P1663The impact of highest doses of ACEi/ARB therapy on mortality of patients suffering from heart failure with reduced ejection fraction: a long-term follow-up, propensity-matched cohort study
Authors: Muk B , Vamos M , Bogyi P , Majoros Z S , Vagany D , Borsanyi T , Szogi E , Juhasz I , Kosa K , Dekany M , Nyeki L C S , Kiss R G , Nyolczas N 
Published: October 2019

Abstract

The angiotensin-converting enzyme inhibitors (ACEi) as cornerstone of neurohormonal drug regime reduce mortality and morbidity in heart failure with reduced ejection fraction (HFrEF) hence these drugs are recommended for every HFrEF patients without presence of contraindication or intolerance. However, there are controversial results regarding the incremental survival benefit of higher doses of these drugs used in HFrEF. In addition, achieving the highest doses (TD1) (20 mg < enalapril daily dose≤40 mg, or dose equivalent ACEi/ARB), of these drugs often accompanies side effects related to the uptitration, which may make it impossible to start other therapies proven to result in undoubtful mortality benefit (i.e. sacubitril/valsartan).

Aim
To assess the effect of TD1 of ACEi/ARB on mortality of HFrEF patients followed at a heart failure outpatient clinic (HFOC).

Methods
Data of 579 consecutive HFrEF patients, who hadn't been treated with an ACEi/ARB or were receiving ≤50% of doses equivalent with 20mg enalapril daily (TD2) at the time of initiation of care (NYHA: 3.1±0.8; LVEF: 27.5±6.6%; age: 61.1±13.0 years; male: 76.1%; ischemic: 46.8%; atrial fibrillation: 27.6%; diabetes: 34.9%; hypertension: 72.5%), followed at our HFOC was analysed. After therapy optimization (TO) ACEis/ARBs were applied in 96.5% and at least TD2 was reached in 55.9% of the total cohort, while TD1 of an ACEi/ARB was applied in 111 patients (19.2% of total cohort). BBs in 88.4%, target doses of BBs in 46.8%, MRAs in 57.0% of total cohort were used. To adjust for possible confounders, patients were matched based on the ACEi/ARB doses reached during TO applying propensity score matching (PSM) using the nearest neighbor matching (caliper: 0.2). All-cause mortality (ACM) was assessed using the Kaplan-Meier method and compared with the Cox proportional hazard model.

Results
After 7.1±4.7 years follow-up ACM of patients treated with TD1 of ACEis/ARBs was significantly lower than those treated with lower doses in the total cohort (HR=0.67; 95% CI=0.50–0.89; p=0.005). Applying multivariate Cox regression analysis the use of TD1 of an ACEi/ARB didn't remain independent predictor of survival; creatinine, NYHA f.c., age, sex, ischemic etiology were proved to be significant predictor of mortality. After PSM the survival of patients receiving TD1 of an ACEi/ARB didn't differ from those treated with lower doses (HR=0.84; 95% CI=0.61–1.14; p=0.27).

Conclusions
The current ESC guidelines recommend the use of target doses or maximal tolerated doses of ACEis or ARBs in HFrEF. In a real-world patient cohort whom all the effort was made to reach the target doses, ACM of patients treated with TD1 of an ACEi/ARB was significantly lower than those treated with lower doses, however this result wasn't independent from the patient characteristics. Beside that, after PSM the survival of patients treated with TD1 or with lower doses of an ACEi/ARB did not differ significantly.