Prophylactic ACE inhibition in anthracycline-induced cardiotoxicity: signal, context, and clinical uncertainty

Anthracyclines remain a cornerstone of cancer therapy but are associated with a spectrum of cardiovascular toxicity, ranging from subclinical myocardial injury to overt heart failure (HF). Despite strong biological rationale, the role of universal pharmacologic prophylaxis remains uncertain. In this context, the recent meta-analysis by Pizzi et al. provides a timely synthesis of randomized evidence evaluating angiotensin-converting enzyme inhibitors (ACEi) for the prevention of anthracycline-related cardiotoxicity. The analysis demonstrates a statistically significant attenuation of left ventricular ejection fraction decline with ACEi prophylaxis, although the absolute effect size is modest and accompanied by substantial heterogeneity. Importantly, the magnitude of benefit appears to be context-dependent, with more consistent effects observed in higher-risk settings, such as combined anthracycline and trastuzumab exposure or in patients with early markers of myocardial injury. Contemporary data suggest that declining event rates and improved supportive care may limit the ability of prophylaxis trials to detect clinically meaningful differences in low-risk populations. Furthermore, the absence of significant effects on clinical endpoints underscores the limitations of current surrogate markers and trial design. Emerging evidence supports a more nuanced, risk-adapted approach, integrating early detection strategies such as global longitudinal strain and biomarker-guided intervention. Within this framework, ACEi prophylaxis may be most appropriately targeted to patients with higher baseline risk or early evidence of myocardial injury, rather than applied universally. Future studies should prioritize risk enrichment, standardized imaging protocols, and clinically meaningful outcomes to better define the role of cardioprotective strategies in cardio-oncology.