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Brief Report
August 26, 2021

Cardioprotective Strategy for Patients With Nonmetastatic Breast Cancer Who Are Receiving an Anthracycline-Based Chemotherapy: A Randomized Clinical Trial

Author Affiliations
  • 1Department of Experimental and Clinical Biomedical Sciences, University of Florence, Florence, Italy
  • 2Oncology Department, Careggi University Hospital, Florence, Italy
  • 3Diagnostic Cardiology, Cardiothoracic, and Vascular Department, Careggi University Hospital, Florence, Italy
  • 4Breast and Medical Oncology Units, Oncology Department, Azienda USL Toscana Centro, Florence, Italy
  • 5Cancer Risk Factors and Lifestyle Epidemiology Unit, Institute for Cancer Research Prevention and Clinical Network, Florence, Italy
  • 6Medical Oncology Unit 2, Città della Salute e della Scienza University Hospital, Turin, Italy
  • 7Medical Oncology Unit, Ospedale Versilia, Lido di Camaiore, Lucca, Italy
  • 8Medical Oncology Unit, Livorno Hospital, Azienda USL Toscana Nord Ovest, Livorno, Italy
  • 9Breast Surgery Unit, Careggi University Hospital, Florence, Italy
  • 10Diagnostic Senology Unit, Careggi University Hospital, Florence, Italy
  • 11Division of Pathological Anatomy, Department of Health Sciences, University of Florence, Florence, Italy
  • 12Cardiomyopathy Unit, Careggi University Hospital, Florence, Italy
JAMA Oncol. 2021;7(10):1544-1549. doi:10.1001/jamaoncol.2021.3395
Key Points

Question  Can pharmacological cardioprevention avoid subclinical damage in patients with breast cancer who are undergoing cardiotoxic therapy?

Findings  In this randomized clinical trial of 262 patients with breast cancer, 174 of whom were analyzed, at 12 months, left ventricular ejection fraction as evaluated by 3-dimensional echocardiography worsened by 4.4% in the placebo arm and 3%, 1.9%, 1.3% in the ramipril, bisoprolol, and ramipril plus bisoprolol arms, respectively. Global longitudinal strain worsened by 6.0% in the placebo arm and 1.5% and 0.6% in the ramipril and bisoprolol arms, respectively, whereas it was unchanged (0.1% improvement) in the ramipril plus bisoprolol arm.

Meaning  The results of this trial suggest that during cardiotoxic therapy for breast cancer, the use of pharmacological cardioprevention may be warranted.

Abstract

Importance  Several studies have evaluated cardioprotective strategies to prevent myocardial dysfunction in patients who are receiving cardiotoxic therapies. However, the optimal approach still represents a controversial issue.

Objective  To determine whether pharmacological cardioprevention could reduce subclinical heart damage in patients with breast cancer who are being treated with anthracycline-based chemotherapy.

Design, Setting, and Participants  The SAFE trial was a 4-arm, randomized, phase 3, double-blind, placebo-controlled, national multicentric study conducted at 8 oncology departments in Italy. It was a prespecified interim analysis on the first 174 patients who had completed cardiac assessment at 12 months. The study recruitment was conducted between July 2015 and June 2020. The interim analysis was performed in 2020. Patients were eligible for trial inclusion if they had indication to receive primary or postoperative systemic therapy using an anthracycline-based regimen. Patients with a prior diagnosis of cardiovascular disease were excluded.

Interventions  Cardioprotective therapy (bisoprolol, ramipril, or both drugs compared with placebo) was administered for 1 year from the initiation of chemotherapy or until the end of trastuzumab therapy in case of ERBB2-positive patients. Doses for all groups were systematically up-titrated up to the daily target dose of bisoprolol (5 mg, once daily), ramipril (5 mg, once daily), and placebo, if tolerated.

Main Outcomes and Measures  The primary end point was defined as detection of any subclinical impairment (worsening ≥10%) in myocardial function and deformation measured with standard and 3-dimensional (3D) echocardiography, left ventricular ejection fraction (LVEF), and global longitudinal strain (GLS).

Results  The analysis was performed on 174 women (median age, 48 years; range, 24-75 years) who had completed a cardiological assessment at 12 months and reached the end of treatment. At 12 months, 3D-LVEF worsened by 4.4% in placebo arm and 3.0%, 1.9%, 1.3% in the ramipril, bisoprolol, ramipril plus bisoprolol arms, respectively (P = .01). Global longitudinal strain worsened by 6.0% in placebo arm and 1.5% and 0.6% in the ramipril and bisoprolol arms, respectively, whereas it was unchanged (0.1% improvement) in the ramipril plus bisoprolol arm (P < .001). The number of patients showing a reduction of 10% or greater in 3D-LVEF was 8 (19%) in the placebo arm, 5 (11.5%) in the ramipril arm, 5 (11.4%) in the bisoprolol, arm and 3 (6.8%) in the ramipril plus bisoprolol arm; 15 patients (35.7%) who received placebo showed a 10% or greater worsening of GLS compared with 7 (15.9; ramipril), 6 (13.6%; bisoprolol), and 6 (13.6%; ramipril plus bisoprolol) (P = .03).

Conclusions and Relevance  The interim analysis of this randomized clinical trials suggested that cardioprotective pharmacological strategies in patients who were affected by breast cancer and were receiving an anthracycline-based chemotherapy are well tolerated and seem to protect against cancer therapy–related LVEF decline and heart remodeling.

Trial Registration  ClinicalTrials.gov identifier: NCT2236806

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