Background: Several studies have evaluated cardioprotective strategies to prevent myocardial dysfunction in patients receiving cardiotoxic therapies. However, the optimal approach still represents a controversial issue. We aim to determine whether pharmacological cardiac prevention could reduce subclinical heart damage in breast cancer (BC) patients treated with anthracycline-based chemotherapy. Methods: The SAFE trial is a four-arm, randomised, phase 3, double-blind, placebo-controlled study. Patients were eligible for trial inclusion if they had indication to primary or postoperative systemic therapy using an anthracycline-based regimen. Patients with prior diagnosis of cardiovascular disease were excluded. Cardioprotective therapy (bisoprolol (B), ramipril (R), or both drugs (B+R), as compared to placebo) was administered for 1 year from the initiation of chemotherapy or until the end of trastuzumab therapy in case of HER2 positive patients. Doses for all groups were systematically up-titrated, up to the daily target dose of B (5 mg, once daily), R (5 mg, once daily), and placebo, if tolerated. The primary endpoint was defined as detection of any subclinical impairment (worsening ≥10%) in myocardial function and deformation measured with standard and 3-dimensional (3D) echocardiography, left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS). Results: 262 women (median 48 years; range24-75 years) were enrolled and treated in the study. We analysed patients who had completed the pre-planned cardiological assessment at 24 months. All patients received an anthracycline-based chemotherapy, 215 patients received at least 3 cycles of anthracyclines (range 1-6) and 128 patients had postoperative radiation therapy. At Univariate logistic analysis to evaluate the risk of GLS worsening > 10% at 24 months, Odds ratios (OR) for improvement were 0.055, 0.083 and 0.060 for B, R and B+R, respectively (P < 0.0001), if compared to placebo arm. At Univariate logistic analysis to evaluate the risk of 3DLVEF worsening > 10% at 24 months, OR for improvement were 0.019, 0.048 and 0.054 for B, R and B+R, respectively (P < 0.0001), if compared to placebo arm. 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 affected by BC receiving an anthracycline-based chemotherapy are well tolerated and seem to protect against cancer therapy-related LVEF decline and heart remodelling. Clinical trial information: NCT2236806.