title: Is blood pressure reduction a valid surrogate endpoint for stroke prevention? An analysis incorporating a systematic review of randomised controlled trials, a by-trial weighted errors-in-variables regression, the surrogate threshold effect (STE) and the Biomarker-Surrogacy (BioSurrogate) Evaluation Schema (BSES).
abstract: BACKGROUND
  Blood pressure is considered to be a leading example of a valid surrogate endpoint. The aims of this study were to (i) formally evaluate systolic and diastolic blood pressure reduction as a surrogate endpoint for stroke prevention and (ii) determine what blood pressure reduction would predict a stroke benefit.
  
  
  METHODS
  We identified randomised trials of at least six months duration comparing any pharmacologic anti-hypertensive treatment to placebo or no treatment, and reporting baseline blood pressure, on-trial blood pressure, and fatal and non-fatal stroke. Trials with fewer than five strokes in at least one arm were excluded. Errors-in-variables weighted least squares regression modelled the reduction in stroke as a function of systolic blood pressure reduction and diastolic blood pressure reduction respectively. The lower 95% prediction band was used to determine the minimum systolic blood pressure and diastolic blood pressure difference, the surrogate threshold effect (STE), below which there would be no predicted stroke benefit. The STE was used to generate the surrogate threshold effect proportion (STEP), a surrogacy metric, which with the R-squared trial-level association was used to evaluate blood pressure as a surrogate endpoint for stroke using the Biomarker-Surrogacy Evaluation Schema (BSES3).
  
  
  RESULTS
  In 18 qualifying trials representing all pharmacologic drug classes of antihypertensives, assuming a reliability coefficient of 0.9, the surrogate threshold effect for a stroke benefit was 7.1 mmHg for systolic blood pressure and 2.4 mmHg for diastolic blood pressure. The trial-level association was 0.41 and 0.64 and the STEP was 66% and 78% for systolic and diastolic blood pressure respectively. The STE and STEP were more robust to measurement error in the independent variable than R-squared trial-level associations. Using the BSES3, assuming a reliability coefficient of 0.9, systolic blood pressure was a B + grade and diastolic blood pressure was an A grade surrogate endpoint for stroke prevention. In comparison, using the same stroke data sets, no STEs could be estimated for cardiovascular (CV) mortality or all-cause mortality reduction, although the STE for CV mortality approached 25 mmHg for systolic blood pressure.
  
  
  CONCLUSIONS
  In this report we provide the first surrogate threshold effect (STE) values for systolic and diastolic blood pressure. We suggest the STEs have face and content validity, evidenced by the inclusivity of trial populations, subject populations and pharmacologic intervention populations in their calculation. We propose that the STE and STEP metrics offer another method of evaluating the evidence supporting surrogate endpoints. We demonstrate how surrogacy evaluations are strengthened if formally evaluated within specific-context evaluation frameworks using the Biomarker- Surrogate Evaluation Schema (BSES3), and we discuss the implications of our evaluation of blood pressure on other biomarkers and patient-reported instruments in relation to surrogacy metrics and trial design.
authors.affiliation: School of Public Health and Community Medicine, Faculty of Medicine, University of New South Wales, Sydney 2052, NSW, Australia. marissa.lassere@sesiahs.health.nsw.gov.au
authors.forename: Marissa N
authors.initials: MN
authors.lastname: Lassere
authors.forename: Kent R
authors.initials: KR
authors.lastname: Johnson
authors.forename: Michal
authors.initials: M
authors.lastname: Schiff
authors.forename: David
authors.initials: D
authors.lastname: Rees
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000032:analysis*; D001699:Biometry; D001794:Blood Pressure; D023381:Endpoint Determination; D004812:Epidemiologic Methods; D005260:Female; D006801:Humans; D006973:Hypertension / Q000517:prevention & control*; D016013:Likelihood Functions; D008297:Male; D008875:Middle Aged; D016032:Randomized Controlled Trials as Topic / Q000706:statistics & numerical data; D012044:Regression Analysis; D015203:Reproducibility of Results; D020521:Stroke / Q000401:mortality / Q000503:physiopathology / Q000517:prevention & control*; D020711:Threshold Limit Values
chemical_list: D015415:Biomarkers