title: Comparison of valsartan/hydrochlorothiazide combination therapy at doses up to 320/25 mg versus monotherapy: a double-blind, placebo-controlled study followed by long-term combination therapy in hypertensive adults.
abstract: BACKGROUND
  One third of patients treated for hypertension attain adequate blood pressure (BP) control, and multidrug regimens are often required. Given the lifelong nature of hypertension, there is a need to evaluate the long-term efficacy and tolerability of higher doses of combination anti-hypertensive therapies.
  
  
  OBJECTIVE
  This study investigated the efficacy and tolerability of valsartan (VAL) or hydrochlorothiazide (HCTZ)-monotherapy and higher-dose combinations in patients with essential hypertension.
  
  
  METHODS
  The first part of this study was an 8-week, multicenter, randomized, double-blind, placebo controlled, parallel-group trial. Patients with essential hypertension (mean sitting diastolic BP [MSDBP], > or =95 mm Hg and <110 mm Hg) were randomized to 1 of 8 treatment groups: VAL 160 or 320 mg; HCTZ 12.5 or 25 mg; VAL/HCTZ 160/12.5, 320/12.5, or 320/25 mg; or placebo. Mean changes in MSDBP and mean sitting systolic BP (MSSBP) were analyzed at the 8-week core study end point. VAL/HCTZ 320/12.5 and 320/25 mg were further investigated in a 54-week, open-label extension. Response was defined as MSDBP <90 mm Hg or a > or =10 mm Hg decrease compared to baseline. Control was defined as MSDBP <90 mm Hg compared with baseline. Tolerability was assessed by monitoring adverse events at randomization and all subsequent study visits and regular evaluation of hematology and blood chemistry.
  
  
  RESULTS
  A total of 1346 patients were randomized into the 8-week core study (734 men, 612 women; 924 white, 291 black, 23 Asian, 108 other; mean age, 52.7 years; mean weight, 92.6 kg). All active treatments were associated with significantly reduced MSSBP and MSDBP during the core 8-week study, with each monotherapy significantly contributing to the overall effect of combination therapy (VAL and HCTZ, P < 0.001). Each combination was associated with significantly greater reductions in MSSBP and MSDBP compared with the monotherapies and placebo (all, P < 0.001). The mean reduction in MSSBP/MSDBP with VAL/HCTZ 320/25 mg was 24.7/16.6 mm Hg, compared with 5.9/7.0 mm Hg with placebo. The reduction in MSSBP was significantly greater with VAL/HCTZ 320/25 mg compared with VAL/HCTZ 160/12.5 mg (P < 0.002). Rates of response and BP control were significantly higher in the groups that received combination treatment compared with those that received monotherapy. The incidence of hypokalemia was lower with VAL/HCTZ combinations (1.8%-6.1%) than with HCTZ monotherapies (7.1%-13.3%). The majority of adverse events in the core study were of mild to moderate severity. The efficacy and tolerability of VAL/HCTZ combinations were maintained during the extension (797 patients).
  
  
  CONCLUSIONS
  In this study population, combination therapies with VAL/HCTZ were associated with significantly greater BP reductions compared with either monotherapy, were well tolerated, and were associated with less hypokalemia than HCTZ alone.
authors: Center for Experimental Therapeutics, Baylor College of Medicine, Houston, Texas 77030, USA. jpool@bcm.tmc.edu
authors: James L
authors: JL
authors: Pool
authors: Robert
authors: R
authors: Glazer
authors: Myron
authors: M
authors: Weinberger
authors: Roxanne
authors: R
authors: Alvarado
authors: Jie
authors: J
authors: Huang
authors: Alan
authors: A
authors: Graff
mesh_terms: D000368:Aged; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000009:adverse effects; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004338:Drug Combinations; D005260:Female; D006801:Humans; D006852:Hydrochlorothiazide / Q000008:administration & dosage* / Q000009:adverse effects; D006973:Hypertension / Q000188:drug therapy*; D007008:Hypokalemia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D013777:Tetrazoles / Q000008:administration & dosage* / Q000009:adverse effects; D014633:Valine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D000068756:Valsartan
chemical_list: D000959:Antihypertensive Agents; D004338:Drug Combinations; D013777:Tetrazoles; D006852:Hydrochlorothiazide; D000068756:Valsartan; D014633:Valine