Approximately half a million people in the United States are survivors of cancer diagnosed in childhood or adolescence. Over 50% of pediatric cancer patients have been treated with curative, but cardiotoxic, anthracycline-based therapies.1 Cardiac dysfunction associated with anthracyclines may progress to heart failure (HF) even decades later—long after the patient has survived cancer.2 Over the next 30 years, the cumulative incidence of HF in survivors who received ≥250 mg/mL2 doxorubicin-equivalent exposure is 7.2%, over 20-fold higher than in their nonexposed siblings.3 Radiation therapy further increases this risk, predominantly through increasing atherosclerotic risk and alterations in cardiometabolic profiles. Once HF has occurred, mortality risks among survivors of childhood cancer are seven times higher than in nonexposed siblings with HF from other etiologies,1 emphasizing the need for an approach across an entire lifespan to delay the progression of cardiac dysfunction.1-3

Primary- and secondary-prevention measures are essential components of cardio-oncology care. Primary-prevention strategies are integrated into frontline cancer treatments to mitigate toxicity.3 In this expert analysis, the current landscape of secondary-prevention efforts are described, which includes postcancer treatment strategies for HF prevention critical to the longitudinal care of asymptomatic survivors. Results of recent pharmacological trials, considerations for agent and dosing regimens, optimal timing of intervention/latency of disease, and markers of early subtle changes in left ventricular (LV) systolic function are also discussed. Further, the importance of cardiovascular risk factor (CRF) management and tailored, lifespan-based care as children transition to adult care is underscored.

To date, the PREVENT-HF (Progressive Ventricular Dysfunction Prevention in Pacemaker Patients) trial (n = 182) was the largest randomized controlled trial (RCT) of a pharmacological agent for asymptomatic survivors of childhood cancer at risk of HF.4 This phase 2b study was designed to determine whether 2 years of low-dose carvedilol can prevent anthracycline-induced LV dysfunction, defined by the surrogate marker of standardized left ventricular wall thickness–dimension ratio z score (LVWT/Dz). Because children grow and cardiac dimensions change with age, z scores are used to indicate the standard deviation from normative values. The PREVENT-HF results showed no significant difference in the primary outcome of LVWT/Dz. However, a subgroup analysis showed that, among those with a baseline elevated blood N-terminal pro–B-type natriuretic peptide (NT-proBNP) level, primary and secondary endpoints significantly improved with carvedilol compared with placebo.5

The PREVENT-HF trial was designed to use validated surrogate markers for HF in children.4 This trial built on the AAA (ACE Inhibitor After Anthracycline) trial, whose results showed that low-dose enalapril was associated with temporary short-term changes in left ventricular end-systolic wall stress (LVESWS), LV dimensions, afterload, fractional shortening, and mass. Enalapril was not associated with improved left ventricular wall thickness (LVWT), a more permanent hallmark of anthracycline-induced cardiotoxicity in children.

RCTs have not provided clear evidence favoring a specific secondary-prevention pharmacological strategy in young survivors, but data from numerous studies highlight that CRF management is critical. Anthracycline-exposed survivors who develop dyslipidemia and hypertension are significantly more likely (>35-fold) to experience serious cardiovascular (CV) events, such as HF, than are survivors without these risk factors.1,3 The magnitude of this risk is not broadly recognized, but newly developed risk calculators may positively influence primary care providers’ and pediatric and adult cardiologists’ attention to timing and aggressiveness of CRF management as well as increase patient adherence.6

Future research may uncover whether the choice of cardioprotective agent(s) and dosing strategy can influence the progression of LV dysfunction. The PREVENT-HF trial used low-dose carvedilol alone (up to 12.5 mg/day) and the AAA trial used a maximal daily enalapril dose of 0.15 mg/kg. Coupling an angiotensin-converting enzyme inhibitor and beta-blocker, a regimen common in adults, may prove to be more efficacious than single-drug prevention regimens in children.

The latency and heterogeneity of cardiac dysfunction after cancer, which depend on treatment exposures and other risk factors, complicate commencement of secondary pharmacological prevention. PREVENT-HF participants had a median time-since-diagnosis of 13.6 years; adjusting for this variable, carvedilol had a greater effect among survivors further from cancer therapy.4 Clarifying the trajectory of asymptomatic cardiac dysfunction is necessary to optimize the timing of secondary prevention.

The early asymptomatic nature of treatment-associated cardiac dysfunction necessitates the use of surrogate markers such as decreasing LVWT and increasing LVESWS, which have been validated to precede HF in children. However, additional markers of cardiac remodeling in young adults could help guide secondary-prevention efforts. Multiomics approaches and genetic analysis of variants associated with anthracycline-related cardiomyopathy may eventually help clarify the trajectory of asymptomatic disease and more effectively stratify patients by cardiomyopathy risk, facilitating research design and execution.3

Notably, the PREVENT-HF subgroup analysis highlighted that NT-proBNP levels may identify a population for whom secondary prevention with carvedilol could be beneficial.5 Likewise, findings from the St. Jude Lifetime Cohort indicate NT-proBNP levels and global longitudinal strain (GLS) may identify survivors at high risk of future cardiomyopathy.7 However, the advantage of GLS-guided cardioprotection therapy over left ventricular ejection fraction (LVEF)–guided interventions remains unproven.8 Presently, clinical adoption of GLS at pediatric centers is limited. Echocardiographic indexes and methodologies can diverge in pediatric versus adult settings. LV GLS values change as children age, and more normative pediatric data are necessary.

Future pharmacological interventions among young survivors of childhood cancers may build on promising new developments in adult cardio-oncology. High-dose atorvastatin decreased the incidence of LV dysfunction at 1-year follow-up in anthracycline-exposed adults. In this trial, the odds of LVEF decline by 10% to <55% were almost three times greater in the placebo group than in the atorvastatin group.9 Spironolactone is regularly used in pediatric patients with HF, but data specific to survivors of childhood cancer are lacking. Sacubitril/valsartan has only been evaluated in survivors of adult cancer.3,10

Clinicians should be aware that initiating secondary prevention in young, asymptomatic survivors can be challenging, especially as they transition from pediatric to adult care settings. Multidisciplinary care teams may improve collaboration across pediatric and adult caregivers and facilitate greater continuity of care, patient adherence, and longer-term follow-up. Greater insight into the latency of anthracycline- and radiation-associated cardiac dysfunction and validation of additional surrogate markers for changes in LV function may enhance the design characteristics of future RCTs. As it stands, there is strong evidence in favor of judicious, proactive CRF management for survivors of childhood cancer. Additional studies can elucidate whether secondary pharmacological prevention further improves CV outcomes when appropriately timed and tailored to specific subgroups of survivors of childhood cancer.

References

Bottinor W, Im C, Doody DR, et al. Mortality after major cardiovascular events in survivors of childhood cancer. J Am Coll Cardiol. 2024;83(8):827-838. doi:10.1016/j.jacc.2023.12.022
Ehrhardt MJ, Leerink JM, Mulder RL, et al. Systematic review and updated recommendations for cardiomyopathy surveillance for survivors of childhood, adolescent, and young adult cancer from the International Late Effects of Childhood Cancer Guideline Harmonization Group. Lancet Oncol. 2023;24(3):e108-e120. doi:10.1016/S1470-2045(23)00012-8
Ryan TD, Bates JE, Kinahan KE, et al. Cardiovascular toxicity in patients treated for childhood cancer: a scientific statement from the American Heart Association. Circulation. 2025;151(15):e926-e943. doi:10.1161/CIR.0000000000001308
Armenian SH, Hudson MM, Lindenfeld L, et al. Effect of carvedilol versus placebo on cardiac function in anthracycline-exposed survivors of childhood cancer (PREVENT-HF): a randomised, controlled, phase 2b trial. Lancet Oncol. 2024;25(2):235-245. doi:10.1016/S1470-2045(23)00637-X
Armenian SH, Hudson MM, Lindenfeld L, et al. Carvedilol to improve cardiac remodeling in anthracycline-exposed childhood cancer survivors: subgroup analysis of COG ALTE1621. JACC CardioOncol. 2024;6(5):791-793. Published 2024 Sep 17. doi:10.1016/j.jaccao.2024.07.015
Petrykey K, Chen Y, Neupane A, et al. Predicting the 10-year risk of cardiomyopathy in long-term survivors of childhood cancer. Ann Oncol. 2025;36(10):1203-1211. doi:10.1016/j.annonc.2025.05.539
Ehrhardt MJ, Liu Q, Mulrooney DA, et al. Improved cardiomyopathy risk prediction using global longitudinal strain and N-terminal-pro-B-type natriuretic peptide in survivors of childhood cancer exposed to cardiotoxic therapy. J Clin Oncol. 2024;42(11):1265-1277. doi:10.1200/JCO.23.01796
Negishi T, Thavendiranathan P, Penicka M, et al. Cardioprotection using strain-guided management of potentially cardiotoxic cancer therapy: 3-year results of the SUCCOUR trial. JACC Cardiovasc Imaging. 2023;16(3):269-278. doi:10.1016/j.jcmg.2022.10.010
Neilan TG, Quinaglia T, Onoue T, et al. Atorvastatin for anthracycline-associated cardiac dysfunction: the STOP-CA randomized clinical trial. JAMA. 2023;330(6):528-536. doi:10.1001/jama.2023.11887
Chen Z, Zhang C, Zhu Y, Gao D, Mao M, Zuo Z. Sacubitril/valsartan can improve the cardiac function in heart failure patients with a history of cancer: an observational study. Medicine (Baltimore). 2024;103(12):e37613. doi:10.1097/MD.0000000000037613


Keywords:
Cancer, Cancer Survivors, Anthracyclines, Secondary Prevention, Cardiomyopathies, Risk Management, Risk Factors, Cardio-oncology