Cardioprotection beyond the guidelines: the SAFE trial results
Authors: Barletta G , Meattini I , Del Bene M R , Martella F , Becherini C , Pilato G , Visani L , Salvestrini V , Airoldi M , Amoroso D , Coltelli L , Parisi F , Saieva C , Livi L 
Published: November 2023

Abstract

ESC 2022 Guidelines suggest that low-risk patients receiving anthracyclines and/or anti-HER2 therapies can be followed within the oncology program with appropriate referral to cardio-oncology if cancer therapy-related cardiovascular toxicity or new or uncontrolled cardiovascular risks emerges. ACE-I or ARB and beta-blockers should not be considered for primary prevention.

Design
The SAFE trial is a four-arm, randomized, phase 3, double-blind, placebo-controlled, national multicentric study conducted at eight oncology departments in Italy. Between July 2015 and June 2020 patients with breast cancer were recruited and considered eligible for trial inclusion if they had indicated primary or postoperative systemic therapy using an anthracycline-based regimen. Patients with a prior diagnosis of cardiovascular disease or high-risk features were excluded. Cardioprotective therapy (bisoprolol (B), ramipril (R), or both drugs, as compared to placebo (P)) was administered for 1 year since the initiation of chemotherapy or until the end of trastuzumab therapy in the case of HER2 positive patients. All drugs were systematically titrated, up to the target daily dose of B (5 mg, OD), R (5 mg, OD), and P, if tolerated. The primary endpoint was defined as the detection of any subclinical impairment (worsening ≥10%) in left ventricular ejection fraction measured with 3-dimensional echocardiography (3DLVEF), and in global longitudinal strain (GLS) at the end-of-therapy (EOT) and at 2-year follow-up (EOF).

Results
262 women (median age, 48 years; range, 24-75 years) were enrolled and treated. We analyzed 222 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 anthracyclines, 215 at least three cycles (range 1-6), 217 patients also received taxane, and 77 adjuvant trastuzumab. Forty-nine patients were treated with neoadjuvant chemotherapy, 154 had adjuvant endocrine therapy, and 124 had postoperative radiation therapy. 3DLVEF and GLS data are reported in the Table as means±SE (95% CI). Statistical analysis was performed by ANCOVA. The percent changes from the baseline are reported in the Figure. At EOF GLS worsened by 10% or greater in 65 % of patients enrolled in the P arm, in 13%, 9%, and 10% of patients enrolled in the R, B, and R+B arms, respectively (P &lt; 0.05). A reduction of 10% or greater in 3DLVEF was observed in 49% in the P arm, 4% in the R arm, 2% in the B arm, and 5% in the R+B arm (P &lt; 0.05). Study drugs were well tolerated with no serious adverse events, the R+B arm showed significantly more side effects and had a significantly higher rate of allocated treatment discontinuation/reduction as compared to the other arms.

Conclusion
The results of the SAFE trial suggest that primary prevention should be considered also in low-risk breast cancer receiving anthracyclines and/or anti-HER2 therapies.TableFigure