• Saro H Armenian, Melissa M Hudson, Lanie Lindenfeld, Sitong Chen, Eric J Chow, Steven Colan, Willem Collier, Xiaohong Su, Edward Marcus, Meagan Echevarria, Aleksi Iukuridze, Leslie L Robison, F Lennie Wong, Ming Hui Chen, and Smita Bhatia.
• Department of Population Sciences, City of Hope Comprehensive Cancer Center, Duarte, CA, USA; Department of Pediatrics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA. Electronic address: sarmenian@coh.org.
• Lancet Oncol. 2024 Feb 1; 25 (2): 235245235-245.

BackgroundCarvedilol improves cardiac function in patients with heart failure but remains untested as cardioprotective therapy in long-term childhood cancer survivors (ie, those who have completed treatment for childhood cancer and are in remission) at risk for heart failure due to high-dose anthracycline exposure. We aimed to evaluate the activity and safety of low-dose carvedilol for heart failure risk reduction in childhood cancer survivors at highest risk for heart failure.MethodsPREVENT-HF was a randomised, double-blind, phase 2b trial done at 30 hospitals in the USA and Canada. Patients were eligible if they had any cancer diagnosis that resulted in at least 250 mg/m2 cumulative exposure to anthracycline by age 21 years; completed their cancer treatment at least 2 years previously; an ejection fraction of at least 50% or fractional shortening of at least 25%, or both; and bodyweight of at least 40 kg. Patients were randomly assigned (1:1) with automated computer-generated permuted block randomisation (block size of 4), stratified by age at diagnosis, time since diagnosis, and history of chest-directed radiotherapy, to carvedilol (up-titrated from 3·125 g per day to 12·5 mg per day) or placebo orally for 2 years. Participants, staff, and investigators were masked to study group allocation. The primary endpoint was to establish the effect of carvedilol on standardised left ventricular wall thickness-dimension ratio Z score (LVWT/Dz). Treatment effects were analysed with a linear mixed-effects model for normally distributed data with a linear time effect and testing the significance of treatment*time interaction in the modified intention-to-treat (mITT) cohort (ie, all randomly assigned participants who had a baseline and at least one subsequent echocardiogram measurement). Safety was assessed in the ITT population (ie, all randomly assigned participants). This trial was registered with ClinicalTrials.gov, NCT027175073, and enrolment and follow-up are complete.FindingsBetween July 3, 2012, and June 22, 2020, 196 participants were enrolled, of whom 182 (93%) were eligible and randomly assigned to either carvedilol (n=89) or placebo (n=93; ITT population). Median age was 24·7 years (IQR 19·6-36·6), 91 (50%) participants were female, 91 (50%) were male, and 119 (65%) were non-Hispanic White. As of data cutoff (June 10, 2022), median follow-up was 725 days (IQR 378-730). 151 (n=75 in the carvedilol group and n=76 in the placebo group) of 182 participants were included in the mITT population, among whom LVWT/Dz was similar between the two groups (-0·14 [95% CI -0·43 to 0·16] in the carvedilol group vs -0·45 [-0·77 to -0·13] in the placebo group; difference 0·31 [95% CI -0·10 to 0·73]; p=0·14). Two (2%) of 89 patients in the carvedilol group two adverse events of grade 2 or higher (n=1 shortness of breath and n=1 arthralgia) and none in the placebo group. There were no adverse events of grade 3 or higher and no deaths.InterpretationLow-dose carvedilol appears to be safe in long-term childhood cancer survivors at risk for heart failure, but did not result in significant improvement of LVWT/Dz compared with placebo. These results do not support the use of carvedilol for secondary heart failure prevention in anthracycline-exposed childhood cancer survivors.FundingNational Cancer Institute, Leukemia & Lymphoma Society, St Baldrick's Foundation, Altschul Foundation, Rally Foundation, American Lebanese Syrian Associated Charities.Copyright © 2024 Elsevier Ltd. All rights reserved.

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