title: Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial.
abstract: BACKGROUND
  Angiotensin-receptor blockers (ARBs) are effective treatments for patients with heart failure, but the relation between dose and clinical outcomes has not been explored. We compared the effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure.
  
  
  METHODS
  This double-blind trial was undertaken in 255 sites in 30 countries. 3846 patients with heart failure of New York Heart Association class II-IV, left-ventricular ejection fraction 40% or less, and intolerance to angiotensin-converting-enzyme (ACE) inhibitors were randomly assigned to losartan 150 mg (n=1927) or 50 mg daily (n=1919). Allocation was by block randomisation stratified by centre and presence or absence of beta-blocker therapy, and all patients and investigators were masked to assignment. The primary endpoint was death or admission for heart failure. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00090259.
  
  
  RESULTS
  Six patients in each group were excluded because of poor data quality. With 4.7-year median follow-up in each group (IQR 3.7-5.5 for losartan 150 mg; 3.4-5.5 for losartan 50 mg), 828 (43%) patients in the 150 mg group versus 889 (46%) in the 50 mg group died or were admitted for heart failure (hazard ratio [HR] 0.90, 95% CI 0.82-0.99; p=0.027). For the two primary endpoint components, 635 patients in the 150 mg group versus 665 in the 50 mg group died (HR 0.94, 95% CI 0.84-1.04; p=0.24), and 450 versus 503 patients were admitted for heart failure (0.87, 0.76-0.98; p=0.025). Renal impairment (n=454 vs 317), hypotension (203 vs 145), and hyperkalaemia (195 vs 131) were more common in the 150 mg group than in the 50 mg group, but these adverse events did not lead to significantly more treatment discontinuations in the 150 mg group.
  
  
  CONCLUSIONS
  Losartan 150 mg daily reduced the rate of death or admission for heart failure in patients with heart failure, reduced left-ventricular ejection fraction, and intolerance to ACE inhibitors compared with losartan 50 mg daily. These findings show the value of up-titrating ARB doses to confer clinical benefit.
  
  
  BACKGROUND
  Merck (USA).
authors.affiliation: Tufts Medical Center, Tufts University School of Medicine, Boston, MA, USA. mkonstam@tuftsmedicalcenter.org
authors.forename: Marvin A
authors.initials: MA
authors.lastname: Konstam
authors.forename: James D
authors.initials: JD
authors.lastname: Neaton
authors.forename: Kenneth
authors.initials: K
authors.lastname: Dickstein
authors.forename: Helmut
authors.initials: H
authors.lastname: Drexler
authors.forename: Michel
authors.initials: M
authors.lastname: Komajda
authors.forename: Felipe A
authors.initials: FA
authors.lastname: Martinez
authors.forename: Gunter A  J
authors.initials: GA
authors.lastname: Riegger
authors.forename: William
authors.initials: W
authors.lastname: Malbecq
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Smith
authors.forename: Soneil
authors.initials: S
authors.lastname: Guptha
authors.forename: Philip A
authors.initials: PA
authors.lastname: Poole-Wilson
mesh_terms: D000368:Aged; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D019808:Losartan / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D019808:Losartan