title: Efficacy and safety of nebivolol and valsartan as fixed-dose combination in hypertension: a randomised, multicentre study.
abstract: BACKGROUND
  The fixed-dose combination of any two antihypertensive drugs from different drug classes is typically more effective in reducing blood pressure than a dose increase of component monotherapy. We assessed the efficacy and safety of a fixed-dose combination of a vasodilating β blocker (nebivolol) and an angiotensin II receptor blocker (valsartan) in adults with hypertension.
  
  
  METHODS
  We did an 8-week, phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group trial at 401 US sites. Participants (age ≥18 years) with hypertension but with blood pressure less than 180/110 mm Hg were randomly assigned (2:2:2:2:2:2:2:1) by a 24-h interactive web response system in blocks of 15 to 4 weeks of double-blind treatment with nebivolol and valsartan fixed-dose combination (5 and 80 mg/day, 5 and 160 mg/day, or 10 and 160 mg/day), nebivolol (5 mg/day or 20 mg/day), valsartan (80 mg/day or 160 mg/day), or placebo. Doses were doubled in weeks 5-8; results are reported according to the final dose. Participants and research staff were masked to treatment allocation. The primary and key secondary endpoints were changes from baseline to week 8 in diastolic and systolic blood pressure, respectively. The primary statistical comparison was between the highest fixed-dose combination dose and the highest monotherapy doses; lower doses were then compared if this comparison was positive (Hochberg method for multiple testing). Efficacy analyses were by intention to treat. Safety assessments included monitoring of adverse events. Continuous efficacy parameters were analysed using an ANCOVA model; binary outcomes were analysed using a logistic regression model. This study is registered with ClinicalTrials.gov, NCT01508026.
  
  
  RESULTS
  Between Jan 6, 2012, and March 15, 2013, 4161 patients were randomly assigned (277 to placebo and 554-555 to each active comparator group), 4118 of whom were included in the primary analysis. At week 8, the fixed-dose combination 20 and 320 mg/day group had significantly greater reductions in diastolic blood pressure from baseline than both nebivolol 40 mg/day (least-squares mean difference -1·2 mm Hg, 95% CI -2·3 to -0·1; p=0·030) and valsartan 320 mg/day (-4·4 mm Hg, -5·4 to -3·3; p<0·0001); all other comparisons were also significant, favouring the fixed-dose combinations (all p<0·0001). All systolic blood pressure comparisons were also significant (all p<0·01). At least one treatment-emergent adverse event was experienced by 30-36% of participants in each group.
  
  
  CONCLUSIONS
  Nebivolol and valsartan fixed-dose combination is an effective and well-tolerated treatment option for patients with hypertension.
  
  
  BACKGROUND
  Forest Research Institute.
authors.affiliation: Department of Medicine, Tulane University, New Orleans, LA, USA. Electronic address: tgiles4@cox.net.
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Giles
authors.affiliation: Division of Cardiovascular Medicine, State University of New York, Downstate College of Medicine, Brooklyn, NY, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Weber
authors.affiliation: Department of Medicine, Division of Cardiology, Medical University of South Carolina, Charleston, SC, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Basile
authors.affiliation: Department of Medicine, Temple University School of Medicine, Pittsburgh, PA, USA.
authors.forename: Alan H
authors.initials: AH
authors.lastname: Gradman
authors.affiliation: Department of Clinical Development, Forest Research Institute, Jersey City, NJ, USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Bharucha
authors.affiliation: Department of Biostatistics, Forest Research Institute, Jersey City, NJ, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.affiliation: Department of Clinical Development, Forest Research Institute, Jersey City, NJ, USA.
authors.forename: Manoj
authors.initials: M
authors.lastname: Pattathil
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000328:Adult; D000368:Aged; D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D001578:Benzopyrans / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004983:Ethanolamines / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D000068577:Nebivolol; D013777:Tetrazoles / Q000008:administration & dosage* / Q000009:adverse effects / Q000627:therapeutic use; D016896:Treatment Outcome; D014633:Valine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000068756:Valsartan; D055815:Young Adult
chemical_list: D000319:Adrenergic beta-Antagonists; D047228:Angiotensin II Type 1 Receptor Blockers; D000959:Antihypertensive Agents; D001578:Benzopyrans; D004338:Drug Combinations; D004983:Ethanolamines; D013777:Tetrazoles; D000068577:Nebivolol; D000068756:Valsartan; D014633:Valine