Cancer represents one of the most significant burdens of public health as a leading cause of mortality worldwide. Chemotherapy plays a prominent role in cancer treatment, particularly with anthracyclines, which are extensively utilized for both solid tumors and hematological malignancies due to their potent anti-tumor capability, including in breast cancer, lung cancer, lymphoma, and leukemia (1). However, the cardiotoxicity associated with anthracyclines is still considered by practitioners to be a substantial challenge in clinical practice. Congestive heart failure has become a primary cause of morbidity and mortality in cancer survivors, negatively impacting treatment outcomes and potentially jeopardizing their long-term quality of life (2, 3).

Anthracyclines and their derivative compounds (such as doxorubicin, idarubicin, epirubicin, and mitoxantrone) constitute a class of chemotherapeutic drugs known for their significant cardiotoxicity (4). This cardiotoxicity is primarily characterized by dose-related, delayed, and irreversible heart failure (5), which can result in various complications, including coronary artery disease, arrhythmias, pericardial disease, valvular disease, myocardial fibrosis, and left ventricular dysfunction (6, 7). Anthracyclines increase the risk of clinical cardiotoxicity by 5.43 times, subclinical cardiotoxicity by 6.25 times, any cardiotoxicity by 2.27 times, and cardiac mortality by 4.94 times compared to non-anthracycline regimens (8). The cardiotoxic effects of anthracyclines are progressive and irreversible, potentially causing myocardial damage even with initial administration (9). As the cumulative dose increases, the risk of cardiotoxicity escalates significantly (10, 11). Furthermore, cardiotoxicity is not confined to acute-phase reactions; it also encompasses chronic and delayed cardiac adverse effects, which may manifest years after the cessation of chemotherapy, thereby heightening the long-term health risks for patients (12). Although the implementation of liposome technology can mitigate cardiotoxicity to some extent, certain risks remain (13). Additionally, anthracyclines are associated with severe dose-dependent acute toxicity, which restricts their long-term repeated use.

In recent years, numerous studies have explored various pharmacological intervention strategies to reduce cardiotoxicity associated with anthracycline chemotherapy (14). Prophylactic dexrazoxane is the sole pharmacological agent sanctioned for the clinical prevention and management of anthracycline-induced cardiotoxicity (15). Studies have shown that combining dexrazoxane and anthracyclines can significantly mitigate cardiotoxicity (16). Additionally, beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs) are also considered to possess potential cardioprotective effects (17). This study seeks to update previous research by integrating the most recent data to provide evidence-based guidance and recommendations for preventing cardiotoxicity from anthracycline chemotherapy.

This review is presented in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extended Statement, and our review is registered with PROSPERO (CRD42024567684) (18).

Anthracycline chemotherapeutic agents play a crucial role in the treatment of various malignancies, including breast cancer and lymphoma. However, their associated cardiotoxicity has increasingly garnered clinical attention. Numerous studies have confirmed that anthracyclines can lead to a reduction in LVEF, which is closely related to the cumulative dose of the drug (20). systematically evaluated the impact of anthracycline chemotherapy on left ventricular remodeling using cardiac magnetic resonance imaging (CMR) technology. The study included 61 patients who received anthracycline chemotherapy, 15 patients who received non-anthracycline chemotherapy, and 24 healthy control participants without cancer. The results indicated that, in patients treated with anthracycline-based chemotherapy, LVEF significantly decreased by 5% within 6 months after treatment while no significant changes in LVEF were observed in patients treated with non-anthracycline-based chemotherapy or in the control group.This reduction in LVEF not only indicates impaired cardiac systolic function but is also significantly associated with the risk of adverse cardiovascular events, such as myocardial infarction and arrhythmias. A related prospective cohort study (21)further evaluated the relationship between LVEF and the risk of cardiovascular diseases, finding that when LVEF falls below 55%, the risk of heart failure significantly increases (HR = 1.15, 95% CI = 1.02–1.30).Left ventricular end-diastolic diameter (LVEDD) and end-systolic diameter (LVESD) are important indicators for assessing ventricular remodeling (22)., through the analysis of 15 randomized controlled trials, found that neurohormonal blockers may have cardioprotective effects. Among the studies, it was noted that patients treated with Nebivolol maintained stable LVEDD and LVESD after chemotherapy, whereas patients receiving placebo experienced an increase in LVEDD from 47.2 ± 3.8 mm to 52.0 ± 4.6 mm, and in LVESD from 29.7 ± 3.4 mm to 33.4 ± 4.5 mm. Additionally, changes in the diastolic function index, the E/A ratio, are also noteworthy. The systematic review and meta-analysis by (23) included 13 studies with a total of 892 breast cancer patients who underwent echocardiography both before and after anthracycline chemotherapy. The results showed a significant decrease in the E/A ratio in patients after anthracycline chemotherapy [MD = −0.14, 95% CI (−0.22, −0.06)], which may indicate early impairment of left ventricular diastolic function.

This systematic review and network meta-analysis synthesized evidence from 28 randomized controlled trials involving 2,858 patients, evaluating the comparative efficacy of 21 drug interventions for preventing anthracycline-induced cardiotoxicity across five outcome measures.The analysis revealed Spironolactone as the most effective intervention for improving both LVEF and LVESD, suggesting its potential advantages in maintaining or restoring cardiac function. This finding aligns with the network meta-analysis conducted by (24) and the cohort study by (25). This may be attributed to the fact that Spironolactone can effectively inhibit the apoptosis of cardiomyocyte during ischemia-reperfusion, reduce the occurrence of myocardial damage and fibrosis, promote the positive remodeling of cardiac structure and functional recovery while reducing sodium and water retention and lowering blood pressure, consequently alleviating the strain on the heart (26–28). Additionally, Lisinopril + Bisoprolol and Astragalus polysaccharide also demonstrated favorable improvements in LVEF, suggesting that multi-target interventions may offer greater cardioprotective potential compared to single-drug therapies. Notably, Panax ginseng exhibited paradoxical effects. Although it is significantly associated with a decrease in LVEF [OR = −6.90, 95% CI (−10.46, −3.34)], it ranks best in reducing cardiac events in the SUCRA analysis [OR = 0.07, 95% CI (0.00, 1.47)]. This contradiction may stem from heterogeneity among studies, insufficient sample size, or varying effects of ginseng on different cardiac function indicators. Panax ginseng may reduce myocardial injury events through improves antioxidant or myocardial tolerance, but it might have adverse effects on cardiac contractile function (LVEF), suggesting the need for larger-scale, more rigorously designed clinical studies to further validate the true impact of Panax ginseng on anthracycline-induced cardiotoxicity. Dexrazoxane and Vitamin E + Levocarnitine are more effective than conventional chemotherapy and placebo in reducing the incidence of cardiac events. As an iron chelator, Dexrazoxane can effectively prevent anthracycline-induced cardiotoxicity without compromising antineoplastic efficacy (29), and has been recommended by multiple guidelines for cardiac protection in anthracycline therapy. Similarly, carvedilol (both as monotherapy and in combination with candesartan) showed dual benefits in preserving LVEF while decreasing cardiac events, attributable to its pleiotropic effects including antioxidant, anti-inflammatory and anti-fibrotic properties (30). The superior performance of Nebivolol in improving E/A ratio is related to its characteristics as a beta-blocker, which can reduce heart rate and blood pressure, decrease cardiac load, and improve diastolic function (31, 32). In this study, the effects of various drug interventions on LVEDD were not significant, which may suggest that existing drug interventions still need further optimization and exploration for this indicator.

In recent years, Chinese herbal medicine has garnered significant attention in the prevention and treatment of cardiovascular diseases due to its multi-target pharmacological actions and favorable safety profile. Salidroside, a natural compound extracted from Rhodiola rosea, has demonstrated notable biological activities in various experimental models, including anti-tumor, antioxidant, anti-inflammatory, neuroprotective, and cardiovascular protective effects (33). It can mitigate anthracycline-induced myocardial injury by inhibiting oxidative stress and mitochondrial apoptosis through the activation of the Nr2/Keap-1/HO-1 and PI3K/Akt pathways (34). Astragalus polysaccharides, the most abundant and immunologically active components in Astragalus, can activate macrophages and T/B lymphocytes, upregulate the secretion of immune factors, and function as natural immune enhancers (35). The study further confirmed that Astragalus polysaccharides induce macrophage polarization toward the anti-inflammatory M2 phenotype by enhancing the Nrf2/HO-1 pathway, thereby improving vascular endothelial dysfunction in diabetic patients (36). Hong Huang decoction, a traditional Chinese medicine formula composed of various herbal ingredients including Astragalus and Salvia miltiorrhiza, exhibits synergistic antioxidant, anti-inflammatory, and microvascular dilation effects (37). This study found that the formula outperformed the control group in reducing overall cardiac events, suggesting its comprehensive effects may surpass those of single components. Rg3, one of the main active components of Panax ginseng, enhances cardiac function in a dose-dependent manner. Rg3 inhibits oxidative stress and apoptosis by downregulating miR-128-3p and upregulating the expression of double minute 4 protein (MDM4) (38). However, achieving efficacy comparable to conventional drugs requires higher doses, and its clinical application is still limited due to its low oral bioavailability (≈10%) and poor intestinal absorption (39, 40).

Compared to previous studies, this research has updated the latest findings and comprehensively evaluated the relative efficacy of various interventions using multiple objective outcome measures. However, certain limitations in the study design remain. Firstly, approximately half of the original studies were rated as having a high risk of bias, primarily due to insufficient description of blinding; given that all outcomes were objectively measured (e.g., laboratory indicators, incidence rates, etc.), the impact of the lack of blinding on the results may be limited, but it could still slightly overestimate the efficacy due to other potential biases (e.g., incomplete allocation concealment). Secondly, some studies had small sample sizes, which reduced the stability of the effect estimates. In the existing evidence network, comparisons of certain intervention pairs relied solely on direct evidence, lacking closed-loop indirect comparisons, which may limit precision. Future research should focus on conducting more high-quality, large-sample randomized controlled trials and further validate and consolidate the conclusions of this study through more comprehensive literature inclusion.

This systematic evaluation reveals significant heterogeneity in the cardioprotective efficacy of various pharmacological interventions against anthracycline-induced cardiotoxicity. Spironolactone demonstrates outstanding performance in improving LVEF and LVESD. Additionally, Lisinopril + Bisoprolol and Astragalus polysaccharides also show clinically meaningful improvements in LVEF, suggesting their value as alternative or adjunctive therapies. Dexrazoxane and Vitamin E + Levocarnitine demonstrate superior efficacy in reducing cardiac event rates compared to conventional chemotherapy regimens. Meanwhile, the treatment regimen of Carvedilol alone or in combination with Candesartan provides comprehensive protection by simultaneously preserving systolic function and reducing cardiac events. However, the effects of Panax ginseng on cardiac function present a paradox: while it is associated with a potential adverse effects on LVEF, it also exhibits a protective effect in reducing cardiac events. This paradox underscores the need for mechanistic studies to elucidate its complex pharmacodynamics and rigorously designed, large-scale clinical trials with standardized endpoints. For optimal patient management, we recommend that patients undergoing anthracycline chemotherapy, especially those at high risk of cardiotoxicity, should adopt individualized cardioprotective strategies. Clinical decision-making should comprehensively consider the patient's specific conditions, drug characteristics, and existing evidence-based medical data to achieve optimal cardioprotective outcomes. Through rational pharmacological interventions, the risk of cardiotoxicity can be effectively reduced, thereby improving patients' quality of life and prognosis.

Although this analysis focuses on efficacy, the safety profile is equally important for clinical decision-making and efficacy evaluation.

Spironolactone is a potassium-sparing diuretic that may lead to hyperkalemia, especially in patients with renal insufficiency or those concurrently using other medications that increase potassium levels, such as ACE inhibitors (41). During its use, close monitoring of the patient's electrolyte balance, liver and kidney function, and endocrine system changes is essential.

Some studies suggest that prolonged or excessive use of Panax ginseng may lead to “ginseng abuse syndrome,” characterized by symptoms such as hypertension, insomnia, anxiety, and skin reactions (42). When used concurrently with anticoagulant drugs like warfarin, Panax ginseng may interfere with blood clotting and increase the risk of bleeding (43).

Dexrazoxane can significantly reduce the cardiotoxicity of anthracyclines, but its primary side effect is bone marrow suppression (reduction in white blood cells, neutrophils, and platelets). Additionally, long-term or high-dose use is associated with an increased risk of secondary malignancies and infertility (44).

Vitamin E is generally safe at conventional doses, but long-term or high-dose supplementation can inhibit the synthesis of vitamin K-dependent coagulation factors, reduce platelet aggregation, and thereby increase the risk of nosebleeds, hematuria, intraoperative and postoperative bleeding, and cerebral hemorrhage, especially when used in combination with anticoagulants such as warfarin and aspirin, or in individuals with pre-existing bleeding disorders (45).

The common side effects of Levocarnitine are mainly gastrointestinal discomfort (nausea, diarrhea, stomach cramps) and abnormal body odor; occasionally, dizziness, headache, or rash may occur; seizures and elevated blood pressure may occur with high doses or in patients with renal insufficiency.

The adverse reactions of Nebivolol are usually mild and occur less frequently than traditional beta-blockers (such as Atenolol, Metoprolol). Its nitric oxide(NO)-potentiating vasodilation may reduce some typical beta-blocker side effects (such as erectile dysfunction). However, liver dysfunction, bradycardia, and hypotension still require vigilance, especially in special populations (46).