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.

中文翻译：

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接受蒽环类化疗的非转移性乳腺癌患者的心脏保护策略：一项随机临床试验。

重要性 几项研究评估了心脏保护策略，以防止正在接受心脏毒性治疗的患者出现心肌功能障碍。然而，最优方法仍然是一个有争议的问题。目的 确定药物心脏预防是否可以减少接受蒽环类化疗的乳腺癌患者的亚临床心脏损伤。设计、设置和参与者 SAFE 试验是一项 4 臂、随机、3 期、双盲、安慰剂对照、国家多中心研究，在意大利的 8 个肿瘤科进行。这是对前 174 名在 12 个月时完成心脏评估的患者进行的预设中期分析。研究招募于 2015 年 7 月至 2020 年 6 月期间进行。中期分析于 2020 年进行。如果患者有使用基于蒽环类药物的方案接受初次或术后全身治疗的指征，则他们有资格被纳入试验。先前诊断为心血管疾病的患者被排除在外。干预 心脏保护治疗（比索洛尔、雷米普利或两种药物与安慰剂相比）在 ERBB2 阳性患者的情况下，从化疗开始或曲妥珠单抗治疗结束后持续 1 年。如果耐受，所有组的剂量都系统地增加至比索洛尔（5 mg，每天一次）、雷米普利（5 mg，每天一次）和安慰剂的每日目标剂量。主要结果和措施 主要终点定义为通过标准和 3 维 (3D) 超声心动图、左心室射血分数 (LVEF) 和全纵向应变（GLS）。结果 对 174 名女性（中位年龄 48 岁；范围 24-75 岁）进行了分析，她们在 12 个月时完成了心脏评估并达到治疗结束。12 个月时，安慰剂组 3D-LVEF 恶化 4.4%，雷米普利、比索洛尔、雷米普利加比索洛尔组分别恶化 3.0%、1.9%、1.3% (P = .01)。安慰剂组的整体纵向应变恶化了 6.0%，雷米普利和比索洛尔组分别恶化了 1.5% 和 0.6%，而它没有变化（0. 雷米普利加比索洛尔组改善 1%（P < .001）。显示 3D-LVEF 降低 10% 或更多的患者数量为：安慰剂组 8 例（19%），雷米普利组 5 例（11.5%），比索洛尔组 5 例（11.4%）和 3 例（ 6.8%）在雷米普利加比索洛尔组中；与 7 名（15.9；雷米普利）、6 名（13.6%；比索洛尔）和 6 名（13.6%；雷米普利加比索洛尔）相比，接受安慰剂的 15 名患者（35.7%）显示 GLS 恶化 10% 或更多（P = .03 ）。结论和相关性 这项随机临床试验的中期分析表明，在受乳腺癌影响并接受蒽环类化疗的患者中，心脏保护药理学策略耐受性良好，似乎可以防止癌症治疗相关的 LVEF 下降和心脏重塑。试验注册 临床试验。