Synergistic Effect of Hypertension and Smoking on Ischemic Stroke Risk: A Case-Control Study With Additive and...

Ischemic stroke remains a leading cause of death and disability worldwide. This single-center retrospective case-control study evaluated the independent and interactive effects of smoking, alcohol consumption, and traditional cardiovascular risk factors on first-ever ischemic stroke. Cases with radiologically confirmed first-ever ischemic stroke and controls were matched in a 1:2 ratio by age (±3 years) and sex between January 2018 and June 2025. Smoking status, pack-years, alcohol intake, hypertension, diabetes mellitus, and lipid variables were assessed. Conditional logistic regression with pre-specified covariates was applied, with interaction evaluated on both multiplicative and additive scales. Firth's penalization was used to address sparse data, and multiple imputation by chained equations was used to handle missing data. A total of 312 cases and 624 controls were included. Current smoking (odds ratio [OR] 2.34, 95% confidence interval [CI] 1.82-3.01), heavy alcohol consumption (>100 g/wk; OR 1.89, 95% CI 1.34-2.67), hypertension (OR 3.21, 95% CI 2.54-4.06), and diabetes mellitus (OR 2.12, 95% CI 1.56-2.88) were independently associated with ischemic stroke. Hypertension and current smoking demonstrated significant interaction on both multiplicative (interaction OR 1.58, 95% CI 1.12-2.24; P = 0.009) and additive scales (relative excess risk due to interaction 2.87, 95% CI 1.21-4.53; attributable proportion 0.32, 95% CI 0.15-0.49; synergy index 2.18, 95% CI 1.35-3.52). Model discrimination was good (area under the curve 0.82, 95% CI 0.79-0.85). These findings support integrated prevention strategies for individuals with coexisting hypertension and smoking exposure.