Effects of Angiotensin Receptor-Neprilysin Inhibitors Versus Enalapril or Valsartan on Patients With Heart Failure: A Systematic Review and Meta-Analysis

Abstract

Recent studies have focused on treating heart failure, primarily mitigating symptoms and reducing the risk of mortality and other cardiovascular complications. A promising new treatment approach involves using LCZ696, an angiotensin receptor-neprilysin inhibitor (ARNI) comprising sacubitril and valsartan. This treatment is superior to the conventional drugs enalapril or valsartan in patients diagnosed with heart failure. A systematic search was conducted on PubMed, the Cochrane Library, and Elsevier's ScienceDirect databases to identify studies comparing sacubitril/valsartan with other drugs in heart failure patients with reduced ejection fraction (HFrEF) and preserved ejection fraction (HFpEF). The analyses were conducted using the random-effects model. The study's primary outcomes included all-cause mortality, death from cardiovascular causes, first hospitalization for heart failure, congestive heart failure, and changes in the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical score. The pooled analysis showed that treatment with the sacubitril/valsartan combination was associated with a significantly decreased rate of first hospitalization for heart failure (RR: 0.86; 95% CI: 0.79, 0.98, p: 0.03; I2: 57%) and significantly increased KCCQ clinical score (WMD: 2.20; 95% CI: 0.33, 4.06, p: 0.02; I2: 100%). However, the two groups had no significant difference in all-cause mortality (RR: 0.90; 95% CI: 0.80, 1.01, p: 0.08; I2: 20%), death from cardiovascular causes (RR: 0.96; 95% CI: 0.87, 1.05, p: 0.34; I2: 0%), or congestive heart failure (RR: 0.97; 95% CI: 0.75, 1.25, p: 0.19; I2: 38%). The research findings suggest that sacubitril/valsartan (LCZ696) reduces hospitalizations due to heart failure and improves KCCQ clinical scores. This treatment also reduces the decline in renal function and side effects associated with enalapril or valsartan. Nonetheless, further high-quality randomized controlled trials with large sample sizes are needed to assess other impacts of this therapy on heart failure patients. Overall, the use of LCZ696 represents a promising new approach to the treatment of heart failure.

Keywords: angiotensin receptor–neprilysin inhibitors; arni; enalapril; heart failure; meta-analysis; sacubitril/valsartan; systematic review; valsartan.

Figure 1. Preferred reporting items for systematic reviews and meta-analyses (PRISMA).

PRISMA flow diagram illustrating the search strategy and study selection process for the meta-analysis. The initial search yielded 1,500 articles, which were subsequently screened for duplicates and evaluated based on title and abstract. Nine randomized controlled trials (RCTs) met the inclusion criteria for the analysis, with only comparative studies being included.

Figure 2. Quality assessment of the included randomized controlled trials.

Source: References [10-18].

Figure 3. Funnel plots for (A) all-cause mortality, (B) congestive heart failure.

SE: standard error, RR: relative risk.

Figure 4. Funnel plots for (A) death from cardiovascular causes, (B) change in Kansas City cardiomyopathy questionnaire (KCCQ) clinical score.

SE: standard error, RR: relative risk.

Figure 5. Funnel plot for first hospitalization for heart failure.

SE: standard error, RR: relative risk.

Figure 6. Forest plot of All-cause mortality.

The figure displays the non-significant results of the pooled analysis comparing the effects of sacubitril/valsartan combination treatment to the control group on all-cause mortality risk in heart failure patients. The analysis shows a trend towards a decreased risk of all-cause mortality with sacubitril/valsartan treatment, particularly in patients with a reduced ejection fraction. RR: Relative risk; CI: Confidence interval; M-H: Mantel Hansel. Source: References [10,11,13-16].

Figure 7. Forest plot of death from cardiovascular causes.

Figure illustrating the results of the pooled analysis, which showed no significant difference in death from cardiovascular causes between the two groups across four out of nine studies, regardless of ejection fraction. RR: Relative risk; CI: Confidence interval; M-H: Mantel Hansel. Source: References [10,13,15,17].

Figure 8. Forest plot of the first hospitalization for heart failure.

Figure demonstrating the pooled analysis results revealed a significantly lower rate of first hospitalization for heart failure in the sacubitril valsartan group compared to the control group across four out of nine studies. Subgroup analysis showed this effect was particularly significant in patients with a preserved ejection fraction. RR: Relative risk; CI: Confidence interval; M-H: Mantel Hansel. Source: References [10,11,13,15,17].

Figure 9. Forest plot of congestive heart failure.

Figure displaying the results of the pooled analysis, which demonstrated no significant difference in the number of patients with congestive heart failure following treatment between the sacubitril valsartan group and control group across four out of nine studies, irrespective of ejection fraction. RR: Relative risk; CI: Confidence interval; M-H: Mantel Hansel Source: References [10,11,13,14].

Figure 10. Forest plot of change in Kansas City cardiomyopathy questionnaire (KCCQ) clinical score.

Figure presenting the results of the pooled analysis, which showed a significantly higher KCCQ clinical score following treatment with the sacubitril/valsartan combination compared to the control group across four studies WMD: weighted mean difference; CI: Confidence interval; M-H: Mantel Hansel Source: References [10,12,13,15].