The beta blocker carvedilol may improve important markers of heart injury sustained as a result of chemotherapy exposure among long-term childhood cancer survivors.
Carvedilol, a blood vessel relaxing medication, was deemed safe in long-term childhood cancer survivors when given at a low dose. However, the PREVENT-HF trial (NCT027175073) did not achieve its goal of decreasing the thinning of the heart muscle and enlargement of its chambers.1
According to findings published in The Lancet Oncology, carvedilol may improve important markers of heart injury sustained because of chemotherapy exposure, including heart left ventricular end-systolic wall stress, which is an early biomarker of worsening heart health.
”In our study, the greatest benefit was seen in participants who were very long-term survivors, as well as in those who were highly adherent to the study medication. Importantly, of the 8 patients who developed clinically significant decline in heart function while on the study, 6 were randomized to placebo and 2 were receiving carvedilol,” Saro H. Armenian, DO, MPH, Barron Hilton Chair in Pediatrics at City of Hope Children’s Cancer Center and corresponding author of the study, told Targeted OncologyTM.
One of the long-term adverse effects (AE) often linked with anthracycline, a class of chemotherapy, is increased risk of heart failure.2 Over time, this potent drug thins the heart muscle and enlarges its chambers, progressively setting the stage for heart failure. The nature of this process underscores the need for early intervention strategies.
The double-blind, phase 2b study, which was conducted by City of Hope in cooperation with the Children’s Oncology Group (COG), is the largest clinical trial to date aiming to reduce the risk of developing heart failure among those who have survived childhood cancer. The study took place at 30 COG-member hospitals in the United States and Canada.
“We sought to use a “gold standard” therapy for treating heart failure — as well as 1 that would be accessible — and the low-cost, generic carvedilol met these criteria. Because we would be treating patients who were asymptomatic, carvedilol was a good choice because there is evidence that it helps patients with mild heart failure even at low doses. Other options such as angiotensin-converting enzyme inhibitors carry warnings for patients who might be pregnant, which would be likely among women in the study’s age group,” said Armenian.
A total of 182 patients were enrolled and treated with relatively low doses of carvedilol or placebo given at an equivalent dose for the span of 2 years.1 Eligible patients were those with any cancer diagnosis that resulted in at least 250 mg/m2 cumulative exposure to anthracycline by the age of 21. Patients must have completed their cancer treatment at least 2 years prior and have an ejection fraction of at least 50%, fractional shortening of at least 25%, or both.
Once enrolled, patients were randomly assigned in a 1:1 fashion to carvedilol or placebo orally for 2 years and stratified by age at diagnosis, time since diagnosis, and history of chest-directed radiotherapy. Investigators assessed the primary end point of the effect of carvedilol on standardized left ventricular wall thickness–dimension ratio Z score (LVWT/Dz).
“LVWT/Dz Z-score was used as a primary end point because it is the most widely recognized biomarker of anthracycline-related cardiac remodeling in childhood cancer survivors. That said, there are many other established biomarkers of cardiac remodeling in this population, which were also examined in the trial. In fact, we saw a significant improvement in 1 of those biomarkers called left ventricular end-systolic wall stress, which is an earlier biomarker of worsening heart health. We also noted that survivors who were highly adherent to carvedilol were significantly less likely to have clinically meaningful declines in their heart function during the study follow-up period,” added Armenian.
There were 196 patients enrolled between July 3, 2012, and June 22, 2020. Among the 196, 182 (93%) were eligible and randomized to receive carvedilol (n = 89) or placebo (n = 93). Baseline characteristics showed that the median age of patients was 24.7 years (interquartile range [IQR], 19.6-36.6), 50% (n = 91) were female, 50% (n = 91) were male, and 65% (n = 119) were non-Hispanic White.
“The greatest challenge was asking survivors to take a low dose of the study medication (carvedilol or placebo) as a preventive measure, rather than for treatment of disease, which is what most people are used to,” said Armenian. “That said, this community of survivors has long been aware of the potential long-term heart failure risk associated with high-dose anthracycline therapy. As such, we were able to speak to the importance of proactive intervention to mitigate future disease risk.”
The median follow-up at the data cutoff date of June 10, 2022, was 725 days (IQR, 378-730). A total of 75 patients in the carvedilol group and 76 in the placebo group were included in the modified intention-to-treat (mITT) population. Of these 2 groups, LVWT/Dz was similar at -0.14 (95% CI, -0.43-0.16] in the carvedilol group compared with -0.45 (95% CI, -0.77--0.13) in the placebo group, making for a difference of 0.31 (95% CI, -0.10-0.73; P =.14).
Safety findings showed there to be no significant differences in regard to AEs between the 2 study arms. Of the 89 patients enrolled to receive carvedilol, 2 (2%) of 89 patients in the carvedilol group had 2 adverse events deemed grade 2 or higher, including shortness of breath (n = 1) and arthralgia (n = 1). No patients in the placebo group reported grade 2 or greater AEs. Further, there were no AEs of grade 3 or higher observed, no deaths reported, and overall, carvedilol appeared to be well-tolerated.
Although the clinical trial did not achieve its goal of decreasing the thinning of the heart muscle and enlargement of its chambers, there were significant improvements in heart left ventricular end-systolic wall stress, which is an earlier biomarker of worsening heart health.
According to experts, this study marks an important first step toward developing future studies that will seek to optimize the long-term well-being and health of survivors who are expected to live for decades after their initial cancer diagnosis.
“These findings set the stage for a phase 3 clinical trial that may demonstrate a significant benefit for certain patients who are at an especially high risk of irreversible heart function decline after completion of cancer therapy,” concluded Armenian.