Skip Navigation

European Journal of Heart Failure 2002 4(6):757-763; doi:10.1016/S1388-9842(02)00113-7
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
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 Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Brehm, B. R.
Right arrow Articles by Risler, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Brehm, B. R.
Right arrow Articles by Risler, T.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2002 European Society of Cardiology

Effect of nebivolol on left ventricular function in patients with chronic heart failure: a pilot study

Bernhard R. Brehm*, Sabine C. Wolf, Sandra Görner, Nina Buck-Müller and Teut Risler

Medizinische Klinik III, Otfried-Müllerstr. 10, 72076 Tübingen, Germany

* Corresponding author. Tel.: +49-7071-2982711; fax: +49-7071-360245. E-mail address: bernhard.brehm{at}onlinehome.de


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Background: Sympathetic activity is a significant predictor of a poor prognosis in heart failure. Beta-blockers have been shown to improve the prognosis of patients with heart failure.

Aim: This pilot study examined the tolerability and efficacy of the new β-blocker nebivolol on left ventricular function in patients with chronic heart failure.

Methods and Results: Twelve patients with an ejection fraction of 13–39% were included in this double blind, placebo-controlled randomized trial of nebivolol administered in addition to standard therapy. Exercise time, heart rate, left ventricular function and tolerability were examined at baseline and after 3 months of orally administered nebivolol (2.5 and 5 mg, n=6) or placebo (n=6). Nebivolol was well tolerated and the NYHA class improved in four patients. Heart rate decreased while the maximal exercise duration and performance remained stable. Left ventricular function increased (ejection fraction 31.5±10.11 to 42.0±10.99%, P≤0.01) after 12 weeks of nebivolol. The left ventricular end-systolic diameter decreased in the nebivolol-group from 56.5±9.40 to 50.2±9.43 mm (P≤0.02).

Conclusion: These data indicate that nebivolol might improve cardiac function in patients with reduced left ventricular function.

Key Words: β-Blocker • Chronic heart failure • Left ventricular function

Received December 17, 2001; Revised March 19, 2002; Accepted May 21, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Sympathetic activity is a significant predictor for a poor prognosis in heart failure. Excessive stimulation with norepinephrine produces increased apoptosis in cardiomyocytes, tachycardia and arrhythmias in patients with heart failure, thereby leading to progression of left ventricular dysfunction and worsening of clinical outcome. Beta-blockers like metoprolol, bisoprolol and carvedilol have been shown to reduce morbidity and improve cardiac function [1]. The potential mechanisms of the benefit of beta-blockers in patients with heart failure are, cardiac protection from β-adrenoceptor over-stimulation, antiarrhythmic effects, reduction in heart rate and positive energetic effects or a combination of these factors. These effects are observed in addition to treatment with angiotensin-converting enzyme (ACE) inhibitors, diuretics and digitalis [2,3]. However, this effect is not shown for all β-blockers, as some like bucindolol do not influence overall survival of patients with heart failure as shown in the BEST trial [4].

Nebivolol is a new selective and lipophilic β1-adrenergic receptor antagonist which in addition to β1-adrenergic receptor inhibition, also increases endothelial nitric oxide release thereby inducing vasodilation [5,6]. Furthermore, antioxidant and anti-proliferative properties have been demonstrated in vitro in cardiac muscle fibers and in human coronary smooth muscle cells [7,8]. The aim of this pilot study was to assess the tolerability and effect of nebivolol on left ventricular function given in addition to standard therapy with digitalis, diuretics and ACE-inhibitors. Heart rate, blood pressure, NYHA class, and exercise capacity were also monitored.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Study patients
The study was performed at the University of Tuebingen, Department of Cardiology and Nephrology. All patients gave informed consent after written and oral information. The study was approved by the local Ethics Committee. Thirteen patients were recruited for the study. One patient was excluded after 1 week due to compliance problems with the standard medication. Inclusion criteria comprised an angiography prior enrollment into the study, and a stable clinical condition for at least 4 weeks before entry while receiving a standard therapy consisting of ACE-inhibitors, diuretics and digitalis. The echocardiographic left ventricular ejection fraction at the baseline averaged 29.7±7.6% (range 13–39%). A total of 12 patients with chronic heart failure designated as New York Heart Association (NYHA) functional class II or III, with a left ventricular ejection fraction of 39% or lower, were randomly assigned to double-blind treatment with either nebivolol (6 patients) or placebo (6 patients) and followed up for 3 months.

2.2. Study design
Baseline measurements included a symptom-limited bicycle exercise test and echocardiography. The patients were randomly allocated to one of the treatment groups: placebo once daily or nebivolol 2.5 mg once per day. For the first 13 days of therapy patients in the active treatment group received 2.5 mg of nebivolol. At day 14, the dose was increased to 5 mg once daily, provided heart rate was not lower than 60 b.p.m. and systolic blood pressure was at least 110 mmHg. All patients tolerated the full dose of 5 mg of nebivolol. Patients were followed up at weeks 2, 3, 5, 8, and 12. Compliance was assessed from the number of returned tablets at each visit. The NYHA class was recorded at baseline and after 12 weeks.

2.3. Exercise testing
A symptom-limited bicycle exercise tolerance test was performed at baseline and at the final assessment after 12 weeks. The initial work load was 25 W, increased by 25-W increments after every second minute until the patient was unable to continue due to exhausting dyspnea, anginal pain, or both [9]. Each test was performed under the same conditions with respect to time of day, room temperature and time interval after eating and drug administration. The electrocardiogram was monitored continuously, and blood pressure was measured at the end of each stage.

2.4. Blood pressure and heart rate
Supine blood pressure was taken at least 24 h from drug ingestion and recorded after 5 min of rest. The blood pressure was calculated from three measurements. Heart rate was counted at each blood pressure measurement.

2.5. Echocardiography
The echocardiography was performed in m-mode and two-dimensional mode by an independent investigator. Representative pictures were documented by a print out. Measurements comprised left atrial diameter, end-diastolic left ventricular dimensions (long and short axis), left ventricular systolic diameter, left ventricular ejection fraction (calculated mean of at least three different measurements, according to the method of Simons), and fractional shortening.

2.6. Statistical analysis
This was an explorative study focusing on tolerability and the effect of nebivolol on the left ventricular function. The randomized patients were divided in two groups (nebivolol group and control group). All statistical tests reported are two-tailed t-tests and P-values ≤0.05 were considered to be significant (*). Statistical analysis was performed by an independent investigator.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
3.1. Patient characteristics
Thirteen patients were enrolled in the study and randomized into the nebivolol group or into the control group (Table 1). In each study group five patients suffered from cardiomyopathy and one patient had coronary heart disease with a history of angioplasty performed in the past. Arterial hypertension was present in one patient in each group. Diabetes mellitus was recorded in two patients in the nebivolol group. All patients were Caucasians. Ten were male and two female. All patients received diuretic, digitalis and ACE-inhibitor medication in addition to the study medication. Twelve patients on study medication completed the study. All patients started the study with a 2.5-mg dose. If tolerance was good, the dose was increased to the intended maximum dose of 5 mg after 2 weeks. In the nebivolol group two patients were not put on 5 mg until week 5 due to bradycardia. In the placebo group, one patient was put on the final dose after 3 weeks and another after 5 weeks due to dyspnea. None of the remaining 12 patients discontinued their medication.


View this table:
[in this window]
[in a new window]

  		Table 1 Characteristics of the patients

 
3.2. Heart rate
Heart rate decreased in the nebivolol group from a baseline of 74.3±9.16 to 64.0±8.00 b.p.m. after 12 weeks (P≤0.036). In the placebo group heart rate remained constant (baseline 82.0±14.03 vs. 76.3±10.61 b.p.m., n.s.) for the study period. The reduction in heart rate was observable after 5 weeks in the treatment group with a decrease of 15 b.p.m. (P≤0.012) and continued for another 12 weeks with a reduction of 10 b.p.m. (P≤0.048, Fig. 1).


Figure 1
View larger version (10K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Changes of heart rate and blood pressure at rest. Patients were set on placebo or nebivolol 2.5 mg. After 2 weeks the dosage was increased to 5 mg OD ({blacktriangledown}----{blacktriangledown} heart rate, {blacktriangleup}—{blacktriangleup} diastolic blood pressure, {blacksquare}—{blacksquare} systolic blood pressure).

 
3.3. Blood pressure
At baseline, systolic blood pressure was 125.0±10.49 mmHg in the nebivolol group and 120.0±10.95 mmHg in the control group. In the nebivolol group blood pressure increased after 3 weeks of treatment to 127.8±21.73 mmHg (P=n.s.) and was 126.7±28.93 mmHg (P=n.s.) at the end of the study (Fig. 1). After 8 weeks of treatment a reduction of the systolic blood pressure was evident in the control group (–7.5 mmHg, P≤0.045), however, after 12 weeks it was only slightly reduced to 116.7±10.33 mmHg (control at baseline 120.5±10.95 mmHg, P=n.s.).

At baseline diastolic blood pressure was 81.7±9.83 mmHg in the nebivolol group. After 12 weeks, diastolic blood pressure decreased to 72.5±11.73 mmHg. This decrease was discernible in the nebivolol group after 2 weeks of treatment, when diastolic blood pressure was reduced by 10 mmHg (P≤0.019). After 5 weeks and after 12 weeks, diastolic blood pressure was reduced by 10 mmHg (P≤0.041) and 9 mmHg (P≤0.058), respectively. In the placebo group no significant changes were observed (Fig. 1).

3.4. NYHA class
At baseline, all patients were in NYHA class III in both groups. In the placebo group four patients improved from NYHA class III to NYHA class II during the study. Two patients remained stable in NYHA class III.

In the nebivolol group four patients improved from NYHA class III to NYHA class II. The NYHA class of two patients was unchanged during the study. None of the patients in the treatment group worsened according to the NYHA class, due to fast titration from 2.5 mg to 5 mg of nebivolol.

3.5. Bicycle test
The maximal working capacity at baseline in the nebivolol group was 112.5±41.08 W and 83.3±34.16 W in the control group. After 12 weeks of treatment the performance in the nebivolol group remained constant (100.0±41.83 W). In the placebo group the maximal working capacity was 91.7±20.41 W (P=n.s.). The maximal duration of the bicycle test (nebivolol: 8.1±3.43 min, control 6.2±2.98 min) was not different after treatment with nebivolol (5.9±1.91 min) or in the control group (5.5±2.30 min). The maximal heart rate during exercise decreased in the treatment group from baseline 134.7±24.45 to 112.7±17.51 b.p.m. (–15.5%, P≤0.004), whereas in the control group the heart rate was not different after 12 weeks of treatment (142.7±24.39 vs. 142.0±23.94 b.p.m. after 12 weeks, P=n.s.). Treatment with nebivolol did not change maximal systolic blood pressure (baseline 165.0±13.78 mmHg, 12 weeks 167.5±15.90 mmHg, Fig. 2). Maximal diastolic blood pressure during exercise remained constant during nebivolol treatment (baseline 87.5±5.43 mmHg, 12 weeks 80.0±4.47 mmHg).


Figure 2
View larger version (6K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Maximal systolic and diastolic blood pressure at baseline and after 12 weeks treatment at ergometry. Maximum systolic and diastolic blood pressure during ergometry were compared at baseline (0) and after 12 weeks of treatment with placebo or nebivolol ({blacktriangleup}—{blacktriangleup} diastolic blood pressure, {blacksquare}—{blacksquare} systolic blood pressure).

 
3.6. Electrocardiogram
Recorded electrocardiograms did not show any significant pathologic alterations during treatment. No patient developed electrocardiographic evidence for atrio-ventricular conduction disturbance (PQ-interval baseline 173.2±15.62 ms, 12 weeks of nebivolol: 179.3±33.27, placebo 166.0±16.15 ms).

3.7. Echocardiography
The end-systolic diameter of the left ventricle decreased in the nebivolol group from 56.5±9.40 mm at baseline to 50.2±9.43 mm after 12 weeks of treatment with nebivolol (P≤0.019, Fig. 3). In the control group the left ventricular end-systolic diameter remained unchanged (Table 2). The left ventricular function improved after 12 weeks of treatment in the nebivolol group by 33.5% (P≤0.01, Table 2). In one patient left ventricular ejection fraction was severely reduced which improved only slightly under nebivolol treatment. In the control group one patient showed a marked improvement leading to an increased ejection fraction. Left ventricular end-diastolic diameter remained constant in both groups after 12 weeks. The left atrium diameter decreased in nebivolol treated patients, but this did not reach statistical significance (Table 2).


Figure 3
View larger version (8K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Ejection fraction after treatment with placebo or nebivolol for 12 weeks. Ejection fraction was determined using echocardiography at baseline (0) and after 12 weeks of treatment. After treatment with nebivolol the ejection fraction increased significantly whereas the ejection fraction in the placebo group remained constant.

 


View this table:
[in this window]
[in a new window]

  		Table 2 Echocardiographic parameters

 
3.8. Tolerability
During the first 24 h after initiation of treatment, no significant bradycardia, hypotension or any major cardiocirculatory complication was observed. None of the patients had signs of orthostasis or an episode of syncope. The nebivolol dose was increased 2 weeks after initiation of therapy in four patients without any symptoms of significant bradycardia or hypotension. Two patients were not increased to 5 mg until week 5 due to initial bradycardia of <60 b.p.m. After the increase in the dose of nebivolol from 2.5 mg to 5 mg diuretics were kept constant. All patients were seen in an out-patient clinic. Serious clinical adverse experiences were not reported by any of the patients.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
The aim of the study was to investigate both the tolerability of nebivolol as well as the effect of this new selective β1-blocker on the left ventricular function in patients with chronic heart failure NYHA class II and III.

The safety of nebivolol was demonstrated even when the dose was increased within the first 2 weeks from 2.5 to 5 mg daily. There was no deterioration in cardiac function and diuretics were kept constant during the study in both groups. This observation is different to that with metoprolol reported by Waagstein and co-workers [10], who demonstrated that the acute application of metoprolol reduced the cardiac index and increased left ventricular filling pressure. Therefore, in the MERIT-HF and in the CIBIS II trials patients were put initially on very low doses of metoprolol or bisoprolol [1,11]. Although the nebivolol dosage was increased quite rapidly the left ventricular ejection fraction increased by 33.5% in the active treatment group after 12 weeks. The improvement in cardiac function might depend on the peripheral vasodilation. Nebivolol at 5 mg daily did not reduce systolic blood pressure at rest although this dose is used for treatment of hypertension [12,13]. In contrast, diastolic blood pressure was reduced significantly in the nebivolol group, indicating that nebivolol might not act as a classic β-blocker and additionally decreases afterload. This peripheral vasodilation explains the improvement of cardiac function keeping the blood pressure constant. However, the NYHA class was not changed.

It was shown that nebivolol clearly blocked β-adrenergic receptors leading to a reduction in heart rate at rest. However, the decrease in heart rate was not as pronounced as with atenolol [14,15]. During exercise testing the maximal heart rate was also reduced but the maximal duration of the bicycle test and maximal work load were not altered in contrast to propranolol, atenolol and pindolol [16,17]. Wisenbaugh et al. [18] have shown that nebivolol significantly reduced left ventricular end-diastolic pressure as a result of the improvement in systolic performance and exercise tolerance remained constant. Although nebivolol showed only a moderate reduction in heart rate [15,19] in the present study, left ventricular function was increased. Therefore, an additional mechanism of nebivolol, such as the liberation of low concentrations of nitric oxide might be of substantial benefit [5,7]. Both nebivolol and its metabolites induce a β2-adrenergic receptor stimulation, thereby inducing nitric oxide liberation [20]. Nebivolol not only increases nitric oxide release but also inhibits endothelin-1 synthesis [6,7]. Circulating endothelin-1 concentrations are elevated in chronic heart failure with reduced cardiac function and contribute to vascular resistance [21,22]. Inhibition of cardiac endothelin-1 synthesis, antioxidant properties, and increase in nitric oxide production [21,23] might decrease systemic vascular resistance suggesting that the vasodilatory effects of nebivolol play a significant role leading to decreased afterload.

As shown in the BEST Trail with bucindolol β1/2-blockade alone did not improve mortality. However, the additional {alpha}1-adrenergic receptor antagonism of carvedilol induced a reduction of afterload improving survival of patients with chronic heart failure [24]. Therefore, the improved diastolic filling, reduction in afterload and the reversibility of endothelial dysfunction represent important and promising characteristics of nebivolol justifying further studies.

4.1. Study limitations
The major limitation of this study is the small number of patients enrolled. All patients with atrial fibrillation were excluded to obtain a homogeneous study population and to exclude further variables. The duration of only 3 months follow-up does not allow any projection on mortality as to the long-term benefit compared with other β-blockers like carvedilol. No conclusions can be drawn regarding how nebivolol affects the development of heart failure.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
The present study shows that nebivolol is well tolerated with no side effects in patients with reduced left ventricular function who are in a stable condition at NYHA class II and III. In most patients the titration of the β-blocker could be performed within 2 weeks to a maximum dose of 5 mg daily; however, this cannot be recommended for every patient with heart failure. With long-term treatment, nebivolol reduced heart rate and also showed positive inotropic effects with a reduction of end-systolic diameter and an increase in ejection fraction. Furthermore, it seems that nebivolol reduces peripheral resistance and afterload. The exercise tolerance remained constant after treatment with nebivolol for 12 weeks. Further prospective randomized trials are needed to identify the potential effect of nebivolol on mortality in patients with chronic heart failure in NYHA class II and III.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

  1. The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II). A randomised trial. Lancet (1999) 353:9–13.[CrossRef][Web of Science][Medline]
  2. US Carvedilol Heart Failure Study Group. Packer M., Bristow M.R., Cohn J.N., et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med (1996) 334:1349–1355.[Abstract/Free Full Text]
  3. Heidenreich P.A., Lee T.T., Massie B.M. Effect of beta-blockade on mortality in patients with heart failure: a meta-analysis of randomized clinical trials. J Am Coll Cardiol (1997) 30:27–34.[Abstract]
  4. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med 2001;344:1659–67.
  5. Cockroft J.R., Chowenczyk P.H.J., Brett S.E., et al. Nebivolol vasodilates human forearm vasculature: evidence for L-arginin/NO-dependent mechanism. J Pharmacol Exp Ther (1995) 274:1067–1071.[Abstract/Free Full Text]
  6. Brehm B.R., Bertsch D., Wolf S.C. Nebivolol hemmt die Proliferation sowohl von humanen koronararteriellen glatten Muskelzellen als auch von Endothelzellen und steigert die NO-Freisetzung. Perfusion (1998) 11:475–484.[Web of Science]
  7. Brehm B.R., Wolf S.C., Bertsch D., et al. Effects of nebivolol on proliferation and apoptosis on human coronary artery smooth muscle and endothelical cells. Cardiovasc Res (2001) 49:430–439.[Abstract/Free Full Text]
  8. Janssen P.M., Zeitz O., Hasenfuss G. Transient and sustained impacts of hydroxyl radicals on sarcoplasmic reticulum function: protective effects of nebivolol. Eur J Pharmacol (1999) 366:223–232.[CrossRef][Web of Science][Medline]
  9. Melin J.A., Piret L.V., Vanbutsele R.J.M., et al. Diagnostic value of exercise electrocardiography and thallium myocardial scintigraphy in patients without previous myocardial infarction: a bayesian approach. Circulation (1989) 63:1019–1024.
  10. Waagstein F., Caidahl K., Wallentin I., Bergh C.H., Hjalmarson A. Long-term beta-blockade in dilated cardiomyopathy. Effects of short- and long-term metoprolol treatment followed by withdrawal and readministration of metoprolol. Circulation (1989) 80:551–563.[Abstract/Free Full Text]
  11. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomised intervention trial in congestive heart failure (MERIT-HF). Lancet 1999;353:2001–7.
  12. McNeely W., Goa K.L. Nebivolol in the management of essential hypertension. Drugs (1999) 57:633–651.[CrossRef][Web of Science][Medline]
  13. Van Nueten L., Schelling A., Vertommen C., Dupont A.G., Robertson J.I. Nebivolol vs enalapril in the treatment of essential hypertension: a double-blind randomised trial. J Hum Hypertens (1997) 11:813–819.[CrossRef][Web of Science][Medline]
  14. van Bortel L.M.A.B., van Baak M.A. Exercise tolerance with nebivolol and atenolol. Cardiovasc Drug Ther (1992) 6:239–247.[CrossRef][Web of Science][Medline]
  15. Clements I.P., Miller W.L. Effect of metoprolol on rest and exercise left ventricular systolic and diastolic function in idiopathic dilated cardiomyopathy. Am Heart J (2001) 141:259–262.[Web of Science][Medline]
  16. De Cree J., Geukens H., Cobo C., Verhaegen H. Subacute hemodynamic effects of nebivolol in man at rest and during exercise. Angiology (1987) 38:440–448.[CrossRef][Web of Science][Medline]
  17. De Cree J., Cobo C., Geukens H., Verhaegen H. Comparison of the subacute hemodynamic effects of atenolol, propranolol, pindolol, and nebivolol. Angiology (1990) 41:95–105.[CrossRef][Web of Science][Medline]
  18. Wisenbaugh T., Katz I., Davis J., et al. Long-term (3-month) effects of a new beta-blocker (nebivolol) on cardiac performance in dilated cardiomyopathy. J Am Coll Cardiol (1993) 21:1094–1100.[Abstract]
  19. Clements I.P., Miller W.L., Olson L.J. Resting heart rate and cardiac function in dilated cardiomyopathy. Int J Cardiol (1999) 72:27–37.[CrossRef][Web of Science][Medline]
  20. Broeders M.A.W., Doevendans P.A., Bekkers B.C.A.M., et al. Nebivolol: a third-generation beta-blocker that augments vascular nitric oxide release endothelial beta(2)-adrenergic receptor-mediated nitric oxide production. Circulation (2000) 102:677–684.[Abstract/Free Full Text]
  21. MacCarthy P.A., Grocott-Mason R., Prendergast B.D., Shah A.M. Contrasting inotropic effects of endogenous endothelin in the normal and failing human heart: studies with an intracoronary ET(A) receptor antagonist. Circulation (2000) 101:142–147.[Abstract/Free Full Text]
  22. Love M.P., Ferro C.J., Haynes W.G., et al. Endothelin receptor antagonism in patients with chronic heart failure. Cardiovasc Res (2000) 47:166–172.[Abstract/Free Full Text]
  23. Sakai S., Miyauchi T., Kobayashi M., Yamaguchi I., Goto K., Sugishita Y. Inhibition of myocardial endothelin pathway improves long-term survival in heart failure. Nature (1996) 384:353–355.[CrossRef][Medline]
  24. Louis A., Cleland J.G., Crabbe S., et al. Clinical trials update: CAPRICORN, COPERNICUS, MIRACLE, STAF, RITZ-2, RECOVER and RENAISSANCE and cachexia and cholesterol in heart failure. Highlights of the scientific sessions of the American College of Cardiology, 2001. Eur J Heart Fail (2001) 3:381–387.[Abstract/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
 Eur J Heart FailHome page
J. Abdulla, L. Kober, E. Christensen, and C. Torp-Pedersen
Effect of beta-blocker therapy on functional status in patients with heart failure -- A meta-analysis
Eur J Heart Fail, August 1, 2006; 8(5): 522 - 531.
[Abstract] [Full Text] [PDF]

Home page
 Eur J Heart FailHome page
I. Edes, Z. Gasior, and K. Wita
Effects of nebivolol on left ventricular function in elderly patients with chronic heart failure: results of the ENECA study
Eur J Heart Fail, June 1, 2005; 7(4): 631 - 639.
[Abstract] [Full Text] [PDF]

Home page
 Eur J Heart FailHome page
J. G.F. Cleland, P. H. Loh, N. Freemantle, A. L. Clark, and A. P. Coletta
Clinical trials update from the European Society of Cardiology: SENIORS, ACES, PROVE-IT, ACTION, and the HF-ACTION trial
Eur J Heart Fail, October 1, 2004; 6(6): 787 - 791.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
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 Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Brehm, B. R.
Right arrow Articles by Risler, T.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Brehm, B. R.
Right arrow Articles by Risler, T.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?