Abstract Background. Several studies demonstrated the prophylactic benefit of beta-blockers and angiotensin-converting enzyme (ACE) inhibitors for anthracyclines-based chemotherapy-induced cardiotoxicity. However, there is no consensus on management strategies at the time being. We present the interim analysis of the SAFE trial. Methods. The SAFE trial is a 2 × 2 factorial design randomized phase 3 study evaluating the impact of bisoprolol (B) (5 mg), ramipril (R) (5 mg), or both drugs as compared to placebo (P) on subclinical heart damage evaluated by speckle-tracking cardiac ultrasound. Enrolled patients included non-metastatic histology-proven breast cancer, treated with primary systemic therapy or adjuvant regimens based on anthracyclines with or without trastuzumab. Primary endpoint is evaluation of reduction in both systolic and diastolic, early and late subclinical cardiotoxicity measured with traditional echocardiography, pulsed tissue doppler, global linear strain (GLS), and 3-dimesional left ventricular ejection fraction (3D-LVEF). CT registry ID: NCT2236806; EudraCT number: 2015-000914-23. Results. A total of 191 out of 480 patients have been enrolled; overall 123 patients were available for the analysis (P=34; R=28; B=31; R+B=30). 3D-LVEF decreased at 3-month (-3.3%; p<0.001), at 6-month (-5.2%; p<0.001) and at 12-month (-3.7%; p=0.004) respect to T0 in P; at 3-month (-2.4%; p=0.001), at 6-month (-1.9%; p=0.010), at 12-month (-2.2%; p=0.045) in R. In B and R+B patients no significant changes were observed at 3- and 12-month, with a decrease at 6-month (-2.5% and 3.0%, respectively; p=0.002). Arm differences were significant (p=0.038). GLS increased at 3-mos (5.7%; p<0.001), at 6-mos (7.8%; p<0.001) and at 12-mos (7.1%; p<0.001) respect to T0 in P; at 3-month (2.7%; p=0.002), at 6-month (3.2%; p=0.014), but not at 12-month in R; no significant changes at 3-month, a significant increase at 6-month (2.7%; p=0.035), at 12-month (3.2%; p=0.008) in B; no significant changes at 3-, 6-, and 12-month in R+B. Arm differences were significant (p=0.002). Both R+B and the R arms showed a withdraw rate of 7%, with a dose reduction rates of 21% and 17%, respectively. Conclusion. At the interim analysis, a cardiovascular disease prevention strategy using beta-blockers and/or ACE inhibitors significantly impacted on subclinical heart damage. Citation Format: Lorenzo Livi, Icro Meattini, Francesca Martella, Calogero Saieva, Carlotta Becherini, Francesca Terziani, Isacco Desideri, Vieri Scotti, Carlotta Bacci, Mario Airoldi, Giacomo Allegrini, Domenico Amoroso, Luisa Fioretto, Giuseppe Barletta. Interim analysis of the SAFE trial (NCT2236806): A randomized phase 3 study evaluating a cardiovascular disease prevention strategy using beta-blockers and/or ACE inhibitors in non-metastatic breast cancer patients treated with anthracyclines [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-24.