Sacubitril/valsartan 24/26 Mg Dose Is A Predictor For Higher Mortality Rate In Patients With Heart Failure With Reduced Ejection Fraction Receiving Sacubitril/valsartan: Interim Results

Introduction Currently, the American College of Cardiology (ACC)/ American Heart Association (AHA)/ Heart Failure Society of America (HFSA) guideline recommends replacing angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blocker (ARB) with angiotensin receptor-neprilysin inhibitor (ARNI) to further reduce mortality or heart failure (HF) rehospitalization rate. However, little evidence is available for low (24/26 mg) and middle (49/51 mg) doses because the Prospective Comparison of ARNI with ACE-I to Determine Impact on Global Mortality and Morbidity of Patients with Chronic Heart Failure (PARADIGM-HF) trial required dose titration up to high dose (97/103 mg) prior to randomization. Thus, our study in the real-world setting seeks to evaluate the effect of sacubitril/valsartan dose (low vs. middle vs. target dose) on mortality rate in patients with heart failure with reduced ejection fraction (HFrEF). Methods Patients receiving sacubitril/valsartan diagnosed as HFrEF from July 2015 to December 2019 were included in this retrospective cohort study. Patients receiving sacubitril/valsartan less than 1 year and receiving dialysis were excluded. The primary outcome was all-cause mortality. The follow-up period was up to 3.5 years after sacubitril/valsartan initiation. The hazard ratios and their 95% confidence intervals (CIs) were calculated. The survival data regression analysis using the Cox proportional hazards model was performed to examine the association between Entresto doses and mortality while controlling age, body mass index, brain natriuretic peptide, creatinine, ejection fraction, gender, systolic blood pressure, and prior ACE-I or ARB use. The significant level was set at 0.05. Results A total of 164 patients in 24/26 mg group, 78 patients in 49/51 mg group, and 80 patients in 97/103 mg group were included in this preliminary analysis. The all-cause mortality rate was significantly higher in 24/26 mg group compared with 97/103 mg group (27.4 vs. 11.3 %; hazard ratio = 2.77; 95% CI 1.35-5.67; p=0.0054). There was no significant difference in mortality rate between 49/51 mg and 97/103 groups (12.8 vs. 11.3 %; hazard ratio = 1.08; 95% CI 0.44-2.68; p=0.859). After controlling for the pre-specified variables, the significant difference between 24/26 and 97/103 mg groups was not retained (HR = 3.96, 95% CI 0.435-35.949, p=0.222) but the hazard of mortality at any given time was greatest in 24/26 mg group compared with 49/59 and 97/103 mg groups. Conclusions The results of this study indicate that sacubitril/valsartan 24/26 mg use is a predictor for a higher mortality rate in patients receiving sacubitril/valsartan. The final analysis with a larger sample size will be needed for further investigation.