Pathophysiology of Heart Failure with Reduced Ejection Fraction
Andreas P. Kalogeropoulos, Hal A. Skopicki, Javed Butler in Heart Failure, 2023
Based on their physiological mechanisms, multiple natriuretic peptide analogues and endopeptidase inhibitors have progressed through preclinical studies to human trials. Nesiritide, a recombinant BNP, although showing hemodynamic benefits in earlier studies, did not reduce death or rehospitalization compared to placebo in a large long-term trial. Neprilysin is a membrane-bound metalloproteinase that cleaves and inactivates various peptide hormones, including natriuretic peptides, bradykinin, substance P, and beta amyloids. Early neprilysin inhibitors were shown to promote natriuresis, but the effect was not sustained, likely because AT II breakdown was also inhibited. Consequently, dual blockade of neprilysin and ACE was thought to be the solution. The neprilysin-ACE inhibitor omapatrilat was compared with ACE inhibitor alone in the phase III trial OVERTURE,4 showing no reduction in the composite primary endpoint of all-cause mortality and HF hospitalization, but causing a reduction in the secondary endpoint of all-cause mortality and cardiovascular hospitalization. However, on account of the unacceptable rise in the angioedema rate in the treatment group, related to omapatrilat inhibition of bradykinin breakdown, further development of this agent was ceased. The more recently developed agent sacubitril-valsartan carries the dual advantage that sacubitrilat (active metabolite of sacubitril) does not inhibit aminopeptidase P, which breaks down bradykinin, and that valsartan does not inhibit ACE, which also contributes to bradykinin inactivation (Figure 3.2). Accordingly, sacubitril-valsartan was compared with enalapril for HFrEF patients in the recent phase III trial PARADIGM-HF,5 demonstrating the marked superiority of sacubitril-valsartan in terms of all-cause mortality, cardiovascular mortality, and HF hospitalization, with a non-significant rise in non-serious angioedema. Replacing ACE inhibitor or ARB with sacubitril-valsartan now holds a level I class of recommendation in all major international guidelines for HFrEF.6,7Sacubitril-valsartan mechanism of action in heart failure. (Reproduced with permission from: Vardeny, Miller, and Solomon, JACC Heart Fail 2014;2:663–70.)
Safety and efficacy considerations amongst the elderly population in the updated treatment of heart failure: a review
Published in Expert Review of Cardiovascular Therapy, 2022
In addition, two trials were performed amongst those patients with heart failure while taking sacubitril/valsartan to further define benefits. The first study was titled the EVALUATE-HF trial, average age of 67.3 years old, which aimed to determine if the ARNI aids in aortic stiffness and cardiac remodeling when compared to enalapril [19]. Again, study details are provided in Table 2. The study concluded that there was no difference in, measuring aortic characteristic impedance (Zc), between the two classes of medications, but encourages conceptualizing further mechanisms providing heart failure aid [19]. Another trial, PROVE-HF trial, determined there was an LVEF increase in those patients with HFrEF taking the ARNI [20]. In this trial, the average age was 65.1 years old, and the investigators saw an increase of ejection fraction from 28.2% to 37.8%, a 9.4% increase (95% CI 8.8 to 9.9, p < 0.001) [20]. Thus, these trials underscore the efficacy of the ARNI in those patients ≥65 years old, as well as offering some evidence in those ≥75 years old.
An evaluation of the fixed-dose combination sacubitril/valsartan for the treatment of arterial hypertension
Published in Expert Opinion on Pharmacotherapy, 2020
Markus Wehland, Ulf Simonsen, Niels Henrik Buus, Marcus Krüger, Daniela Grimm
Inadequately controlled hypertension is a significant health problem, and there is a need for more effective BP-lowering medications. Angiotensin II receptor blockade (ARB) constitutes a cornerstone in antihypertensive treatment, but monotherapy is often not sufficient to reach the BP goals. The co-crystallization of valsartan with the neutral endopeptidase inhibitor prodrug sacubitril has resulted in a novel drug (LCZ696) with more potent antihypertensive effects than ARB alone. The efficacy in essential hypertension is now documented in several thousand patients revealing a difference in office BP reduction of about 5/2 mmHg systolic/diastolic BP. This difference is clinically highly relevant and could result in more patients being controlled to the desired BP target. Importantly, the addition of neprilysin inhibition with sacubitril does not result in more side effects.
Inhibition of neprilysin with sacubitril without RAS blockage aggravates renal disease in Dahl SS rats
Published in Renal Failure, 2021
Iuliia Polina, Morgan J. Spicer, Mark Domondon, Ryan S. Schibalski, Elizaveta Sarsenova, Regina F. Sultanova, Daria V. Ilatovskaya
Recently, the NEPi sacubitril was approved for chronic administration in heart failure, in combination with valsartan, an angiotensin receptor blocker (ARB) [32,33]. The combination of NEPi and RAS blockade has been researched as a treatment option for diabetes-related cardiorenal pathologies. A 2016 study that demonstrated a significant reduction in heart failure hospitalizations in diabetic patients treated with sacubitril/valsartan also showed it to be a safe and sustainable treatment for a subset of patients with ESRD [39,40]. More recently, an analysis of the PARADIGM-HF trial examined changes in estimated GFR (eGFR) in patients with and without diabetes [41]. This study found that patients treated with sacubitril/valsartan had a slower rate of decline in eGFR, and that diabetic patients had a more drastic attenuation of eGFR decline than patients without diabetes [41]. In a follow-up review to the PARADIGM-HF study, it was suggested that because patients with type 2 diabetes display a decreased response to endogenous NPs, neprilysin has a higher detrimental effect, and therefore NEPis can be more beneficial for renal health [42]. Overall, there has been little research done into the efficacy of sacubitril in regard to renal as opposed to cardiac health; however, this is a promising line of research.
Related Knowledge Centers
- Ace Inhibitor
- Bradykinin
- Edema
- Valsartan
- Antihypertensive Drug
- Pulmonary Edema
- Prodrug
- Heart Failure
- Sacubitril/Valsartan
- Priority Review