Cardioprotection in patients with anthracycline-treated breast cancer: final analysis from the 2 × 2 randomized, placebo-controlled, double-blind SAFE trial

Background: Anthracycline-based chemotherapy is a cornerstone in breast cancer treatment but is associated with cardiotoxicity, including subclinical cardiac damage. This study evaluates the efficacy of ramipril and bisoprolol in preventing subclinical cardiac impairment in patients with nonmetastatic breast cancer undergoing anthracycline-based chemotherapy. Patients and methods: The SAFE trial is a multicenter, 2 × 2 factorial, randomized, placebo-controlled, double-blind study involving 262 patients. Participants were allocated to one of four groups: placebo–placebo, ramipril–placebo, bisoprolol–placebo, or ramipril–bisoprolol, administered concurrently with chemotherapy. Subclinical cardiac damage was assessed at 24 months using echocardiographic measures, specifically a ≥10% reduction in three-dimensional left ventricular ejection fraction (3D-LVEF) or global longitudinal strain (GLS). Results: At 24 months, patients receiving ramipril, bisoprolol, or their combination experienced significantly smaller declines in 3D-LVEF compared with placebo (−2.1%, −2.2%, and −3.4%, respectively; all P < 0.001). GLS results were consistent with these findings (P < 0.001). Subclinical cardiac damage occurred in 11.4% of patients receiving ramipril versus 39.3% without ramipril (P < 0.001), and in 9.6% of patients receiving bisoprolol versus 43.5% without bisoprolol (P < 0.001). Conclusions: Ramipril and bisoprolol significantly reduce the incidence of subclinical cardiac damage in patients with breast cancer undergoing anthracycline-based chemotherapy, thus supporting their use as early prevention cardioprotective strategies.