SAFE trial (NCT2236806) is a phase 3 study comparing the effect on subclinical heart damage of bisoprolol (B), ramipril (R), or both drugs (R+B), as compared to placebo (P), in breast cancer treated ...with (neo)adjuvant anthracyclines +/- trastuzumab.
Primary endpoint is subclinical cardiotoxicity measured with echocardiography and global linear strain (GLS). This interim analysis was pre-specified on the first 120 patients who had completed cardiological assessments at 12-mos. Stopping rules per arm were: dose reduction >15%, study withdraw rate >5%, and no significant impact on 3D-left ventricular ejection fraction (3D-LVEF) as compared to T0 at 12-mos assessment.
A total of 191 out of 480 patients have been enrolled; overall 123 patients were available for the analysis (P=34; R=28; B=31; R+B=30). 3D-LVEF decreased at 3-mos (-3.3%; p<0.001), at 6-mos (-5.2%; p<0.001) and at 12-mos (-3.7%; p=0.004) respect to T0 in P; at 3-mos (-2.4%; p=0.001), at 6-mos (-1.9%; p=0.010), at 12-mos (-2.2%; p=0.045) in R. In B and R+B patients no significant changes were observed at 3- and 12-mos, with a decrease at 6-mos (-2.5% and 3.0%, respectively; p=0.002). Arm differences were significant (p=0.038). GLS increased at 3-mos (5.7%; p<0.001), at 6-mos (7.8%; p<0.001) and at 12-mos (7.1%; p<0.001) respect to T0 in P; at 3-mos (2.7%; p=0.002), at 6-mos (3.2%; p=0.014), but not at 12-mos in R; no significant changes at 3-mos, a significant increase at 6-mos (2.7%; p=0.035), at 12-mos (3.2%; p=0.008) in B; no significant changes at 3-, 6-, and 12-mos in R+B. Arm differences were significant (p=0.002). Both R+B and the R arms showed a withdraw rate of 7%, with a dose reduction rates of 21% and 17%, respectively. R arm showed a significant decrease on 3D-LVEF at 12-mos as compared to T0 and will be evaluate for closure.
Following the stopping rules, the closure of the R arm is required and the study will continue with 3 arms. At the interim analysis, a cardioprevention strategy significantly impact on subclinical heart damage.
NCT2236806.
University of Florence.
Has not received any funding.
All authors have declared no conflicts of interest.
The official biotoxicological (MBA) method for the determination of lipophilic marine toxins shows important gaps with regard to reproducibility, specificity and quality of the data provided and ...serious ethical contraindications. The Commission Regulation (EU) No 15/2011 establishes the date of December 31, 2014 as the deadline for replacement of the mouse test with a LC-MS/MS method by the laboratories of the member states responsible for the monitoring of marine biotoxins. In order to facilitate the interpretation of the MBA during this transition period, we further evaluated the specificity and selectivity of this assay in comparison with a LC-MS/MS method in detecting lipophilic marine toxins on mussels of the middle Adriatic Sea. Data show a high percentage of false-positive results on MBA due to interference by yessotoxins. It was also possible to evaluate the toxic profile of the samples analyzed.
Bonardi, S., Paris, A., Bacci, C., D'Incau, M., Ferroni, L. and Brindani, F., 2007. Detection and characterization of Yersinia enterocolitica from pigs and cattle. Veterinary Research Communications, ...31(Suppl. 1), 347-350 PUBLICATION ABSTRACT
Phage tail recombinant protein technology developed by VIDAS UP O157 was used to detect E. coli O157 from bovine raw milk and milk filters. Sensitivity and specificity of VIDAS UP O157 was identical ...to a m-PCR assay for verocytotoxigenic E. coli detection.
New limits on the mean lifetime of the electron for decay into non-ionizing particles have been achieved by using a low activity liquid xenon scintillator at the Gran Sasso National Laboratory.
Abstract
Background
Benefit of anthracyclines and trastuzumab therapies on disease-free survival in breast cancer is well known. Cardiotoxicity is a feared potential complication of both drugs. It ...usually progresses from cardiomyocyte injury to silent left ventricular dysfunction (LVD) which often becomes symptomatic and irreversible. Therefore, its prevention and early detection are of paramount importance in these cancer patients.
Purpose
SAFE trial (CT registry ID: NCT2236806) is a randomized phase 3, four-arm, single-blind, placebo-controlled study that aims to evaluate the effects of Bisoprolol (B) (5 mg, twice daily), Ramipril (R) (5 mg, twice daily) or the combination of the two (R + B), compared to placebo (P), on subclinical heart heart damage. Interim data of left ventricular function monitored with 3D Echo and Myocardial Strain Imaging are presented.
Methods
Out of 225 patients asked to participate, 191 were enrolled (mean age 48.9 ± 9.0 years). Follow-up monitoring (at 3, 6, 12 monthsm) comprised 3D ejection fraction (3D-LVEF) and Global Longitudinal Strain (GLS). One patient had sub-acute anthracyclines cardiotoxicity. Data at one year of 123 patients were available (34 P, 28 R, 31 B, 30 R + B).
Results
At time 0, no significant differences in age, body mass index, hemodynamic parameters were observed among arms. Data of 3D-LVEF and GLS at time 0 and during follow-up are reported in the figure (p level versus time 0 – GLS repeated measures). There was a significant reduction in 3D LVEF and increase in GLS in P arm (3D LVEF: 3m: -3.3%, 6m: - 5.2%, 12m: -3.7%; GLS: 3m: +5,7%, 6m: +7.8%, 12m: + 7,1%). A similar, though less significant, worsening of 3D LVEF (-2.4%,-1.9%,-2.2% at 3, 6, 12m, respectively) and GLS (+2.7%, +3.2% at 3 and 6m, respectively) was found in R arm. In B and B +R arms there was a worsening at 6m (3D LVEF -2.5%, GLS +2.7%), whereas at 12m only GLS increased (+3.2%) in B, not in B + R. Arm differences were significant (repeated measures two ways) both for 3D LVEF (two-way repeated measures ANOVA, p level = 0.038, observed power 0.855) and GLS (p level = 0.002, observed power 0.973).
Conclusions
This interim analysis of the SAFE trial shows that demonstration of subclinical cardiotoxicity is feasible with 3D echo and myocardial strain imaging. Significant subclinical damage potentially leading to LVD is present at one year. Both B alone on in combination with R may be a successful cardioprotective strategy in patients treated with anthracyclines and trastuzumab.
Abstract 1029 Figure. Time course of GLS and 3D LVEF
We have searched for the C-violating decay η→γγγ in a sample of ∼18 million η mesons produced in φ→ηγ decays, collected with the KLOE detector at the Frascati φ-factory DAΦNE. No signal is observed ...and we obtain the upper limit BR(η→γγγ)⩽1.6×10−5 at 90% CL.
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