Abstract PD8-03: Beta blockers and/or ACE inhibitors as cardioprotective strategy for patients affected by nonmetastatic breast cancer who are receiving an anthracycline-based chemotherapy (SAFE - NCT02236806): final results of a randomized trial
Authors: Meattini Icro , Becherini Carlotta , Visani Luca , Saieva Calogero , Salvestrini Viola , Martella Francesca , Bacci Carlotta , Molinara Elena , Airoldi Mario , Del Bene Maria Riccarda , Amoroso Domenico , Coltelli Luigi , Desideri Isacco , Scotti Vieri , Bernini Marco , Orzalesi Lorenzo , Nori Jacopo , Bianchi Simonetta , Barletta Giuseppe , Livi Lorenzo 
Published: March 2023

Abstract
Introduction. Several studies have evaluated cardioprotective strategies to prevent myocardial dysfunction in patients who are receiving cardiotoxic therapies. Angiotensin-converting enzyme inhibitors and β-blockers are recommended first-line agents for heart failure. However, the optimal approach still represents a controversial issue. We hypothesized whether pharmacological cardioprevention could reduce subclinical heart damage in patients with breast cancer who are being treated with an anthracycline-based chemotherapy. Patients and methods. The SAFE trial was a 4-arm, randomized, phase 3, double-blind, placebo-controlled, national multicentric study conducted at eight oncology departments in Italy. The study recruitment was conducted between July 2015 and June 2020. A prespecified interim analysis on 174 women at 12 months was reported in 2020. Patients were eligible for trial inclusion if they had indication to receive primary or postoperative systemic therapy using an anthracycline-based regimen. Patients with a prior diagnosis of cardiovascular disease were excluded. Cardioprotective therapy (bisoprolol, ramipril, or both drugs compared with placebo) was administered for one year from the initiation of chemotherapy or until the end of trastuzumab therapy in case of ERBB2-positive patients. Doses for all groups were systematically up-titrated up to the daily target dose of bisoprolol (5mg, once daily), ramipril (5mg, once daily), and placebo, if tolerated. The primary end point was defined as detection of any subclinical impairment (worsening 10%) in myocardial function and deformation measured at 24 months using 3-dimensional (3D) echocardiography, left ventricular ejection fraction (LVEF), and global longitudinal strain (GLS). ClinicalTrials.gov identifier: NCT2236806. Results. 262 women (median age, 48 years; range, 24-75 years) were enrolled and treated in the study. We analyzed patients who had completed the pre-planned cardiological assessment at 24 months. Baseline demographic, tumor, and cardiovascular profiles were similar between groups. All patients received an anthracycline-based chemotherapy, 215 patients received at least three cycles of anthracyclines (range 1-6), 223 patients received also a taxanes-based chemotherapy, and 84 cases were treated with adjuvant trastuzumab. Sixty patients were treated with neoadjuvant chemotherapy, 157 cases received adjuvant endocrine therapy, and 128 patients had postoperative radiation therapy. GLS worsened 10% or greater in 68% of patients enrolled in the placebo arm, 15%, 13%, and 13% in the ramipril, bisoprolol, and ramipril plus bisoprolol arms, respectively (P &lt; 0.05). A reduction of 10% or greater in 3D-LVEF was observed in 19% in the placebo arm, 11% in the ramipril arm, 11% in the bisoprolol arm, and 7% in the ramipril plus bisoprolol arm (P &lt; 0.05). Study drugs were well tolerated with no serious adverse events, the ramipril plus bisoprolol arm showed significantly more toxic effects and had a significantly higher rate of allocated treatment discontinuation as compared to the other arms. Conclusions. Cardioprotective pharmacological strategies in patients who were affected by breast cancer and were receiving an anthracycline-based chemotherapy are well tolerated and protect against cancer therapy–related LVEF decline and heart remodeling.
Citation Format: Icro Meattini, Carlotta Becherini, Luca Visani, Calogero Saieva, Viola Salvestrini, Francesca Martella, Carlotta Bacci, Elena Molinara, Mario Airoldi, Maria Riccarda Del Bene, Domenico Amoroso, Luigi Coltelli, Isacco Desideri, Vieri Scotti, Marco Bernini, Lorenzo Orzalesi, Jacopo Nori, Simonetta Bianchi, Giuseppe Barletta, Lorenzo Livi. Beta blockers and/or ACE inhibitors as cardioprotective strategy for patients affected by nonmetastatic breast cancer who are receiving an anthracycline-based chemotherapy (SAFE - NCT02236806): final results of a randomized trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD8-03.