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

Azusa Hara, Lutgarde Thijs, Kei Asayama, Lotte Jacobs, Ji Guang Wang, Jan A. Staessen

Research output: Contribution to journalArticle

24 Citations (Scopus)


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. Findings: 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. Trial Registration: ClinicalTrials.gov NCT02088450

Original languageEnglish
Article numbere103169
JournalPloS one
Issue number8
Publication statusPublished - 2014 Aug 4


ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this