Integrating genetic and imaging information to enhance cardiovascular risk stratification: rationale and design of the CVRISK-IT randomised controlled trial

Introduction: Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide. Current guidelines recommend algorithms to estimate 10-year cardiovascular diseases (CVD) risk in apparently healthy individuals, but their precision remains limited. Whether the integration of imaging and genetic information can improve individual risk stratification remains uncertain. Methods and analysis: : The CVRISK-IT trial is a multicentre, open-label, randomised controlled study designed to enhance CVD prevention through precision-based risk assessment and targeted communication strategies. A total of 30,000 adults aged 40-80 years without previous CVD or diabetes are recruited across Italy. In Phase I, participants undergo a baseline assessment including clinical examination, blood sampling, and calculation of CVD risk. Approximately 12,000 eligible enter Phase II and are randomised equally into four intervention arms: (i) standard care (control), (ii) imaging-based risk refinement (coronary artery calcium score or carotid ultrasound), (iii) polygenic risk score (PRS), or (iv) combination of imaging and PRS. The co-primary endpoints are differences in estimated 10-year CVD risk at 12 months and the incidence of major CVD events, CVD mortality, and all-cause mortality at 5 years. Secondary endpoints include differences in CVD risk factors, prescription and adherence to preventive drug adherence, and behavioural or psychological measures. Conclusion: By prospectively evaluating the feasibility and impact of incorporating genetic and imaging information in CVD risk stratification, CVRISK-IT will generate robust evidence to inform its integration into routine screening practices and public health policy. Trial registration: ClinicalTrials.gov Identifier NCT06832644.