Advertisement

Effect of Beta-blockade and ACE Inhibition on B-type Natriuretic Peptides in Stable Patients with Systolic Heart Failure

  • Jens RosenbergEmail author
  • Finn Gustafsson
  • Willem J. Remme
  • Günter A. J. Riegger
  • Per Rossen Hildebrandt
Article

Abstract

Introduction

The long-term effect of beta-blockade on the plasma levels of natriuretic peptides BNP and its N-terminal counterpart, NT-proBNP, as risk markers in heart failure (HF) is obscure.

Methods

Stable systolic HF patients from the CARMEN study were divided in groups matching their randomised treatment allocation: Carvedilol, enalapril or carvedilol+enalapril. Changes in BNP and NT-proBNP from baseline to 6 months maintenance visit were evaluated in each treatment arm. Furthermore, the prognostic value of BNP and NT-proBNP during monotherapy with carvedilol was assessed with univariate Cox proportional hazards models using a combined endpoint of all cause mortality and cardiovascular hospitalisation.

Results

NT-proBNP and BNP were significantly reduced after six months treatment with enalapril (NT-proBNP 1,303 to 857 pg/ml (P < 0.001), BNP 119 to 85 pg/ml (P < 0.001)) or carvedilol+enalapril (NT-proBNP 1,223 to 953 pg/ml (P = 0.003), BNP 117 to 93 pg/ml (P = 0.01)). In contrast, no change was observed in the carvedilol group (NT-proBNP 907 to 1,082 pg/ml (P = 0.06), BNP 114 to 130 pg/ml (P = 0.15). The prognostic value of NT-proBNP and BNP was maintained in the carvedilol group (NT-proBNP HR 1.018 95% CI (1.005–1.032), BNP 1.171 (1.088–1.260)).

Conclusion

Treatment of HF patients with carvedilol alone does not reduce levels of natriuretic peptides, but treatment with enalapril does. Both BNP and NT-proBNP predict death and hospitalisation in HF patients treated with carvedilol for six months. The clinical implication of our results is that NT-proBNP and BNP can be used as risk markers of death and cardiovascular hospitalisations in systolic HF patients receiving carvedilol without ACE inhibition.

Key words

brain natriuretic peptide adrenergic beta-antagonists carvedilol angiotensin-converting enzyme inhibitors enalapril prognosis congestive heart failure 

Notes

Acknowledgements

The work was funded by a grant from The Danish Heart Foundation.

References

  1. 1.
    Anand IS, Fisher LD, Chiang YT, et al. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT). Circulation. 2003;107:1278–83.PubMedCrossRefGoogle Scholar
  2. 2.
    Hartmann F, Packer M, Coats AJ, et al. Prognostic impact of plasma N-terminal pro-brain natriuretic peptide in severe chronic congestive heart failure: a substudy of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial. Circulation. 2004;110:1780–6.PubMedCrossRefGoogle Scholar
  3. 3.
    Jourdain P, Jondeau G, Funck F, et al. Plasma brain natriuretic peptide-guided therapy to improve outcome in heart failure: the STARS-BNP Multicenter Study. J Am Coll Cardiol. 2007;49:1733–9.PubMedCrossRefGoogle Scholar
  4. 4.
    Troughton RW, Frampton CM, Yandle TG, Espiner EA, Nicholls MG, Richards AM. Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet. 2000;355:1126–30.PubMedCrossRefGoogle Scholar
  5. 5.
    van Veldhuisen DJ, Genth-Zotz S, Brouwer J, et al. High- versus low-dose ACE inhibition in chronic heart failure: a double-blind, placebo-controlled study of imidapril. J Am Coll Cardiol. 1998;32:1811–8.PubMedCrossRefGoogle Scholar
  6. 6.
    Feola M, Menardi E, Ribichini F, et al. Effects of the addition of a low dose of spironolactone on brain natriuretic peptide plasma level and cardiopulmonary function in patients with moderate congestive heart failure. Med Sci Monit. 2003;9:CR341–CR345.PubMedGoogle Scholar
  7. 7.
    Macdonald JE, Kennedy N, Struthers AD. Effects of spironolactone on endothelial function, vascular angiotensin converting enzyme activity, and other prognostic markers in patients with mild heart failure already taking optimal treatment. Heart. 2004;90:765–70.PubMedCrossRefGoogle Scholar
  8. 8.
    Paterna S, Di PP, Parrinello G, et al. Changes in brain natriuretic peptide levels and bioelectrical impedance measurements after treatment with high-dose furosemide and hypertonic saline solution versus high-dose furosemide alone in refractory congestive heart failure: a double-blind study. J Am Coll Cardiol. 2005;45:1997–2003.PubMedCrossRefGoogle Scholar
  9. 9.
    Fruhwald FM, Fahrleitner-Pammer A, Berger R, et al. Early and sustained effects of cardiac resynchronization therapy on N-terminal pro-B-type natriuretic peptide in patients with moderate to severe heart failure and cardiac dyssynchrony. Eur Heart J. 2007;28:1592–7.PubMedCrossRefGoogle Scholar
  10. 10.
    Swedberg K, Cleland J, Dargie H, et al. 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;26:1115–40.PubMedCrossRefGoogle Scholar
  11. 11.
    Bettencourt PM. Clinical usefulness of B-type natriuretic peptide measurement: present and future perspectives. Heart. 2005;91:1489–94.PubMedCrossRefGoogle Scholar
  12. 12.
    Lainchbury JG, Troughton RW, Frampton CM, et al. NTproBNP-guided drug treatment for chronic heart failure: design and methods in the “BATTLESCARRED” trial. Eur J Heart Fail. 2006;8:532–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Davis ME, Richards AM, Nicholls MG, Yandle TG, Frampton CM, Troughton RW. Introduction of metoprolol increases plasma B-type cardiac natriuretic peptides in mild, stable heart failure. Circulation. 2006;113:977–85.PubMedCrossRefGoogle Scholar
  14. 14.
    CIBIS-II Investigators and Committees. The cardiac insufficiency bisoprolol study II (CIBIS-II): a randomised trial. Lancet 1999;353:9–13.CrossRefGoogle Scholar
  15. 15.
    MERIT-HF Study Group. 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.CrossRefGoogle Scholar
  16. 16.
    Remme WJ, Riegger G, Hildebrandt P, et al. The carvedilol and ACE-inhibitor remodelling mild heart failure evaluation trial (CARMEN): rationale and design. Cardiovasc Drugs Ther. 2001;15:69–77.PubMedCrossRefGoogle Scholar
  17. 17.
    Remme WJ, Riegger G, Hildebrandt P, et al. The benefits of early combination treatment of carvedilol and an ACE-inhibitor in mild heart failure and left ventricular systolic dysfunction. The carvedilol and ACE-inhibitor remodelling mild heart failure evaluation trial (CARMEN). Cardiovasc Drugs Ther. 2004;18:57–66.PubMedCrossRefGoogle Scholar
  18. 18.
    Karl J, Borgya A, Gallusser A, et al. Development of a novel, N-terminal-proBNP (NT-proBNP) assay with a low detection limit. Scand J Clin Lab Invest Suppl. 1999;230:177–81.PubMedCrossRefGoogle Scholar
  19. 19.
    McDonagh TA, Holmer S, Raymond I, Luchner A, Hildebrandt P, Dargie HJ. NT-proBNP and the diagnosis of heart failure: a pooled analysis of three European epidemiological studies. Eur J Heart Fail. 2004;6:269–73.PubMedCrossRefGoogle Scholar
  20. 20.
    Clerico A, Iervasi G, Mariani G. Pathophysiologic relevance of measuring the plasma levels of cardiac natriuretic peptide hormones in humans. Horm Metab Res. 1999;31:487–98.PubMedCrossRefGoogle Scholar
  21. 21.
    Ry SD, Clerico A, Giannessi D, et al. Measurement of brain natriuretic peptide in plasma samples and cardiac tissue extracts by means of an immunoradiometric assay method. Scand J Clin Lab Invest. 2000;60:81–90.PubMedCrossRefGoogle Scholar
  22. 22.
    Lin DY, Wei LJ, Ying Z. Checking the cox model with cumulative sums of martingale-based residuals. Biometrika. 1993;80:557–72.CrossRefGoogle Scholar
  23. 23.
    Collett D, editor. Modelling survival data in medical research. New York: Chapman & Hall/CRC; 2003.Google Scholar
  24. 24.
    Cohn JN, Tognoni G, Glazer R, Spormann D. Baseline demographics of the Valsartan Heart Failure Trial. Val-HeFT Investigators. Eur J Heart Fail. 2000;2:439–46.PubMedCrossRefGoogle Scholar
  25. 25.
    Yan RT, White M, Yan AT, et al. Usefulness of temporal changes in neurohormones as markers of ventricular remodeling and prognosis in patients with left ventricular systolic dysfunction and heart failure receiving either candesartan or enalapril or both. Am J Cardiol. 2005;96:698–704.PubMedCrossRefGoogle Scholar
  26. 26.
    Hartmann F, Packer M, Coats AJ, et al. NT-proBNP in severe chronic heart failure: rationale, design and preliminary results of the COPERNICUS NT-proBNP substudy. Eur J Heart Fail. 2004;6:343–50.PubMedCrossRefGoogle Scholar
  27. 27.
    Brunner-La Rocca HP, Weilenmann D, Kiowski W, Maly FE, Candinas R, Follath F. Within-patient comparison of effects of different dosages of enalapril on functional capacity and neurohormone levels in patients with chronic heart failure. Am Heart J. 1999;138:654–62.PubMedCrossRefGoogle Scholar
  28. 28.
    Yoshimura M, Mizuno Y, Nakayama M, et al. B-type natriuretic peptide as a marker of the effects of enalapril in patients with heart failure. Am J Med 2002;112:716–20.PubMedCrossRefGoogle Scholar
  29. 29.
    Seferian KR, Tamm NN, Semenov AG, et al. The Brain Natriuretic Peptide (BNP) Precursor is the major immunoreactive form of BNP in patients with heart failure. Clin Chem. 2007;53:866–73.PubMedCrossRefGoogle Scholar
  30. 30.
    Groenning BA, Nilsson JC, Hildebrandt PR, et al. Neurohumoral prediction of left-ventricular morphologic response to beta-blockade with metoprolol in chronic left-ventricular systolic heart failure. Eur J Heart Fail. 2002;4:635–46.PubMedCrossRefGoogle Scholar
  31. 31.
    Hara Y, Hamada M, Shigematsu Y, et al. Effect of beta-blocker on left ventricular function and natriuretic peptides in patients with chronic heart failure treated with angiotensin-converting enzyme inhibitor. Jpn Circ J. 2000;64:365–9.PubMedCrossRefGoogle Scholar
  32. 32.
    Stanek B, Frey B, Hulsmann M, et al. Prognostic evaluation of neurohumoral plasma levels before and during beta-blocker therapy in advanced left ventricular dysfunction. J Am Coll Cardiol. 2001;38:436–42.PubMedCrossRefGoogle Scholar
  33. 33.
    Yoshizawa A, Yoshikawa T, Nakamura I, et al. Brain natriuretic peptide response is heterogeneous during beta-blocker therapy for congestive heart failure. J Card Fail. 2004;10:310–5.PubMedCrossRefGoogle Scholar
  34. 34.
    Sliwa K, Norton GR, Kone N, et al. Impact of initiating carvedilol before angiotensin-converting enzyme inhibitor therapy on cardiac function in newly diagnosed heart failure. J Am Coll Cardiol. 2004;44:1825–30.PubMedCrossRefGoogle Scholar
  35. 35.
    Schou M, Gustafsson F, Kjaer A, Hildebrandt PR. Long-term clinical variation of NT-proBNP in stable chronic heart failure patients. Eur Heart J. 2007;28:177–82.PubMedCrossRefGoogle Scholar
  36. 36.
    Willenheimer R, van Veldhuisen DJ, Silke B, et al. Effect on survival and hospitalization of initiating treatment for chronic heart failure with bisoprolol followed by enalapril, as compared with the opposite sequence: results of the randomized Cardiac Insufficiency Bisoprolol Study (CIBIS) III. Circulation. 2005;112:2426–35.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Jens Rosenberg
    • 1
    Email author
  • Finn Gustafsson
    • 2
  • Willem J. Remme
    • 3
  • Günter A. J. Riegger
    • 4
  • Per Rossen Hildebrandt
    • 5
  1. 1.Cardiology DepartmentFrederiksberg University HospitalFrederiksbergDenmark
  2. 2.Cardiology DepartmentRigshospitaletCopenhagenDenmark
  3. 3.Sticares Cardiovascular Research FoundationRhoonThe Netherlands
  4. 4.Department of Internal Medicine 2University of RegensburgRegensburgGermany
  5. 5.Cardiology DepartmentRoskilde County HospitalRoskildeDenmark

Personalised recommendations