Impact of Model Choice When Studying the Relationship Between Blood Pressure Variability and Risk of Stroke Recurrence

Long-term blood pressure variability (BPV), an increasingly recognized vascular risk factor, is challenging to analyze. The objective was to assess the impact of BPV modeling on its estimated effect on the risk of stroke. We used data from a secondary stroke prevention trial, PROGRESS (Perindopril Protection Against Stroke Study), which included 6105 subjects. The median number of blood pressure (BP) measurements was 12 per patient and 727 patients experienced a first stroke recurrence over a mean follow-up of 4.3 years. Hazard ratios (HRs) of BPV were estimated from 6 proportional hazards models using different BPV modeling for comparison purposes. The 3 commonly used methods first derived SD of BP measures observed over a given period of follow-up and then used it as a fixed covariate in a Cox model. The 3 more advanced modeling accounted for changes in BP or BPV over time in a single-stage analysis. While the 3 commonly used methods produced contradictory results (for a 5 mmHg increase in BPV, HR=0.75 [95% CI, 0.68–0.82], HR=0.99 [0.91–1.08], HR=1.19 [1.10–1.30]), the 3 more advanced modeling resulted in a similar moderate positive association (HR=1.08 [95% CI, 0.99–1.17]), whether adjusted for BP at randomization or mean BP over the follow-up. The method used to assess BPV strongly affects its estimated effect on the risk of stroke, and should be chosen with caution. Further methodological developments are needed to account for the dynamics of both BP and BPV over time, to clarify the specific role of BPV.