Effect of Neprilysin Inhibition on Left Ventricular Remodeling in Patients With Asymptomatic Left Ventricular Systolic Dysfunction Late After Myocardial Infarction

Abstract

Background: Patients with left ventricular systolic dysfunction (LVSD) following myocardial infarction (MI) are at high risk of developing heart failure. The addition of neprilysin inhibition to renin angiotensin system (RAS) inhibition may result in greater attenuation of adverse LV remodeling due to increased levels of substrates for neprilysin with vasodilatory, anti-hypertrophic, anti-fibrotic and sympatholytic effects. Methods: We performed a prospective, multi-center, randomized, double-blind, active-comparator trial comparing sacubitril/valsartan 97/103mg twice daily with valsartan 160mg twice daily in patients ≥3 months following MI with a LV ejection fraction (LVEF) ≤40% who were taking a RAS inhibitor (equivalent dose of ramipril ≥2.5mg twice daily), and a beta-blocker unless contraindicated or intolerant. Patients in New York Heart Association functional classification ≥II or with signs and symptoms of HF were excluded. The primary outcome was change from baseline to 52-weeks in LV end-systolic volume index (LVESVI) measured using cardiac magnetic resonance imaging (MRI). Secondary outcomes included other MRI measurements of LV remodeling, change in N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (hs-TnI), and a patient global assessment of change questionnaire. Results: From July 2018 to June 2019, 93 patients were randomized: mean age 60.7±10.4 years, median time from MI 3.6 years (IQR 1.2-7.2), mean LVEF 36.8%±7.1, median NT-proBNP 230pg/mL (124-404). Sacubitril/valsartan, compared with valsartan, did not significantly reduce LVESVI; adjusted between-group difference -1.9mL/m 2 (95%CI -4.9, 1.0); p=0.19. There were no significant between-group differences in NT-proBNP, hs-TnI, LV end-diastolic volume index, left atrial volume index, LVEF, LV mass index, or patient global assessment of change. Conclusions: In patients with asymptomatic LVSD following MI, treatment with sacubitril/valsartan did not have a significant reverse remodeling effect compared with valsartan. Clinical Trial Registration: URL: https://www.clinicaltrials.gov Unique identifier: NCT03552575

Efficacy and safety of early initiation of Sacubitril/Valsartan in patients after acute myocardial infarction: A meta‐analysis

“…Considering that Sacubitril/ Valsartan could inhibit the activation of RAAS, many researchers hypothesized that Sacubitril/Valsartan have benefits in patients after AMI. 20,21 For these patients, there were still confusions about the benefits and risks of Sacubitril/Valsartan and ACEI. After a comprehensive search and strict screening, a total of four studies involving 6154 patients were included.…”

Angiotensin Receptor-Neprilysin Inhibitor (ARNI) and Cardiac Arrhythmias

“…Sacubitril/valsartan also significantly decreased plasma NT-proBNP and reverted clinical features of cardiac remodeling (i.e., improved LVEF and cardiac volume) in HFrEF patients with and without type-2 diabetes mellitus in the PROVE-HF registry [21]. However, sacubitril/valsartan was not significantly different from valsartan alone in reverting structural remodeling in patients with asymptomatic post-myocardial infarction (MI) LV systolic dysfunction [22], although the efficacy of ARNI in this subset of patients is still being investigated in the PARADISE-MI trial [23]. Sacubitril/valsartan significantly lowered cardiovascular mortality, improved clinical outcomes (e.g., rehospitalization) and markedly reduced plasma NT-proBNP concentration, without major adverse events in acute decompensated HF, irrespective of the HF history or prior treatment with RAAS blockers [24,25].…”

“…Nonetheless, the interpretation of such prospective observational data may be confounded by the natural progression of arrhythmia substrates over time, increasing the arrhythmogenic risk. Furthermore, the fact that sacubitril/valsartan did not significantly improve LVEF and HF class after 12 months [46] could be indicative for limited ARNI-induced reverse remodeling, possibly due to the ischemic origin of the HFrEF in the majority (60%) of patients [22]. Additionally, a relatively high incidence of ventricular arrhythmic storm has also been documented shortly after sacubitril/valsartan initiation in 19/218 (8.7%) HFrEF males previously on RAAS blockers [47].…”

Does sacubitril/valsartan work in acute myocardial infarction? The PARADISE-AMI study

“…After a mean follow-up of 52 weeks, the combination therapy did not show a significant improvement on left ventricular remodelling compared to sartan alone: in fact, no significant differences were found between the two groups in end-diastolic volume and left ventricular EF evaluated by magnetic resonance, in the levels of NT-proBNP, of ultrasensitive troponin and in the functional capacity. 12 …”