Neprilsyin Plus RAS Inhibition Did Not Significantly Reverse Post-MI LV Remodeling

Following myocardial infarction (MI), the addition of a neprilsyin inhibitor to renin angiotensin system (RAS) inhibitor did not reverse remodeling or improve biomarkers associated with left ventricular (LV) wall stress in patients with asymptomatic LV systolic dysfunction (LVSD), according to research results published in Circulation.

In order to evaluate effects of neprilysin inhibition in conjunction with RAS inhibition on left ventricular volumes in patients with asymptomatic LVSD, researchers conducted a prospective, multicenter, randomized, double-blind, active-comparator clinical trial (ClinicalTrials.gov identifier NCT03552575).

Participants included eligible adults with left ventricular ejection fraction (LVEF) ≤40% at least 3 months after acute myocardial infarction without signs or symptoms of heart failure. Participants were also taking a minimum or greater dose of an angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB)­—or were able to tolerate this dose—and had systolic blood pressure ≥100 mmHg.

Participants were randomly assigned in a 1:1 ratio to receive either sacubitril valsartan (97/103 mg twice daily) or valsartan (160 mg twice daily).

The primary outcome was change from baseline over a 52-week period in LVESVI, measured via cardiac magnetic resonance imaging (MRI) and indexed for body surface area. Secondary outcomes included change in N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin 1 (hs-cTNT), LV end-diastolic volume indexed for body surface area (LVEDVI), left atrial volume indexed for body surface area, LVEF, LV mass indexed for body surface area, and change in patient well being assessed through a patient global assessment questionnaire.

Exploratory outcomes included a range of biomarkers related to neprilysin inhibition, neurohumoral activities, and cardiac remodeling.

A total of 158 patients from 7 sites in the greater Glasgow area were screened; 93 were included in the study and randomly assigned to 1 of 2 treatment groups (sacubitril/valsartan n=47, valsartan n=46). At baseline, mean age was 60.7±10.4 years (91.4% men). Median time from MI was 3.6 years (interquartile range [IQR], 1.2-7.2). Index MI was an ST-elevation MI in 96.8% of patients, in the anterior location in 94.6% of patients, and most—95.7%—had received either percutaneous or surgical revascularization as an MI treatment.

Beta blockers were taken by 93.5% of patients; 43% took a mineralocorticoid-receptor antagonist and 11.8% took a loop diuretic. Mean cardiac MRI LVEF was 36.8%±7.1% and median NT-proBNP was 230 pg/mL (IQR, 124-404).

Forty-six of the 47 patients in the sacubitril/valsartan group had complete primary outcome data at both baseline and week 52; in the valsartan group, 100% of patients remained on randomized therapy and 44 had complete data at both timepoints. One death was recorded in the sacubitril/valsartan group.

At the conclusion of the trial, 91.3% and 100% of each group, respectively, were taking the target medication dose.

Investigators found that LVESVI decreased by 4.0±6.6 mL/m2 and 2.0±7.3 mL/m2 in each group, respectively, over the trial period (adjusted between-group difference, -1.9 mL/m2; 95% CI, -4.9 to 1.0). Results of a post-hoc analysis showed a “nominally significant” interaction between baseline NT-proBNP and randomized treatment effect, while subgroup analyses of patients at or below the median NT-proBNP level at baseline “suggested an effect” with sacubitril/valsartan therapy at or above the median, but not below the median (adjusted between-group difference, -5.1 mL/m2 and 1.3 mL/m2).

No significant between-group differences were noted at 52 weeks in either treatment group in terms of NT-proBNP or hs-cTnT. LVEDVI, left atrial volume index, and LV mass index all decreased to a greater degree in the sacubitril/valsartan group. However, no between-group differences were statistically significant.

Ninety-two patients had patient global assessment data available (n=46 in each group) at the conclusion of the study. Overall, 47.8 and 54.3% of each group reported an improvement in general well-being from baseline.

Compared with valsartan, sacubitril/valsartan increased plasma levels of ANP, midregional proadrenomedulin, GLP-1, galectin-3, and urinary cGMP. In particular, midregional proatrial natriuretic peptide was reduced significantly with sacubitril/valsartan therapy. No other significant between-group biomarker differences were noted.

Numerically, there were more cases of symptomatic hypotension in the sacubitril/valsartan group (7 vs 1), but no cases required permanent treatment discontinuation. Change in systolic blood pressure was -5.8±16.5 mmHg and 0.17±16.8 mmHg in each group, respectively, at 52 weeks. The between-group adjusted mean difference was -5.3 mmHg (95% CI, -11.5 to 1.0).

Study limitations include the recruitment of patients only with LVSD as a result of previous MI and the recruitment of patients 3 months after an acute MI event, limiting the conclusions that can be drawn during the early and distinctive remodeling phase. Additional limitations include the lack of patients with atrial fibrillation, the 52-week treatment period, and differences in patients studied and comparator therapy, meaning that findings are not directly comparable.

“The addition of a neprilysin inhibitor to standard therapy with a RAS inhibitor and [beta]-blocker did not have a significant reverse remodeling effect or improve biomarkers associated with LV wall stress or myocardial damage,” the researchers concluded. 

Disclosure: This clinical trial was supported by Novartis Pharmaceuticals UK Limited. Please see the original reference for a full list of authors’ disclosures.

Reference

Docherty KF, Campbell RT, Brooksbank KJM, et al. Effect of neprilysin inhibition on left ventricular remodeling in patients with asymptomatic left ventricular systolic dysfunction late after myocardial infarction. Circulation. 2021;144(3):199-209. doi:10.1161/CIRCULATIONAHA.121.054892