The Role of ARNI in Enhancing Outcomes of Cardiac Resynchronization Therapy: A Comprehensive Review

Background/Objectives: Cardiac resynchronization therapy (CRT) and angiotensin receptor–neprilysin inhibitors (ARNIs) are cornerstone therapies for patients with heart failure with reduced ejection fraction (HFrEF). However, nearly 30% of patients show no significant response to CRT alone. The potential of ARNI to enhance CRT outcomes—especially in non-responders—is an emerging field of interest. The objective of this review is to systematically evaluate and synthesize the available evidence on the clinical outcomes of combining CRT with ARNI therapy in patients with HFrEF. Methods: We conducted a comprehensive search of PubMed, Scopus, and Google Scholar up to September 2024, using the keywords “CRT and ARNI” and “cardiac resynchronization therapy and sacubitril/valsartan”. We included retrospective and prospective clinical studies, observational studies, and review articles reporting on patients with HFrEF treated with both CRT and ARNI. Studies not in English, animal studies, and those without full-text availability were excluded. Study selection and data extraction were performed in duplicate by independent reviewers, using PRISMA guidelines for transparency. The final selection included 8 studies published in the last four years, summarized by design, population, outcomes, and statistical significance. Results: The reviewed studies suggest that ARNI therapy, when combined with CRT, may contribute to improvements in left ventricle ejection fraction (LVEF), NYHA functional class, and ventricular remodeling, particularly in CRT non-responders. Some studies also report a potential reduction in ventricular arrhythmias and implantable cardioverter-defibrillator (ICD) interventions. However, outcomes varied across subgroups, and the influence of ARNI timing relative to CRT implantation remains inconclusive. Limitations: Heterogeneity in study designs and small sample sizes in some included studies limited the ability to conduct a meta-analysis. This review is not registered. Conclusions: ARNI therapy shows promise in enhancing CRT response in patients with HFrEF, particularly in non-responders. Further large-scale, prospective studies are needed to clarify optimal patient selection and treatment sequencing.