Pre-specified interim analysis of the SAFE trial (NCT2236806): A 4-arm randomized, double-blind, controlled study evaluating the efficacy and safety of cardiotoxicity prevention in non-metastatic breast cancer patients treated with anthracyclines with or without trastuzumab

Livi, Lorenzo; Barletta, Giuseppe; Martella, Francesca; Desideri, Isacco; Scotti, Vieri; Becherini, Carlotta; Saieva, Calogero; Terziani, Francesca; Bacci, Carlotta; Airoldi, Mario; Allegrini, Giacomo; Amoroso, Domenico; Venditti, F.; Tarquini, Roberto; Orzalesi, Lorenzo; Sanchez, Luis; Bernini, Marco; Nori, Jacopo; Fioretto, Luisa; Meattini, Icro

doi:10.1093/annonc/mdz240.039

Cited by 2 publications

(3 citation statements)

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“…The results of our subsequent sensitivity analysis are consistent with the previous results. Second, in three of our included trials [5][6][7], a small fraction of patients were also treated with trastuzumab. The combination of anthracycline and trastuzumab further increases cardiotoxicity.…”

Section: Discussionmentioning

confidence: 99%

“…There were 3 studies [4][5][6] described the method of random sequence generation clearly, of which 2 studies [5,6] also described allocation concealment. Three studies [4,5,7] described a rigorous blinding method for participants, while 4 RCTs [4,5,7,8] used standard blinding method to assess the outcomes of studies. Except for 2 conference abstracts that were not explicitly reported [7,9], other 5 studies were evaluated as having a low risk of attrition bias and reporting bias.…”

Section: Quality Evaluationmentioning

confidence: 99%

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Protective Effects of ACEI/ARB on Left Ventricular Function in Anthracycline-Induced Chronic Cardiotoxicity: A Meta-Analysis of Randomized Controlled Trials

Lin

Liang

et al. 2021

Cardiology

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Purpose: Cardiotoxicity is an important side effect of anthracycline. Cardioprotective drugs for anthracycline remain inconclusive. We attempted to determine the role of angiotensin-converting enzyme inhibitors (ACEI) and angiotensin-receptor blockers (ARB) in the prevention of anthracycline-induced cardiotoxicity. Hypothesis: Prophylactic use of ACEI/ARB reduces the clinical or subclinical cardiotoxicity of anthracycline. Methods: Randomized controlled trials (RCTs) of ACEI/ARB in the prevention of anthracycline-induced cardiotoxicity were obtained by searching Pubmed, Embase, Web of Science, and Cochrane databases. 7 studies were finally included. A meta-analysis was performed on the 7 studies. The end points were changes in left ventricle ejection fraction (LVEF), early and late diastolic peak velocity ratio (E/A), and occurrence of hypotensive events. Results: Prophylactic use of ACEI/ARB has potential benefits for anthracycline-induced cardiotoxicity. LVEF was better preserved in the experimental group than in the control group (weighted mean difference [WMD] −3.16%, 95% confidence interval [CI] [−5.78, −0.54], p = 0.02). Follow-up time, tumor type, drug type, and geographical region did not affect the results. There was no significant benefit of E/A in the experimental group (WMD 0.02, 95% CI [−0.06, 0.11], p = 0.58), and no increase in the incidence of hypotension (risk ratio 3.79, 95% CI [0.44, 32.89], p = 0.23). Conclusions: We found that prophylactic use of ACEI/ARB reduced the clinical or subclinical cardiotoxicity of anthracycline, and the increase in hypotensive events was not significant. Due to the relatively small number of clinical studies and participants, more related studies are necessary to further verify our results.

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Section: Discussionmentioning

confidence: 99%

Section: Quality Evaluationmentioning

confidence: 99%

Protective Effects of ACEI/ARB on Left Ventricular Function in Anthracycline-Induced Chronic Cardiotoxicity: A Meta-Analysis of Randomized Controlled Trials

Lin

Liang

et al. 2021

Cardiology

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“…The SAFE trial (NCT2236806) is an ongoing phase III study comparing the effect of bisoprolol, ramipril, or both drugs compared to placebo on prevention of subclinical myocardial injury (early and late subclinical cardiotoxicity measured with traditional echocardiography) in breast cancer treated with (neo) adjuvant anthracyclines +/− trastuzumab. The most recent interim analysis, following the recruitment of 191 of 480 patients, led to the closure of the ramipril arm due to futility [ 47 ]. The results of this study, which will continue with only three arms, are awaited with great interest.…”

Section: Discussionmentioning

confidence: 99%

Heart Failure Therapies for the Prevention of HER2-Monoclonal Antibody-Mediated Cardiotoxicity: A Systematic Review and Meta-Analysis of Randomized Trials

Brown

Meredith

et al. 2021

Cancers

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Monoclonal antibodies including trastuzumab, pertuzumab, and antibody-drug conjugates, form the backbone of HER2-positive breast cancer therapy. Unfortunately, an important adverse effect of these agents is cardiotoxicity, occurring in approximately 10% of patients. There is increasing published data regarding prevention strategies for cardiotoxicity, though seldom used in clinical practice. We performed a systematic review and meta-analysis of randomized-controlled trials to evaluate pharmacotherapy for the prevention of monoclonal HER2-directed antibody-induced cardiotoxicity in patients with breast cancer. Online databases were queried from their inception until October 2021. Effects were determined by calculating risk ratios (RRs) and 95% confidence intervals (CI) or mean differences (MD) using random-effects models. We identified five eligible trials. In the three trials (n = 952) reporting data on the primary outcome of cardiotoxicity, there was no clear effect for patients assigned active treatment compared to control (RR = 0.90, 95% CI 0.63 to 1.29, p = 0.57). Effects were similar for ACE-I/ARB and beta-blockers (p homogeneity = 0.50). Active treatment reduced the risk of HER2 therapy interruptions (RR = 0.57, 95% CI 0.43 to 0.77, p < 0.001) with similar findings for ACE-I/ARB and beta-blockers (p homogeneity = 0.97). Prophylactic treatment with ACE-I/ARB or beta-blocker therapy may be of value for cardio-protection in patients with breast cancer prescribed monoclonal antibodies. Further, adequately powered randomized trials are required to define the role of routine prophylactic treatment in this patient group.

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Pre-specified interim analysis of the SAFE trial (NCT2236806): A 4-arm randomized, double-blind, controlled study evaluating the efficacy and safety of cardiotoxicity prevention in non-metastatic breast cancer patients treated with anthracyclines with or without trastuzumab

Cited by 2 publications

References 0 publications

Protective Effects of ACEI/ARB on Left Ventricular Function in Anthracycline-Induced Chronic Cardiotoxicity: A Meta-Analysis of Randomized Controlled Trials

Protective Effects of ACEI/ARB on Left Ventricular Function in Anthracycline-Induced Chronic Cardiotoxicity: A Meta-Analysis of Randomized Controlled Trials

Heart Failure Therapies for the Prevention of HER2-Monoclonal Antibody-Mediated Cardiotoxicity: A Systematic Review and Meta-Analysis of Randomized Trials

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