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

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.