Effects of the Angiotensin-Receptor Neprilysin Inhibitor on Cardiac Reverse Remodeling: Meta-Analysis

Abstract

Background The angiotensin-receptor neprilysin inhibitor (ARNI) sacubitril/valsartan was shown to be superior to the angiotensin-converting enzyme inhibitor enalapril in terms of reducing cardiovascular mortality in the PARADIGM-HF (Prospective Comparison of ARNI with angiotensin-converting enzyme inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) study. However, the impact of ARNI on cardiac reverse remodeling (CRR) has not been established. Methods and Results We conducted a meta-analysis to compare the effects of ARNI versus angiotensin-converting enzyme inhibitors or angiotensin receptor blockers on CRR indices. We searched databases for studies published between 2010 and 2019 that reported CRR indices following ARNI administration. Effect size was expressed as mean difference (MD) with 95% CIs. Twenty studies enrolling 10 175 patients were included. ARNI improved functional capacity in patients with heart failure (HF) and a reduced ejection fraction (EF), including increasing New York Heart Association functional class (MD -0.79, 95% CI -0.86, -0.71) and 6-minute walking distance (MD 27.62 m, 95% CI 15.76, 39.48). ARNI outperformed angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in terms of CRR indices, with striking changes in left ventricular EF, diameter, and volume. However, there were no significant improvements in indices except left ventricular mass index (MD -3.25 g/m², 95% CI -3.78, -2.72) and left atrial volume (MD -7.20 mL, 95% CI -14.11, -0.29) in HF patients with preserved EF treated with ARNI. Improvements in CRR indices were observed at 3 months and became more significant with longer follow-up to 12 months. The regression equation for the relationship between left ventricular EF and end-diastolic dimension was y=0.041+0.071x+0.045x²+0.006x³. Conclusions ARNI distinctly improved left ventricular size and hypertrophy compared with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers in HF with reduced EF patients, even after short-term follow-up. Patients appeared to benefit more in terms of CRR treated with ARNI as early as possible and for at least 3 months. Further large sample trials are required to determine the effects of ARNI on CRR in HF with preserved EF patients.

Keywords: angiotensin‐receptor neprilysin inhibitor; cardiac reverse remodeling; end‐diastolic dimension; heart failure with a reduced ejection fraction; meta‐analysis.

Figure 1

PRISMA (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses) flow diagram showing detailed study selection process.

Figure 2

Forest plot showing changes in functional capacity including (A) NYHA functional class, (B) 6MWD following ARNI, and (C) changes of NYHA functional class comparing ARNI with ACEIs/ARBs. 6MWD indicates 6‐minute walking distance; ACEI, angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin‐receptor neprilysin inhibitor; df, degrees of freedom; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; IV, intravenous; NYHA, New York Heart Association.

Figure 3

Forest plots for (A) effect of ARNI on LVEF and (B) other CRR indices of HFrEF patients. ARNI indicates angiotensin‐receptor neprilysin inhibitor; df, degrees of freedom; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; IV, intravenous; LAV, left atrial volume; LVEF, left ventricular ejection fraction; LVEDD, left ventricular end‐diastolic dimension; LVEDV, left ventricular end‐diastolic volume; LVESD, left ventricular end‐systolic dimension; LVESV, left ventricular end‐systolic volume; LVMI, left ventricular mass index.

Figure 4

Forest plots for effect of ARNI on remodeling indexes (LVESV, LVEDV, LVESD, LVEDD, LAV, LVMI) (A) in HFpEF patients following ARNI and (B) effect of ARNI on LVEF compared with ACEIs/ARBs. ACEI indicates angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin‐receptor neprilysin inhibitor; df, degrees of freedom; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; IV, intravenous; LAV indicates left atrial volume; LVEDV, left ventricular end‐diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end‐systolic volume; LVMI, left ventricular mass index.

Figure 5

Forest plots for effect of ARNI on main remodeling indices (LVESV, LVEDV, LVESD, LVEDD, LAV, LVMI) (A) in HFrEF patients and (B) in HFpEF patients following ARNI compared with ACEIs/ARBs. ACEI indicates angiotensin‐converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin‐receptor neprilysin inhibitor; df, degrees of freedom; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; IV, intravenous; LAV, left atrial volume; LVEDD, left ventricular end‐diastolic dimension; LVEDV, left ventricular end‐diastolic volume; LVESD, left ventricular end‐systolic dimension; LVESV, left ventricular end‐systolic volume; LVMI, left ventricular mass index.

Figure 6

Fitting curve using cubic curve model to explore the relationship between LVEF and EDD changes. EDD indicates end‐diastolic dimension; LVEF, left ventricular ejection fraction.