Carvedilol No Help in Preventing Heart Failure in Childhood Cancer Survivors

The use of low-dose carvedilol did not significantly improve certain cardiac measures of heart failure risk in long-term survivors of childhood cancer exposed to anthracycline compared with placebo, the randomized phase IIb PREVENT-HF study showed.

At a median follow-up of 725 days, the standardized left ventricular wall thickness-dimension ratio Z score (LVWT/Dz) was -0.14 (95% CI -0.43 to 0.16) in the carvedilol group versus -0.45 (95% CI -0.77 to -0.13) in the placebo group (P=0.14), reported Saro H. Armenian, DO, MPH, of the City of Hope Comprehensive Cancer Center in Duarte, California, and colleagues.

“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,” they wrote in Lancet Oncology. “These results do not support the use of carvedilol for secondary heart failure prevention in anthracycline-exposed cancer survivors.”

Of note, the study did show that patients treated with carvedilol had significantly better measures of left ventricular end-systolic wall stress — an early biomarker of worsening heart health — compared with placebo (P=0.023), and that the greatest benefit seen with carvedilol was in very long-term survivors.

While anthracyclines are commonly used in the treatment of childhood cancer, one of the most recognized side effects of the therapy is a dose-dependent association with heart failure that can occur many years after exposure.

In a commentary accompanying the study, Jan M. Leerink, MD, and Elizabeth A.M. Feijen, PhD, both of the Princess Maxima Medical Center in Utrecht, the Netherlands, suggested that there could be several reasons why the study was negative. For example, they posited that the trial could have been underpowered with a follow-up that was too short to detect a statistically significant difference in the primary outcome.

They also noted that PREVENT-HF included survivors exposed to cumulative anthracycline doses of at least 250 mg/m² — a level the authors believed would be most beneficial for survivors. However, Leerink and Feijen observed that while the lifetime risk of heart failure in this group is high, “a substantial number of these survivors are not at risk of developing heart failure in the near future and they might not yet benefit from secondary preventive treatment.”

Finally, they pointed out that the association of LVWT/Dz with future heart failure is not as well established as other echocardiographic measures, and that future studies should use more established measures such as left ventricular ejection fraction or natriuretic peptide concentrations.

“The findings will pave the way for future larger secondary prevention trials,” they wrote.

The double-blind PREVENT-HF trial was conducted at 30 hospitals in the U.S. and Canada. Patients were eligible if they had any cancer diagnosis that resulted in at least 250 mg/m² cumulative exposure to anthracycline by the age of 21; completed their cancer treatment at least 2 years previously; had an ejection fraction of at least 50%, a fractional shortening of at least 25%, or both; and had a body weight of at least 40 kg.

Of the 196 patients enrolled in the study, 182 were eligible, with 89 randomly assigned to carvedilol (up-titrated from 3.125 g per day to 12.5 mg per day) and 93 to placebo for 2 years. Median age was 24.7 years, 65% were white, and 50% were male. Median time since cancer diagnosis was 13.6 years. Diagnoses included acute myeloid leukemia, osteosarcoma, acute lymphoblastic leukemia, Ewing’s sarcoma, non-Hodgkin lymphoma, Hodgkin lymphoma, soft-tissue sarcoma, and neuroblastoma.

There were no significant differences between the groups in other secondary measures such as left ventricular ejection fraction, left ventricular diameters, and natriuretic peptide concentrations.

In a subgroup analysis, Armenian and colleagues found that carvedilol had greater efficacy among survivors with >20 years since diagnosis compared with survivors with <10 years since diagnosis. There were no differences by sex, cumulative anthracycline dose, and chest radiotherapy dose.

Two participants in the carvedilol group developed grade 2 adverse events, both “probably attributable” to carvedilol. There were no grade 2 or higher adverse events in the placebo group. Two patients in the carvedilol group and six in the placebo group developed cardiac events during the 2-year study period that necessitated unblinding and study discontinuation.

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