Enalapril does not prevent chemotherapy-related heart damage in breast cancer, lymphoma
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Key takeaways:
- Enalapril was not superior to standard care for preventing chemotherapy-related cardiotoxicity for breast cancer and lymphoma.
- The ACE inhibitor also did not appear to affect cardiac function outcomes.
ATLANTA — Enalapril plus standard care was not superior to standard care alone for preventing cardiotoxicity in patients receiving treatment for breast cancer or lymphoma, according to new data from the PROACT trial.
Results of the phase 3, randomized, open-label superiority PROACT trial of the ACE inhibitor enalapril for the prevention of anthracycline-induced cardiotoxicity were presented at the American College of Cardiology Scientific Session.
“Anthracyclines include drugs such as doxorubicin and epirubicin, which are commonly used in the management of breast cancer, hematological malignancies and other common cancers,” David Austin, MD, consultant cardiologist in the academic cardiovascular unit at The James Cook University Hospital, South Tees, in Middlesbrough, U.K., said during a press conference. “We enrolled an enriched population of patients receiving the highest contemporary doses of anthracyclines, and this is because dose is the one of the most important factors in increasing the risk of subsequent heart failure.”
Austin and colleagues enrolled 111 patients receiving six cycles of high-dose anthracyclines — 300 mg/m2 doxorubicin-equivalent or more — for the treatment of breast cancer and non-Hodgkin lymphoma (mean age, 58 years; > 75% women; > 52% white).
Participants were randomly assigned to enalapril on top of usual care or usual care alone. Sixty-two percent had breast cancer while 38% had non-Hodgkin lymphoma.
The primary endpoint was myocardial injury, which was defined as a cardiac troponin T level of 14 ng/L or more. Secondary endpoints included myocardial injury, defined as a cardiac troponin I level more than 26.2 ng/L; absolute left ventricular global longitudinal strain decline of more than 15% from baseline; and absolute LV ejection fraction decline of 10% from baseline.
The target dose of enalapril 10 mg twice daily was achieved in more than 75% of patients, with an average daily dose of 17.7 mg per day.
Austin and colleagues reported that, by the sixth cycle of chemotherapy, myocardial injury as indicated by cardiac troponin T level was similarly prevalent in both groups (78% enalapril vs. 83% usual care; P = .405).
While less prevalent overall, myocardial injury as indicated by cardiac troponin I was also similar between groups (47% enalapril vs. 45% usual care; P = .819), according to the results.
Additionally, decline in absolute LV global longitudinal strain and LVEF from baseline were also similar between the enalapril and usual care groups (P for LV global longitudinal strain = .921; P for LVEF = .236).
“Just over 80% of patients had myocardial injury by cardiac troponin T. We saw a discrepancy in the other endpoint of cardiac troponin I that only 46% of patients measured at the same time points, the same patients had an injury by cardiac troponin I criteria,” Austin said during a press conference. “This has implications for some of the definitions of cancer therapy-related cardiac dysfunction. One in five had a relative decrease in global longitudinal strain, and 4% had a greater than 10% reduction in LVEF. But we did not see effect on either myocardial injury or cardiac function outcomes with treatment with enalapril.”
Discussing the results, Bonnie Ky, MD, MSCE, director of the Penn Cardio-Oncology Translational Center of Excellence at Penn Medicine, highlighted the difficulty of enrolling patients undergoing active cancer treatment into a cardiology trial and the important need for pragmatic trial in the cardio-oncology space.
“In terms of the field of cardio-oncology, it is still a clinically relevant question: ‘What is the role of cardioprotection prophylaxis?’ There have been some positive studies but many negative and neutral as well,” Ky said. “There are a number of key strengths to the PROACT study, including enrichment of a high-risk population based on dose, multicenter-randomized design and enalapril to reasonable dosages. There is enhanced generalizability by the inclusion of both breast and lymphoma cancer, blinded endpoints and detailed imaging measures.
“We need to better define the role of biomarkers in terms of diagnosis in risk prediction and in clinical management. ... As a field, we need to come to a consensus definition of what is cardiotoxicity and move to hard clinical outcomes and endpoint. And then also we need to bring pragmatic, adaptive trials to cardio-oncology,” she said.
Reference:
- ACE inhibitor not protective against heart damage from chemotherapy. https://www.acc.org/About-ACC/Press-Releases/2024/04/08/13/17/ace-inhibitor-not-protective-against-heart-damage-from-chemotherapy. Published April 8, 2024. Accessed April 8, 2024.
Perspective
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[Patients receiving 300 mg/m2 doxorubicin-equivalent or more are] an important patient population, the right patient population to look for, because of the dose.
Biomarkers and troponin in previous studies suggested that [cardiac troponin I is] a good biomarker to predict whether patients will get cardiotoxicity or not, like LVEF going down. But those data were with regular troponin. These are with high-sensitivity troponin and I think we’re picking up noise. Not really the high-risk population. Troponin has been shown to be a good negative predictor in the sense that if it didn’t go up, those patients are unlikely to develop cardiotoxicity. As a positive predictor, it’s not as good yet.
The second point is what are they going to do further and what will we see? Usually, the cardiotoxicity of the EF going down occurs either during therapy or in that first year after they complete therapy. Here, however, the troponin goes up during therapy, and the endpoint was 2 months after they finished therapy, which is the right time. Troponin that remains elevated is probably a risk marker. But if they were to look at this [cohort in] 2 years, the troponin would probably be down. So they can’t look at troponin too far out. The LVEF fall can occur anytime during that 1 year after they complete therapy. That’s why following that EF, and maybe other echo markers to at least 1 year out from therapy, is important. Whether we see any difference in that endpoint, it’s too early to comment on the EF part at 2 months after therapy.
This was a modest-sized trial. It was not powered to look at EF changes. To look at EF changes by echo, you would need a larger population.
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Austin D, et al. Joint American College of Cardiology/Journal of the American Medical Association Late-breaking clinical trials IV. Presented at: American College of Cardiology Scientific Session; April 6-8, 2024; Atlanta.
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