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

Summary

A retrospective age- and sex-matched case–control study showed that hypertension and current smoking were independently associated with first-ever ischemic stroke and jointly produced a supra-additive increase in risk.

Abstract

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.

Introduction

Ischemic stroke represents a major global health burden, accounting for over 6.55 million deaths and 12.2 million incident cases worldwide in 2020^1,2. Despite advances in acute treatment and secondary prevention, the incidence of ischemic stroke continues to rise, driven by population aging and the increasing prevalence of modifiable risk factors^2,3. Understanding the independent and synergistic effects of these risk factors is critical for developing effective primary prevention strategies and identifying high-risk populations for targeted interventio....

Protocol

This study was conducted in accordance with the Declaration of Helsinki and approved by the Research Ethics Committee of Hebei General Hospital (IRB approval number: LW-104). Due to the study's retrospective nature and the use of anonymized patient information, the Ethics Committee of Hebei General Hospital waived the requirement for informed consent. The research tools used in this protocol are listed in the Table of Materials.

1. Study design

This investigation constituted a single-center retrospective case–control study conducted at Hebei General Hospital. Cases comprised indi....

Results

Sample derivation and matching success
Figure 2 depicts the participant flow diagram following Strengthening the Reporting of Observational Studies in Epidemiology guidelines. From an initial pool of 3,847 patients with suspected cerebrovascular events between January 2018 and June 2025, 892 with hemorrhagic stroke, 456 with TIA without infarction, 127 with cerebral venous thrombosis, 1,238 with recurrent strokes, and 822 with insufficient data were excluded. This yielded 312 cases o.......

Discussion

This case–control study, with EPV = 26.0, pre-registration, Firth’s penalization, multiple imputation, and dual-scale interaction assessment, generated several findings. First, independent associations between modifiable risk factors—current smoking, heavy alcohol consumption, hypertension, and diabetes mellitus—and first-ever ischemic stroke were confirmed, with effect sizes consistent with international literature. Second, a significant synergistic interaction between hypertension and current sm.......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Computed tomography (CT) imaging system	Hebei General Hospital Department of Radiology	N/A	Clinical CT platform used as part of routine neuroimaging assessment for suspected cerebrovascular events.
Electronic health record (EHR) system	Hebei General Hospital	N/A	Institutional clinical record system used to retrieve demographic information, diagnoses, medical history, medication use, and clinical encounter data for de-identified participants.
Health examination database	Hebei General Hospital	N/A	Institutional health examination database used as one source for control identification and matching.
Laboratory information management system (LIMS)	Hebei General Hospital	N/A	Institutional laboratory database used to extract LDL-C, HDL-C, eGFR, homocysteine, and other laboratory variables.
Magnetic resonance imaging (MRI) system with diffusion-weighted imaging (DWI)	Hebei General Hospital Department of Radiology	N/A	Clinical MRI/DWI platform used to confirm acute cerebral infarction where available.
Medical record abstraction form	Study-developed form, Hebei General Hospital	N/A	Standardized abstraction sheet used by independent researchers to extract exposure, covariate, medication, and outcome data.
Microsoft Excel	Microsoft Corporation	Microsoft 365/Excel-compatible workbook	Used to organize tabular source data and prepare the supplementary data workbook.
Picture archiving and communication system (PACS)	Hebei General Hospital	N/A	Institutional neuroimaging archive used to review CT and MRI/DWI studies for ischemic stroke confirmation and adjudication.
R package: boot	CRAN/R package authors	boot	Used to calculate bootstrap confidence intervals.
R package: dagitty	CRAN/dagitty project	dagitty	Used for directed acyclic graph specification and adjustment-set verification.
R package: epiR	CRAN/R package authors	epiR	Used to estimate additive interaction measures including RERI, AP, and synergy index.
R package: ggplot2	CRAN/R package authors	ggplot2	Used to generate statistical figures and visualizations.
R package: logistf	CRAN/R package authors	logistf	Used for Firth's penalized logistic regression to address sparse-data bias.
R package: mice	CRAN/R package authors	mice	Used for multiple imputation by chained equations.
R package: rms	CRAN/R package authors	rms	Used for restricted cubic splines and model diagnostics.
R package: survival	CRAN/R package authors	survival	Used for conditional logistic regression in the matched case-control analysis.
R statistical software	R Foundation for Statistical Computing	Version 4.3.x or later	Primary statistical environment used for regression modeling, imputation, interaction analysis, bootstrapping, diagnostics, and visualization.
STROBE reporting checklist	STROBE Initiative	N/A	Reporting framework used to structure the observational-study flow and manuscript reporting.
Structured interview form	Study-developed form, Hebei General Hospital	N/A	Standardized form used to collect or verify smoking status, pack-years, alcohol intake, and relevant historical exposure information.
TOAST ischemic stroke subtype classification	Trial of Org 10172 in Acute Stroke Treatment classification system	N/A	Clinical classification system used by neurologists to categorize ischemic stroke subtypes.