Background: The combination drug sacubitril/valsartan was approved by the European Medicines Agency in 2015 for the treatment of HF with reduced ejection fraction (HFrEF) following the results of the large prospective randomized clinical trial PARADIGM-HF where sacubitril/valsartan was superior to enalapril regarding major clinical endpoints. In our study, we aimed to further elucidate specific patient characteristics that might predict response to ARNI treatment.

Methods: In this single center study we retrospectively analyzed a cohort of n=304 consecutive HF patients with impaired left ventricular ejection fraction (LVEF). LVEF was determined via echocardiography at the time of first initiation of sacubitril/valsartan and at a one-year follow-up. We evaluated differences in patient characteristics and their association with median absolute changes of LVEF. Parameters associated with differences in absolute LVEF change were further tested for reciprocal dependency and predictive value by linear regression.

Results: LVEF increase was significantly greater in patients with non-ischemic compared to ischemic etiology (LVEF; median, IQR; non-ischemic 5.0 % (0.0-15.0) versus ischemic 0.0 % (0.0-7.0), p<0.001), with age ≤ 75 compared to > 75 years (LVEF; median, IQR; age ≤ 75 years 5.0 % (0.0-15.0) versus age > 75 years 0.0 % (0.0-8.0), p=0.001) and with normal compared to impaired renal function (LVEF; median, IQR; GFR ≥ 60 mL/min/1,73m² 5.0 % (0.0-12.5) versus GFR < 60 mL/min/1,73m² 0.0 % (0.0-5.0), p<0.001). Initiation of sacubitril/valsartan within the first year after first diagnosis of HF showed significantly superior improvement of LVEF compared to initiation after the first year (LVEF; median, IQR; initiation ≤ 12 months 10.0 % (3.5-15.0) versus > 12 months 0.0 % (0.0-5.0), p<0.001). LVEF improvement was also significantly greater in patients naïve to ARB/ACEI compared to pre-existing ARB/ACEI therapy (LVEF; median, IQR; naïve to ARB/ACEI 10.0 % (0.0-17.0) versus pre-existing ARB/ACEI 3.0 % (0.0-10.0), p<0.001) as well as when dose at follow-up exceeded 24/26 mg bid compared to 24/26 mg bid or less (LVEF; median, IQR; dose > 24/26 mg bid 5.0 % (0.0-15.0) versus dose ≤ 24/26 mg bid 2.0 % (0.0-9.5), p=0.004). No differences in LVEF alterations were found in association with gender and body-mass-index. Linear regression analysis identifies etiology of HF (p=0.001), renal function (p=0.034), time between diagnosis and initiation of sacubitril/valsartan treatment (p<0.001), and preceding ARB/ACEI therapy (p=0.007) as strong and independent predictors of LVEF alterations. Age (p=0.572) and treatment dose at follow-up (p=0.061) could not predict improvement of LVEF.

Conclusion: Our results present real world data of an “all-comers cohort” of HF patients with impaired LVEF. In our study, patients with non-ischemic HF, normal renal function, naïve to ARB/ACEI therapy and short time period between first diagnosis of HF and initiation of sacubitril/valsartan showed most favorable outcome and were also independent predictors of changes in LVEF over time.  Our observations may help to identify high risk patients who might not benefit from an ARNI treatment and might therefore benefit from an intensified HF patient management. Large-scale randomized trials are needed to verify our findings and further investigate the clinical implications by testing for clinical endpoints.