Efficacy and safety profile of angiotensin receptor neprilysin inhibitors in the management of heart failure: a systematic review and meta-analysis of randomized controlled trials

Study selection

In primary screening, we retrieved 108 full-text studies, which, after removal of duplicates, become 103 studies. These studies undergone secondary screening in addition to the three articles retrieved from the bibliography of the screened articles. Finally, we included data from 34 studies satisfying the inclusion criteria (Fig. 1) [22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55].

Fig. 1figure 1Study characteristics

Only RCTs were included in the review. Most studies (17 out of 34 studies) were conducted in China, followed by United States (US) and multi-country studies. The mean age of study participants in the intervention arm ranged from 53 to 74.4 years, while that in the control arm ranged from 55 to 75.9 years. The sample sizes amongst the included studies varied from 16 to 4187 in the intervention arm and 15 to 4212 in the control arm (Table 1).

Table 1 Characteristics of the included studies (N = 34)Risk of bias assessment

Almost one-third of studies (11 out of 34 studies) had a low risk of bias with respect to randomization process and deviation from intended intervention. Only nine studies had a low risk of bias with respect to missing outcome data. Majority of the studies had a high risk of bias with respect to selective reporting of results and measurement of outcomes. Most studies (22 out of 34 studies) had a higher risk of bias (Table 2).

Table 2 Risk of bias assessment (N = 34)Efficacy parametersAll-cause mortality

In total, 17 studies with 19,176 participants have reported on the efficacy of sacubitril–valsartan on the all-cause mortality amongst heart failure patients. The pooled RR was 0.88 (95% CI: 0.82 to 0.95; I2 = 0%), indicating that the patients receiving sacubitril–valsartan had a significantly lower risk of having all-cause mortality when compared to patients receiving standard care or placebo (p = 0.001) (Fig. 2).

Fig. 2figure 2

Forest plot showing the difference in all-cause mortality between sacubitril–valsartan and control group patients

Subgroup analysis based on the status of ejection fraction revealed that the patients with reduced ejection fraction had a significant reduction in all-cause mortality (pooled RR = 0.85; 95% CI: 0.78–0.93; p < 0.001), while patients with preserved or medium ejection fraction had non-significant reduction in all-cause mortality (pooled RR = 0.91; 95% CI: 0.67–1.22; p = 0.52) following administration of sacubitril–valsartan (Supplementary Fig. 1). Subgroup analysis based on the control group showed that the sacubitril–valsartan showed maximum efficacy against placebo or usual care arm (pooled RR = 0.22; 95% CI: 0.05–0.94; p = 0.04) followed by ACE inhibitors (pooled RR = 0.85; 95% CI: 0.78–0.93; p < 0.001), while it was non-significant against ARBs (pooled RR = 0.96; 95% CI: 0.84–1.10; p = 0.56) (Supplementary Fig. 2). Only one study was conducted amongst acute heart failure patients while the rest of the studies are conducted amongst chronic heart failure patients. Hence, subgroup analysis based on the duration of heart failure could not be conducted for any of the outcomes. Subgroup analysis based on the dose of sacubitril–valsartan could not be performed as one study each has used a dose of 50 mg and 100 mg, while the rest of the studies used a dose of 200 mg twice daily.

Assessment of publication bias revealed a symmetrical funnel plot with non-significant Egger’s test (p = 0.30), indicating the absence of publication bias (Supplementary Fig. 3). Meta-regression was not performed as there was no statistical heterogeneity for the all-cause mortality outcome.

Cardiovascular mortality

In total, 10 studies with 14,909 participants have reported on the efficacy of sacubitril–valsartan on the cardiovascular mortality amongst heart failure patients. The pooled RR was 0.84 (95% CI: 0.77 to 0.92; I2 = 0%), indicating that the patients receiving sacubitril–valsartan had a significantly lower risk of having cardiovascular mortality when compared to patients receiving any other medications (p < 0.001) (Fig. 3).

Fig. 3figure 3

Forest plot showing the difference in cardiovascular mortality between sacubitril–valsartan and control group patients

Subgroup analysis based on the status of ejection fraction revealed that the patients with reduced ejection fraction had a significant reduction in cardiovascular mortality (pooled RR = 0.81; 95% CI: 0.73–0.90; p < 0.001), while patients with preserved or medium ejection fraction had non-significant reduction in all-cause mortality (pooled RR = 0.95; 95% CI: 0.79–1.13; p = 0.54) following administration of sacubitril–valsartan (Supplementary Fig. 4). Subgroup analysis based on the control group showed that the sacubitril–valsartan showed maximum efficacy against ACE inhibitors (pooled RR = 0.81; 95% CI: 0.73–0.90; p < 0.001), while it was non-significant against ARBs (pooled RR = 0.95; 95% CI: 0.79–1.14; p = 0.60) (Supplementary Fig. 5). Subgroup analysis based on the dose of sacubitril–valsartan could not be performed as almost all the studies for this outcome used a dose of 200 mg twice daily.

Assessment of publication bias revealed a symmetrical funnel plot with non-significant Egger’s test (p = 0.50), indicating the absence of publication bias (Supplementary Fig. 6). Meta-regression was not performed as there was no statistical heterogeneity for the cardiovascular mortality outcome.

Hospitalization

In total, 14 studies with 15,866 participants have reported on the efficacy of sacubitril–valsartan on the rate of hospitalization amongst heart failure patients. The pooled RR was 0.78 (95% CI: 0.70 to 0.87; I2 = 23%), indicating that the patients receiving sacubitril–valsartan had a significantly lower risk of having hospitalizations when compared to patients receiving any other medications (p < 0.001) (Fig. 4).

Fig. 4figure 4

Forest plot showing the difference in hospitalization between sacubitril–valsartan and control group patients

Subgroup analysis based on the status of ejection fraction revealed that the patients with either reduced ejection fraction or preserved ejection fraction had a significant reduction in hospitalizations following the administration of sacubitril–valsartan (Supplementary Fig. 7). Subgroup analysis based on the control group also showed that the administration of sacubitril–valsartan was efficacious against ACE inhibitors and ARBs for hospitalizations (Supplementary Fig. 8). Subgroup analysis based on the dose of sacubitril–valsartan could not be performed as almost all the studies for this outcome used a dose of 200 mg twice daily.

Assessment of publication bias revealed an asymmetrical funnel plot with significant Egger’s test (p = 0.04), indicating the presence of publication bias (Supplementary Fig. 9). Meta-regression was not performed as there was only mild statistical heterogeneity for the hospitalization outcome.

Quality of life

In total, 3 studies with 3080 participants have reported on the efficacy of sacubitril–valsartan on the quality of life amongst heart failure patients. The pooled SMD was 0.04 (95% CI: − 0.03 to 0.11; I2 = 0%), indicating no significant difference between sacubitril–valsartan and control group patients in terms of quality of life (p = 0.23) (Supplementary Fig. 10). Subgroup analysis and publication bias assessment could not be performed due to limitation in the number of studies.

Improvement in NYHA functional status

In total, 6 studies with 7854 participants have reported on the efficacy of sacubitril–valsartan on the improvement in NYHA functional status amongst heart failure patients. The pooled RR was 1.21 (95% CI: 0.99 to 1.47; I2 = 58.9%), indicating no significant difference between sacubitril–valsartan and control group patients in terms of improvement in NYHA functional status (p = 0.06) (Supplementary Fig. 11). Subgroup analysis and publication bias assessment could not be performed due to limitation in the number of studies.

Echocardiographic parametersLVEF

In total, 15 studies with 1994 participants have reported on the efficacy of sacubitril–valsartan on the LVEF amongst heart failure patients. The pooled MD was 3.74 (95% CI: 1.93 to 5.55; I2 = 89.4%), indicating that the patients receiving sacubitril–valsartan had significantly higher LVEF when compared to patients receiving any other medications (p < 0.001) (Fig. 5A).

Fig. 5figure 5

Forest plot showing the difference in echocardiographic parameters between sacubitril–valsartan and control group patients. A Left ventricular ejection fraction. B Left atrial volume index. C Left ventricular end-diastolic dimension. D E/E′ ratio

Subgroup analysis based on the status of ejection fraction cannot be performed as all the studies reporting this outcome were conducted amongst reduced ejection fraction patients. Subgroup analysis based on the control group showed that the administration of sacubitril–valsartan was efficacious in improving LVEF irrespective of the type of control medications (ACE inhibitors/ARBs/placebos/conventional treatment) (Supplementary Fig. 12). Subgroup analysis based on the dose of sacubitril–valsartan showed that the 50 mg and 100 mg twice daily dosages showed significant improvement in LVEF, while studies with 200 mg twice daily dosage did not show statistical significance in the improvement of LVEF (Supplementary Fig. 13).

Assessment of publication bias revealed a symmetrical funnel plot with non-significant Egger’s test (p = 0.84), indicating the absence of publication bias (Supplementary Fig. 14). Univariable meta-regression was performed with variables such as country/study region, follow-up duration, dose of sacubitril–valsartan and type of control group. Amongst these variables, sacubitril–valsartan dose and control group had a p value less than 0.20 and it was included in the multivariable meta-regression model. The multivariable meta-regression model with these two variables was able to explain about 80% of the between-study variability.

LAVI

In total, 4 studies with 913 participants have reported on the efficacy of sacubitril–valsartan on the LAVI amongst heart failure patients. The pooled MD was −2.16 (95% CI: −3.58 to −0.74; I2 = 0%), indicating that the patients receiving sacubitril–valsartan had significantly lower LAVI when compared to patients in the control group (p = 0.003) (Fig. 5B). Subgroup analysis and publication bias assessment could not be performed due to limitation in the number of studies.

LVED

In total, 7 studies with 668 participants have reported on the efficacy of sacubitril–valsartan on the LVED amongst heart failure patients. The pooled MD was −3.80 (95% CI: −6.60 to −1.00; I2 = 96.8%), indicating that the patients receiving sacubitril–valsartan had significantly lower LVED when compared to patients in the control group (p = 0.008) (Fig. 5C). Subgroup analysis, meta-regression and publication bias assessment could not be performed due to limitation in the number of studies.

E/E′ ratio

In total, 4 studies with 913 participants have reported on the efficacy of sacubitril–valsartan on the E/E′ ratio amongst heart failure patients. The pooled MD was −1.16 (95% CI: −1.98 to −0.35; I2 = 96.8%), indicating that the patients receiving sacubitril–valsartan had a significantly lower E/E′ ratio when compared to patients in the control group (p = 0.005) (Fig. 5D). Subgroup analysis, meta-regression and publication bias assessment could not be performed due to limitation in the number of studies.

Arrhythmia endpointsAtrial arrhythmias

In total, 6 studies with 17,053 participants have reported on the efficacy of sacubitril–valsartan on the atrial arrhythmias amongst heart failure patients. The pooled RR was 1.05 (95% CI: 0.93 to 1.17; I2 = 0%), indicating no significant difference between sacubitril–valsartan and control group patients in terms of atrial arrhythmias (p = 0.43) (Fig. 6A). Subgroup analysis and publication bias assessment could not be performed due to limitation in the number of studies.

Fig. 6figure 6

Forest plot showing the difference in arrhythmia endpoints between sacubitril–valsartan and control group patients. A Atrial arrhythmia. B Ventricular arrhythmia

Ventricular arrhythmias

In total, 4 studies with 1402 participants have reported on the efficacy of sacubitril–valsartan on the ventricular arrhythmias amongst heart failure patients. The pooled RR was 1.69 (95% CI: 0.38 to 7.54; I2 = 0%), indicating no significant difference between sacubitril–valsartan and control group patients in terms of ventricular arrhythmias (p = 0.49) (Fig. 6B). Subgroup analysis and publication bias assessment could not be performed due to limitation in the number of studies.

Adverse eventsSymptomatic hypotension

In total, 13 studies with 19,150 participants have reported on the safety of sacubitril–valsartan against symptomatic hypotension amongst heart failure patients. The pooled RR was 1.55 (95% CI: 1.31 to 1.85; I2 = 57.9%), indicating that the patients receiving sacubitril–valsartan had a significantly higher risk of having symptomatic hypotension when compared to patients receiving any other medications (p < 0.001) (Fig. 7A).

Fig. 7figure 7

Forest plot showing the difference in adverse events between sacubitril–valsartan and control group patients. A Symptomatic hypotension. B Worsening renal function. C Hyperkalaemia. D Angioedema

Subgroup analysis based on the status of ejection fraction revealed that the patients with either reduced ejection fraction or preserved ejection fraction had a significantly higher risk of symptomatic hypotension following the administration of sacubitril–valsartan (Supplementary Fig. 15). Subgroup analysis based on the control group also showed that the administration of sacubitril–valsartan had a higher risk of symptomatic hypotension when compared to ACE inhibitors or ARBs (Supplementary Fig. 16). Subgroup analysis based on the dose of sacubitril–valsartan could not be performed as almost all the studies for this outcome used a dose of 200 mg twice daily. Assessment of publication bias revealed a symmetrical funnel plot with non-significant Egger’s test (p = 0.86), indicating the absence of publication bias (Supplementary Fig. 17).

Worsening of renal function

In total, 12 studies with 18,940 participants have reported on the safety of sacubitril–valsartan against worsening of renal function amongst heart failure patients. The pooled RR was 0.93 (95% CI: 0.78 to 1.11; I2 = 35.2%), indicating that the patients receiving sacubitril–valsartan did not have a significantly higher risk of having worsening of renal function when compared to patients receiving any other medications (p = 0.42) (Fig. 7B).

Subgroup analysis based on the status of ejection fraction revealed that the patients with either reduced ejection fraction or preserved ejection fraction did not have a higher risk of worsening of renal function following the administration of sacubitril–valsartan (Supplementary Fig. 18). Subgroup analysis based on the control group showed that the administration of sacubitril–valsartan had a significantly lower risk of worsening renal function (pooled RR = 0.79; 95% CI: 0.68–0.92) when compared to ARBs (Supplementary Fig. 19). Subgroup analysis based on the dose of sacubitril–valsartan could not be performed as almost all the studies for this outcome used a dose of 200 mg twice daily. Assessment of publication bias revealed a symmetrical funnel plot with non-significant Egger’s test (p = 0.87), indicating the absence of publication bias (Supplementary Fig. 20).

Hyperkalaemia

In total, 11 studies with 18,866 participants have reported on the safety of sacubitril–valsartan against hyperkalaemia amongst heart failure patients. The pooled RR was 1.09 (95% CI: 0.94 to 1.26; I2 = 49.6%), indicating that the patients receiving sacubitril–valsartan did not have a significantly higher risk of having hyperkalaemia when compared to patients receiving any other medications (p = 0.42) (Fig. 7C).

Subgroup analysis based on the status of ejection fraction revealed that the patients with either reduced ejection fraction or preserved ejection fraction did not have a higher risk of hyperkalaemia following the administration of sacubitril–valsartan (Supplementary Fig. 21). Subgroup analysis based on the control group also did not show any difference in the risk of hyperkalaemia depending on the type of control group (Supplementary Fig. 22). Subgroup analysis based on the dose of sacubitril–valsartan could not be performed as almost all the studies for this outcome used a dose of 200 mg twice daily. Assessment of publication bias revealed an asymmetrical funnel plot with significant Egger’s test (p = 0.007), indicating the presence of publication bias (Supplementary Fig. 23).

Angioedema

In total, 8 studies with 18,289 participants have reported on the safety of sacubitril–valsartan against angioedema amongst heart failure patients. The pooled RR was 1.29 (95% CI: 0.67 to 2.50; I2 = 23.7%), indicating that the patients receiving sacubitril–valsartan did not have a significantly higher risk of having angioedema when compared to patients receiving any other medications (p = 0.44) (Fig. 7D). Subgroup analysis and publication bias assessment could not be performed due to limitation in the number of studies.

Blood parameterNT-proBNP

In total, 9 studies with 2149 participants have reported on the efficacy of sacubitril–valsartan on the NT-proBNP amongst heart failure patients. The pooled MD was −0.70 (95% CI: −1.06 to −0.34; I2 = 92.2%), indicating that the patients receiving sacubitril–valsartan had significantly lower NT-proBNP when compared to patients in the control group (p < 0.001) (Fig. 8). Subgroup analysis, meta-regression and publication bias assessment could not be performed due to limitation in the number of studies.

Fig. 8figure 8

Forest plot showing the difference in NT-proBNP between sacubitril–valsartan and control group patients

Additional analysis

Sensitivity analysis has showed that there was no significant difference in the outcome in terms of magnitude of association or its direction for any of the above-mentioned outcomes.

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