title: Influence of order and type of drug (bisoprolol vs. enalapril) on outcome and adverse events in patients with chronic heart failure: a post hoc analysis of the CIBIS-III trial.
abstract: OBJECTIVE
  Angiotensin-converting enzyme inhibitors (ACE-Is) and beta-blockers are associated with improved outcome in patients with chronic heart failure (CHF). In this post hoc analysis of the CIBIS III trial, we examined the influence of the order of drug administration on clinical events and achieved dose. We also assessed the relations between dose levels and baseline variables or adverse events.
  
  
  RESULTS
  In the CIBIS III trial, 1010 patients (mean age: 72.4 years; mean ejection fraction: 28.8%; male: 68.2%) with stable CHF were randomized to up-titration of monotherapy with either bisoprolol (target dose 10 mg o.d.) or enalapril (target dose 10 mg b.i.d.) for 6 months, followed by their combination for 6-24 months. Endpoints were mortality or all-cause hospitalization, mortality alone and mortality or cardiovascular hospitalization. The study drug (ACE-I or beta-blocker) was last prescribed at ≥50% of target dose to significantly more patients for the first initiated drug in both treatment groups (both P< 0.001). Sixty per cent of endpoints were reached during the monotherapy phase and randomized treatment during monotherapy was not a predictor of the three assessed outcomes. Monotherapy phase was the strongest independent predictor of outcome (P< 0.0001 for all endpoints). Older age, NYHA class III, impaired renal function, lower body weight and blood pressure at baseline, and hypotension, bradycardia and heart failure during treatment were associated with the inability to reach high dose of both study drugs.
  
  
  CONCLUSIONS
  The order of drug administration plays an important role in whether CHF patients reach target doses of bisoprolol and enalapril. For both study drugs, the dose level reached was associated with baseline characteristics and adverse events. In CHF patients not treated with an ACE-I or a beta-blocker, the duration of monotherapy with either type of drug should be shorter than 6 months.
authors.affiliation: Faculty of Medicine, Department of Pharmacology, UPMC-Univ. Paris 06, Paris, France. christian.funck-brentano@upmc.fr
authors.forename: Christian
authors.initials: C
authors.lastname: Funck-Brentano
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: van Veldhuisen
authors.forename: Louis L M
authors.initials: LL
authors.lastname: van de Ven
authors.forename: Ferenc
authors.initials: F
authors.lastname: Follath
authors.forename: Michael
authors.initials: M
authors.lastname: Goulder
authors.forename: Ronnie
authors.initials: R
authors.lastname: Willenheimer
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000009:adverse effects / Q000627:therapeutic use*; D000368:Aged; D000704:Analysis of Variance; D057911:Angiotensin Receptor Antagonists / Q000009:adverse effects / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D017298:Bisoprolol / Q000009:adverse effects / Q000627:therapeutic use*; D004656:Enalapril / Q000009:adverse effects / Q000627:therapeutic use*; D005260:Female; D005919:Glomerular Filtration Rate; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D008297:Male; D015999:Multivariate Analysis; D013223:Statistics as Topic; D016896:Treatment Outcome
chemical_list: D000319:Adrenergic beta-Antagonists; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D004656:Enalapril; D017298:Bisoprolol