Background: Cardiovascular risk stratification is a cornerstone of modern preventive medicine, particularly in patients with multiple comorbidities, where risk estimation is inherently complex. Existing tools such as SCORE2 and the CUORE project provide important insights into cardiovascular risk but are limited in their ability to account for the interplay of multiple coexisting conditions.

Objective: The primary aim of this prospective cohort study is to develop and validate a novel cardiovascular risk prediction model specifically tailored for patients with at least two concomitant chronic diseases. Secondary objectives include comparing the predictive performance of the new model with that of SCORE2 and the CUORE project, and quantifying the incidence of venous thromboembolism (VTE), bleeding, and overall mortality in this high-risk population.

Methods: This is a prospective, monocentric, observational cohort study with an expected duration of 144 months. Patients ≥18 years with at least two of a predefined list of chronic conditions will be recruited at the Thrombosis Unit of Fondazione Policlinico Universitario A. Gemelli IRCCS. Clinical, laboratory, and instrumental data will be collected at baseline and during annual follow-up visits, for a maximum follow-up period of 10 years. Major cardiovascular events, VTE, bleeding, and mortality will be recorded. A Fine & Gray competing risks model will be applied for risk modeling, with subsequent validation in an independent cohort. Model discrimination and calibration will be evaluated using time-dependent ROC curves and calibration plots.

Expected Outcomes: The study aims to generate a robust and clinically applicable cardiovascular risk prediction model that better reflects the complexity of patients with multimorbidity. The model is expected to improve individualized prevention strategies and optimize resource allocation in clinical practice.

Ethical Considerations: The study will be conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Informed consent will be obtained from all participants.

Inclusion Criteria:

• History of at least two of the following conditions: arterial hypertension, dyslipidemia, type 2 diabetes mellitus, ischemic heart disease, heart failure with reduced or preserved ejection fraction, atrial fibrillation, cardiac valvular disease, cerebrovascular disease, obesity, chronic obstructive pulmonary disease, chronic kidney disease, neoplasia (except localized basal cell or squamous cell skin neoplasms), active or previous venous thromboembolism.
• Age greater than 18 years.
• Expression of Informed Consent.

Exclusion Criteria:

• Unable or unwilling to perform follow-up visits.
• Life expectancy < 3 months.

The study population will consist of patients already affected by at least two pathologies at the time of the visit, prospectively recruited at the time of the first outpatient visit at the U.O.S.D. Percorso Trombosi of the I.R.C.C.S. Fondazione Policlinico Universitario Agostino Gemelli in Rome.