Carvedilol for prevention of heart failure in anthracycline-exposed survivors of childhood cancer: Results from COG ALTE1621.

Abstract

10013 Background: Carvedilol improves cardiac function in patients with heart failure (HF), but remains untested as cardioprotective therapy in long-term childhood cancer survivors at risk for HF due to high-dose anthracycline exposure. We hypothesized that low-dose carvedilol would be safe and efficacious in reducing anthracycline-related heart failure risk in long-term survivors without evidence of HF. Methods: This was a randomized, double-blind, placebo-controlled phase 2B trial (NCT02717507) conducted at 28 sites. Eligibility included ≥250 mg/m2 cumulative anthracycline exposure by age 21 years (y), ≥2y from completion of cancer treatment, and preserved systolic function (ejection fraction [EF] ≥55% and/or fractional shortening [FS] ≥28%) at enrollment. Patients were randomized 1:1 to take low-dose carvedilol (12.5 mg/day) or placebo for 2y; dose up-titration started at 3.125 mg/day. The primary objective was to determine the impact of carvedilol on echocardiographic indices of HF risk: standardized left ventricular (LV) wall thickness/dimension ratio (LVWT/Dz; primary endpoint), LV end-systolic wall stress (ESWS), LV chamber diameters, systolic and diastolic function. These indices were obtained every 6 months and measured centrally in a blinded fashion. Common Terminology Criteria for Adverse Events (CTCAE v4.0) was used to assess toxicity. Cardiac event was defined as relative EF/FS decline < 20% from baseline or both < 55% [EF] and < 28% [FS]. Treatment effects were analyzed using the Generalized Estimating Equation for normally distributed data, assuming linear time-trend. Group differences were evaluated by treatment*time interaction. Results: Of 196 participants enrolled, 182 were eligible and randomized. Characteristics (median, range): age at enrollment, 24.7y (10.4-53.9); time from cancer diagnosis, 13.4y (2.9-43.6); anthracycline dose, 374 mg/m2 (250-1760); 19% had received chest-directed radiotherapy. There were no group differences in baseline participant demographics, cardiotoxic treatment exposure, or cardiac endpoints. LVWT/Dz was similar (+0.053, p = 0.15) between arms at 2y. However, treatment effects varied by time since diagnosis (p = 0.008) suggesting greater efficacy among longer-term survivors. Compared to placebo, carvedilol arm participants had significantly better LV end-diastolic diameter (-0.16 cm, p = 0.005) and LVESWS (-7.53, p = 0.027) at 2y. There were no CTCAE grade ≥3 events; all except 2 participants tolerated full dose escalation. Six out of eight cardiac events occurred on the placebo arm; longer-term follow-up of study participants is ongoing. Conclusions: In this randomized trial of long-term survivors of childhood cancer treated with high-dose anthracyclines, low-dose carvedilol was safe and effective in reducing established biomarkers of HF risk and could serve as a risk reduction strategy. Clinical trial information: NCT02717507 .

Improved Cardiomyopathy Risk Prediction Using Global Longitudinal Strain and N-Terminal-Pro-B-Type Natriuretic Peptide in Survivors of Childhood Cancer Exposed to Cardiotoxic Therapy

“…Our results are timely, given the recently reported findings from the randomized, double-blind, placebo-controlled phase IIB trial (ClinicalTrials.gov identifier: NCT02717507), which suggested that among survivors exposed to doxorubicin-equivalent anthracycline doses ≥250 mg/m 2 with a baseline LVEF ≥55% and/or shortening fraction ≥28%, 2-year administration of low-dose carvedilol was significantly associated with better left ventricular end-diastolic diameter and end-systolic wall stress compared with placebo. 68 Notably, treatment effects varied by time since cancer diagnosis ( P = .008), suggesting a greater benefit to cardioprotective therapy with carvedilol in longer-term survivors. In a second trial, randomized atorvastatin administration in adults with lymphoma receiving anthracyclines was shown to be associated with a reduction in the incidence of an absolute decline in LVEF ≥10% from baseline to an LVEF <55% at 1 year (9% atorvastatin v 22% placebo; P = .002).…”

Primary Care Utilization and Cardiovascular Screening in Adult Survivors of Childhood Cancer

“…Although the overall adherence to cardiovascular screening recommendations among this selected population is disconcerting, our findings provide hope that streamlined communication between oncologists, patients, and primary care could improve awareness, adherence, and overall cardiovascular outcomes. As strategies emerge to prevent or treat anthracycline-associated cardiomyopathy, either through the reduction of modifiable disease risk factors or cardiac remodeling as heart function begins to worsen, 6 , 32 , 33 multimodal strategies to address guideline-concordant survivorship care are needed. The CHIIP intervention trial in progress focuses on providing personalized SCPs to patients and PCPs.…”

Artificial intelligence-enhanced risk stratification of cancer therapeutics-related cardiac dysfunction using electrocardiographic images

“…16 However, trials of screening strategies using advanced echocardiographic indices, such as global longitudinal strain (GLS) 17 have suggested possible benefit from flagging subclinical left ventricular systolic dysfunction and guiding the deployment of potentially disease-modifying therapies. [18][19][20][21][22][23][24][25] Therefore, there is an unmet need to design scalable yet personalized tools to enable the timely identification of patients who might benefit from more intensive follow-up. Furthermore, it is critical that these tools are accessible and affordable, ensuring equitable and broad access across high and low-resource settings.…”