From Cardioprotection to Trial Design: Rethinking Cardiac Safety in Oncology

Purpose of Review 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. Recent Findings 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. Summary 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. Graphical Abstract Key question Can cardiovascular therapies and strategies routinely used in clinical cardiology mitigate cardiovascular toxicity related to cancer treatments? In parallel, how consistently are cardiovascular adverse events identified, monitored, and reported within contemporary oncology randomised clinical trials? Key findings Several pharmacological and non-pharmacological interventions commonly employed in cardiovascular medicine, including neurohormonal inhibition, statins, and exercise-based strategies, have been evaluated in small randomised trials for the prevention of cancer therapy–related cardiovascular dysfunction. While these approaches have not demonstrated consistent reductions in major clinical cardiovascular outcomes, they have shown signals of benefit on surrogate endpoints, such as myocardial remodelling, biomarkers of injury, and subclinical ventricular dysfunction. In oncology trials, cardiovascular adverse events are variably reported, with heterogeneous definitions, monitoring protocols, and frequent exclusion of patients with pre-existing cardiovascular disease. Take-home message Cardiovascular and oncological diseases are increasingly intertwined. Current evidence highlights the need for standardised cardiovascular safety frameworks, harmonised monitoring strategies, and integration of emerging tools, including AI-based approaches, to improve cardiotoxicity detection and reporting in future oncology trials.