title: Randomised double-blind comparison of placebo and active drugs for effects on risks associated with blood pressure variability in the Systolic Hypertension in Europe trial.
abstract: BACKGROUND
  In the Systolic Hypertension in Europe trial (NCT02088450), we investigated whether systolic blood pressure variability determines prognosis over and beyond level.
  
  
  METHODS
  Using a computerised random function and a double-blind design, we randomly allocated 4695 patients (≥60 years) with isolated systolic hypertension (160-219/<95 mm Hg) to active treatment or matching placebo. Active treatment consisted of nitrendipine (10-40 mg/day) with possible addition of enalapril (5-20 mg/day) and/or hydrochlorothiazide (12.5-25.0 mg/day). We assessed whether on-treatment systolic blood pressure level (SBP), visit-to-visit variability independent of the mean (VIM) or within-visit variability (WVV) predicted total (n = 286) or cardiovascular (n = 150) mortality or cardiovascular (n = 347), cerebrovascular (n = 133) or cardiac (n = 217) endpoints.
  
  
  RESULTS
  At 2 years, mean between-group differences were 10.5 mm Hg (p<0.0001) for SBP, 0.29 units (p = 0.20) for VIM, and 0.07 mm Hg (p = 0.47) for WVV. Active treatment reduced (p≤0.048) cardiovascular (-28%), cerebrovascular (-40%) and cardiac (-24%) endpoints. In analyses dichotomised by the median, patients with low vs. high VIM had similar event rates (p≥0.14). Low vs. high WVV was not associated with event rates (p≥0.095), except for total and cardiovascular mortality on active treatment, which were higher with low WVV (p≤0.0003). In multivariable-adjusted Cox models, SBP predicted all endpoints (p≤0.0043), whereas VIM did not predict any (p≥0.058). Except for an inverse association with total mortality (p = 0.042), WVV was not predictive (p≥0.15). Sensitivity analyses, from which we excluded blood pressure readings within 6 months after randomisation, 6 months prior to an event or both were confirmatory.
  
  
  CONCLUSIONS
  The double-blind placebo-controlled Syst-Eur trial demonstrated that blood-pressure lowering treatment reduces cardiovascular complications by decreasing level but not variability of SBP. Higher blood pressure level, but not higher variability, predicted risk.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT02088450.
authors.affiliation: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium.
authors.forename: Azusa
authors.initials: A
authors.lastname: Hara
authors.affiliation: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium.
authors.forename: Lutgarde
authors.initials: L
authors.lastname: Thijs
authors.affiliation: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium; Department of Hygiene and Public Health, Teikyo University School of Medicine, Tokyo, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Asayama
authors.affiliation: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium.
authors.forename: Lotte
authors.initials: L
authors.lastname: Jacobs
authors.affiliation: Center for Epidemiological Studies and Clinical Trials, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
authors.forename: Ji-Guang
authors.initials: JG
authors.lastname: Wang
authors.affiliation: Studies Coordinating Centre, Research Unit Hypertension and Cardiovascular Epidemiology, KU Leuven Department of Cardiovascular Diseases, University of Leuven, Leuven, Belgium; Department of Epidemiology, Maastricht University, Maastricht, the Netherlands.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Staessen
mesh_terms: D000368:Aged; D000959:Antihypertensive Agents / Q000494:pharmacology / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D023381:Endpoint Determination; D005060:Europe / Q000453:epidemiology; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000401:mortality / Q000503:physiopathology*; D008297:Male; D015999:Multivariate Analysis; D010919:Placebos; D016016:Proportional Hazards Models; D012307:Risk Factors; D013599:Systole / Q000187:drug effects
chemical_list: D000959:Antihypertensive Agents; D010919:Placebos
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