Hemodynamic Effects of Sacubitril-Valsartan in Heart Failure with Reduced-Ejection Fraction: Are All Doses Created Equal?

Abstract

Paradigm HF trial showed that Sacubitril/Valsartan (LCZ696) 97/103 mg bid reduces the risk of death and hospitalizations for heart failure (HF). We tested the hypothesis that this clinical benefit is reflected by changes in hemodynamic profile in a population of patients (pts) affected by advanced HF. Among pts included in our prospective HF Registry, we enrolled those who underwent two right heart catheterizations (RHC) and started LCZ696 in between, from May 2017 to April 2019. Baseline and follow-up RHC were compared in a matched paired fashion. We collected hemodynamic, clinical and echocardiographic data at both RHC. The dose of LCZ696 was expressed as a percentage of the target dose (TD,97/103 mg bid). The endpoint were hemodynamic changes between the two RHC. Changes in symptoms, echo parameters and medical therapy were also assessed. 44 pts (88% males; 54±8 yrs; 50% DCM; systolic blood pressure 108±17 mmHg; LVEF: 27±5%; NYHA III-IV: 46%) underwent a baseline RHC, started LCZ696 few days after, then repeated a RHC 178±59 days after the beginning of LCZ696. All pts were on diuretics (including MRAs), ACE-i/ARBs and beta-blockers at baseline. By comparing the two RHC, we observed a significant reduction in right atrial (from 7.5±2.5 to 5.6±2.5 mmHg), mean pulmonary artery (from 31.0±10.4 to 26.5±10.2 mmHg), pulmonary capillary wedge pressures (from 19.8±7.7 to 17.9±8.5 mmHg), transpulmonary gradient (from 10.4±4.6 to 8.6±3.8 mmHg) and pulmonary vascular resistances (from 2.7±1.5 to 2.2±1.3 WU), (p ≤ 0.01 for all), without significant change in systolic and mean systemic pressure. 50% of pts were taking ≤ 37.5% % of the TD; the hemodynamic changes were not influenced by LCZ696 dose. NYHA class improved (III-IV: 40.4 vs 16.7%, p<0.01) and mitral regurgitation greater than moderate was numerically reduced (40.4 vs 28.5%, p=0.09). Diuretics and beta-blockers doses did not change significantly after starting LCZ696. LCZ696 was not interrupted due to hypotension or side effects during the study period. Our study shows that LCZ696 improves hemodynamic profile and symptoms in pts with advanced HF by reducing pulmonary and left ventricular filling pressures. This effect seems to be dose-independent. Our results suggest that LCZ696 can lead to a significant clinical and hemodynamic improvement even at low doses.