The right ventricle is not spared by the cardiotoxic effects of chemotherapy for breast cancer. Results of SAFE trial
Authors: Del Bene M R , Meattini I , Barletta G , Martella F , Pilato G , Becherini C , Visani L , Parisi F , Salvestrini V , Livi L 
Published: November 2023

Abstract

Functional abnormalities of the right ventricle(RV) have been demonstrated in cancer patients receiving anthracyclines and trastuzumab. AHA/ACC 2022 guidelines for heart failure recommend angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and beta-blockers for asymptomatic LV dysfunction. It would be important to determine whether these neurohormonal modulators are beneficial for the RV as well.

Design
The SAFE trial (NCT: 2236806) is a four-arm, randomized, phase 3, double-blind, placebo-controlled, national multicentric study. Patients with breast cancer were recruited between July 2015 and June 2020, and considered eligible if they had indicated primary or postoperative systemic chemotherapy with an anthracycline-based egimen. Patients with known cardiovascular disease or with high-risk features were excluded. Cardioprotective therapy [bisoprolol(B), Ramipril(R), or B+R], or placebo(P) were administered for 1 year since the initiation of chemotherapy or until the end of trastuzumab therapy in the case of HER2-positive patients. The drugs were systematically titrated up to the target daily dose of B (5 mg OD) and R (5 mg, OD) if tolerated. The primary endpoint was defined as the detection of any subclinical impairment (worsening ≥10%) in echocardiographic 3-dimensional left ventricular ejection fraction(3DLVEF) and global longitudinal strain(GLS) at the end-of-therapy (EOT) and at a 2-year follow-up (EOF).
Echocardiographic measures of RV function (diastolic basal diameter, fractional area change(FAC), tricuspid annular plane systolic excursion(TAPSE), tissue Doppler-derived tricuspid lateral annular systolic wave velocity(S’RV) were analyzed.

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 arms. All patients received at least 1 cycle of anthracyclines (range 1-6) and 97% at least three cycles; 217 patients 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 EOF 3DLVEF decreased by -10.5% in the P arm, by -3.0%, -2.4%, and -3.6% in the R, B, and R+B arms, respectively (P&lt;0.001). At EOF GLS decreased by -13.1% in the P arm, by -3.6%, -3.0%, and -4.2% in the R, B, and R+B arms, respectively (P&lt;0.001).
At EOF the RV diameter increased by 6.7%, and FAC, TAPSE, and S’RV reduced by 10.5%, 9.6%, and 12.2%, respectively, in the P arm. In the drug arms, the changes in RV diameter, FAC, TAPSE, and S’RV were significantly less (Table and Figure).

Conclusion
Chemotherapy causes similar damage to the left and right ventricular function in breast cancer patients. Cardioprotective therapy significantly reduced both LV and RV damage in the low-risk patients of the SAFE study.TableFigure