A meta-analysis of the effects of sacubitril-valsartan on surrogate markers of systemic right ventricular dysfunction in congenital heart disease

Abstract Introduction Dysfunction of systemic right ventricle (sRV) in adult congenital heart disease (ACHD) patients is expectable and often associated with heart failure and other dismal cardiovascular events. Despite limited evidence, several neurohormonal modulators approved for heart failure with reduced ejection fraction (HFrEF) have been used off-label in patients with RV dysfunction1. Sacubitril-valsartan (ARNI) effects on sRV remains poorly studied, with current evidence being limited to small cohorts. Purpose Review and summarize current evidence about the effects of ARNI in ACHD patients with sRV. Methods We performed a systematic review on MEDLINE, EMBASE, COCHRANE, and SCOPUS for articles that included "systemic right ventricle" and "sacubitril valsartan" until January 2024. Two investigators screened the literature and extracted data. Treatment effects were measured by Cohen's d effect-size (EZ) pre and post-ARNI, with a 95% confidence interval (CI), using a restricted maximum likelihood model. Results From 197 publications screened, five studies fulfilled our criteria, comprising a total of 135 patients. Follow-up after ARNI therapy ranged from 12 to 27 months. No randomized clinical trials were found, and only two studies had a prospective design. Dextro-transposition of the great arteries (D-TGA) after atrial switch operation was the most common type of congenital heart disease with sRV (n=95; 70%). Meta-analysis demonstrates that ARNI reduced NT-proBNP levels during follow-up (EZ= -0.34, CI -0.59 to 0.08; p=0.01; I2=4.0%). Regarding RV function, ARNI improved RV fractional area change (RVFAC) (EZ= 0.75, CI 0.01 to 1.50; p= 0.048; I2=85.0%). A trend for RV global longitudinal strain improvement was also observed with ARNI (EZ= 1.74, CI -0.05 to 3.54; p=0.06; I2=95.9%) but not for tricuspid annular plane systolic excursion (EZ= -0.07, CI -0.33 to 0.20; p=0.62; I2=0.0%). RV diastolic diameter did not change significantly with ARNI (EZ= 0.07, CI -0.43 to 0.56; p=0.79; I2=68.2%). A trend for improvement on the 6-minute walk test was observed (EZ= 1.89, CI -0.13 to 3.91; p=0.07; I2=96.3%), but no effect on exercise oxygen consumption (VO2) (EZ= -0.09, CI -1.32 to 1.15; p=0.89; I2=91.4%). During follow-up ARNI did not change significantly systolic blood pressure (EZ= -0.32, CI -0.74 to 0.11; p=0.15; I2=58.4%) or serum creatinine (EZ= 0.23, CI -0.04 to 0.49; p=0.09; I2=0.0%). Conclusions Despite heterogeneity among these studies, this meta-analysis demonstrates that ARNI might improve NT-proBNP levels and RV function. ARNI seems safe and well tolerated, with no significant effect on blood pressure and renal function. More well-powered studies are needed to confirm the beneficial effects of ARNI in ACHD with sRV.