medwireNews: The results of the PREVENT-HF trial do not support the use of low-dose carvedilol for heart failure risk reduction in anthracycline-exposed childhood cancer survivors.
Compared with placebo, low-dose carvedilol did not significantly improve the primary endpoint of left-ventricular wall thickness–dimension ratio Z score (LVWT/Dz), which the researchers explain “is a load-independent and objective measure of cardiac remodelling.”
They continue: “Findings from the current study could inform future prevention approaches that integrate a β blockade as a backbone for hypertension management in survivors at high-risk for anthracycline-related heart failure, or set the stage for a phase 3 prevention trial with longer follow-up and with primary clinical cardiovascular endpoints (eg, clinical heart failure) on the basis of findings from this phase 2B trial.”
The double-blind study enrolled 182 patients with any cancer diagnosis that resulted in a cumulative exposure to anthracycline of 250 mg/m2 by age 21 years and who had completed cancer treatment at least 2 years previously. Participants were also required to have an ejection fraction of at least 50% or fractional shortening of at least 25%, or both, and a body weight of at least 40 kg.
Analysis of the modified intention-to-treat population, which comprised 151 patients with a baseline and at least one subsequent echocardiogram measurement, showed that at 2 years, the LVWT/Dz decreased by a mean of 0.14 points among the 75 patients who were randomly assigned to receive carvedilol at a dose of 12.5 mg/day (up-titrated from 3.125 mg/day) for 2 years.
This did not differ significantly from the decrease of 0.45 points among the 76 patients who instead received placebo, report Saro Armenian (City of Hope Comprehensive Cancer Center, Duarte, California, USA) and co-investigators in The Lancet Oncology.
They did, however, observe a significant interaction between treatment group and time since diagnosis, which suggested “greater activity of carvedilol among longer-term survivors” with more than 20 years since their diagnosis versus less than 10 years.
“This is a clinically relevant observation, given the long latency of anthracycline-related heart failure, and these longer-term survivors might be the population to consider for enrolment onto subsequent secondary cardioprotective clinical trials,” writes the team.
Carvedilol treatment appeared to be associated with significantly lower left ventricular end-systolic wall stress than placebo after adjusting for age, time since diagnosis, receipt of chest radiation, and other confounding factors. But the authors of a linked commentary believe this may be “due to a reduction in blood pressure rather than a beneficial effect on cardiac function, because all other secondary outcomes, such as left ventricular ejection fraction, left ventricular diameters, and natriuretic peptide concentrations, were not significantly different” between groups.
Jan Leerink and Elizabeth Feijen, both from the Princess Maxima Medical Center in Utrecht, the Netherlands, say that “the results of PREVENT-HF do not support the use of low-dose carvedilol for preserving cardiac function in childhood cancer survivors who are at risk for heart failure.”
But they nevertheless describe the trial as “an important effort,” and commend the investigators “for conducting one of the first randomised controlled trials in the growing population of childhood cancer survivors, in whom secondary preventive measures are much needed to decrease the high burden of heart failure.”
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Lancet Oncol 2024; doi:10.1016/ S1470-2045(23)00637-X
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