Study-Level Versus Patient-Level Effect Modification by Chronic Hypertension in Mean Arterial Pressure Targets for Septic Shock: A Meta-Analysis Demonstrating Ecological Fallacy

Introduction: Optimal mean arterial pressure (MAP) targets in septic shock remain controversial, with prior study-level meta-regression suggesting that chronic hypertension modifies treatment effects. However, ecological associations may not reflect individual-level causation. We investigated whether study-level hypertension prevalence predicts treatment effects and compared this to within-study hypertension subgroup analyses. Methods: We conducted a systematic review and meta-analysis following the PRISMA 2020 guideline through multiple literature databases up to October 8, 2025. We included randomized controlled trials (RCTs) comparing higher versus standard MAP targets in septic shock that reported mortality outcomes. We performed random-effects meta-analysis and univariable meta-regression testing six study-level covariates, and pooled within-study hypertension subgroup data using inverse-variance methods. Results: Six RCTs enrolling 4,060 patients were included. Overall mortality showed no significant difference between higher versus standard MAP targets (random-effects risk ratio [RR] 1.03, 95% confidence interval [CI] 0.90-1.17, P-value = 0.72, I² = 22.5%). Study-level meta-regression found no significant effect modification by hypertension prevalence or other covariates (all P-values > 0.05) in this six-study subset. However, within-study hypertension subgroup analysis (two trials, 1,405 patients) revealed higher MAP targets increased mortality in hypertensive patients (pooled RR 1.22, 95% CI 1.05-1.41, P-value = 0.009), demonstrating ecological fallacy where aggregate associations contradicted individual-level effects. Conclusions: Our performed study-level meta-regression demonstrated unreliable evidence for effect modification. Within-study hypertension subgroup data suggest higher MAP targets may harm rather than benefit hypertensive patients, contradicting ecological inferences and highlighting the necessity of individual patient data meta-analyses in further, better-sampled studies.