Carvedilol fails to prevent heart failure in anthracycline-exposed survivors of childhood cancer: PREVENT-HF trial

The researchers found low-dose carvedilol to be safe but did not appear to significantly improve certain measures of heart failure (HF) risk in long-term survivors of childhood cancer exposed to anthracycline compared with a placebo. The study findings do not support carvedilol use for secondary heart failure prevention in anthracycline-exposed childhood cancer survivors.

"The standardized left ventricular wall thickness-dimension ratio Z score (LVWT/Dz) was -0.14 in the carvedilol group versus -0.45 in the placebo group at a median follow-up of 725 days," the researchers reported.

"Low-dose carvedilol appears to be safe in long-term childhood cancer survivors at risk for heart failure, but did not significantly improve LVWT/Dz compared with placebo," they wrote.

In patients with heart failure, carvedilol improves cardiac function but remains untested as cardioprotective therapy in long-term childhood cancer survivors (i.e. those who have completed treatment for childhood cancer and are in remission) at risk for HF due to high-dose anthracycline exposure.

To fill this knowledge gap, Prof Saro H Armenian, Department of Population Sciences, City of Hope Comprehensive Cancer Center, Duarte, CA, USA, and colleagues aimed to evaluate the safety and activity of low-dose carvedilol for HF risk reduction in childhood cancer survivors at highest heart failure risk.

PREVENT-HF is a randomized, double-blind, phase 2b trial performed at 30 hospitals in Canada and the USA. Patients were eligible if they had a cancer diagnosis that led to 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 body weight of at least 40 kg.

Patients were randomly assigned in a ratio of 1:1 to carvedilol (up-titrated from 3·125 g per day to 12·5 mg per day) or placebo orally for 2 years. Staff, participants, and investigators were masked to study group allocation.

The study's primary endpoint was to establish carvedilol's effect on standardized LVWT/Dz. Safety was evaluated in the ITT population (ie, all randomly assigned participants).

Of the 196 study enrollees, 182 were eligible, 89 were randomly assigned to carvedilol (up-titrated from 3.125 g per day to 12.5 mg per day) and 93 to placebo for two years. The median age was 24.7 years, and 50% were male. The median time since cancer diagnosis was 13.6 years. Diagnoses included osteosarcoma,

The median time since cancer diagnosis was 13.6 years. Diagnoses included osteosarcoma, acute myeloid leukemia, acute lymphoblastic leukemia, non-Hodgkin lymphoma, soft-tissue sarcoma, Ewing's sarcoma, Hodgkin lymphoma, and neuroblastoma.

The study led to the following findings:

• As of the data cutoff (June 10, 2022), the median follow-up was 725 days.
• 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 in the carvedilol group vs −0·45 in the placebo group; difference 0·31).
• 2% of 89 patients in the carvedilol group had 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.

"Low-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," the researchers wrote.

"These findings do not support carvedilol use for secondary heart failure prevention in anthracycline-exposed childhood cancer survivors," they concluded.

Reference:

Armenian SH, 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; DOI: 10.1016/S1470-2045(23)00637-X.