Variability independent of mean blood pressure as a real-world measure of cardiovascular risk

Abstract

Background: Individual-level blood pressure (BP) variability, independent of mean BP levels, has been associated with increased risk for cardiovascular events in cohort studies and clinical trials using standardized BP measurements. The extent to which BP variability relates to cardiovascular risk in the real-world clinical practice setting is unclear. We sought to determine if BP variability in clinical practice is associated with adverse cardiovascular outcomes using clinically generated data from the electronic health record (EHR).

Methods: We identified 42,482 patients followed continuously at a single academic medical center in Southern California between 2013 and 2019 and calculated their systolic and diastolic BP variability independent of the mean (VIM) over the first 3 years of the study period. We then performed multivariable Cox proportional hazards regression to examine the association between VIM and both composite and individual outcomes of interest (incident myocardial infarction, heart failure, stroke, and death).

Findings: Both systolic (HR, 95% CI 1.22, 1.17-1.28) and diastolic VIM (1.24, 1.19-1.30) were positively associated with the composite outcome, as well as all individual outcome measures. These findings were robust to stratification by age, sex and clinical comorbidities. In sensitivity analyses using a time-shifted follow-up period, VIM remained significantly associated with the composite outcome for both systolic (1.15, 1.11-1.20) and diastolic (1.18, 1.13-1.22) values.

Interpretation: VIM derived from clinically generated data remains associated with adverse cardiovascular outcomes and represents a risk marker beyond mean BP, including in important demographic and clinical subgroups. The demonstrated prognostic ability of VIM derived from non-standardized BP readings indicates the utility of this measure for risk stratification in a real-world practice setting, although residual confounding from unmeasured variables cannot be excluded.

Funding: This study was funded in part by National Institutes of Health grants R01-HL134168, R01-HL131532, R01-HL143227, R01-HL142983, U54-AG065141; R01-HL153382, K23-HL136853, K23-HL153888, and K99-HL157421; China Scholarship Council grant 201806260086; Academy of Finland (Grant no: 321351); Emil Aaltonen Foundation; Finnish Foundation for Cardiovascular Research.

Keywords: BP variability; Electronic health record; Hypertension; Preventive cardiology; Risk stratification.

Figure 1

Primary cohort development.

Figure 2

Association of variability independent of the mean BP and new-onset cardiovascular disease or death. Hazard of outcomes of interest associated with (A) systolic BP VIM among the entire cohort, (B) sex-disaggregated systolic BP and VIM, (C) diastolic BP VIM among the entire cohort, (D) sex-disaggregated diastolic BP and VIM. Hazard ratios were calculated using multivariable Cox proportional hazards regression, controlling for age, sex, race/ethnicity, smoking status, diabetes mellitus, chronic kidney disease, atrial fibrillation or flutter, coronary artery disease, use of antihypertensive medications and the number of visits at which a BP was recorded, as well as mean SBP and DBP. Horizontal black lines represent 95% confidence intervals; colored boxes represent point estimates. P-values in panels B and D represent significance of the interaction term of VIM and sex on each respective outcome. HF, heart failure. MI, myocardial infarction. VIM, variability independent of the mean BP.

Figure 3

New-onset cardiovascular disease risk or death by decile of variability independent of mean BP. Hazard of composite outcome and (A) mean systolic BP by deciles of systolic BP VIM, and (B) mean diastolic BP by deciles of diastolic BP VIM. VIM, variability independent of the mean. Vertical black lines represent 95% confidence intervals; colored boxes represent point estimates. SBP, systolic BP. DBP, diastolic BP. HR, hazard ratio.

Figure 4

Association of variability independent of the mean BP and new-onset cardiovascular disease or death, stratified by clinical conditions. Hazard of outcomes of interest, stratified by clinical conditions, associated with (A) systolic BP VIM, and (B) diastolic BP VIM. Hazard ratios were calculated using multivariable Cox proportional hazards regression, controlling for age, race/ethnicity, smoking status, diabetes mellitus, chronic kidney disease, atrial fibrillation or flutter, coronary artery disease, use of antihypertensive medications and the number of visits at which a BP was recorded, as well as mean SBP and DBP. Horizontal black lines represent 95% confidence intervals; colored boxes represent point estimates. P-values represent significance of the interaction term of VIM and each clinical condition on new-onset cardiovascular disease or death. VIM, variability independent of the mean BP. CAD, coronary artery disease.