Cardioprotection without risk? meta-analysis of prophylactic agents in low-risk cancer patients on anthracyclines

Abstract Background Anthracyclines are essential treatments for various cancers but can cause significant, potentially irreversible cardiotoxicity. While cardioprotective agents are established in high-risk patients, their role in low-risk individuals without baseline cardiovascular disease is unclear. We conducted a systematic review and meta-analysis of prophylactic cardioprotective therapy versus placebo in low-risk adult cancer patients receiving anthracyclines. Methods We searched PubMed, Scopus, and Web of Science through August 2025 following PRISMA guidelines. We included randomized controlled trials (RCTs) of prophylactic ACE inhibitors, ARBs, beta-blockers, statins, dexrazoxane, or SGLT2 inhibitors in adults without pre-existing cardiovascular risk factors. Two reviewers independently extracted data on study characteristics, baseline demographics, intervention details, and clinical outcomes. The primary outcome was the incidence of cardiotoxicity, defined as ≥10% decline in LVEF or clinical heart failure. Secondary outcomes included absolute LVEF change and cardiac-related hospitalizations or mortality. Meta-analysis was conducted using a random-effects model. Results Seven RCTs (n=668; 402 treatment, 266 control) were included. Most patients were women with breast cancer; others had lymphoreticular or early solid tumors. Agents studied included beta-blockers (nebivolol, carvedilol, bisoprolol), ACE inhibitors (ramipril), ARBs (telmisartan), and spironolactone. Treatment duration ranged from 4 months to 1 year; anthracycline doses reached up to 689 mg/m² (epirubicin) or 536 mg/m² (doxorubicin). One study included trastuzumab (36%). Prophylactic therapy reduced LVEF decline compared to placebo (mean difference: -4.07%, 95% CI [-7.78, -0.37], P=0.03; I²=92%). Prophylactic cardioprotective therapies varied significantly in efficacy, from substantial LVEF preservation observed with spironolactone and ramipril-bisoprolol combination therapy, to minimal or no benefit with nebivolol, carvedilol, and telmisartan. A trend toward fewer cardiotoxicity events was observed (risk difference: -0.19, 95% CI [-0.40, 0.01], P=0.07; I²=97%). Subgroup analysis showed greater LVEF preservation with non-beta-blockers (MD: -8.43%, 95% CI [-12.45, -4.42], P<0.0001) versus beta-blockers (MD: -2.81%, 95% CI [-7.23, 1.62], P=0.21). No cardiac-related hospitalizations or deaths occurred. The protective benefit was greater in contexts involving higher cumulative anthracycline doses and concurrent cardiotoxic therapies such as trastuzumab. Conclusions Prophylactic cardioprotective therapy may reduce anthracycline-induced cardiotoxicity and loss of ejection fraction in low-risk patients, particularly with non-beta-blocker cardioprotective therapies and high-dose anthracycline regimens. However, high heterogeneity limits firm conclusions. Given the moderate effect size and heterogeneity, further large-scale, well-formulated trials are essential to identify optimal cardioprotective agents and precise patient selection criteria.