Cardioprotective effects of sacubitril/valsartan according to baseline cardiovascular risk during adjuvant breast cancer therapy: a randomized placebo-controlled trial

Background The Heart Failure Association–International Cardio-Oncology Society (HFA-ICOS) risk tool is recommended by guidelines to stratify baseline cardiovascular risk before cardiotoxic cancer therapy. Whether HFA-ICOS risk classification differentiates subclinical myocardial injury, predicts cancer therapy–related cardiac dysfunction (CTRCD), or modifies cardioprotective treatment response in randomized settings remains uncertain. Purpose To assess longitudinal changes in myocardial function across HFA-ICOS risk categories and determine whether the cardioprotective effect of sacubitril/valsartan varies by baseline cardiovascular risk in a randomized placebo-controlled trial of adjuvant breast cancer therapy. Methods In this predefined substudy, 138 breast cancer patients (placebo n = 69, sacubitril-valsartan n = 69) receiving anthracycline-based chemotherapy underwent echocardiography at baseline, post-anthracycline therapy, and at 18 months. Patients were categorized as low, moderate, high or very high risk by HFA-ICOS. The primary endpoint was change in left ventricular global longitudinal strain (GLS). Secondary endpoints included 2D left ventricular ejection fraction (LVEF), right ventricular function, diastolic echocardiographic parameters, and cardiac biomarkers. Mild CTRCD was defined as > 15% relative GLS decline and/or biomarker increase. Linear mixed-effects models estimated longitudinal trajectories and treatment effects within each risk category. Results Most patients were low (n=59) or moderate (n=59) risk; 20 were high risk and none very high risk. Mild CTRCD increased numerically across categories at 18 months, Table 1. No consistent risk-dependent differences were observed in GLS, LVEF, right ventricular function, or diastolic changes. The effect of sacubitril/valsartan on GLS was similar across risk groups, with between-group differences from baseline to 18 months of −1.26% (95% CI −2.62 to 0.09) in low, −1.48% (95% CI −2.89 to −0.07) in moderate, and −1.72% (95% CI −4.26 to 0.81) in high risk (Figure 1). No significant interaction by risk category was observed. Overall, GLS remained stable with sacubitril–valsartan but deteriorated with placebo (between-group difference −1.26%, 95% CI −2.19 to −0.33; p = 0.008). Conclusion Mild CTRCD occurred across all risk categories, increasing numerically with higher risk. Sacubitril/valsartan attenuated GLS deterioration, with broadly similar effects across baseline risk categories. Findings should be interpreted cautiously, given the limited number of high-risk participants and the exploratory nature of subgroup analyses.