New results were presented from the Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA) trial at ACC 2021 on May 16 and published concurrently in Circulation . The authors found that medications administered in addition to surgery, adjuvant breast cancer (BC) therapy with anthracylines with or without anti-human epidermal growth factor receptor 2 (HER2) therapy, and radiotherapy may not significantly attenuate the reduction in left ventricular ejection fraction (LVEF), nor improve cardiac troponins in early-stage BC patients.
Anti-HER2 targeted therapies are usually well tolerated, but cardiotoxicity, including reduced LVEF and heart failure, are known adverse events, particularly for patients who are or who have received anthracycline-based chemotherapy regimens. In an effort to prevent and treat such cardiotoxicities, beta-blockers (BBs) or angiotensin-converting enzyme (ACE) receptor inhibitors are often prescribed to help reduce or attenuate left ventricular remodeling.
During the PRADA trial, the authors evaluated the long-term effects of the ACE inhibitor candesartan, the BB metropolol, or their combination in 120 early-stage patients with breast cancer. The patients ranged in age from 18-70 years, with a median age of 51 years. In this 2 x 2 randomized, placebo-controlled, double-blind trial, participants were randomly assigned to take candesartan, metropolol, combined therapy, or placebo in additional to standard BC treatment. Participants received a cardiac MRI both at baseline as well as at 23 months. The study’s primary outcome measure was change in LVEF as seen on cardiac MRI from initial baseline to the follow-up MRI.
The investigators found that there was a small decline in LVEF in the group who received concomitant treatment with the ACE inhibitor, candesartan. Yet for those who received metoprolol, the BB attenuated an increase in cardiac troponins, specific and sensitive markers for detecting myocardial injury and predicting treatment-related reductions in LVEF, cardiac dysfunction, and heart failure. Further, there were insignificant differences between treatment groups, leading the investigators to conclude that candesartan and metoprolol during adjuvant therapy for early BC were not effective prophylaxis for long-term decline in LVEF.
Those treated with candesartan were found to have significant reductions in LV end-diastolic volume. They were also found to have an attenuated decline in global longitudinal strain, a significant predictor of heart failure and abnormal systolic function before loss of ejection fraction is apparent.
Strengths of the study included its use of serial cardiac magnetic resonance imaging to assess LVEF, its 2 x 2 randomized trial design, and the long-term two-year follow-up. However, the study had limitations, including that the trial was conducted at a single center; 18% of trial participants did not undergo their follow-up MRI, and the results that showed less reduction in LVEF than anticipated at the trial’s onset.
Though the trial results were negative, indicating that these cardioprotective medications may not be needed as part of adjuvant therapy for early-stage BC patients, the results of the PRADA trial do have important implications. Lead author of the publication and the presenter of the data at ACC, Siri Lagethon Heck, MD, PhD, a cardiovascular radiologist at Akershus University Hospital, in Lørenskog, Norway, noted that overtreatment is always a concern for cancer patients, and described the takeaway point from the study as the need to identify those patients who are at higher risk for cardiotoxicities and those who are more likely to benefit from such cardioprotective therapies.
Heck S, Mecinaj A, Hansen Ree A, Hoffmann P, Schulz-Menger J, Fargerland M, et al. Prevention of Cardiac Dysfunction During Adjuvant Breast Cancer Therapy (PRADA): Long-term Follow-up of a 2 x 2 Factorial, Randomized, Placebo-Controlled, Double-Blind Clinical Trial of Candesartan and Metoprolol. Presented at: American College of Cardiology Scientific Sessions; May 15-17, 2021.