Skip Navigation

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Funck-Brentano, C.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Funck-Brentano, C.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Beta-blockade in CHF: from contraindication to indication

Christian Funck-Brentano1,2,3,*

1 Pierre et Marie Curie University, Department of Pharmacology, Paris, F-75012, France
2 AP-HP, Saint-Antoine Hospital, Division of Clinical Pharmacology, Paris, F-75012, France
3 INSERM–AP-HP, Clinical Investigation Center, CIC-9304, Hôpital St-Antoine, 184, rue du Faubourg Saint-Antoine, Paris, F-75012, France

* Corresponding author. Tel: +33 1 49 28 22 00; fax: +33 1 49 28 28 13. E-mail address: christian.funck-brentano{at}sat.aphp.fr


   Abstract
Top
 Abstract
Introduction
 Conclusions
 References
 
When beta-blockers were first introduced, they were initially tested in chronic heart failure (CHF) at full doses and without slow upward titration. In this context, they rapidly became contraindicated in CHF because of their negative inotropic properties. Later, however, it became clear that sympathetic activation was closely associated with CHF and that the degree of activation was, to some extent, proportional to the severity of left ventricular dysfunction. This suggested that beta-blockers should be beneficial in CHF, but in practice they were still avoided, despite a small number of encouraging early uncontrolled studies. It was not until the 1990s that large randomized controlled trials provided unequivocal proof of the mortality and morbidity benefits of beta-blockade with bisoprolol, controlled-release metoprolol succinate, and carvedilol. In the landmark studies, the beta-blocker, given on top of standard treatment, consistently reduced the all-cause mortality by 34–35%, with very good tolerability. Beta-blockade also reduced cardiovascular mortality, sudden cardiac death, and death due to progression of heart failure, reduced hospitalizations (all-cause, cardiovascular, and worsening heart failure), and improved NYHA functional class. All the landmark trials were performed with a very low initial dose of the beta-blocker (compared with the dose used in patients without CHF), with a slow individualized upward titration towards full beta-blockade. Such a progressive and individualized method of administration appears to be critical for the transformation of beta-blockers from contraindicated agents in CHF to agents that are not only indicated, but considered a critical component of standard treatment.

Key Words: Dose-response • Side-effects • Bisoprolol • Carvedilol • Metoprolol • Dose titration


   Introduction
Top
 Abstract
 Introduction
Conclusions
 References
 
Shortly after their introduction in the early 1960s, the negative inotropic properties of beta-blockers were identified as a reason for not exposing patients with chronic heart failure (CHF) to these drugs. The first published report of beta-blocker administration in CHF came in 1966, when three cases were reported in which full-dose (75 mg) i.v. pronethanol led to dramatic worsening in patients in heart failure with sinus tachycardia.1 One patient, a man aged 52, with a recent myocardial infarction (MI), was in left ventricular (LV) failure with a heart rate of 120/min. By the time the injection was completed, his heart rate had slowed to 80 bpm, but his clinical condition was worse. During the next 20 min, his heart progressively slowed and finally stopped in asystole. In the other two patients, the heart rate also slowed during the injection, but both were clinically worse. In view of such experiences, it is not surprising that beta-blockers continued to be considered contraindicated in CHF for nearly 30 years.

Early reports of beta-blocker benefit
It had been known since the early 1970s that sympathetic activation is closely associated with CHF.2 Initially, this activation was considered to be a consequence and not a cause of CHF, but gradually, attention shifted to a neurohormonal model of the pathophysiology of the disease.3 In 1984, Cohn et al.4 analysed data from 106 patients with moderate to severe CHF, followed up for one to 62 months, and found that plasma norepinephrine independently predicted mortality risk (P=0.002) (Figure 1). The degree of sympathetic activation increases as patients progress from asymptomatic LV dysfunction to symptomatic CHF.5 Moreover, early sympathetic activation is a strong predictor of later morbidity and mortality. Data from the Studies on Left Ventricular Dysfunction (SOLVD) prevention trial show that raised plasma norepinephrine levels in patients with asymptomatic LV dysfunction predict all-cause and cardiovascular mortality, development of CHF, death and hospitalization for CHF, and the development of MI or unstable angina (Figure 2).6


Figure 0101
View larger version (13K):
[in this window]
[in a new window]
  		Figure 1 Data from 106 patients with moderate to severe CHF showed a close relationship between sympathetic activation (plasma norepinephrine levels) and prognosis. Reproduced with permission from Cohn et al.4

 

Figure 0102
View larger version (13K):
[in this window]
[in a new window]
  		Figure 2 Data from the SOLVD prevention trial showed that raised plasma norepinephrine levels in patients with asymptomatic LV dysfunction (n=514, LVEF ≤35%) predict all-cause and cardiovascular mortality, development of CHF, death, and hospitalization for CHF, and the development of MI or unstable angina. Reproduced with permission from Benedict et al. Prognostic significance of plasma norepinephrine in patients with asymptomatic left ventricular dysfunction. SOLVD Investigators. Circulation 1996;94:690–697.

 
Even though evidence was accumulating of the critical role of sympathetic activation in CHF, beta-blockers remained contraindicated throughout the 1970s and 80s. In 1975, a case series was published describing seven patients with intractable heart failure in whom beta-blocker therapy was associated with prolonged improvement of symptoms and exercise capacity.7 In 1979, Swedberg et al.8 reported a non-randomized study in 24 patients with congestive cardiomyopathy who received beta-blockers plus standard treatment with digitalis and diuretics, compared with 13 retrospective controls who only received digitalis and diuretics. A three-year survival rate was 52% among patients receiving beta-blockers, but only 10% in the control group.

However, it was not until 1993 that a series of prospective clinical trials that would continue into the 2000s began to test the hypothesis that beta-blockade would improve morbidity and mortality in patients with CHF.9–18 In the meantime, investigation of another class of neurohormonal inhibitors, the ACE-inhibitors, proceeded rapidly during the 1980s. Unlike the beta-blockers, ACE-inhibitors were never considered contraindicated in CHF. Thus, the findings of the major ACE-inhibitor trials19–27 were published earlier than the major beta-blocker trials. By the time the major beta-blocker trials began, ACE-inhibitors were already considered a part of the standard treatment. Hence, in the landmark trials of beta-blockers (Figure 3), a vast majority of patients were already receiving ACE-inhibitors.


Figure 0103
View larger version (15K):
[in this window]
[in a new window]
  		Figure 3 Chronological progression of landmark studies on ACE-inhibitors and beta-blockers. AIRE, Acute Infarction Ramipril Efficacy;26 CIBIS;11 CIBIS II;11 CONSENSUS, Cooperative North Scandinavian Enalapril Survival Study;19 COPERNICUS;16 Hy-C, Hydralazine vs. Captopril;20 ISIS-4, Fourth international study of infarct survival;25 MERIT-HF;13 MDC, Metoprolol in Dilated Cardiomyopathy;9 SAVE, Survival and Ventricular Enlargement;24 SOLVD;22,23 TRACE, Trandolapril Cardiac Evaluation;27 USCP;14 V-HeFT II, Vasodilator-Heart Failure Trial Study Group.21 Original figure from Pr Piotr Ponikowski, with permission and thanks.

 
Long-term randomized trials of beta-blockade
The first major long-term study to evaluate the effects of beta-adrenergic blockade on morbidity was the metoprolol in dilated cardiomyopathy (MDC) study.9 The MDC trial included 383 patients with non-ischaemic dilated cardiomyopathy and mild-to-moderate heart failure, randomized to immediate-release metoprolol tartrate (maximum dose 150 mg/day) or placebo, in addition to conventional therapy. Treatment with metoprolol was associated with a substantial reduction in clinical deterioration to the point of requiring heart transplantation, which occurred in only two patients in the metoprolol group compared with 19 in the placebo group (P=0.0001). However, the MDC trial did not demonstrate any significant effect of metoprolol on the all-cause mortality or the combined primary endpoint (mortality/need for heart transplantation).

The first trial of a beta-blocker in CHF with mortality as the main endpoint was with bisoprolol—the Cardiac Insufficiency Bisoprolol Study (CIBIS) trial.10 Unfortunately, CIBIS was not sufficiently powered to demonstrate significant effects on mortality, although there was a non-significant 20% reduction in the all-cause mortality in the bisoprolol group (P=0.22). In addition, the trial did show significant improvements in survival in some subgroups, and led to the larger CIBIS II trial (see below).11,28

Early evidence suggesting a mortality benefit of carvedilol in CHF came from the US Carvedilol Heart Failure Program (USCP). This consisted of four coordinated studies in 1094 patients with CHF [mean ejection fraction (EF) 23%] in NYHA class II, III, or IV, who were randomized to carvedilol or placebo. The primary endpoints were measures of morbidity (exercise tolerance or hospitalization); in three of the four studies there was no significant improvement. All-cause mortality was not a prospective primary or secondary endpoint, but retrospective analysis indicated a mortality reduction of 65% in the carvedilol group compared with the placebo group.14

The Australia and New Zealand study evaluated the effect of carvedilol in 415 patients with chronic stable heart failure of ischaemic aetiology (NYHA class I, II, or III, EF<45%). Most patients were already receiving a diuretic (75%) and an ACE-inhibitor (85%).29 Six-month treatment with carvedilol improved the LV function and maintained exercise performance at a lower rate-pressure product, but heart failure symptoms were slightly worsened.29 After 18 months or more of treatment, there was no significant reduction in mortality (20 deaths in the carvedilol group and 26 in the placebo group) and a reduction in hospitalization of borderline significance. However the combined endpoint of death or hospitalization showed a significant reduction in risk.15

CIBIS II was the first trial to show a significant beneficial effect of beta-blockade on mortality in CHF.11 It compared bisoprolol (up to 10 mg daily) with placebo in 2647 patients with CHF (ischaemic or non-ischaemic) in NYHA III or IV with LVEF ≤35%. It found a 34% reduction in the all-cause mortality (P<0.0001). There was also a 44% reduction in sudden death (P<0.0011), a 20% reduction in the all-cause hospital admissions (P<0.0006), and a 36% reduction in hospital admissions due to worsening heart failure (P<0.0001). Treatment effects were independent of the severity or cause of CHF.

CIBIS II was followed by two more landmark trials—metoprolol CR/XL randomized intervention trial in congestive heart failure(MERIT-HF)13 and the carvedilol prospective randomized cumulative survival (COPERNICUS) with carvedilol.16 MERIT-HF included 3991 patients with an ischaemic or non-ischaemic cardiomyopathy and mild, moderate, or severe heart failure (predominantly NYHA class II–III). Patients were randomized to placebo or metoprolol succinate sustained release at up to 200 mg/day, in addition to conventional therapy. Over a mean follow-up of one year, metoprolol reduced the all-cause mortality by 34% (P=0.00015), sudden deaths by 41%, and death due to worsening heart failure by 49%.

COPERNICUS16 was a double-blind randomized trial of carvedilol vs. placebo in 2289 patients in NYHA class IV CHF, with an LVEF<25%. Patients received carvedilol or placebo for a mean of 10.4 months, in addition to standard therapy with diuretics and ACE-inhibitors. Carvedilol reduced the all-cause mortality by 35% and the combined risk of death or hospitalization by 24% (P<0.001). Reductions in mortality were consistent across all subgroups, regardless of age, sex, ethnicity, aetiology of heart failure (ischaemic vs. non-ischaemic), or baseline LVEF.

Thus, all three key beta-blocker trials (CIBIS II, MERIT-HF, and COPERNICUS) showed a remarkably consistent effect, with a reduction in the all-cause mortality of 34–35% when the beta-blocker was added to standard therapy (diuretics, ACE-inhibitors, and optional digitalis glycosides). In these trials, beta-blockers also achieved significant long-term reductions in cardiovascular mortality, sudden death, and death due to progression of heart failure. In addition, they reduced hospitalizations (the all-cause, cardiovascular, and worsening heart failure), improved functional class (NYHA) and reduced heart failure worsening.

Recently, a further beta-blocker trial was published: the Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in Seniors with Heart Failure (SENIORS).18 This was conducted in 2128 elderly patients (≥70 years) with CHF. Nebivolol (target dose 10 mg) was compared with placebo (mean follow-up 21 months). The composite primary endpoint of the all-cause mortality or cardiovascular hospital admissions was significantly reduced by 14% (P=0.039). The main secondary outcome, the all-cause mortality, showed only a non-significant reduction of 12%. These effects are less marked than those of bisoprolol, metoprolol succinate and carvedilol in CIBIS II,11 MERIT-HF,13 and COPERNICUS.16 However, meaningful comparisons across the trials are hard to make because of the unique age group studied and the better LV function of the patients in SENIORS compared with the other studies (LVEF>45% in about 20% of patients). Thus, from SENIORS alone, it is impossible to determine whether nebivolol has less efficacy than bisoprolol, metoprolol, or carvedilol.30

Only one placebo-controlled study, the Beta-blocker Evaluation of Survival (BEST)17 with bucindolol, has failed to show a survival benefit. The reason for the discrepancy between BEST and the other landmark trials is unclear. Bucindolol has sympatholytic activity due to its strong beta2-adrenergic blockade, and only weak alpha1-blocking vasodilatory properties. However, unlike the beta-blockers shown to reduce mortality, it also has intrinsic sympathomimetic activity,31 and this might counteract any beneficial effects it may have in CHF.32 In addition, a post hoc analysis of BEST showed benefits in a subpopulation of the trial selected, to have baseline characteristics similar to those of CIBIS II, MERIT-HF, and COPERNICUS.33 This suggests that the original population included in BEST, which differed from the other trials, may have contributed to the negative results of the study.

Meta-analyses of the effects of beta-blockade
In a meta-analysis by Bouzamundo et al.32 of placebo-controlled clinical trials of beta-blockers in CHF, beta-blockers reduced the all-cause mortality by 22%, with a significant heterogeneity because of BEST. This heterogeneity was no longer observed when BEST was excluded from the analysis, and the all-cause mortality was reduced by 32% for all compounds. Benefit was similar for bisoprolol, metoprolol, and carvedilol, and occurred in all NYHA classes.

A similar meta-analysis by Shibata et al.34 using data from 14 trials 9,10,13–15,28,35–43 found a reduction of 34% in the composite endpoint of mortality or hospital admission. Inclusion of COPERNICUS16 and BEST17 in this analysis (unpublished results) yields a composite endpoint of 29% (Figure 4).


Figure 0104
View larger version (24K):
[in this window]
[in a new window]
  		Figure 4 Odds ratios and 95% confidence limits for randomized trials of beta-blockers for the composite of mortality or hospital admission.9,10,13–15,28,35–43 The size of the central symbols represents the statistical weight of the trial in the meta-analysis. Adapted and reprinted with permission from European Society of Cardiology.34

 
Tolerability of beta-blockers in CHF
What changed during the 1990s that made it possible to use beta-blockers beneficially in CHF and turn a contra-indication into an indication? The answer appears to lie in the starting doses used in the landmark CHF trials (which were lower than in other indications such as hypertension or angina pectoris). In the landmark trials, the beta-blocker dose was slowly up-titrated, accepting that the final dose depends on the patient's individual tolerance.

Despite concerns about the possibility of side-effects due to the negative inotropic effects of beta-blockade, tolerability in the major placebo-controlled beta-blocker trials was very good. For example, the examination of side-effects leading to treatment withdrawal in MERIT-HF showed that withdrawal due to bradycardia, hypotension, dizziness, fatigue, and dyspnoea was slightly more common in the metoprolol group than in the placebo group (Table 1).44 However, the cumulative net difference for bradycardia, dizziness, and hypotension was only 0.9%. In contrast, the most frequent adverse events necessitating withdrawal of study drug were worsening heart failure, atrial fibrillation, and angina pectoris, which all occurred more frequently in the placebo group. In MERIT-HF, the incidence of withdrawal due to any adverse event was 17% lower in the metoprolol group than in the placebo group (P=0.06).44 Moreover, the incidence of withdrawal due to worsening heart failure was 25% lower in the metoprolol group than in the placebo group (P=0.08). Thus, although transient worsening of heart failure is a potential side-effect of beta-blockade, in practice, it does not appear to be a major concern provided treatment is started at low doses.


View this table:
[in this window]
[in a new window]
  		Table 1 Cause-specific adverse events leading to the withdrawal of study drug according to the absolute value for net difference between randomization groups in MERIT-HF

 
The other major mortality studies confirm the good tolerability of beta-blockade in CHF. In CIBIS-II, 42% of the participants achieved the target dose of 10 mg daily.11 At a mean follow-up of 1.3 years, withdrawal from the study drug was reported in 192 patients (15%) in the bisoprolol group and 194 patients (15%) in the placebo group. In COPERNICUS (mean follow-up, 10.4 months), the mean dose of carvedilol achieved was 37 mg daily.16 Withdrawal rates at 1 year were 18.5% in the placebo group and 14.8% in the carvedilol group. Analysis of the reports of the individual component trials of the USCP also gives overall discontinuation rates of 18.3% in the placebo group and 10.8% in the carvedilol group.45

Dose-response relationships
CHF appears to increase the sensitivity to beta-blockade, increasing the percentage of receptor occupancy compared with patients who do not have CHF. Adverse events tend to occur at a lower dose in CHF than in non-CHF patients, and with a smaller gap between the therapeutic dose and the dose at which adverse events become apparent. In patients with CHF, the dose-response curve is probably shifted to the left, so that the patients are more sensitive to beta-blockers than, for example, patients with hypertension. Furthermore, the adverse events curve is probably also closer to the dose-response curve than it is in patients without CHF. These hypothetical relationships are illustrated in Figure 5.


Figure 0105
View larger version (16K):
[in this window]
[in a new window]
  		Figure 5 Hypothetical dose-response and adverse events curves for beta-blockers in patients without CHF (A) and with CHF (B). In CHF, the dose-response curve may be shifted to the left, so that the patients are more sensitive to beta-blockers than those without CHF, and the adverse events curve is closer to the dose-response curve than it is in patients without CHF.

 
Individual variation in sensitivity and tolerance
The maximum tolerated dose of a beta-blocker depends both on the individual variation in sensitivity and the severity of CHF. The higher the NYHA class, the more sensitive patients appear to be to both the beneficial and the deleterious effects of beta-blockade. Krum et al.46 performed a retrospective analysis of tolerance to carvedilol in 808 consecutive patients with CHF, defining ‘tolerance’ as currently receiving carvedilol or receiving it at the time of death or heart transplantation. Overall, 88% of patients tolerated carvedilol. Factors associated with impaired tolerance by univariate analysis were age, low diastolic blood pressure, raised plasma urea concentration, and NYHA class (Figure 6). By multivariate analysis, no single baseline variable was an independent marker of inability to tolerate carvedilol. Tolerance was unrelated to the presence or absence of traditional precautions or relative contraindications to beta-blockade, being 85% in chronic obstructive airways disease/asthma, 86% in diabetes, 84% in peripheral vascular disease, 83% in patients receiving concomitant amiodarone treatment, and 84% in those with heart rate <70 bpm.


Figure 0106
View larger version (14K):
[in this window]
[in a new window]
  		Figure 6 Percentage of patients unable to tolerate carvedilol treatment, grouped according to NYHA functional class in a retrospective analysis of 808 consecutive patients with CHF. Reproduced with permission from the BMJ Publishing Group from Krum et al.46 Heart 2000;84:615–619.

 
Some patients are more sensitive to beta-blockade than others, allowing a similar degree of beta-blockade to be achieved on a lower dose than in less sensitive individuals. A post hoc analysis of MERIT-HF data examined heart rate response (indicating the degree of beta-blockade) and clinical outcomes in two dosage subgroups.47 These were a high-dose group who reached more than 100 mg of metoprolol CR/XL once daily (n=1202; mean 192 mg) and a low-dose group who reached 100 mg or less (n=412; mean 76 mg). Heart rate was reduced to a similar degree in the two dose groups, indicating greater sensitivity to beta-blockade in the low-dose group (Figure 7). Both groups showed a similar reduction in total mortality with metoprolol CR/XL compared with placebo: 38% in the high-dose group [95% confidence interval (CI) 16–55; P=0.0022] and 38% in the low-dose group (95% CI, 11–57; P=0.010). It is not known why some patients respond with a marked heart rate reduction and reduced mortality risk on a relatively small dose of a beta-blocker, but the data certainly support the idea of an individualized dose titration regimen guided by tolerability and the heart rate response.


Figure 0107
View larger version (26K):
[in this window]
[in a new window]
  		Figure 7 Sensitivity to metoprolol CR/XL in MERIT-HF in the subgroup surviving at the end of the three-month titration period. A similar degree of heart rate reduction was achieved in both the high- and low-dose groups. Reproduced with permission from The American College of Cardiology Foundation.47

 
Target dose or maximum tolerated dose?
Titrating the beta-blocker up to the maximum tolerated dose as opposed to the target dose is probably all that is needed to achieve the maximum benefits of beta-blockade in a specific patient, as the maximum tolerated dose may be presumed to be related to maximum receptor occupancy. An analysis of CIBIS II data by Simon et al.48 divided the CIBIS II patients into three tertiles according to the last tolerated dose before their final follow-up visit or before an event. The three bisoprolol dose tertiles were: low-dose: 1.25, 2.5, or 3.75 mg/day; n=434 (33%); moderate-dose: 5.0 or 7.5 mg/day; n=328 (25%); high-dose: 10 mg/day; n=565 (43%). The patients in the placebo group were similarly divided into low-, moderate-, and high-dose tertiles according to the level of dose reached. In all three dose groups, bisoprolol significantly reduced the all-cause mortality (Table 2). The risk of cardiovascular death, the all-cause hospitalization, and cardiovascular hospitalization were lower in the high- and moderate-dose groups than in the low-dose group. Compared with patients treated with moderate and high doses of bisoprolol, those receiving low doses were significantly older, and had more severe CHF and a lower systolic and diastolic blood pressure.


View this table:
[in this window]
[in a new window]
  		Table 2 Risks of various outcomes with bisoprolol vs. placebo in three dose tertiles

 
Notably, discontinuation of bisoprolol was associated with a significantly increased risk of mortality. Bisoprolol-treated patients withdrawn from treatment were approximately twice as likely to die as those who remained on treatment (relative hazard 2.13; CI 1.43–3.17; P<0.0002). This study reinforces the proposal that beta-blockers should be up-titrated guided by tolerance, and that, wherever possible, physicians should aim to maintain a beta-blocker at a low dose rather than interrupting the treatment. In addition, an event history analysis of competitive risks in CIBIS II showed that all attempts to resume bisoprolol therapy should be made if temporary withdrawal is clinically required.49

The maximum tolerated dose of a beta-blocker varies widely between individuals. In the Bisoprolol Experience study, which included 328 patients treated for CHF in general practice, the maximum tolerated dose of bisoprolol ranged from 1.25 to 10 mg daily (Figure 8).50


Figure 0108
View larger version (16K):
[in this window]
[in a new window]
  		Figure 8 Distribution of maximum tolerated dose of bisoprolol in 328 CHF patients in primary care. Reproduced with permission from European Society of Cardiology.50

 

   Conclusions
Top
 Abstract
 Introduction
 Conclusions
References
 
All the major beta-blocker mortality trials in CHF—CIBIS II, MERIT-HF, and COPERNICUS—used a very low initial dose of the beta-blocker (compared with the dose used in patients without CHF), with a slow, individualized upward titration towards full beta-blockade. This progressive and individualized method of beta-blocker administration has allowed a perceived contraindication for beta-blockade to become a well-documented indication. The secret of using beta-blockers successfully in CHF is to ‘start low and go slow’. The aim is to individualize the treatment by slowly working towards the maximum tolerated dose, at which full receptor occupancy may be attained.


   References
Top
 Abstract
 Introduction
 Conclusions
 References
 

  1. Stock JP. Beta adrenergic blocking drugs in the clinical management of cardiac arrhythmias. Am J Cardiol 1966; 18: 444–449.[CrossRef][ISI][Medline]
  2. Rutenberg HL, Spann JF. Alterations of cardiac sympathetic neurotransmitter activity in congestive heart failure. Am J Cardiol 1973; 32: 472–480.[CrossRef][ISI][Medline]
  3. Cohn JN, Levine TB, Francis GS, Goldsmith S. Neurohumoral control mechanisms in congestive heart failure. Am Heart J 1981; 102: 509–514.[CrossRef][ISI][Medline]
  4. Cohn JN, Levine TB, Olivari MT . Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med 1984; 311: 819–823.[Abstract]
  5. Francis GS, Benedict C, Johnstone DE . Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the studies of left ventricular dysfunction (SOLVD). Circulation 1990; 82: 1724–1729.[Abstract/Free Full Text]
  6. Benedict CR, Shelton B, Johnstone DE . Prognostic significance of plasma norepinephrine in patients with asymptomatic left ventricular dysfunction. SOLVD investigators. Circulation 1996; 94: 690–697.[Abstract/Free Full Text]
  7. Waagstein F, Hjalmarson A, Varnauskas E, Wallentin I. Effect of chronic beta-adrenergic receptor blockade in congestive cardiomyopathy. Br Heart J 1975; 37: 1022–1036.[Abstract/Free Full Text]
  8. Swedberg K, Hjalmarson A, Waagstein F, Wallentin I. Prolongation of survival in congestive cardiomyopathy by beta-receptor blockade. Lancet 1979; 1: 1374–1376.[ISI][Medline]
  9. Waagstein F, Bristow MR, Swedberg K . Beneficial effects of metoprolol in idiopathic dilated cardiomyopathy. Metoprolol in dilated cardiomyopathy (MDC) trial study group. Lancet 1993; 342: 1441–1446.[CrossRef][ISI][Medline]
  10. CIBIS Investigators and Committees. A randomized trial of beta-blockade in heart failure. The cardiac insufficiency bisoprolol study (CIBIS). Circulation 1994; 90: 1765–1773.[Abstract/Free Full Text]
  11. CIBIS II Investigators and Committees. The cardiac insufficiency bisoprolol study II (CIBIS-II): a randomised trial. Lancet 1999; 353: 9–13.[CrossRef][ISI][Medline]
  12. Erdmann E, Lechat P, Verkenne P, Wiemann H. Results from post-hoc analyses of the CIBIS II trial: effect of bisoprolol in high-risk patient groups with chronic heart failure. Eur J Heart Fail 2001; 3: 469–479.[CrossRef][ISI][Medline]
  13. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). Lancet 1999; 353: 2001–2009.[CrossRef][ISI][Medline]
  14. Packer M, Bristow MR, Cohn JN . The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. U.S. carvedilol heart failure study group. N Engl J Med 1996; 334: 1349–1355.[Abstract/Free Full Text]
  15. Australia/New Zealand Heart Failure Research Collaborative Group. Randomised, placebo-controlled trial of carvedilol in patients with congestive heart failure due to ischaemic heart disease. Lancet 1997; 349: 375–380.[CrossRef][ISI][Medline]
  16. Packer M, Coats AJ, Fowler MB . Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001; 344: 1651–1658.[Abstract/Free Full Text]
  17. The Beta-blocker Evaluation of Survival (BEST) Investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001; 344: 1659–1667.[Abstract/Free Full Text]
  18. Flather MD, Shibata MC, Coats AJ . Randomized trial to determine the effect of nebivolol on mortality and cardiovascular hospital admission in elderly patients with heart failure (SENIORS). Eur Heart J 2005; 26: 215–225.[Abstract/Free Full Text]
  19. The CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987; 316: 1429–1435.[Abstract]
  20. Fonarow GC, Chelimsky-Fallick C, Stevenson LW . Effect of direct vasodilation with hydralazine versus angiotensin-converting enzyme inhibition with captopril on mortality in advanced heart failure: the Hy-C trial. J Am Coll Cardiol 1992; 19: 842–850.[Abstract]
  21. Cohn JN, Johnson G, Ziesche S . A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991; 325: 303–310.[Abstract]
  22. The SOLVD Investigators. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325: 293–302.[Abstract]
  23. The SOLVD Investigators. Effect of enalapril on mortality and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Engl J Med 1992; 327: 685–691.[Abstract]
  24. Pfeffer MA, Braunwald E, Moye LA . Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. Results of the survival and ventricular enlargement trial. The SAVE Investigators. N Engl J Med 1992; 327: 669–677.[Abstract]
  25. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58 050 patients with suspected acute myocardial infarction. Lancet 1995; 345: 669.[CrossRef][ISI][Medline]
  26. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993; 342: 821–828.[ISI][Medline]
  27. Kober L, Torp-Pedersen C, Carlsen JE . A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. Trandolapril Cardiac Evaluation (TRACE) Study Group. N Engl J Med 1995; 333: 1670–1676.[Abstract/Free Full Text]
  28. The CIBIS II Scientific Committee. Design of the Cardiac Insufficiency Bisoprolol Study II (CIBIS II). Fundam Clin Pharmacol 1997; 11: 138–142.[ISI][Medline]
  29. Australia-New Zealand Heart Failure Research Collaborative Group. Effects of carvedilol, a vasodilator-beta-blocker, in patients with congestive heart failure due to ischemic heart disease. Circulation 1995; 92: 212–218.[Abstract/Free Full Text]
  30. Swedberg K, Cleland J, Dargie H . Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Eur Heart J 2005; 26: 1115–1140.[Free Full Text]
  31. Andreka P, Aiyar N, Olson LC . Bucindolol displays intrinsic sympathomimetic activity in human myocardium. Circulation 2002; 105: 2429–2434.[Abstract/Free Full Text]
  32. Bouzamondo A, Hulot JS, Sanchez P, Cucherat M, Lechat P. Beta-blocker treatment in heart failure. Fundam Clin Pharmacol 2001; 15: 95–109.[CrossRef][ISI][Medline]
  33. Domanski MJ, Krause-Steinrauf H, Massie BM . A comparative analysis of the results from 4 trials of beta-blocker therapy for heart failure: BEST, CIBIS-II, MERIT-HF, and COPERNICUS. J Card Fail 2003; 9: 354–363.[CrossRef][ISI][Medline]
  34. Shibata MC, Flather MD, Wang D. Systematic review of the impact of beta blockers on mortality and hospital admissions in heart failure. Eur J Heart Fail 2001; 3: 351–357.[CrossRef][ISI][Medline]
  35. Anderson JL, Lutz JR, Gilbert EM . A randomized trial of low-dose beta blockade therapy for idiopathic dilatedcardiomyopathy. Am J Cardiol 1985; 55: 471–475.[CrossRef][ISI][Medline]
  36. 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.[Abstract/Free Full Text]
  37. Cucchini F, Compostella L, Papalia D, de Domenico R, Iavernaro A, Zeppellini R. [Chronic treatment of dilated cardiomyopathy by beta blocking agents. Clinical and hemodynamic follow-up]. G Ital Cardiol 1988; 18: 835–842.[Medline]
  38. Fisher ML, Gottlieb SS, Plotnick GD . Beneficial effects of metoprolol in heart failure associated with coronary artery disease: a randomized trial. J Am Coll Cardiol 1994; 23: 943–950.[Abstract]
  39. 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.[Abstract]
  40. Krum H, Sackner-Bernstein JD, Goldsmith RL . Double-blind, placebo-controlled study of the long-term efficacy of carvedilol in patients with severe chronic heart failure. Circulation 1995; 92: 1499–1506.[Abstract/Free Full Text]
  41. Packer M, Colucci WS, Sackner-Bernstein JD . Double-blind, placebo-controlled study of the effects of carvedilol in patients with moderate to severe heart failure. The PRECISE Trial. Prospective Randomized Evaluation of Carvedilol on Symptoms and Exercise. Circulation 1996; 94: 2793–2799.[Abstract/Free Full Text]
  42. US Carvedilol Heart Failure Study Group. Carvedilol efficacy in severe heart failure. Proceedings of the Cardiorenal Advisory Panel Meeting of the Food and Drug Administration, 2 May 1996, Protocol 239.
  43. Colucci WS, Packer M, Bristow MR . Carvedilol inhibits clinical progression in patients with mild symptoms of heart failure. US Carvedilol Heart Failure Study Group. Circulation 1996; 94: 2800–2806.[Abstract/Free Full Text]
  44. Hjalmarson A, Goldstein S, Fagerberg B . Effects of controlled-release metoprolol on total mortality, hospitalizations, and well-being in patients with heart failure: the Metoprolol CR/XL Randomized Intervention Trial in congestive heart failure (MERIT-HF). JAMA 2000; 283: 1295–1302.[Abstract/Free Full Text]
  45. McMurray JJ. Major beta blocker mortality trials in chronic heart failure: a critical review. Heart 1999; 82 (Suppl. 4): IV14–IV22.
  46. Krum H, Ninio D, MacDonald P. Baseline predictors of tolerability to carvedilol in patients with chronic heart failure. Heart 2000; 84: 615–619.[Abstract/Free Full Text]
  47. Wikstrand J, Hjalmarson A, Waagstein F . Dose of metoprolol CR/XL and clinical outcomes in patients with heart failure: analysis of the experience in metoprolol CR/XL randomized intervention trial in chronic heart failure (MERIT-HF). J Am Coll Cardiol 2002; 40: 491–498.[Abstract/Free Full Text]
  48. Simon T, Mary-Krause M, Funck-Brentano C, Lechat P, Jaillon P. Bisoprolol dose-response relationship in patients with congestive heart failure: a subgroup analysis in the cardiac insufficiency bisoprolol study(CIBIS II). Eur Heart J 2003; 24: 552–559.[Abstract/Free Full Text]
  49. Funck-Brentano C, Lancar R, Hansen S, Hohnloser SH, Vanoli E. Predictors of medical events and of their competitive interactions in the Cardiac Insufficiency Bisoprolol Study 2 (CIBIS-2). Am Heart J 2001; 142: 989–997.[CrossRef][ISI][Medline]
  50. Schuchert A. Effects of bisoprolol treatment for chronic heart failure initiated and followed up by primary care physicians. Eur J Heart Fail 2005; 7: 604–611.[CrossRef][ISI][Medline]
  51. Packer M, Poole-Wilson PA, Armstrong PW . Comparative effects of low and high doses of the angiotensin-converting enzyme inhibitor, lisinopril, on morbidity and mortality in chronic heart failure. ATLAS Study Group. Circulation 1999; 100: 2312–2318.[Abstract/Free Full Text]
  52. Remme WJ, Swedberg K. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001; 22: 1527–1560.[Free Full Text]

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Arch Intern MedHome page
C.-H. Tseng
It Is Time We Ended the Myth of Insulin as an Atherogenic Hormone--Reply
Arch Intern Med, April 23, 2007; 167(8): 859 - 859.
[Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow E-letters: Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when E-letters are posted
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Request Permissions
Google Scholar
Right arrow Articles by Funck-Brentano, C.
Right arrow Search for Related Content
PubMed
Right arrow Articles by Funck-Brentano, C.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?