Advertisement

Cardiovascular Drugs and Therapy

, Volume 18, Issue 1, pp 57–66 | Cite as

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)

  • Willem J. Remme
  • Guenter Riegger
  • Per Hildebrandt
  • Michel Komajda
  • Wybren Jaarsma
  • Marco Bobbio
  • Jordi Soler-Soler
  • Armin Scherhag
  • Beatrix Lutiger
  • Lars Rydén
Article

Abstract

Aims: Heart failure (HF) treatment guidelines of the ESC recommend ACE-inhibitors (ACE-I) as first-line treatment and β-blockers added if patients remain symptomatic. CARMEN explored the need for combined treatment for remodelling and order of introduction by comparing the ACE-I enalapril against carvedilol and their combination.

Methods: In a parallel-group, 3-arm study of 18 months duration, 572 mild heart failure patients were randomly assigned to carvedilol (N = 191), enalapril (N = 190) or their combination (N = 191). In the latter, carvedilol was up-titrated before enalapril. Left ventricular (LV) remodelling was assessed by transthoracic echocardiography (biplane, modified Simpson) at baseline and after 6, 12 and 18 months of maintenance therapy. Primary comparisons considered the change in LV end-systolic volume index (LVESVI) from baseline to month 18 between the combination and enalapril, and between carvedilol and enalapril.

Results: In the first primary comparison, LVESVI was reduced by 5.4 ml/m2 (p = 0.0015) in favour of combination therapy compared to enalapril. The second primary comparison tended to favour carvedilol to enalapril (NS). In the within treatment arm analyses, carvedilol significantly reduced LVESVI by 2.8 ml/m2 (p = 0.018) compared to baseline, whereas enalapril did not. LVESVI decreased by 6.3 ml/m2 (p = 0.0001) with combination therapy. All three arms showed similar safety profiles and withdrawal rates.

Conclusion: CARMEN is the first study to demonstrate that early combination of ACE-I and carvedilol reverses LV remodelling in patients with mild to moderate HF and LV systolic dysfunction. The results of the CARMEN study support a therapeutic strategy in which the institution of β-blockade should not be delayed.

carvedilol ACE inhibition heart failure ventricular remodelling guidelines echocardiography first-line therapy combined treatment monotherapy CARMEN randomised controlled trial 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Remme WJ, Swedberg K. Task force for the diagnosis and treatment of chronic heart failure, European Society of Cardiology Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001;22:1527–1560.CrossRefPubMedGoogle Scholar
  2. 2.
    Hobbs FDR, Jones MI, Allan TF, Wilson S, Tobias R. European survey of primary care physician perceptions on heart failure diagnosis and management (EURO-HF). Eur Heart J 2000;21:1877–1887.CrossRefPubMedGoogle Scholar
  3. 3.
    Cleland JGF, Cohen-Solal A, Cosin Aguilar J, et al. Management of heart failure in primary care (the IMPROVEMENT of Heart Failure Programme): An international survey. Lancet 2002;360:1631–1639.CrossRefPubMedGoogle Scholar
  4. 4.
    Komajda M, Follath F, Swedberg K, et al. The euro heart failure survey programme: A survey on the quality of care among patients with heart failure in Europe: Treatment. Eur Heart J 2003;24:464–474.CrossRefPubMedGoogle Scholar
  5. 5.
    Greenberg B, Quinones MA, Koilpillai C, et al. Effects of long term enalapril therapy on cardiac structure and function in patients with left ventricular dysfunction. Results of the SOLVD echocardiographic study. Circulation 1995;91:2573–2581.PubMedGoogle Scholar
  6. 6.
    Doughty RN, Whalley GA, Gamble G, MacMahon S, Sharpe N. Left ventricular remodeling with carvedilol in patients with congestive heart failure due to ischemic heart disease. Australia-New Zealand heart failure research collaborative group. J Am Coll Cardiol 1997;29:1060–1066.CrossRefPubMedGoogle Scholar
  7. 7.
    Senior R, Basu S, Kinsey C, Schaeffer S, Lahiri A. Carvedilol prevents remodelling in patients with left ventricular dysfunction after acute myocardial infarction. Am Heart J 1999;137:646–652.PubMedGoogle Scholar
  8. 8.
    Yue TL, Cheng HY, Lysko PG, et al. Carvedilol, a new vasodilator and beta adrenoceptor antagonist, is an antioxidant and free radical scavenger. J Pharmacol Exp Ther 1992;263:92–98.PubMedGoogle Scholar
  9. 9.
    Yue T, McKenna PJ, Lysko PG, Ruffolo RRJ, Feuerstein GZ. Carvedilol, a new anti-hypertensive prevents oxidation of human low density lipoprotein by macrophages and copper. Atherosclerosis 1992;97:209–216.PubMedGoogle Scholar
  10. 10.
    Metra M, Giubbini R, Nodari S, Boldi E, Modena MG, Dei CL. Differential effects of beta-blockers in patients with heart failure: A prospective, randomized, double-blind comparison of the long-term effects of metoprolol versus carvedilol. Circulation 2000;102:546–551.PubMedGoogle Scholar
  11. 11.
    Sanderson JE, Chan SKW, Yip G, et al. Beta-blockade in heart failure: A comparison between carvedilol with metoprolol. J Am Coll Cardiol 1999;34:1522–1528.CrossRefPubMedGoogle Scholar
  12. 12.
    Packer M, Antonopoulos GV, Berlin JA, Chittams J, Konstam MA, Udelson JE. Comparative effects of carvedilol and metoprolol on left ventricular ejection fraction in heart failure: Results of a meta-analysis. Am Heart J 2001;141:899–907.CrossRefPubMedGoogle Scholar
  13. 13.
    Feuerstein GZ, Yue TL. A potent antioxidant, SB209995, inhibits oxygen-radical-mediated lipid peroxidation and cytotoxicity. Pharmacology 1994;48:385–391.PubMedGoogle Scholar
  14. 14.
    Groenning BA, Nilsson JC, Sondergaard L, et al. Antiremodelling effects on the left ventricle during beta-blockade with metoprolol in the treatment of chronic heart failure. J Am Coll Cardiol 2000;6:2072–2080.CrossRefGoogle Scholar
  15. 15.
    Remme WJ on behalf of the CARMEN Steering Committee and Investigators. The Carvedilol and ACE-Inhibitor Remodelling Mild Heart Failure EvaluatioN trial (CARMEN)—rationale and design. Cardiovasc Drugs Ther 2001;15:69–77.CrossRefGoogle Scholar
  16. 16.
    The Task Force on Heart Failure of the European Society of Cardiology. Guidelines for the diagnosis of heart failure. Eur Heart J 1995;16:741–751.Google Scholar
  17. 17.
    Schiller NB, Shah PM, Crawford M, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. J Am Soc Echocardiog 1989;2:358.PubMedGoogle Scholar
  18. 18.
    Kingma JH, van Gilst WH, Peels CH, Dambrink JH, Verheugt FW, Wielenga RP. Acute intervention with captopril during thrombolysis in patients with first anterior myocardial infarction. Results from the captopril and thrombolysis study (CATS). Eur Heart J 1994;15:898–907.PubMedGoogle Scholar
  19. 19.
    Dunnett CW. Multiple comparisons between treatments and a control. Biometrics 1961;20:482–491.Google Scholar
  20. 20.
    Schafer JL. Multiple imputation: A primer. Stat Methods Med Res 1999;8:3–15.CrossRefPubMedGoogle Scholar
  21. 21.
    Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for the evaluation and management of chronic heart failure in the adult: Executive summary. Circulation 2001;104:2996–3007.PubMedGoogle Scholar
  22. 22.
    Cohn JN, Johnson GR, Shabetai R, et al. Ejection fraction, peak exercise oxygen consumption, cardiothoracic ratio, ventricular arrhythmias and plasma norepinephrine as determinants of prognosis in heart failure. The V-HeFT VA cooperative studies group. Circulation 1993;87:V15–V16.Google Scholar
  23. 23.
    White HD, Norris RM, Brown MA, et al. Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation 1987;76:44–51.PubMedGoogle Scholar
  24. 24.
    Cohn JN, Ferrari R, Sharpe N on behalf of an International Forum on Cardiac Remodeling: Cardiac Remodeling: Concepts and Clinical Implications: A Consensus Paper from an International Forum on Cardiac Remodeling. J Am Coll Cardiol 2000;35:569–582.CrossRefPubMedGoogle Scholar
  25. 25.
    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.CrossRefPubMedGoogle Scholar
  26. 26.
    Metra M, Nardi M, Giubbini R, Dei Cas 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.PubMedGoogle Scholar
  27. 27.
    Bristow MR. Beta adrenergic receptor blockade in chronic heart failure. Circulation 2000;101:558–569.PubMedGoogle Scholar
  28. 28.
    Poole-Wilson PA, Swedberg K, Cleland JGF, et al. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure. Results of the Carvedilol or Metoprolol European Trial (COMET). Lancet 2003;362:7–13.CrossRefPubMedGoogle Scholar

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Willem J. Remme
    • 1
  • Guenter Riegger
    • 2
  • Per Hildebrandt
    • 3
  • Michel Komajda
    • 4
  • Wybren Jaarsma
    • 5
  • Marco Bobbio
    • 6
  • Jordi Soler-Soler
    • 7
  • Armin Scherhag
    • 8
  • Beatrix Lutiger
    • 8
  • Lars Rydén
    • 9
  1. 1.Sticares FoundationRhoonThe Netherlands
  2. 2.University of RegensburgRegensburgGermany
  3. 3.Frederiksberg HospitalFrederiksbergDenmark
  4. 4.Centre Hospitalier Pitié SalpetrièreParisFrance
  5. 5.St. Antonius HospitalNieuwegeinThe Netherlands
  6. 6.Hospital Le MolinetteTorinoItaly
  7. 7.University Hospital Vall d’HebronBarcelonaSpain
  8. 8.F. Hoffmann-La RocheBaselSwitzerland
  9. 9.Karolinska HospitalStockholmSweden

Personalised recommendations