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

PLoS One. 2014 Aug 4;9(8):e103169. doi: 10.1371/journal.pone.0103169. eCollection 2014.

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.

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.

Publication types

  • Comparative Study
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Antihypertensive Agents / pharmacology
  • Antihypertensive Agents / therapeutic use
  • Blood Pressure* / drug effects
  • Double-Blind Method
  • Drug Therapy, Combination
  • Endpoint Determination
  • Europe / epidemiology
  • Female
  • Follow-Up Studies
  • Humans
  • Hypertension / drug therapy*
  • Hypertension / mortality
  • Hypertension / physiopathology*
  • Male
  • Multivariate Analysis
  • Placebos
  • Proportional Hazards Models
  • Risk Factors
  • Systole* / drug effects

Substances

  • Antihypertensive Agents
  • Placebos

Associated data

  • ClinicalTrials.gov/NCT02088450

Grants and funding

Bayer AG, Wuppertal, Germany funded the Systolic Hypertension in Europe Trial (1989–1997). The European Union (HEALTH-2011.2.4.2-2-EU-MASCARA, HEALTH-F7-305507 HOMAGE and the European Research Council Advanced Researcher Grant-2011-294713-EPLORE) and the Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Ministry of the Flemish Community, Brussels, Belgium (G.0881.13 and G.088013) currently support the Studies Coordinating Centre in Leuven. A Hara received the Bayer Yakuhin Research Grant Abroad Fellowship from the Japanese Heart Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.