The Efficacy and Safety of Sacubitril/Valsartan Compared to Valsartan in Patients with Heart Failure and Mildly Reduced and Preserved Ejection Fractions: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Abstract

Background: Sacubitril/valsartan improves heart failure (HF) outcomes in patients with heart failure with reduced ejection fraction (HFrEF). However, randomized controlled trials (RCTs) in patients with heart failure and mildly reduced ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF) have shown inconsistent results. We conducted this meta-analysis to comprehensively evaluate the efficacy and safety of sacubitril/valsartan compared to valsartan within this specific patient population. Methods: We searched the MEDLINE database and ClinicalTrials.gov and identified four RCTs that could be included in our analysis, with 3375 patients in the sacubitril/valsartan group and 3362 in the valsartan group. Results: Our study shows that, in patients with HFmrEF and HFpEF, sacubitril/valsartan was superior to valsartan in some of the key HF outcomes, such as the Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ CSS), with a small but significant mean difference of 1.13 (95% confidence interval or CI of 0.15 to 2.11, p-value 0.024), an improvement in the New York Heart Association (NYHA) class (odds ratio or OR of 1.32, 95% CI 1.11 to 1.58, p-value 0.002), and the composite outcome of hospitalizations for HF and cardiovascular death, with a relative risk (RR) of 0.86 (95% CI 0.75 to 0.99, p-value 0.04). However, there was no additional benefit with sacubitril/valsartan compared to valsartan for the outcomes of cardiovascular death and all-cause mortality. In terms of side effects, sacubitril/valsartan was associated with a higher risk of hypotension when compared to valsartan (OR 1.67, 95% CI 1.27 to 2.19, p-value < 0.0001), but did not show an increased risk of hyperkalemia or worsening renal function. Conclusions: In individuals with HFmrEF or HFpEF, sacubitril/valsartan can result in improvements in the HF outcomes of the KCCQ CSS, the NYHA class, and the composite outcome of hospitalization for HF and cardiovascular death when compared to valsartan. While there was a higher risk of hypotension with sacubitril/valsartan compared to valsartan, there was no corresponding increase in the risk of hyperkalemia or worsening renal function.

Keywords: ARNI; HFmrEF; HFpEF; angiotensin receptor-neprilysin inhibitor; heart failure; heart failure with mildly reduced ejection fraction; heart failure with preserved ejection fraction; sacubitril/valsartan; valsartan.

Figure 1

PRISMA algorithm, showing the selection of studies for this meta-analysis. PRISMA—Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Figure 2

The risk of bias for the four studies, assessed using version 2 of the Cochrane risk-of-bias tool (ROB2) [10,11,12,13].

Figure 3

Forest plot showing the change in KCCQ CSS with sacubitril/valsartan compared to valsartan in patients with HFmrEF and HFpEF. KCCQ CSS—Kansas City cardiomyopathy questionnaire clinical summary score, HFmrEF—heart failure with mildly reduced ejection fraction, HFpEF—heart failure with preserved ejection fraction, and ARNI—angiotensin receptor-neprilysin inhibitor, SD—standard deviation, MD—mean difference, CI—confidence interval. In the forest plot, dark blue squares represent the point estimates, and the size of the square is a function of the weight given to each study in the meta-analysis. Horizontal solid black lines represent 95% CI. The bottom light blue diamonds represent the summary estimates, with the width of the diamond illustrating the 95% CI [11,12].

Figure 4

Forest plot showing the participants with improved NYHA class with sacubitril/valsartan compared to valsartan in patients with HFmrEF and HFpEF. NYHA—New York Heart Association, HFmrEF—heart failure with mildly reduced ejection fraction, HFpEF—heart failure with preserved ejection fraction, and ARNI—angiotensin receptor-neprilysin inhibitor, OR—odds ratio, SE—standard error, CI—confidence interval. In the forest plot, dark blue squares represent the point estimates, and the size of the square is a function of the weight given to each study in the meta-analysis. Horizontal solid black lines represent 95% CI. The bottom light blue diamonds represent the summary estimates, with the width of the diamond illustrating the 95% CI [11,12].

Figure 5

Forest plot showing the composite outcome of hospitalizations for heart failure and cardiovascular death with sacubitril/valsartan compared to valsartan in patients with HFmrEF and HFpEF. HFmrEF—heart failure with mildly reduced ejection fraction, HFpEF—heart failure with preserved ejection fraction, and ARNI—angiotensin receptor-neprilysin inhibitor, RR—relative risk, SE—standard error, CI—confidence interval. In the forest plot, dark blue squares represent the point estimates, and the size of the square is a function of the weight given to each study in the meta-analysis. Horizontal solid black lines represent 95% CI. The bottom light blue diamonds represent the summary estimates, with the width of the diamond illustrating the 95% CI [11,13].

Figure 6

Forest plot showing the outcome of cardiovascular death with sacubitril/valsartan compared to valsartan in patients with HFmrEF and HFpEF. HFmrEF—heart failure with mildly reduced ejection fraction, HFpEF—heart failure with preserved ejection fraction, and ARNI—angiotensin receptor-neprilysin inhibitor, RR – relative risk, CI – confidence interval. In the forest plot, dark blue squares represent the point estimates, and the size of the square is a function of the weight given to each study in the meta-analysis. Horizontal solid black lines represent 95% CI. The bottom light blue diamonds represent the summary estimates, with the width of the diamond illustrating the 95% CI [11,13].

Figure 7

Forest plot showing the outcome of all-cause mortality with sacubitril/valsartan compared to valsartan in patients with HFmrEF and HFpEF. HFmrEF—heart failure with mildly reduced ejection fraction, HFpEF—heart failure with preserved ejection fraction, and ARNI—angiotensin receptor-neprilysin inhibitor. RR—relative risk, CI—confidence interval. In the forest plot, dark blue squares represent the point estimates, and the size of the square is a function of the weight given to each study in the meta-analysis. Horizontal solid black lines represent 95% confidence intervals (CI). The bottom light blue diamonds represent the summary estimates, with the width of the diamond illustrating the 95% CI [10,11,12].

Figure 8

Forest plot showing the adverse event of hypotension with sacubitril/valsartan compared to valsartan in patients with HFmrEF and HFpEF. HFmrEF—heart failure with mildly reduced ejection fraction, HFpEF—heart failure with preserved ejection fraction, and ARNI—angiotensin receptor-neprilysin inhibitor. OR—odds ratio, SE—standard error, CI—confidence interval. In the forest plot, dark blue squares represent the point estimates, and the size of the square is a function of the weight given to each study in the meta-analysis. Horizontal solid black lines represent 95% CI. The bottom light blue diamonds represent the summary estimates, with the width of the diamond illustrating the 95% CI [10,11,12,13].

Figure 9

Forest plot showing the adverse event of hyperkalemia with sacubitril/valsartan compared to valsartan in patients with HFmrEF and HFpEF. HFmrEF—heart failure with mildly reduced ejection fraction, HFpEF—heart failure with preserved ejection fraction, and ARNI—angiotensin receptor-neprilysin inhibitor. OR—odds ratio, SE—standard error, CI—confidence interval. In the forest plot, dark blue squares represent the point estimates, and the size of the square is a function of the weight given to each study in the meta-analysis. Horizontal solid black lines represent 95% CI. The bottom light blue diamonds represent the summary estimates, with the width of the diamond illustrating the 95% CI [10,11,12,13].

Figure 10

Forest plot showing the adverse event of worsening renal function with sacubitril/valsartan compared to valsartan in patients with HFmrEF and HFpEF. HFmrEF—heart failure with mildly reduced ejection fraction, HFpEF—heart failure with preserved ejection fraction, and ARNI—angiotensin receptor-neprilysin inhibitor. OR—odds ratio, SE—standard error, CI—confidence interval. In the forest plot, dark blue squares represent the point estimates, and the size of the square is a function of the weight given to each study in the meta-analysis. Horizontal solid black lines represent 95% CI. The bottom light blue diamonds represent the summary estimates, with the width of the diamond illustrating the 95% CI [10,11,12,13].