Opportunities and Challenges of Cardiovascular Disease Risk Prediction for Primary Prevention Using Machine Learning and Electronic Health Records: A Systematic Review

Cardiovascular disease (CVD) remains the foremost cause of morbidity and mortality worldwide. Recent advancements in machine learning (ML) have demonstrated substantial potential in augmenting risk stratification for primary prevention, surpassing conventional statistical models in predictive performance. Thus, integrating ML with Electronic Health Records (EHRs) enables refined risk estimation by leveraging the granularity and breadth of longitudinal individual patient data. However, fundamental barriers persist, including limited generalizability, challenges in interpretability, and the absence of rigorous external validation, all of which impede widespread clinical deployment. This review adheres to the methodological rigor of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) and Scale for the Assessment of Narrative Review Articles (SANRA) guidelines. A systematic literature search was performed in March 2024, encompassing the Medline and Embase databases, to identify studies published since 2010. Supplementary references were retrieved from the Institute for Scientific Information (ISI) Web of Science, and manual searches were curated. The selection process, conducted via Rayyan, focused on systematic and narrative reviews evaluating ML-driven models for long-term CVD risk prediction within primary prevention contexts utilizing EHR data. Studies investigating short-term prognostication, highly specific comorbid cohorts, or conventional models devoid of ML components were excluded. Following an exhaustive screening of 1757 records, 22 studies met the inclusion criteria. Of these, 10 were systematic reviews (four incorporating meta-analyses), while 12 constituted narrative reviews, with the majority published post-2020. The synthesis underscores the superiority of ML in modeling intricate EHR-derived risk factors, facilitating precision-driven cardiovascular risk assessment. Nonetheless, salient challenges endure heterogeneity in CVD outcome definitions, undermine comparability, data incompleteness and inconsistency compromise model robustness, and a dearth of external validation constrains clinical translatability. Moreover, ethical and regulatory considerations, including algorithmic opacity, equity in predictive performance, and the absence of standardized evaluation frameworks, pose formidable obstacles to seamless integration into clinical workflows. Despite the transformative potential of ML-based CVD risk prediction, it remains encumbered by methodological, technical, and regulatory impediments that hinder its full-scale adoption into real-world healthcare settings. This review underscores the imperative circumstances for standardized validation protocols, stringent regulatory oversight, and interdisciplinary collaboration to bridge the translational divide. Our findings established an integrative framework for developing, validating, and applying ML-based CVD risk prediction algorithms, addressing both clinical and technical dimensions. To further advance this field, we propose a standardized, transparent, and regulated EHR platform that facilitates fair model evaluation, reproducibility, and clinical translation by providing a high-quality, representative dataset with structured governance and benchmarking mechanisms. Meanwhile, future endeavors must prioritize enhancing model transparency, mitigating biases, and ensuring adaptability to heterogeneous clinical populations, fostering equitable and evidence-based implementation of ML-driven predictive analytics in cardiovascular medicine.