Effect of Sacubitril/Valsartan on the Right Ventricular Function and Pulmonary Hypertension in Patients With Heart Failure With Reduced Ejection Fraction: A Systematic Review and Meta-Analysis of Observational Studies.

Background Sacubitril/valsartan (S/V) demonstrated significant effects in improving left ventricular performance and remodeling in patients with heart failure with reduced ejection fraction. However, its effects on the right ventricle remain unclear. This systematic review and meta-analysis aimed to assess the impact of S/V on right ventricular function and pulmonary hypertension. Methods and Results We searched PubMed, Embase, Cochrane Library, and Web of Science from January 2010 to April 2021 for studies reporting right ventricular and pulmonary pressure indexes following S/V treatment. The quality of included studies was assessed using the Newcastle-Ottawa scale. Variables were pooled using a random-effects model to estimate weighted mean differences with 95% CIs. We identified 10 eligible studies comprising 875 patients with heart failure with reduced ejection fraction (mean age, 62.2 years; 74.0% men), all of which were observational. Significant improvements on right ventricular function and pulmonary hypertension after S/V initiation were observed, including tricuspid annular plane systolic excursion (weighted mean difference, 1.26 mm; 95% CI, 0.33-2.18 mm; P=0.008), tricuspid annular peak systolic velocity (weighted mean difference, 0.85 cm/s; 95% CI, 0.25-1.45 cm/s; P=0.005), and systolic pulmonary arterial pressure (weighted mean difference, 7.21 mm Hg; 95% CI, 5.38-9.03 mm Hg; P<0.001). Besides, S/V had a significant beneficial impact on left heart function, which was consistent with previous studies. The quadratic regression model revealed a certain correlation between tricuspid annular plane systolic excursion and left ventricular ejection fraction after excluding the inappropriate data (P=0.026). Conclusions This meta-analysis verified that S/V could improve right ventricular performance and pulmonary hypertension in heart failure with reduced ejection fraction, which did not seem to be fully dependent on the reverse remodeling of left ventricle. Registration URL: https://www.crd.york.ac.uk/prospero; Unique identifier: CRD42021247970.

heart failure with reduced ejection fraction

mean pulmonary arterial pressure

pulmonary hypertension

right ventricular dysfunction

sacubitril/valsartan

tricuspid annular peak systolic velocity

systolic pulmonary arterial pressure

tricuspid annular plane systolic excursion

weighted mean difference

Clinical Perspective

What Is New?

Sacubitril/valsartan has shown significant effects in improving left ventricular performance and remodeling in patients with heart failure with reduced ejection fraction; however, its effects on the right ventricle remain unclear.

Our systematic review and meta‐analysis demonstrated that sacubitril/valsartan could improve right ventricular function and pulmonary hypertension in patients with heart failure with reduced ejection fraction, which did not seem to be fully dependent on the reverse remodeling of left ventricle.

What Are the Clinical Implications?

Our meta‐analysis suggested a beneficial effect of sacubitril/valsartan on right heart function for patients with heart failure with reduced ejection fraction in clinical practice.

Multicenter and randomized controlled trials on large cohorts are needed to better elucidate the efficacy and safety of sacubitril/valsartan on the right ventricular system in patients with heart failure with reduced ejection fraction and determine whether the improvement in right ventricular function is exclusively mediated by the improvement in left heart function.

Over the past decades, heart failure with reduced ejection fraction (HFrEF) has attracted considerable attention worldwide because of high morbidity and mortality. Sacubitril/valsartan (S/V), a kind of angiotensin receptor neprilysin inhibitor, was recommended by the 2021 European Society of Cardiology Guidelines as a first‐line therapy for suitable patients with HFrEF, following the results in the PARADIGM‐HF (Prospective Comparison of ARNI with ACEI to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial, which prospectively compared angiotensin receptor neprilysin inhibitor versus angiotensin‐converting enzyme inhibitor to determine the impact on overall mortality and morbidity in HFrEF.

Because of the diverse causes and pathogenesis, it is common for patients with HFrEF to have coexisting right ventricular (RV) dysfunction (RVD). Cardiomyopathy and coronary artery disease could involve both ventricles simultaneously. The passive transmission of elevated left‐sided filling pressure in patients with HFrEF also contributes to adverse changes in the pulmonary vasculature and right heart. Besides, the prevalence of pulmonary hypertension (PH) was reported to be between 40% and 75% in HFrEF. ,

RVD plays a crucial role and indicates a poor prognosis in the progression of HFrEF. Dini et al have confirmed that RV recovery during follow‐up was associated with improved survival in patients with HFrEF. Thus, the therapeutic effect on the right heart should also be concerned when treating HFrEF. To date, the effects of S/V on the left heart function have already been discovered, but its effects on the right heart function remain unclear. Several preclinical trials , showed that S/V could reduce pulmonary pressures, improve vascular remodeling, and prevent maladaptive RV remodeling as well, in the Sugen5416/hypoxia or pulmonary artery banding rat model. Some observational studies , reported that these beneficial effects were also seen in patients with HFrEF in clinical practice. Nevertheless, Bayard et al failed to establish any benefits of S/V on RV function. Thus, the effects of S/V on the RV systems remain controversial.

In this context, we conducted a meta‐analysis to evaluate the impact of S/V on RV function and PH in patients with HFrEF, as well as on left heart function and biomarkers.

METHODS

Meta‐Analysis Protocol

Our study protocol was registered on PROSPERO (International Prospective Register of Systematic Reviews; CRD42021247970). The methods used in practice did not deviate in any way from the prespecified methods in our analysis. We followed the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses and the Meta‐Analysis of Observational Studies in Epidemiology guidelines during all stages of design, implementation, and reporting (Preferred Reporting Items for Systematic Reviews and Meta‐Analyses and Meta‐Analysis of Observational Studies in Epidemiology Checklist). The methods used in the analysis and materials used to conduct the research are available from the corresponding author on reasonable request.

Study Selection

Inclusion criteria were as follows:

Adult patients (aged >18 years) with HFrEF.

Patients subjected to “S/V” treatment at the beginning of the trial.

Patients with baseline and follow‐up data for at least 1 RV function or pulmonary pressure index.

Follow‐up duration for at least 3 months.

Measurement methods were restricted to echocardiography.

Editorials, letters, comments, review articles, case reports, and studies consisting of <10 patients were excluded. Studies in which patients had congenital heart diseases were also excluded. Two independent authors (J.Z. and L.D.) were responsible for performing the study selection process according to titles, abstracts, and full texts, and disagreements were resolved by consultation with a third reviewer (X.G.).

Information Sources and Search Strategy

Two authors (J.Z. and X.Q.) independently performed a systematic search of PubMed, Embase, Cochrane Library, and Web of Science from January 2010 to April 2021. Search terms included “sacubitril‐valsartan,” “angiotensin receptor‐neprilysin inhibitor,” “heart failure,” and “heart decompensation.” The search was restricted to “article.” There were no language restrictions. The complete list of search terms used in each database is outlined in Data S1. We also screened the reference lists of included studies for additional eligible studies not retrieved by our search. Moreover, the search was rerun before the final analysis. All citations were exported to Endnote Reference Manager version X9 (Clarivate Analytics).

Data Extraction

Data extraction was performed independently by 2 authors (J.Z. and L.D.). Any disagreements were resolved by consulting a third author (X.G.). The following data were collected: the first author, year of publication, country, study design, treatments of control groups, sample size, patient characteristics (age, sex, mean baseline systolic blood pressure, and heart failure [HF] cause), settings (advanced or chronic HF), methods of measurement, and follow‐up duration. Three kinds of indexes were then extracted (RV function and PH, left heart function, and biomarker), comprising baseline and follow‐up data.

We extracted indexes representing RV function, including tricuspid annular plane systolic excursion (TAPSE) and tricuspid annular peak systolic velocity (S’), and indexes reflecting pulmonary circulation, including systolic pulmonary arterial pressure (sPAP) and mean pulmonary arterial pressure (mPAP). Meanwhile, indexes of left heart function included left ventricular (LV) ejection fraction (LVEF) and LV end‐diastolic volume (LVEDV). As for biomarkers, we selected NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), which could reflect wall stress.

Risk of Bias

Two independent authors (J.Z. and L.D.) assessed the risk of bias and quality of included studies using the Newcastle‐Ottawa scale for observational studies. Disagreements were resolved in consultation with a third author (X.G.). We assessed the following 3 items: selection of cohort (0–4 stars), comparability (0–2 stars), and outcome (0–3 stars), with overall scores of <5 stars, 5 to 7 stars, and >7 stars indicating high, moderate, and low risk of bias, respectively.

Outcome Measures and Statistical Analysis

The main outcomes were changes in RV function and PH (TAPSE, S’, sPAP, and mPAP), left heart function (LVEF and LVEDV), and NT‐proBNP during the follow‐up period. These indexes were all continuous variables, primarily expressed as mean±SD.

Analyses were performed using the Stata 15.1 software package. Continuous variables were pooled using a random‐effects model to estimate weighted mean differences (WMDs) with 95% CIs, which were plotted as forest plots. Between‐study heterogeneity was quantified using the Cochrane I2 statistic, with I2=25% to 50%, 50% to 75%, and >75%, indicating mild, moderate, and severe heterogeneity, respectively. Each study's effect on the overall effect size was assessed by a sensitivity analysis using the leave‐one‐out approach. Multivariate random‐effects meta‐regression analysis was performed to explore the sources of heterogeneity between studies. Subgroup analysis was conducted on the basis of HF cause (proportion of patients with ischemic heart disease >50% or ≤50%), mean age (>70 or ≤70 years), country (Italy or others), follow‐up durations (>6 or ≤6 months), study design (prospective or retrospective), and sample size (>100 or ≤100). Egger regression tests with a visual inspection of the funnel plot were used to test for publication bias. , P<0.05 was considered statistically significant.

Another outcome was the relationship between changes in the RV system and the left heart function. First, we used the Shapiro‐Wilk test to detect whether the data were normally distributed. If so, Pearson correlation was used. If not, Spearman correlation was used. Analyses were operated using SPSS 26.

RESULTS

Literature Search and Baseline Characteristics

Our literature search identified 3670 publications from January 2010 to April 2021. Following the removal of 1729 duplicates, the titles and abstracts of the remaining 1941 records were screened for eligibility. Of these, we excluded a further 1738 articles. Thus, 10 studies were included in the quantitative and qualitative analyses, with a total of 875 patients, all of which were observational. The literature search process is detailed in the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses flowchart (Figure S1).

The baseline characteristics are presented in Table 1. The year of publication was between 2018 and 2020. The mean age of included patients was 62.2 years, and 74.0% of them were men. The included subjects were all patients with HF with ejection fractions of ≤40%. The mean follow‐up duration ranged from 3 to 17.1 months. Of the 10 included studies, 6 , , , , , were prospective, and 4 , , , were retrospective. One study had a control group that received angiotensin‐converting enzyme inhibitor, whereas the others had no control group. Because it was not meaningful to analyze the only study with a control group separately, we decided to extract the experimental group data from it. Six studies , , , , , were from Italy, one was from Turkey, one was from France, one was from Greece, and one was from Slovenia.

Table 1

Study and Patient Characteristics

First author (y)	Country	Study design	Interventions and controls	Patients, n	Settings	Age, mean±SD, y	Men, %
Nakou (2018) 24	Greece	Observational study (prospectively)	ARNI ACEI	48	Chronic HFrEF	68±10	60.4
Cacciatore (2020) 22	Italy	Observational study (prospectively)	ARNI	37	Advanced HF	57.7±7.6	89.2
Bayard (2019) 15	France	Observational study (prospectively)	ARNI	41	HFrEF	70±10	75.6
Correale (2020) 13	Italy	Observational study (prospectively)	ARNI	60	HFrEF	66±9	88
Poglajen (2020) 25	Slovenia	Observational study (prospectively)	ARNI	228	HFrEF	57±11	83
Mazzetti (2020) 23	Italy	Observational study (prospectively)	ARNI	30	HFrEF	64±10.7	70
Villani (2020) 27	Italy	Observational study (retrospectively)	ARNI	69	HFrEF	67±12	93
Yenercag (2021) 28	Turkey	Observational study (retrospectively)	ARNI	150	HFrEF	63.1±12.5	54
Landolfo (2020) 26	Italy	Observational study (retrospectively)	ARNI	49	HFrEF	76±11	71.4
Masarone (2020) 14	Italy	Observational study (retrospectively)	ARNI	163	HFrEF	57.9±12.3	68.1

ACEI indicates angiotensin‐converting enzyme inhibitor; ARNI, angiotensin receptor neprilysin inhibitor; HF, heart failure; HFrEF, HF with reduced ejection fraction; LVEDV, left ventricular end‐diastolic volume; LVEF, left ventricular ejection fraction; mPAP, mean pulmonary arterial pressure; NA, not applicable; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; S’, tricuspid annular peak systolic velocity; SBP, systolic blood pressure; sPAP, systolic pulmonary arterial pressure; and TAPSE, tricuspid annular plane systolic excursion.

Risk‐of‐Bias Assessment and Publication Bias

The Newcastle‐Ottawa scale scores of the included studies are shown in Table S1, ranging from 6 to 9. Most included studies , , , , , , , , had a moderate risk of bias because of the lack of a control group, 4 , , , of which had a higher risk of bias because of the nature of the retrospective studies. The risk of bias was shown to be low in only one study.

With regard to publication bias, we conducted funnel plot analysis for indexes with at least 10 studies and Egger regression for all indexes. The funnel plot of LVEF was basically symmetrical (Figure S2). No significant publication bias was indicated by Egger regression for all indexes (P>0.05).

Effects of S/V on RV Function and PH

The pooled data from 8 studies , , , , , , , (732 patients) showed increases in TAPSE (WMD, 1.26 mm; 95% CI, 0.33 to 2.18 mm; I2=78.3%; Figure 1 and Table S2). Two studies , (186 patients) reported data on S’, which was improved after the treatment with S/V (WMD, 0.85 cm/s; 95% CI, 0.25–1.45 cm/s; I2=0.0%; Figure 1 and Table S2). Changes in sPAP (419 patients) and mPAP (350 patients) were available in 6 , , , , , and 2 , trials, respectively. We observed significant reductions in sPAP (WMD, 7.21 mm Hg; 95% CI, 5.38–9.03 mm Hg; I2=0%; Figure 1 and Table S2) and mPAP (WMD, 2.92 mm Hg; 95% CI, 0.66–5.19 mm Hg; I2=67.9%; Figure 1 and Table S2). All results were statistically significant (P<0.05).

Figure 1

Forest plots showing changes in tricuspid annular plane systolic excursion (TAPSE), tricuspid annular peak systolic velocity (S’), systolic pulmonary arterial pressure (sPAP), and mean pulmonary arterial pressure (mPAP).

ARNI indicates angiotensin receptor neprilysin inhibitor; ID, identifier; WMD, weighted mean difference; and DL, DerSimonian‐Laird, a method of the random‐effects model.

Effects of S/V on Left Heart Function and NT‐proBNP

The pooled data from 10 studies , , , , , , , , , (850 patients) showed increases in LVEF (WMD, 4.40%; 95% CI, 2.21%–6.60%; I2=93.0%; Figure 2 and Table S3). Five studies , , , , (313 patients) reported data on LVEDV. The mean LVEDV decreased by 19.37 mL (95% CI, 5.44–33.30 mL; I2=44.8%; Figure 2 and Table S3). NT‐proBNP was reported in 4 studies , , , (316 patients), which was significantly decreased following S/V (WMD, 739.42 ng/dL; 95% CI, 558.08–920.76 ng/dL; I2=15.6%; Figure 2 and Table S3).

Figure 2

Forest plots showing changes in left ventricular ejection fraction (LVEF), left ventricular end‐diastolic volume (LVEDV), and NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide).

ARNI indicates angiotensin receptor neprilysin inhibitor; ID, identifier; WMD, weighted mean difference; and DL, DerSimonian‐Laird, a method of the random‐effects model.

Sensitivity Analysis

Results of sensitivity analysis using the leave‐one‐out approach were consistent with those of the initial analysis. Therefore, we thought our results had good robustness and extrapolation.

Meta‐Regression and Subgroup Analysis

Multivariate meta‐regression analysis revealed that the sample size might contribute to the heterogeneity observed in TAPSE (P<0.05; Table 2). In addition, mean age, HF cause, and sample size were also found to be possible sources of heterogeneity in LVEF (P<0.05; Table 2). Meta‐regression was not performed for others because of the low number of studies reporting those indexes.

Table 2

Results of Random‐Effects Meta‐Regression Analysis

Covariate	TAPSE		LVEF
	Coefficient	P value	Coefficient	P value
Mean age, y	0.203	0.125	1.227	0.004*
HF cause, %	−6.562	0.054	−31.150	0.015*
Sample size	0.022	0.016*	0.051	0.026*

HF indicates heart failure; LVEF, left ventricular ejection fraction; and TAPSE, tricuspid annular plane systolic excursion.

Statistically significant.

The results of subgroup analysis are presented in Tables 3 and 4. The proportion of patients with ischemic heart disease >50%, retrospective design, and sample size >100 showed statistically significant improvements in TAPSE, and the increases were also seen in both short‐ and long‐term follow‐up (Figures S3 through S5). Moreover, the I2 statistic of TAPSE was reduced to 0% when the analysis was conducted in accordance with HF cause, country, follow‐up duration, and study design (Figure 3). In terms of sPAP, the results of subgroup analysis conducted on the basis of 6 baseline characteristics were all statistically significant. Improvements in LVEF were also meaningful in most subgroups. NT‐proBNP seemed to decline significantly in studies with patients with ischemic heart disease >50%.

Table 3

Subgroup Analysis of Changes of TAPSE and sPAP Following Treatment With S/V

Subgroup	No. of studies	TAPSE, mm	sPAP, mm Hg
Cause
Ischemic heart diseases >50%	6	1.13 (0.70 to 1.57), I²=0%, z=5.10 (P=0.000)	−7.98 (−10.08 to −5.87), I²=0%, z=−7.43 (P=0.000)
Ischemic heart diseases ≤50%	4	1.44 (−0.75 to 3.63), I²=86%, z=1.29 (P=0.198)	−4.88 (−8.54 to −1.23), I²=0%, z=−2.62 (P=0.009)
Age, y
>70	1	NA	−6.40 (−10.94 to −1.86), z=−2.76 (P=0.006)
≤70	9	1.26 (0.33 to 2.18), I²=92%, z=2.66 (P=0.008)	−7.36 (−9.36 to −5.35), I²=1%, z=−7.19 (P=0.000)
Country
Italy	6	1.07 (0.40 to 1.74), I²=0%, z=3.15 (P=0.002)	−7.24 (−9.36 to −5.12), I²=4%, z=−6.69 (P=0.000)
Others	4	1.60 (−0.04 to 3.24), I²=89%, z=1.91 (P=0.056)	−7.00 (−10.92 to −3.08), z=−3.50 (P=0.000)
Follow‐up duration, mo
>6	6	1.71 (0.02 to 3.40), I²=87%, z=1.99 (P=0.047)	−7.24 (−9.36 to −5.12), I²=4%, z=−6.69 (P=0.000)
≤6	4	1.03 (0.53 to 1.53), I²=0%, z=4.06 (P=0.000)	−7.00 (−10.92 to −3.08), z=−3.50 (P=0.000)
Study design
Retrospective	4	1.24 (0.77 to 1.72), I²=0%, z=5.15 (P=0.000)	−8.37 (−10.86 to −5.88), I²=0%, z=−6.58 (P=0.000)
Prospective	6	1.13 (−0.46 to 2.72), I²=83%, z=1.40 (P=0.163)	−5.87 (−8.54 to −3.19), I²=0%, z=−4.30 (P=0.000)
Sample size
>100	3	2.14 (0.56 to 3.72), I²=92%, z=2.65 (P=0.008)	−9.20 (−12.51 to −5.89), z=−5.44 (P=0.000)
≤100	7	0.60 (−0.17 to 1.37), I²=0%, z=1.53 (P=0.125)	−6.34 (−8.52 to −4.15), I²=0%, z=−5.69 (P=0.000)

Weighted mean differences are pooled estimates with 95% CIs. I2 values were reported as a measure of heterogeneity. Z scores with associated P values were reported as a test for the overall effect. Ischemic heart disease >50% meant the proportion of patients with heart failure caused by ischemic heart disease was >50% in one study. Ischemic heart disease ≤50% meant the proportion of patients with heart failure caused by ischemic heart disease was ≤50% in one study. NA indicates not applicable; sPAP, systolic pulmonary arterial pressure; S/V, sacubitril/valsartan; and TAPSE, tricuspid annular plane systolic excursion.

Table 4

Subgroup Analysis of Changes of LVEF and NT‐proBNP Following Treatment With S/V

Subgroup	No. of studies	LVEF, %	NT‐proBNP, ng/dL
Cause
Ischemic heart diseases >50%	6	4.19 (1.43 to 6.96), I²=94%, z=2.97 (P=0.003)	−726.32 (−856.67 to −595.97), I²=0%, z=−10.92 (P=0.000)
Ischemic heart diseases ≤50%	4	4.76 (1.68 to 7.84), I²=78%, z=3.03 (P=0.002)	−1775.71 (−3674.27 to 122.84), I²=36%, z=−1.83 (P=0.067)
Age, y
>70	1	16.50 (13.16 to 19.84), z=9.68 (P=0.000)	NA
≤70	9	3.10 (1.47 to 4.74), I²=86%, z=3.73 (P=0.000)	−739.42 (−920.76 to −558.08), I²=73%, z=−7.99 (P=0.000)
Country
Italy	6	5.70 (1.92 to 9.48), I²=92%, z=2.95 (P=0.003)	−1107.46 (−2198.07 to −16.85) I²=44%, z=−1.99 (P=0.047)
Others	4	2.83 (−0.22 to 5.87), I²=94%, z=1.82 (P=0.069)	−731.60 (−878.69 to −584.51), z=−9.75 (P=0.000)
Follow‐up duration, mo
>6	6	5.83 (2.49 to 9.16), I²=93.1%, z=3.43 (P=0.001)	−1107.46 (−2198.07 to −16.85), I²=44%, z=−1.99 (P=0.047)
≤6	4	1.77 (0.10 to 3.45), I²=62.0%, z=2.07 (P=0.038)	−731.60 (−878.69 to −584.51), z=−9.75 (P=0.000)
Study design
Retrospective	4	5.54 (1.64 to 9.45), I²=96%, z=2.78 (P=0.005)	−726.32 (−856.67 to −595.97), I²=0%, z=−10.92 (P=0.000)
Prospective	6	3.64 (0.98 to 6.30), I²=85%, z=2.68 (P=0.007)	−1775.71 (−3674.27 to 122.84), I²=36%, z=−1.83 (P=0.067)
Sample size
>100	3	3.44 (0.27 to 6.61), I²=96%, z=2.13 (P=0.033)	−731.60 (−878.69 to −584.51), z=−9.75 (P=0.000)
≤100	7	4.99 (1.32 to 8.66), I²=92%, z=2.67 (P=0.008)	−1107.46 (−2198.07 to −16.85), I²=44%, z=−1.99 (P=0.047)

Weighted mean differences are pooled estimates with 95% CIs. I2 values were reported as a measure of heterogeneity. Z scores with associated P values were reported as a test for the overall effect. Ischemic heart disease >50% meant the proportion of patients with heart failure caused by ischemic heart disease was >50% in one study. Ischemic heart disease ≤50% meant the proportion of patients with heart failure caused by ischemic heart disease was ≤50% in one study. LVEF indicates left ventricular ejection fraction; NA, not applicable; NT‐proBNP, N‐terminal pro‐B‐type natriuretic peptide; and S/V, sacubitril/valsartan.

Figure 3

Forest plots for subgroup analysis of tricuspid annular plane systolic excursion, according to heart failure cause, country, follow‐up duration, study design, and sample size.

ARNI indicates angiotensin receptor neprilysin inhibitor; ID, identifier; WMD, weighted mean difference; and DL, DerSimonian‐Laird, a method of the random‐effects model.

Correlation Analysis

To test whether the improvements in the RV system correlated with those in the left heart function, we did a correlation analysis. After performing the Shapiro‐Wilk test, we adopted Pearson correlations for 2 pairs of indexes (TAPSE and LVEDV; sPAP and LVEDV), and the potential relationships between others were calculated using Spearman correlations.

There was no significant correlation of improvements between RV system and left heart indexes (TAPSE and LVEF, r=0.359, P=0.382; TAPSE and LVEDV, r=0.310, P=0.690; sPAP and LVEF, r=0.543, P=0.266; sPAP and LVEDV, r=0.427, P=0.573) (Figure S6). Nevertheless, a distinct correlation between sPAP and LVEDV (r=1.000) emerged after removing one significantly deviated data point in the scatterplot. Although the scatterplot of TAPSE and LVEF also showed one deviated data point, the preliminary analysis after the data point was discarded did not show a significant correlation. Subsequently, a certain correlation appeared to be found in the quadratic regression model for TAPSE and LVEF (P=0.026). The regression equation was y=1.09−0.87x+0.18x 2 (Figure 4).

Figure 4

Fitting curve using quadratic curve model to explore the relationship between tricuspid annular plane systolic excursion (TAPSE) and left ventricular ejection fraction (LVEF) changes.

 

DISCUSSION

As far as we know, this present study comprising 875 patients is the first meta‐analysis to evaluate the effects of S/V on RV function and PH in patients with HFrEF, which included all appropriate studies to date. The pooled results showed that S/V significantly improved TAPSE and S’, and reduced sPAP and mPAP as well. The former 2 indexes reflect the functional state of the right ventricle, whereas the latter directly reflect the state of the pulmonary circulation. We also observed remarkable improvements in LVEF and reductions in LVEDV, reflecting the benefits of S/V on left heart function, which were in line with the conclusion reported in a previous meta‐analysis.

The mechanisms by which S/V improves RV function and PH have not been fully elucidated. However, the pathogenesis of RVD with the pharmacological mechanism of S/V could offer several possible explanations. The pathogenesis of RVD in HFrEF could be artificially divided into 3 categories: pressure overload, ischemic heart disease, and cardiomyopathy. In a pressure‐overload RV, to accommodate the increased afterload, adaptive cardiomyocyte hypertrophy initially occurs, with subsequent oxygen supply‐demand imbalance and RV ischemia, gradually leading to RV fibrosis, RV dilation, and clinical decompensation eventually. Neurohormonal activation (upregulation of angiotensin II, adrenergic overstimulation, and increased expression of natriuretic peptides), oxidative stress, and cell death play pivotal roles throughout the whole RVD progression. Besides, with regard to arrhythmogenic right ventricular cardiomyopathy being a model of RV cardiomyopathy, it was reported that the upregulated expression of transforming growth factor‐β1 acting downstream of angiotensin II could induce the fibrotic gene expression in vivo, leading to RV fibrosis. , , Sacubitril/valsartan, as the name implies, has dual effects: inhibition of neprilysin and inactivation of the renin‐angiotensin‐aldosterone system. Through inactivation of many neurohormones, such as angiotensin II, aldosterone, and endothelin‐1, modulation of gene expression, such as transforming growth factor‐β1, and promotion of reendothelization, S/V leads to natriuresis, vasodilation, and antiapoptotic, antifibrotic, anti‐inflammatory, and antithrombotic reactions, as well as decreased cardiac hypertrophy, and ultimately improves cardiac decompensation. , , In short, S/V might improve RV function by inducing RV function recovery and decreasing its afterload by multiple mechanisms, which has been demonstrated in a preclinical study.

We conducted subgroup analysis to find the sources of heterogeneity among studies and described the differences of pooled results between the subgroups. HF cause, country, follow‐up duration, and study design contributed to the heterogeneity observed in TAPSE. Interestingly, we observed significant improvements in TAPSE in patients with ischemic heart disease, and significant decreases of sPAP and NT‐proBNP were also found in this population. Together with the significant improvement of S' observed in the ischemic population, our findings suggest that S/V might have better therapeutic effects on the right heart in HFrEF caused by ischemic heart disease than those with nonischemic causes. Notably, this finding might be explained by the hypothesis that the neprilysin level may be higher in such a population, providing more targets for S/V and thus leading to better improvements. More studies are needed to clarify the underlying mechanisms in the future. However, Balmforth et al concluded that the benefits of S/V on the primary composite outcome and cardiovascular mortality over enalapril were similar across causative categories in the analysis of PARADIGM‐HF. It could be explained that the clinical outcomes are influenced by multiple factors, including but not limited to right heart dysfunction. Analysis stratified by follow‐up duration showed striking effects of S/V on all 4 indexes in both short‐ and long‐term follow‐up. This suggested that S/V had a rapid therapeutic effect within 6 months. In a prospective pilot study of 13 patients with HFrEF, Khan et al also observed a short‐term reduction in pulmonary arterial pressure at 1‐week follow‐up after S/V initiation. The PIONEER‐HF (Angiotensin‐Neprilysin Inhibition in Acute Decompensated Heart Failure) trial showed that the greater reduction in the NT‐proBNP concentration was evident as early as week 1. Consequently, it is of great benefit for eligible patients to initiate therapy as early as possible. Notably, because of the small sample size, these results should be interpreted with caution.

The correlation analysis showed a possible relationship between improvements of the RV system and LV reverse remodeling. We found that the improvements in sPAP may depend on that in LVEDV, confirming what Correale et al previously discovered, that sPAP changes were proportional to LV end‐systolic volume changes. It could be explained in such a way that the improved left ventricle reduced the backward transmission of left‐sided filling pressure to the pulmonary circulation, resulting in lower pulmonary arterial pressure. Interestingly, the nonlinear correlation for the quadratic model indicated better improvement in TAPSE was in accordance with that in LVEF within a certain scope. Only when LVEF improves to a certain extent will TAPSE improves. Besides, the scatterplot of TAPSE and LVEDV also showed a delayed improvement trend rather than a linear correlation. This nonlinear relationship makes us speculate that the beneficial effects of S/V on RV function might be related to the reverse remodeling of the LV and a direct effect on the right heart. As we mentioned above, the results need to be interpreted cautiously because of the small sample size. Hence, further studies are necessary to confirm the role of S/V in the treatment of isolated RV dysfunction independent of LV remodeling.

Limitations

Certainly, the present meta‐analysis has several limitations. First, the main limitation was that the included studies were all observational, which did not have the power to infer cause and effect. Although only one included study had a control group, nearly all patients were treated with stable angiotensin‐converting enzyme inhibitor or angiotensin receptor blocker doses for a certain period before S/V initiation, and after switching to S/V, we have observed incremental improvements. Second, inherent to many meta‐analyses, the sample sizes of most included studies were small. Third, because of the restricted numbers of studies about the effect of S/V on the right heart system, the published year and region of studies included in our analysis were relatively concentrated. Hence, because of several limitations, the results of this meta‐analysis should be interpreted cautiously.

CONCLUSIONS

This meta‐analysis suggested a new therapeutic role for S/V, and verified that S/V could improve RV function and PH in HFrEF, which did not seem to be fully dependent on the reverse remodeling of LV. Moreover, these effects may be particularly pronounced in patients with ischemic heart disease. S/V had a significant therapeutic effect on both LV and RV function within 6 months, increasing over time. It is of extreme importance for eligible patients to initiate S/V therapy as early as possible. Multicenter and randomized controlled trials on large cohorts are needed to better elucidate the efficacy and safety of S/V on the RV system in patients with HFrEF and determine whether the improvement in RV function is exclusively mediated by improvement in left heart function.

Sources of Funding

This work was supported by the National Natural Science Foundation of China (82170397).

Disclosures

None.

Data S1

Tables S1–S3

Figures S1–S6

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