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Randomized Controlled Trial
. 2025 Jun;10(6):105116.
doi: 10.1016/j.esmoop.2025.105116. Epub 2025 May 21.

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

I Meattini  1 , C Becherini  2 , F Martella  3 , M R Del Bene  4 , C Saieva  5 , C Bacci  3 , L Coltelli  6 , G Pilato  4 , L Visani  2 , V Salvestrini  2 , G Francolini  2 , L Marrazzo  7 , M Bernini  8 , L Orzalesi  8 , J Nori  9 , S Bianchi  10 , I Olivotto  11 , A Morandi  12 , G Curigliano  13 , G Barletta  4 , L Livi  14
Affiliations
Randomized Controlled Trial

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

I Meattini et al. ESMO Open. 2025 Jun.

Abstract

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.

Keywords: anthracycline-induced cardiotoxicity; breast cancer; cardio-oncology; cardioprotection; randomized controlled trial.

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Figures

Figure 1
Figure 1
The Consolidated Standards of Reporting Trials (CONSORT) flowchart for the study. The primary endpoint analysis was conducted on the intention-to-treat sample consisting of all validly randomized patients with, at a minimum, baseline cardiovascular imaging. EOS, end of study.
Figure 2
Figure 2
Mean (95% CI) (A) 3D LVEF and (B) GLS values at baseline, 12 months, and 24 months, analyzed per intention-to-treat for each arm (placebo, ramipril, bisoprolol, and ramipril plus bisoprolol). All patients receiving cardioprotective treatment were grouped together (all drugs: continuous line). The P values from ANOVA and the Bonferroni t-test shown in the graph are consistent across all drug arms when compared with placebo. 3D-LVEF, three-dimensional left ventricular ejection fraction; ANOVA, analysis of variance; CI, confidence interval; GLS, global longitudinal strain; LV, left ventricle.
Figure 3
Figure 3
Mean (95% CI) (A and B) 3D LVEF and (C and D) GLS values at baseline, 12 months, and 24 months, analyzed per intention to treat using a 2 × 2 factorial design. Comparisons are shown for (A and C) the no ramipril versus ramipril arms and (B and D) the no bisoprolol versus bisoprolol arms. P values are derived from ANOVA and the Bonferroni t-test. 3D-LVEF, three-dimensional left ventricular ejection fraction; ANOVA, analysis of variance; CI, confidence interval; GLS, global longitudinal strain; LV, left ventricle.
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