USA: PREVENT-HF Trial Findings

A randomised, controlled, phase 2b trial (PREVENT-HF) has shed light on the effect of carvedilol versus placebo on cardiac function in anthracycline-exposed survivors of childhood cancer. The findings were published online in The Lancet Oncology on January 09, 2024.

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 (i.e., 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
• Acute myeloid leukemia
• Acute lymphoblastic leukemia
• Non-Hodgkin lymphoma
• Soft-tissue sarcoma
• Ewing's sarcoma
• Hodgkin lymphoma
• Neuroblastoma

Study 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.