Long-term outcomes following Sacubitril/Valsartan therapy for chronic HFrEF. Italian Real-World Multicenter Study

Background and aims: Long-term real-world effects of sacubitril/valsartan (S/V) and the impact of S/V dose reduction or discontinuation are less defined. We assessed longitudinal changes after S/V initiation and the association of dose changes with major adverse cardiovascular events (MACE). Methods: Multicenter retrospective study of 592 HFrEF outpatients starting S/V (83% men; age 68±10 years; LVEF 32±7%). NT-proBNP, Kansas City Cardiomyopathy Questionnaire (KCCQ) and echocardiography were collected at baseline, 12 months and last follow-up. MACE was analyzed with Kaplan-Meier and Cox models. Results: NT-proBNP decreased from 1,000 (494-2,333) to 751 (304-1,726) and 735 (215-1,980) pg/mL (p<0.001). KCCQ improved from 53±15 to 62±14 and 66±15 (p<0.001). LVEF increased from 32±7 to 36±8 and 37±9% (p<0.001) and GLS improved from -10.8±3.2 to -12.3±3.1 and -14.0±2.9% (p<0.001). During a median follow-up of 3.72 years, 225 patients (38%) experienced MACE (36 deaths; 134 HF hospitalizations). MACE incidence was higher in patients with S/V discontinuation and with dose reduction (log-rank p=0.013 and p=0.014). In multivariable Cox analysis, S/V discontinuation (HR 1.52, 95% CI 1.28-1.97; p=0.040), change in GLS (HR 0.81, 95% CI 0.67-0.98; p=0.028) and change in KCCQ (HR 0.95, 95% CI 0.92-0.98; p=0.001) were independently associated with MACE. Conclusions: S/V initiation was associated with sustained improvements in NT-proBNP, quality of life and cardiac remodeling. S/V discontinuation or dose reduction identified patients at higher MACE risk.