Diastolic function is more sensitive than GLS in identifing cardiotoxicity. The SAFE trial results
Authors: Del Bene M R , Meattini I , Barletta G , Pilato G , Visani L , Parisi F , Martella F , Salvestrini V , Becherini C , Livi L 
Published: November 2023

Abstract

Echocardiographic measures of diastolic dysfunction are associated with an increased risk of incident heart failure. Previous studies have shown that changes in diastolic function occur with anthracycline cancer therapy. However, they did not incorporate the newest classification of diastolic function nor evaluated the association with subsequent declines in systolic function.

Design
The SAFE trial is a four-arm, randomized, phase 3, double-blind, placebo-controlled, national multicentric study. Recruitment was conducted between July 2015 and June 2020. Patients with breast cancer were eligible if they had indication to primary or postoperative systemic therapy using an anthracycline-based regimen. Known cardiovascular disease or high-risk features were exclusion criteria. Cardioprotective therapy (bisoprolol(B), ramipril(R), or both drugs, as compared to placebo(P)) was administered for 1 year since chemotherapy initiation or until the end of trastuzumab therapy in the case of HER2-positive patients. Each drug was systematically titrated, up to the target dose of B(5 mg OD), R(5 mg OD), if tolerated. The primary endpoint was defined as any subclinical impairment (worsening ≥10%) of 3D left ventricular ejection fraction and global longitudinal strain (GLS) at the end-of-therapy (EOT) and at 2-year follow-up (EOF).
Individual measures indicative of diastolic function (mitral E/A ratio, septal and lateral e’ velocities, indexed LA volume, TR velocity, and E/e’ ratio) were recorded and diastolic function was graded according to the 2016 ASE/EACVI guidelines.

Results
Out of 262 women (median age 48 years; range, 24-75 years) enrolled and treated, 222 patients completed the pre-planned cardiological assessment at 24 months. Baseline demographic, tumor, and cardiovascular profiles were similar between the study arms. All patients received anthracyclines, 217 also received taxane, and 77 adjuvant trastuzumab. Forty-nine patients were treated with neoadjuvant chemotherapy, 154 with adjuvant endocrine therapy, and 124 had postoperative radiation therapy.
At EOT GLS worsened by 10% or greater in 57% of patients in the P arm, 20%, 13%, and 18% in the R, B, and R+B arms, respectively (P&lt; 0.05). At EOF GLS worsened by 10% or greater in 65 % of patients in the P arm, 13%, 9%, and 10% in the R, B, and R+B arms, respectively (P&lt; 0.05).
In all patients, diastolic function was normal at baseline. Changes in any diastolic parameter were not significant (Table). AT EOT 9% of the patients with &lt;10% GLS decrease showed diastolic dysfunction (22% in P arm, 8%, 6%, and 4% in the R, B, and R+B arms, respectively, P&lt;0.05). At EOF 78% of patients with ≥10% GLS decrease showed diastolic dysfunction (Figure).
Our findings provide evidence that 1. abnormal diastolic function precedes systolic dysfunction, 2 there are significant changes in diastolic function grade over time, 3. cardioprotective therapy may be useful in low-risk breast cancer patients.TableFigure