Clinical outcomes according to the average daily dose of sacubitril/valsartan: a nationwide longitudinal cohort study

Aims A minority of patients with heart failure (HF) are prescribed the maximal dose of the angiotensin receptor–neprilysin inhibitor sacubitril/valsartan. We investigated the effectiveness of submaximal doses of sacubitril/valsartan in a real-world cohort. Methods and results Patients with HF with reduced ejection fraction prescribed sacubitril/valsartan for ≥ 180 days between 2016 and 2020 were included from a nationwide database, and categorized into tertiles based on the average daily sacubitril/valsartan dosage. Baseline characteristics were balanced using inverse probability of treatment weighting with propensity scores. The primary outcome was a composite of HF hospitalization and all-cause mortality. The study included 3,953 patients (age 62.6 ± 12.4 years, 73.0% men). Patients on lower sacubitril/valsartan doses were older, more likely to be women, and had more comorbidities, with lower blood pressure, reduced kidney function, and lower body mass index; however, baseline characteristics were well balanced across the groups after weighting. During a mean follow-up of 2.0 ± 0.7 years, there were 808 events (20.4%). The risk of the primary outcome in the middle (HR 0.93, 95% CI 0.78–1.10) and the highest dosage tertiles (HR 0.88, 95% CI 0.74–1.06) did not significantly differ compared with the lowest dosage tertile ( p -value = 0.384). Regarding individual outcomes, there was no significant difference in HF hospitalization; however, there was a trend toward lower mortality with higher sacubitril/valsartan dose ( p -value = 0.047). Conclusions No significant difference was observed in the composite risk of HF hospitalization and all-cause mortality across different sacubitril/valsartan dosage groups. This suggests that the benefits of sacubitril/valsartan treatment may not necessarily be dose-dependent. Graphical Abstract Clinical characteristics of patients according to sacubitril/valsartan dosage tertiles and their clinical outcomes. Patients in the lowest dosage tertile were more likely to be women and had unfavourable clinical characteristics. However, after inverse probability of treatment weighting, the Kaplan–Meier curves revealed no significant differences with regard to heart failure hospitalization, all-cause mortality, and the combination of these.