After a modest early signal of benefit, candesartan cilexetil (Atacand, Cheplapharm) showed no effect on key markers of heart health 2 years after treatment in patients with early-stage breast cancer in the randomized PRADA trial.
The 2015 study was hailed at the time as the largest randomized trial in breast cancer to look at the effects of angiotensin-receptor blockade with candesartan and the β-blocker metoprolol, both against placebo, on cardiac dysfunction. The 120 patients received adjuvant cancer therapy with anthracyclines with or without trastuzumab and radiotherapy — all well-known to have cardiotoxic adverse effects.
As previously reported, the primary outcome of change in left ventricular ejection fraction (LVEF) from baseline was attenuated by about 3% after cancer treatment in women who took a daily 32-mg dose of candesartan compared with those receiving placebo (P = .026).
At 2 years, however, follow-up with serial MRI showed the benefit on LVEF over placebo had vanished (mean Δ, –1.7% vs –1.8%; P = .91). Candesartan also had no significant effect on troponin I levels (P = .56).
Left ventricular end-diastolic volume was significantly reduced with candesartan compared with placebo (mean Δ, –5 mL vs 2 mL; P = .021), and the decline in global longitudinal strain was less (mean Δ, –0.2% vs 1.0%; P = .046).
“This suggests candesartan has favorable remodeling effects, but the effect sizes were quite small and the clinical relevance of these changes more than a year after endotherapy is unclear,” study author Siri Lagethon Heck, MD, PhD, Akershus University Hospital, Lørenskog, Norway, said.
Metoprolol could not reverse its early lackluster performance, exerting no effect at 2 years on LVEF (P = .73), LV end-diastolic volume (P = .78), or global longitudinal strain (P =.34) vs placebo.
The β-blocker had tamped down the increase in troponin I levels from baseline, but the difference was no longer significant after 2 years (P = .76), according to results published in Circulation and simultaneously presented at the American College of Cardiology (ACC) 2021 Scientific Session.
During a discussion of the late-breaking trial, Heck observed that the decline in LVEF was less than anticipated and that the patients were low-risk, with few comorbidities, a baseline LVEF of at least 50%, and receipt of relatively low doses of anthracyclines.
“Broadly administered cardioprotective therapy may not be required during adjuvant breast cancer therapy, as decline in systolic function was minor and not prevented by neurohormonal blockade,” she said.
Panelist Bonnie Ky, MD, MSCE, director of the Cardio-Oncology Translational Center of Excellence, University of Pennsylvania, Philadelphia, said the study has many important strengths, including careful phenotyping and serial follow-up with cardiac MRI.
“What I think is a critical take-home message for our field is that we need to target cardioprotection therapy according to risk and personalize therapy according to who is at increased risk, either by treatment factors or host factors,” she said.
In a press conference highlighting the study, Ana Barac, MD, PhD, director of the cardio-oncology program at the MedStar Heart and Vascular Institute, Washington, DC, said the results were reassuring in that no one developed heart failure but also point to the need to design cardiovascular prevention trials in oncology patients based on their cardiovascular risk.
“The elephant in the room here is that oncology practice sometimes mandates what the inclusion criteria are for anthracyclines and trastuzumab, which were given in some of your patients, but they are approved only for normal function, and we all know that in clinical practice we see patients who do not have normal function and those are the patients at the highest risk,” she said. “I believe that the next studies, that I hope your group will also take on, will include this high-risk group of patients and show how we can improve their outcomes.”
Heck reported no relevant financial relationships. Ky reported consultant fees/honoraria from Cytokinetics; other relationships with Corvia, Impulse Dynamics, Mardil Medical, and UpToDate; and serving as a speaker for Roche. Barac reported serving on a data safety monitoring board for ACI Clinical.
Circulation. Published online May 16, 2021. Abstract
American College of Cardiology (ACC) 2021 Scientific Session. Abstract 406-17. Presented May 16, 2021.