Low-dose carvedilol may reduce heart failure risk for childhood cancer survivors

Source/Disclosures

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Source:

Armenian S, et al. Abstract 10013. Presented at: ASCO Annual Meeting; June 2-6, 2023; Chicago..

Disclosures:
NIH funded this study. Armenian reports no relevant financial disclosures.

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A low-dose regimen of the blood pressure medication carvedilol demonstrated safety and efficacy in improving heart health of childhood cancer survivors, according to results of a multicenter phase 2b trial.

The findings, presented at ASCO Annual Meeting, suggest a potential role for low-dose carvedilol in preventing heart failure among childhood cancer survivors treated with anthracyclines.

“With the remarkable improvements in long-term survival for children with cancer, we have started to recognize the unique issues that develop in the 10-plus years after treatment,” study lead investigator Saro Armenian, DO, MPH, Barron Hilton chair in pediatrics and director of the division of outcomes research/intervention at City of Hope, told Healio. “The first step in our community was to characterize the late effects of treatment and determine what we can do about them. We can try to minimize the treatments known to cause late effects, but many of these treatments also contribute to the excellent cure rates we see in children with cancer. In essence, there are many cancers where you can’t eliminate these therapeutic exposures.”

Armenian spoke with Healio about his research team’s rationale for the study, what the study showed and how this information may change the approach to long-term follow-up for childhood cancer survivors.

Healio: How did you design the study?

Armenian: We initially thought we could continue to monitor individuals’ heart function through serial echocardiograms, or we could be a bit more proactive for specific subgroups of individuals at highest risk. For this study, we focused on a proactive, preventive approach to minimizing heart failure risk in the folks we identified as being at highest risk. This approach had to balance the adverse events of the intervention with the benefits. We wanted to make sure the benefits would outweigh the risks.

Healio: How did you identify carvedilol as potentially beneficial for this population?

Armenian: Several paradigms inspired our approach. The first is the baby aspirin approach, which is essentially to use a medication at a low dose for purposes other than its original indication. In the case of aspirin, it’s not for pain control, it’s for anti-inflammatory and blood-thinning purposes. So, we wanted to see if there is a similar paradigm in the pediatric population.

There was a randomized trial done in children with a genetic predisposition to developing heart failure later in life. This condition is called Duchenne muscular dystrophy. Instead of waiting until the heart showed clinical evidence of dysfunction, the investigators started trial participants on a low-dose blood pressure medication to see if that could help the heart heal or prevent damage to the heart over time. They showed that, in fact, it does. What we took from this is that if you have a high-risk subgroup that is likely to develop heart problems later on, you can potentially prevent that by being proactive. So, we took those two models and combined them for this trial.

The reason we chose carvedilol is that mechanistically, it provides a more comprehensive reversal of the cardiac injury than other blood pressure medications. It is also very safe, and it’s generic — it’s been around for a long time. The safety profile is great, and there is also evidence in adults that it can be effective in treating heart failure even at lower doses than you would typically use to treat patients. We recognized that the paradigm is there, and that we could use a medication that is readily available, inexpensive and comprehensive in targeting heart healing.

Healio: How did you conduct this study?

Armenian: This was a randomized, placebo-controlled trial. We worked with a third-party pharmaceutical company through which we purchased the study therapy and asked them to manufacture a placebo. There were 28 participating institutions across Children’s Oncology Group and it was double-blind randomization. The goal was to reach a target dose of 12.5 mg of carvedilol per day for everybody. Just to put this in perspective, the typical dose of carvedilol to treat hypertension or heart failure in the general population is somewhere around 25 to 50 mg.

The starting dose was 3.125 mg per day for 2 weeks, increasing to 6.25 mg and then up to 12.5 mg as maintenance. This was done to make sure the study drug was tolerable and safe in people who otherwise had no symptoms of heart disease.

Healio: What did you find?

Armenian: We showed that carvedilol was safe and well-tolerated, and no adverse events occurred. The treatment groups had the same self-reported symptoms. This was very reassuring. Then we looked at efficacy and found that those in the carvedilol group had significant improvements in cardiac measurements associated with heart failure risk. In fact, in the carvedilol arm, the trend was consistently toward improvement, whereas in the placebo arm the indices mirrored what we would expect from the natural progression of this disease. This was all within a 2-year period, which was quite remarkable.

There were eight patients whose heart function deteriorated while on the study, and these patients had to come off the study and be unblinded. Six of the eight were in the placebo arm and two were on the carvedilol arm. Longer follow-up will be needed for us to determine whether these trends hold up over time.

Healio: What implications could this have?

Armenian: This could potentially set the stage for more proactive interventions, like early-use of low-dose carvedilol to prevent heart failure in these patients. So, I think we showed that this strategy is safe and that we can stop and, in some cases, reverse cardiac injury. There is early evidence that you can prevent clinically significant declines in heart function. We need longer follow-up and more time before we can determine whether this is going to be clinically actionable. However, people in our survivorship community are very excited about this. They’re excited about the promise of a paradigm shift toward being more proactive rather than waiting for things to happen. Our patients don’t want us to be passive in their care and management, especially if we hold knowledge that certain late effects are a reality for survivors. As a pediatric oncologist who treats patients every day, I would say that it’s a moral obligation to make sure we’re continuing to keep the patient in mind well beyond their cancer diagnosis. I think this study goes a long way toward fulfilling that moral commitment to our patients, not just during their cancer treatment, but well into adulthood.

For more information:

Saro Armenian, DO, MPH, can be reached at City of Hope, 1500 E. Duarte Road Floor 3, Duarte, CA 91010; email: [email protected].