both effects remained significant even if?90%of the trials were eliminated from the analysis or if a large number of trials with a neutral result were added to the analysis.In contrast,the effect of?-blockade on NYHA functional class was of borderline significance(P?0.04) and disappeared with the addition or removal of only1moderate-size study.Although?-blockade reduced all-cause mortality by32%(P?0.003),this effect was only moderately robust and varied according to the type of?-blocker tested,ie,the reduction of mortality risk was greater for nonselective?-blockers than for?1-selective agents(49% versus18%,P?0.049).However,selective and nonselective?-blockers did not differ in their effects on other measures of clinical efficacy.
Conclusions—These analyses indicate that there is persuasive evidence supporting a favorable effect of?-blockade on ejection fraction and the combined risk of death and hospitalization for heart failure.In contrast,the effect of these drugs on other end points requires additional study.(Circulation.1998;98:1184-1191.)
Key Words:heart failureⅢmeta-analysisⅢreceptors,adrenergic,?Ⅲtrials
I n recent years,there has been considerable interest in the use of?-adrenergic blocking agents for the treatment of heart failure,because such agents may prevent the adverse effects of sympathetic stimulation on the failing heart.1?-Blockade has produced favorable results in a large number of randomized,controlled trials.2,3However,these studies varied considerably in size and duration,enrolled patients at different stages of the diseases,were designed with different objectives,and evaluated?-blockers that differed in their selectivity for adrenergic receptors and their effects on the peripheral circulation.
We performed a meta-analysis of all available placebo-controlled,parallel-group trials with?-blockers in heart failure to evaluate the overall results with this therapeutic approach.Two meta-analyses of the effects of?-blockers in heart failure have been published,2,3but these focused only on mortality and relied on published data from clinical trials, including some that were not double-blind or placebo-controlled.In contrast,in the present analysis,we obtained most of the data from original sources and examined the effect of?-blockers on a range of clinically meaningful end points,including measures not reported in the original publications.
Methods
We performed an extensive MEDLINE search of all controlled trials with?-blockers in heart failure.Additional information was obtained from references included in previously published articles,from a search of abstracts of international meetings,and from communica-tions with colleagues,investigators,and sponsors in the pharmaceutical industry.
Selection of Studies
We included all double-blind,randomized,placebo-controlled, parallel-group trials of?-blockers in patients with chronic heart failure.Trials were excluded if they focused on patients with a recent myocardial infarction,and trials with xamoterol were not considered because this compound has considerable agonist activity.All quali-fying trials were included regardless of sample size or duration, except those that evaluated only a single administration of the drug.
Received November25,1997;revision received May6,1998;accepted May30,1998.
From the Service de Pharmacologie,Ho?pital Pitie′-Salpe?trie`re,Paris,France;the Division of Circulatory Physiology,Columbia University,College of Physicians and Surgeons,New York,NY;and the Unite′de Pharmacologie Clinique,Ho?pitaux de Lyon,Lyon,France.
Reprint requests to Philippe Lechat,MD,PhD,Service de Pharmacologie,Ho?pital Pitie′-Salpe?trie`re,47Blvd de L’Ho?pital,75013Paris,France.
?1998American Heart Association,Inc.
In contrast to earlier meta-analyses,the results of most studies were
obtained through direct communication with the investigators or
sponsors.Consequently,the results presented in this article may not
be identical to the results that appeared in the original publications of
these studies.
Measures of Efficacy
This meta-analysis focused on5measures of efficacy:(1)all-cause
mortality,(2)morbidity(defined as hospitalization for worsening
heart failure),(3)the combined risk of all-cause mortality and
hospitalizations for worsening heart failure(combined morbidity and
mortality),(4)changes in functional status(as assessed by the
NYHA classification),and(5)changes in left ventricular ejection
fraction.
Information on deaths was obtained in all18trials.Data on
hospitalizations for heart failure were collected in all except the
MDC trial4;for this trial,we used the number of hospitalizations for
heart failure and arrhythmias,because its database did not distin-
guish between the2types of hospitalization.Changes in NYHA
class and ejection fraction were each reported https://www.wendangku.net/doc/4a2758241.html,rma-
tion on the combined end point of death and hospitalizations for heart
failure was not included in most of the published articles but was
obtained through direct communication with the investigators or
sponsors.This was successfully achieved for9trials,which enrolled
87%of the total number of patients in this meta-analysis.
Mortality was analyzed according to the intention-to-treat princi-
ple;events were included if they occurred during the intended
duration of the study whether or not patients were receiving
double-blind medication.Morbidity was assessed by determining the
number of patients in each treatment group with at least1hospital-
ization for heart failure;repeat hospitalizations were not considered.
Changes in functional status were evaluated by determining the
number of patients who improved or deteriorated by at least1NYHA
class as assessed during the last visit on double-blind therapy.The
effect of treatment on ejection fraction was analyzed by comparing
mean values in the2treatment groups at protocol-specified time
points(3to12months).
Primary Analysis
For each end point,we pooled the data by weighting the treatment
effect of each trial by the reciprocal of its variance.The significance
of the overall treatment effect was evaluated by a?2statistic (association test).For the analysis of all dichotomous variables(all
variables except ejection fraction),a treatment effect model was
selected(1)by testing for heterogeneity of the effect across the trials
with a?2statistic(to select between a fixed or random effects model) and(2)by determining whether the intercept of the regression line (which plotted the event rate in the placebo groups versus the event rate in the?-blocker groups)was different from zero with a t test(to select between a multiplicative or additive model).5For the analysis of morbidity and mortality(alone and combined),there was no significant heterogeneity among the trials,and the regression line intersected zero.Thus,a fixed multiplicative effect model was used, and significance was evaluated by the methods of Peto,6Mantel-Haenszel,7Cochran,8and the logarithm of the odds ratio.9For the analysis of NYHA class,the regression line intersected zero,but there was significant heterogeneity among the trials.Thus,a random multiplicative effects model was used,and significance was evalu-ated with the random odds ratio.10Finally,for the analysis of ejection fraction(a continuous variable),the ratio of the treatment difference to the standard deviation of the ejection fraction was calculated for each trial,and a z score was used to assess the overall effect size.11 Although the?2test for heterogeneity was significant(P?0.025), this heterogeneity was suppressed after withdrawal of2small trials (representing only2%of the data);both showed a substantial imbalance between treatment groups in the baseline values for ejection fraction.
Secondary Analyses
Subgroup Analysis
We divided the trials into2groups:(1)those using a?1-selective ?-blocker(eg,metoprolol,bisoprolol,and nebivolol)and(2)those using a nonselective?-blocker(eg,carvedilol and bucindolol). Differences in the magnitude of the treatment effects between the2 subgroups were evaluated for significance by2methods:(1)for dichotomous variables,heterogeneity of the odds ratios was assessed by the Mantel-Haenszel procedure,7and(2)for ejection fraction,an ANOVA procedure was performed on the weighted effect size of each trial,followed by an interaction test.
Sensitivity Analyses
To determine whether the results were unduly influenced by a single trial or a small number of trials,we repeated the meta-analyses of all variables after successively withdrawing trials in decreasing order of statistical weight(as determined by the reciprocal of the variance of the treatment effect for each trial);thereby,trials with the largest number of events were eliminated first.A second sensitivity analysis was performed by repeating the meta-analyses after successively withdrawing trials in decreasing order of their odds ratios;thereby, trials with largest treatment effects were eliminated first. Robustness Analysis
The robustness was estimated by computing the number of trials with a neutral treatment effect that,if added to the present database,would produce a nonsignificant result(P?0.05).To perform this analysis, the size of each hypothetical trial was assumed to be equal to the mean of the size of the trials included in the meta-analysis and to have an event rate equal to the overall event rate in the placebo groups.A robustness ratio was calculated by dividing the number of hypothetical trials by the number of real trials in the meta-analysis.
Results
Eighteen clinical trials with?-blockers in heart failure met the criteria for inclusion in the present analysis.4,12–29The study by Gilbert et al30was excluded because it focused on a subset of patients included in the report by Woodley et al.15 The article summarizing the mortality results of the US carvedilol program31was replaced by the individual reports of the4component trials,26–29because these provided informa-tion on nonfatal(as well as fatal)end points.The2reports23,24 presenting the short-and long-term results of the carvedilol trial carried out by the Australia New Zealand Heart Failure Research Collaborative Group were considered as1trial. Patient Characteristics
The18trials enrolled a total of3023patients with heart failure,of whom1305were randomized to treatment with placebo and1718to treatment with a?-blocker(Table1). The cause of heart failure was an idiopathic dilated cardiop-athy in1513patients and ischemic heart disease in1445 patients.Most patients had NYHA class II or III symptoms, despite the use of diuretics and usually digitalis and an ACE inhibitor.Few patients(0%to5%)had class IV symptoms, and only2trials enrolled class I patients.4,24
Effect of?-Blockade on Clinical Measures
For all end points,there was a significant effect(P?0.05)in favor of treatment with a?-blocker.The magnitude and significance of the treatment effect were similar regardless of the statistical model used(Tables2and3,Figures1to3). There were156deaths among1305patients(11.9%) assigned to placebo,but only130deaths among1718patients (7.5%)assigned to a?-blocker(Figure1).This difference reflected a32%reduction in the risk of death(95%CI,12% to47%),P?0.003(Peto’s method).There were223hospi-talizations for heart failure among1305patients(17.1%) Lechat et al September22,19981185
assigned to placebo,but only166such hospitalizations among1718patients(9.6%)assigned to a?-blocker(Figure 2).This difference reflected a41%reduction in risk(95%CI, 26%to52%),P?0.001.When morbidity and mortality were combined,there were293deaths or hospitalizations for heart failure among1155patients(25.4%)assigned to placebo but only239such events among1486patients(16.0%)assigned to a?-blocker(Figure3).This difference reflected a37%
TABLE1.Characteristics of Controlled Clinical Trials of?-Blockers in Heart Failure
Study(Reference)Drug
Cause of
Heart Failure
NYHA
Class
Duration of
Blinded Therapy,mo
No.of Patients
Randomized
(Placebo/?-Blocker)Primary End Point
Engelmeier(12)Metoprolol IDC II–IV1216/9Exercise tolerance
Pollock(13)Bucindolol IDC/CAD III–IV37/12Exercise tolerance,hemodynamics
Lechat(14)Nebivolol IDC/CAD III–IV 1.56/6Exercise tolerance
Woodley(15)Bucindolol IDC/CAD II–III320/29Exercise tolerance,hemodynamics
MDC(4)Metoprolol IDC I–IV12–18189/194Morbidity?mortality
Wisenbaugh(16)Nebivolol IDC II–III313/11Hemodynamics
Fisher(17)Metoprolol CAD III–IV625/25Exercise tolerance
Bristow(18)Bucindolol IDC II–III334/105Functional class
CIBIS(19)Bisoprolol IDC/CAD III–IV4–44321/320Mortality
Eichhorn(20)Metoprolol IDC II–III39/15Hemodynamics
Metra(21)Carvedilol IDC II–III420/20Hemodynamics
Olsen(22)Carvedilol IDC/CAD II–IV423/36Hemodynamics
ANZ(23,24)Carvedilol CAD I–III18–24208/207Exercise tolerance,EF Morbidity?mortality Krum(25)Carvedilol IDC/CAD II–IV 3.516/33Hemodynamics
Bristow(26)Carvedilol IDC/CAD II–IV 6.5–884/261Exercise tolerance
Packer(27)Carvedilol IDC/CAD II–IV 6.5–8145/133Exercise tolerance
Colucci(28)Carvedilol IDC/CAD II–III?15134/232Morbidity?mortality
Cohn(29)Carvedilol IDC/CAD III–IV?835/70Quality of life
IDC indicates idiopathic dilated cardiomyopathy;CAD,coronary artery disease;and EF,ejection fraction.
TABLE2.Effect on Key Hemodynamic and Clinical Measures in Individual Trials
Study(Reference)Drug
All-Cause Mortality Hospitalization for Heart Failure
All-Cause Mortality
?CHF Hospitalization Placebo?-Blocker Placebo?-Blocker Placebo?-Blocker
Engelmeier(12)Metoprolol2/161/94/161/9...... Pollock(13)Bucindolol0/70/120/70/12...... Lechat(14)Nebivolol0/60/60/60/6...... Woodley(15)Bucindolol0/200/292/201/29......
MDC(4)Metoprolol21/18923/19449/18937/19461/18948/194 Wisenbaugh(16)Nebivolol0/131/110/130/11...... Fisher(17)Metoprolol2/251/258/251/25...... Bristow(18)Bucindolol2/344/1053/347/105...... CIBIS(19)Bisoprolol67/32153/32082/32154/320115/32188/320 Eichhorn(20)Metoprolol0/90/152/90/15......
Metra(21)Carvedilol0/200/202/200/20...... Olsen(22)Carvedilol0/231/360/232/362/234/36
ANZ(23,24)Carvedilol29/20821/20733/20823/20849/20835/207 Krum(25)Carvedilol2/163/332/161/336/168/33 Bristow(26)Carvedilol13/8412/2618/8418/26118/8427/261 Packer(27)Carvedilol11/1456/13318/1459/13327/14514/133 Colucci(28)Carvedilol5/1342/2329/1349/23212/13410/232 Cohn(29)Carvedilol2/352/701/353/703/355/70
Total(unweighted)156/1305(11.9%)130/1718(7.5%)223/1305(17%)166/1718(9.6%)293/1155(25.4%)239/1486(16.0%) CHF indicates congestive heart failure.Data on changes in NYHA class is shown as number of patients who improved or deteriorated by at least one class.Ejection fractions were measured at end of double-blind treatment,with the following exceptions:MDC(12months),CIBIS(5months),ANZ(6months),Colucci(6.5–8months), and Cohn(6.5–8months).
1186Analysis of?-Blocker Trials in Heart Failure
reduction in risk (95%CI,24%to 49%),P ?0.001.In addition,patients assigned to treatment with a ?-blocker were 32%more likely to experience an improvement in NYHA class (95%CI,1%to 74%,P ?0.04)and 30%less likely to
experience worsening of NYHA class (95%CI,4%to 50%,P ?0.03).The mean unweighted value for left ventricular ejection fraction was 0.23?0.04in the placebo groups and 0.31?0.04in the ?-blocker groups,reflecting an unweighted 29%mean increase in ejection fraction in patients treated with a ?-blocker,P ?10?9.
Assuming a treatment period identical to the mean duration of follow-up (7months),we determined that physicians would need to treat 38patients to avoid 1death,24patients
TABLE 2.Continued
NYHA Class Improvement NYHA Class Deterioration LV Ejection Fraction (Mean ?SD)Placebo ?-Blocker Placebo ?-Blocker Placebo ?-Blocker 0/161/90/160/922?1419?10............29?1023?80/60/60/60/6......4/2014/292/202/2921?929?1152/18967/1949/1898/19428?1234?14............23?933?126/2515/258/251/25......15/3426/1052/343/10529?830?1248/32168/32035/32141/32025?1130?120/93/150/90/1517?833?138/2011/208/2011/2019?530?1210/2317/364/231/3620?1030?1058/20854/20727/20833/20729?1034?135/1621/335/165/3316?724?1116/8447/26124/8444/26125?831?1227/14535/13345/14520/13324?930?129/13423/23223/13427/23225?1032?127/3510/705/358/7023?931?10265/1285(20.6%)
412/1695(24.3%)
197/1285(15.3%)
204/1695(12.0%)
23?4
31?
4
Figure 1.Effect of ?-blockade on risk of death in chronic heart failure.Effect of ?-blockade in each trial (by ?rst author and year of publication)is represented by horizontal bar whose central vertical tick represents point estimate of odds ratio and whose width displays 95%CIs of estimate (logarithmic scale).Solid vertical line represents odds ratio of 1(neutral treatment effect);dotted vertical line represents odds ratio for treatment effect across all trials.Odds ratio ?1indicates lower risk of death with ?-blockade,whereas odds ratio ?1indicates higher risk of death with active treatment.Overall,?-blockers reduced risk of death by 31%(P ?
0.0029).
Figure 2.Effect of ?-blockade on risk of being hospitalized at least once for heart failure.Format is similar to Figure 1.Overall,?-blockers reduced risk of being hospitalized for heart failure by 41%(P ?0.001).
Lechat et al September 22,19981187
to avoid1hospitalization for heart failure,and15patients to avoid1combined end point.
Analysis of Sensitivity,Robustness,and Subgroups The numbers of trials that would need to be withdrawn to induce a nonsignificant result were4trials for mortality(84% of the total weight),9trials for hospitalizations for heart failure(93%of the total weight),5trials for the combined end point(72%of the total weight),and12trials for ejection fraction(91%of the total weight).In contrast,the withdrawal of only15%of the total weight(1trial)induced a nonsignif-icant result for NYHA class improvement,and the with-drawal of only67%(5trials)induced a nonsignificant result for NYHA class deterioration.When the sensitivity analysis was repeated by subtracting trials with the largest treatment effect first,the numbers of trials that would need to be withdrawn to induce a nonsignificant result were10for hospitalizations for heart failure and6for the combined end point but only1each for mortality,NYHA class improve-ment,and NYHA class deterioration.
The numbers of trials with a neutral result(assuming a sample size equal to the mean number of patients enrolled in the trials and an event rate equal to the event rate in the placebo groups)that would need to be added to induce a nonsignificant overall result were23for mortality(robustness ratio of23/18?1.28),80for hospitalizations for heart failure (robustness ratio of80/18?4.4),40for the combined end point(robustness ratio of40/9?4.44),1for NYHA class improvement(robustness ratio of1/16?0.06),and4for NYHA class deterioration(robustness ratio of4/16?0.25). For ejection fraction,the number of neutral trials required to induce a nonsignificant overall result exceeded the range of the calculation.Thus,we could rank the variables in decreas-
https://www.wendangku.net/doc/4a2758241.html,parative Effects of Selective and Nonselective?-Blockers on Major Clinical End Points
End Points No.of
Trials
Odds
Ratio95%CIs
P,
?2Tests for Association
(Within Subgroups)
P,
?2Test for Homogeneity
(Between Subgroups)
Mortality
All trials160.680.53–0.880.003
Selective agents70.840.61–1.160.30
Nonselective agents110.510.34–0.75?0.0010.049 Hospitalization for CHF
All trials180.590.48–0.74?0.001
Selective agents70.580.43–0.77?0.001
Nonselective agents110.620.44–0.870.0060.77 Combined end point
All trials90.630.51–0.76?0.001
Selective agents20.680.52–0.890.005
Nonselective agents70.560.41–0.75?0.0010.32
NYHA improvement
All trials16 1.32 1.01–1.740.04
Selective trials6 1.59 1.19–2.11?0.01
Nonselective agents10 1.170.82–1.670.390.19
NYHA deterioration
All trials160.700.50–0.960.03
Selective agents60.920.53–1.600.76
Nonselective agents100.640.45–0.930.0180.29 Selective?-blockers are metoprolol,bisoprolol or nebivolol.Nonselective?-blockers are bucindolol or carvedilol. Combined end point is all-cause mortality?hospitalizations for heart failure.A fixed multiplicative effect model (Peto’s method)was used for the analysis of mortality,hospitalizations and the combined end point,whereas the
random odds ratio model was used for the analysis of NYHA functional
class.
Figure3.Effect of?-blockade on combined risk of all-cause mortality and hospitalizations for heart failure.Format is similar
to Figure1.Overall,?-blockers reduced risk of death or hospi-talization for heart failure by37%(P?0.001).
1188Analysis of?-Blocker Trials in Heart Failure
ing order of robustness:ejection fraction?combined mor-bidity and mortality?hospitalizations for heart failure?all-cause mortality?NYHA class deterioration?NYHA class improvement.However,if1large-scale trial with a neutral result were added(assuming the enrollment of1225 patients in each treatment group and a20%mortality rate in the placebo group),the results of the present analysis would not be significant for mortality.
The effects of treatment in trials of nonselective?-blockers were compared with those seen in trials of?1-selective agents (Table3).For mortality,the risk of death was reduced by 49%in trials of nonselective?-blockers(P?0.001)but by only18%in trials of?1-selective agents(P?0.26);the difference in the mortality effects between the2subgroups was significant(P?0.049).In contrast,for all other measures, the magnitude of the treatment effect was similar in trials of selective and nonselective?-blockers.Although an improve-ment in NYHA class was observed in trials of selective ?-blockers and a decrease in risk of NYHA deterioration was noted in trials of nonselective?-blockers,the differences between the2subgroups for these2measures were not significant(Table3).
Discussion
The results of the present meta-analysis indicate that long-term treatment with a?-adrenergic blocking drug can pro-duce important benefits in chronic heart failure.The addition of a?-blocker to conventional therapy was associated with a significant impact on morbidity and mortality,as evidenced by a32%reduction in the risk of death,a41%reduction in the risk of being hospitalized for heart failure,and a37% reduction in the combined risk of morbidity and mortality.In addition,treatment with a?-blocker produced significant hemodynamic and symptomatic benefits,as reflected by a 29%increase in left ventricular ejection fraction,a32% increase in the likelihood of functional improvement,and a 30%decrease in the likelihood of functional deterioration. These findings increase the confidence gained from individ-ual studies that?-blockers can produce a wide range of favorable effects in chronic heart failure.
In the present analysis,the measures that were most consistently improved by?-blockade were ejection fraction, the frequency of hospitalization for heart failure,and the combined risk of morbidity and mortality.The effect on these 3measures was not only highly significant but also so robust that we could negate the effect only by removing80%to90% of the database or by adding to the database an exceedingly large number of trials with a neutral result.The effect on these variables was particularly persuasive because many of the trials were specifically designed to evaluate changes in ejection fraction and the combined risk of morbidity and mortality,and the effect was not accompanied by any important heterogeneity among the trials.In contrast,the favorable effect of?-blockade on NYHA functional class was not robust and could be negated by removing only15% of the database or by adding only1moderate-size trial with a neutral effect.The lack of a persuasive effect of?-blockade on NYHA class may have been related to the fact that most trials had a short duration of follow-up;failed to record changes in NYHA class in patients who were withdrawn from
a study for clinical deterioration between scheduled visits;
and enrolled patients with class II symptoms,in whom
demonstration of clinical benefit may be difficult.Indeed,the
observation that NYHA class improved in trials of selective
agents but not in trials of nonselective agents was probably
related to the fact that class II patients composed only18%of
the patients enrolled in trials of selective?-blockers but51% of the patients enrolled in trials of nonselective?-blockers. The present report confirms the conclusions of2recent
meta-analyses2,3that the use of?-blockers is associated with a reduction in mortality of?30%.However,as in the
previous reports,such an effect was only intermediate in
robustness.On the one hand,we could negate the effect only
with some difficulty:by either removing84%of the database
or adding to the database a large number of moderate-size
trials with a neutral result.On the other hand,a neutral result
in a single,large-scale,long-term study would make the
mortality effect disappear entirely.Uncertainty about the
effect of?-blockers on survival is heightened further by our finding that the magnitude of the mortality reduction may
depend on the pharmacological properties of the drug.
Whereas both selective and nonselective?-blockers were associated with similar increases in ejection fraction and
decreases in the risk of hospitalization,nonselective ?-blockers were associated with a larger survival benefit than ?1-selective agents.All-cause mortality was reduced in trials of nonselective agents by49%(P?0.001)but was reduced by
only18%(P?0.26)in trials of?1-selective agents;the probability value for the difference between the2groups was
significant(P?0.049).This observation is noteworthy be-
cause experience in postinfarction trials has suggested that
agents that block both?1-and?2-receptors may provide more complete protection against catecholamine toxicity than agents that act only on the?1-receptor.32Blockade of?2-receptors may be particularly important in heart failure, because?2-receptors are not downregulated in the failing heart.33Furthermore,blockade of?2-receptors(but not?1-receptors)reduces sympathetic drive to the heart34and may prevent ventricular arrhythmias,either directly35or by mini-mizing the risk of catecholamine-induced hypokalemia.36The latter mechanisms are of interest because earlier studies have ascribed the superior mortality effects of nonselective agents to their ability to prevent sudden death.3,32However,it should be noted that nearly90%of the experience with nonselective ?-blockers in clinical trials is with carvedilol,which blocks ?-adrenergic receptors in addition to?1-and?2-receptors. Because combined?-and?-blockade prevents the toxic effects of catecholamines more effectively than?-blockade alone in experimental studies,37–39it is possible that blockade of?-receptors(rather than of?2-receptors)might account for the larger mortality reduction observed with nonselective agents in the present report.The hypothesis that?-blockers differ in their survival effects is being prospectively evaluated in the Carvedilol or Metoprolol European Trial(COMET), which is comparing the effects of carvedilol and metoprolol on all-cause mortality in chronic heart failure.
The results of this meta-analysis should be interpreted
cautiously.Because meta-analyses are based on the published Lechat et al September22,19981189
literature,publication biases(ie,the tendency to selectively publish favorable results)could invalidate our findings.11For most end points,however,a large number of trials with a neutral result would be necessary to negate the finding of benefit,and we can reasonably assume that all large-scale randomized trials evaluating?-blockers in heart failure are known to us.We recognize the possibility that a meta-anal-ysis can be biased if the overall result is highly dependent on 1or2trials or if the trials observed a high rate of withdrawals from active therapy.However,none of the18randomized trials included in the present meta-analysis had a weight ?50%,and the number of patients lost to follow-up in each study was small(composing only1%to3%of the total randomized).Finally,for some end points(eg,mortality),the number of events may be too small to allow definitive conclusions,even though the reduction in risk was highly significant.Unlike other meta-analyses,however,this present analysis did not confine itself to mortality but rather analyzed nonfatal measures of outcome(eg,hospitalizations).For these other variables,the number of events was large and the treatment effects were robust.
In conclusion,a meta-analysis of more than3000patients enrolled in18randomized trials indicates that the addition of a?-blocker to conventional therapy is associated with hemo-dynamic and symptomatic improvement as well as favorable effects on morbidity and mortality.Our results are particu-larly persuasive for the effect of treatment on the combined risk of all-cause mortality and hospitalizations for heart failure,a measure of efficacy that is receiving increasing attention as a primary end point in clinical trials and as the basis for approval of new drugs by regulatory agencies.In the present analysis,3trials4,24,28were designed to evaluate a combined end point,and2(both with carvedilol24,28)showed a significant effect of treatment.Although the present analy-sis also indicates that?-blockers probably prolong survival, the relatively small number of fatal events and the possibility of a difference in the effects of selective and nonselective ?-blockers on mortality indicate that further studies are needed before we can conclude that prolongation of life is a general property of?-blockers in heart failure.Further insights on this issue will be provided by the results of several ongoing mortality trials of both selective(CIBIS II and MERIT)and nonselective(BEST and COPERNICUS) agents.However,given the persuasive evidence for a favor-able effect of?-blockade on the combined risk of morbidity and mortality,physicians would appear to have sufficient evidence to support the use of?-blockers in heart failure, even before the completion of these large-scale studies.
References
1.Packer M.The neurohormonal hypothesis:a theory to explain the
mechanism of disease progression in heart failure.J Am Coll Cardiol.1992;20:248–254.
2.Doughty RN,Rodgers A,Sharpe N,MacMahon S.Effects of beta-
blocker therapy on mortality in patients with heart failure:a systematic overview of randomized controlled trials.Eur Heart J.1997;18:560–565.
3.Heidenreich PA,Lee TT,Massie BM.Effect of beta-blockade on mor-
tality in patients with heart failure:a meta-analysis of randomized clinical trials.J Am Coll Cardiol.1997;30:27–34.
4.Waagstein F,Bristow MR,Swedberg K,Camerini F,Fowler MB,Silver
MA,Gilbert EM,Johnson MR,Goss FG,Hjalmarson A.Beneficial
effects of metoprolol in idiopathic dilated https://www.wendangku.net/doc/4a2758241.html,ncet.1993;
342:1441–1446.
5.Boissel JP,Blanchard J,Panak E,Peyrieux JC,Sacks H.Considerations
for the meta-analysis of randomized clinical trials:summary of a panel discussion.Control Clin Trials.1989;10:254–281.
6.Yusuf S,Peto R,Lewis J,Collins R,Sleight P.Beta blockade during and
after myocardial infarction:an overview of the randomized trials.Prog Cardiovasc Dis.1985;27:335–371.
7.Mantel N,Haenszel W.Statistical aspects of the analysis of data from
retrospective studies of disease.J Natl Cancer Inst.1959;22:719–748.
8.Cochran WG.The combination of estimates from different experiments.
Biometrics.1954;10:101–129.
9.Baptista J,Pike MC.Exact two sided confidence limits for the odds ratio
in a2x2tables.Algorithm AS115.Appl Stat.1977;26:214–220.
10.D’Agostino RB,Weintraub M.Meta-analysis:a method for synthesizing
research.Clin Pharmacol Ther.1995;58:605–661.
11.Hedges LV,Olkin I.Statistical Methods for Meta-Analysis.Orlando,Fla:
Academic Press;1985.
12.Engelmeier RS,O’Connell JB,Walsh R,Rad N,Scanlon PJ,Gunnar RM.
Improvement in symptoms and exercise tolerance by metoprolol in patients with dilated cardiomyopathy:a double-blind,randomized, placebo-controlled trial.Circulation.1985;72:536–546.
13.Pollock SG,Lystash J,Tedesco C,Craddock G,Smucker https://www.wendangku.net/doc/4a2758241.html,efulness
of bucindolol in congestive heart failure.Am J Cardiol.1990;66: 603–607.
14.Lechat P,Boutelant S,Komajda M,Gagey S,Landault C,Maistre G,
Grosgogeat Y.Pilot study of cardiovascular effects of nebivolol in con-gestive heart failure.Drug Invest.1991;3(suppl1):69–81.
15.Woodley SL,Gilbert EM,Anderson JL,O’Connell JB,Deitchman D,
Yanowitz FG,Mealey PC,Volkman K,Renlund DG,Menlove R, Bristow MR.?-Blockade with bucindolol in heart failure caused by ischemic versus idiopathic dilated cardiomyopathy.Circulation.1991;84: 2426–2441.
16.Wisenbaugh T,Katz I,Davis J,Essop R,Skoularigis J,Middlemost S,
Ro¨thlisberger C,Skudicky D,Sareli P.Long-term(3-month)effects of a new beta-blocker(nebivolol)on cardiac performance in dilated cardio-myopathy.J Am Coll Cardiol.1993;21:1094–1100.
17.Fisher ML,Gottlieb SS,Plotnick GD,Greenberg NL,Patten RD,Bennett
SK,Hamilton BP.Beneficial effects of metoprolol in heart failure asso-ciated with coronary artery disease:a randomized trial.J Am Coll Cardiol.1994;23:943–950.
18.Bristow MR,O’Connell JB,Gilbert EM,French WJ,Leatherman G,
Kantrowitz NE,Orie J,Smucker ML,Marshall G,Kelly P,Deitchman D, Anderson JL.Dose-response of chronic?-blocker treatment in heart failure from either idiopathic dilated or ischemic cardiomyopathy.Cir-culation.1994;89:1632–1642.
19.CIBIS Investigators.A randomized trial of?-blockade in heart failure:
the Cardiac Insufficiency Bisoprolol Study.Circulation.1994;90: 1765–1773.
20.Eichhorn EJ,Heesch CM,Barnett JH,Alvarez LG,Fass SM,Grayburn
PA,Hatfield BA,Marcoux LG,Malloy CR.Effect of metoprolol on myocardial function and energetics in patients with nonischemic dilated cardiomyopathy:a randomized,double-blind,placebo-controlled study.
J Am Coll Cardiol.1994;24:1310–1320.
21.Metra M,Nardi M,Giubbini R,Deilas L.Effects of short-and long-term
carvedilol administration on rest and exercise hemodynamic variables, exercise capacity and clinical conditions in patients with idiopathic dilated cardiomyopathy.J Am Coll Cardiol.1994;24:1678–1687.
22.Olsen SL,Gilbert EM,Renlund DG,Taylor DO,Yanowitz FD,Bristow
MR.Carvedilol improves left ventricular function and symptoms in chronic heart failure:a double-blind randomized study.J Am Coll Cardiol.1995;25:1225–1231.
23.Australia-New Zealand Heart Failure Research Collaborative Group.
Effects of carvedilol,a vasodilator–?-blocker,in patients with congestive heart failure due to ischemic heart disease.Circulation.1995;92:212–218.
24.Australia-New Zealand Heart Failure Research Collaborative Group.
Randomized,placebo-controlled trial of carvedilol in patients with con-gestive heart failure due to ischemic heart https://www.wendangku.net/doc/4a2758241.html,ncet.1997;349: 375–380.
25.Krum H,Sackner-Bernstein JD,Goldsmith RL,Kukin ML,Schwartz B,
Penn J,Medina N,Yushak M,Horn E,Katz SD,Levin HR,Neuberg GW, DeLong G,Packer M.Double-blind,placebo-controlled study of the long-term efficacy of carvedilol in patients with severe chronic heart failure.Circulation.1995;92:1499–1506.
1190Analysis of?-Blocker Trials in Heart Failure
26.Bristow M,Gilbert EM,Abraham WT,Adams KF,Fowler MB,
Hershberger RE,Kubo SH,Narahara KA,Ingersoll H,Krueger S, Young S,Shusterman N for the MOCHA investigators.Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure.Circulation.1996;94: 2807–2816.
27.Packer M,Colucci WS,Sackner-Bernstein JD,Liang C,Goldsher DA,
Freeman I,Kukin ML,Kinhal V,Udelson JE,Klapholz M,Gottlieb SS,Pearle D,Cody RJ,Gregory JJ,Kantrowitz NE,LeJemtel TH, Young ST,Lukas MA,Shusterman NH,for the PRECISE Study Group.Double-blind,placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure.Circu-lation.1996;94:2793–2799.
28.Colucci WS,Packer M,Bristow MR,Gibert EM,Cohn JN,Fowler
MB,Krueger SK,Hershberger R,Uretsky BF,Bowers JA,Sackner-Bernstein JD,Young ST,Holcslaw TL,Lukas AM,for the US Carvedilol Heart Failure Study Group.Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure.Circu-lation.1996;94:2800–2806.
29.Cohn JN,Fowler MB,Bristow MB,Colucci WS,Gilbert EM,Kinhal V,
Krueger SK,LeJemtel TH,Narahara KA,Packer M,Young ST,Holcslau TL,Lukas MA,for the US Carvedilol Heart Failure Study Group.Safety and efficacy of carvedilol in severe heart failure.J Card Fail.1997;3: 173–179.
30.Gilbert EM,Anderson JL,Deitchman D,Yanowitz FG,O’Connell JB,
Renlund DG,Bartholomew M,Mealey PC,Larrabee P,Bristow MR.
Long-term?-blocker vasodilator therapy improves cardiac function in idiopathic dilated cardiomyopathy:a double-blind,randomized study of bucindolol versus placebo.Am J Med.1990;88:223–229.
31.Packer M,Bristow MR,Cohn J,Colucci W,Fowler MB,Gilbert EM,
Shusterman NH,for the US Carvedilol Heart Failure Study Group.The
effect of carvedilol on morbidity and mortality in patients with chronic heart failure.N Engl J Med.1996;334:1349–1355.
32.Johansson BW.Effect of beta-blockade on ventricular fibrillation-and
ventricular tachycardia-induced circulatory arrest in acute myocardial infarction.Am J Cardiol.1986;57:34F–37F.
33.Bristow MR,Ginsburg R,Umans V,Fowler MB,Minobe W,Rasmussen
R,Zera P,Menlove R,Shah P,Jamieson S.Beta1-and beta2-adrenergic receptor subpopulations in nonfailing and failing human ventricular myo-cardium:coupling of both receptor subtypes to muscle contraction and selective beta1-receptor down-regulation in heart failure.Circ Res.1986;
59:297–309.
34.Newton GE,Parker JD.Acute effects of?1-selective and nonselective
?-adrenergic receptor blockade on cardiac sympathetic activity in con-gestive heart failure.Circulation.1996;94:353–358.
35.Billman GE,Castillo LC,Hensley J,Hohl CM,Altshuld RA.
?2-Adrenergic receptor antagonists protect against ventricular fibrillation: in vivo and in vitro evidence for enhanced sensitivity to?2-adrenergic stimulation in animals susceptible for sudden death.Circulation.1997;
96:1914–1922.
36.Reid JL,Whyte KF,Struthers AD.Epinephrine-induced hypokalemia:the
role of beta-adrenoceptors.Am J Cardiol.1986;57:23F–27F.
37.Downey SE,Lee JC.Contribution of?-adrenoceptor activation to the
pathogenesis of norepinephrine cardiomyopathy.Circ Res.1983;52: 471–478.
38.Mann DL,Kent RL,Parsons B,Cooper G IV.Adrenergic effects on the
biology of the adult mammalian cardiocyte.Circulation.1992;85: 790–804.
39.Molina-Viamonte V,Anyukhovsky EP,Rosen MR.An?1-adrenergic
receptor subtype is responsible for delayed afterdepolarizations and triggered activity during simulated ischemia and reperfusion of isolated canine Purkinje fibers.Circulation.1991;84:1732–1740.
Lechat et al September22,19981191