From Cardioprotection to Trial Design: Rethinking Cardiac Safety in Oncology

Cardio-oncology has emerged as a pivotal discipline aimed at preserving cardiovascular health in patients undergoing contemporary cancer therapies. Despite growing awareness of treatment-related cardiac injury, the evidence base supporting preventive strategies and standardized safety assessment remains fragmented. This review critically appraises randomized controlled trials evaluating pharmacological and non-pharmacological interventions for the prevention of cancer therapy-related cardiac dysfunction. In parallel, we examine how cardiovascular events are monitored, defined, and reported in major oncology trials, with particular emphasis on patient selection criteria and the use of structured surveillance protocols.

Across drug classes repurposed from heart failure (HF) prevention and treatment, including neurohormonal antagonists, angiotensin receptor-neprilysin inhibition, lipid-lowering therapies, as well as exercise-based interventions, randomized evidence has demonstrated modest and inconsistent benefits. Reported effects are largely confined to subclinical alterations, such as changes in left ventricular systolic function, myocardial deformation parameters, or circulating cardiac biomarkers. By contrast, convincing reductions in clinically meaningful outcomes, including overt HF, treatment interruption, or cardiovascular mortality, remain limited. Concurrently, oncology trials frequently exhibit heterogeneous cardiovascular event definitions, incomplete safety reporting, and systematic exclusion of patients with pre-existing cardiac disease, thereby constraining external validity and obscuring the true burden of cardiotoxicity and competing cardiovascular risks. Advancing the field will require a paradigm shift toward individualized, risk-enriched prevention strategies anchored in clinically relevant endpoints. Broader inclusion of patients with stable cardiovascular comorbidities, managed under structured specialist supervision, alongside standardized frameworks for cardiovascular safety monitoring and reporting, is essential. Emerging artificial intelligence, as enabled tools applied to cardiac imaging, electrocardiography, and remote monitoring offer a promising opportunity to harmonize early detection of cardiotoxicity across trial sites and refine phenotyping of treatment-related cardiac injury. Integrating these elements into future trial design will be critical to ensure that therapeutic progress in oncology is not undermined by preventable cardiovascular harm.