title: 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).
abstract: OBJECTIVE
  Heart failure (HF) treatment guidelines of the ESC recommend ACE-inhibitors (ACE-I) as first-line treatment and beta-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.
  
  
  CONCLUSIONS
  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 beta-blockade should not be delayed.
authors.affiliation: Sticares Cardiovascular Research Foundation, Rhoon, The Netherlands. w.j.remme@sticares.org
authors.forename: Willem J
authors.initials: WJ
authors.lastname: Remme
authors.forename: Guenter
authors.initials: G
authors.lastname: Riegger
authors.forename: Per
authors.initials: P
authors.lastname: Hildebrandt
authors.forename: Michel
authors.initials: M
authors.lastname: Komajda
authors.forename: Wybren
authors.initials: W
authors.lastname: Jaarsma
authors.forename: Marco
authors.initials: M
authors.lastname: Bobbio
authors.forename: Jordi
authors.initials: J
authors.lastname: Soler-Soler
authors.forename: Armin
authors.initials: A
authors.lastname: Scherhag
authors.forename: Beatrix
authors.initials: B
authors.lastname: Lutiger
authors.forename: Lars
authors.initials: L
authors.lastname: Rydén
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D002227:Carbazoles / Q000008:administration & dosage / Q000627:therapeutic use*; D000077261:Carvedilol; D002908:Chronic Disease; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D004656:Enalapril / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D006333:Heart Failure / Q000188:drug therapy* / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D011412:Propanolamines / Q000008:administration & dosage / Q000627:therapeutic use*; D020257:Ventricular Remodeling / Q000187:drug effects*
chemical_list: D000319:Adrenergic beta-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; D004656:Enalapril