The Role of Sacubitril/Valsartan and Gliflozins in Heart Failure with Reduced Ejection Fraction after Cardiac Resynchronization Therapy

BACKGROUND The angiotensin receptor-neprilysin inhibitor (ARNi) and the sodium- glucose co-transporter 2 inhibitors (SGLT2i) have improved the outcome of patients with heart failure and reduced ejection fraction (HFrEF). However, data characterizing their effectiveness after cardiac resynchronization therapy (CRT) implant are relatively scarce. This study investigated the impact of ARNi and SGLT2i treatment 1) on CRT response at 12 months 2) on the cardiac function and the clinical functional status (NYHA class) at mid- and long-term follow-up 3) on the cardiac and overall survival at long-term follow-up. METHODS AND RESULTS HFrEF patients referred for CRT implant were enrolled in the study and were grouped by the ARNi/SGLT2i therapy. A first analysis investigated the synergistic impact of these drugs started at implant on 1-year CRT response and included all 172 patients enrolled. In order to evaluate whether the time of ARNi/SGLT2i initiation after CRT response assessment is meaningful, a second analysis considered 100 patients with a follow-up ≥ 24 months. The median follow-up was 63.1 (confidence interval [CI] 95%, 52.7 - 73.8) months. At 1-year follow-up, 40 of 51 (78.4%) patients in ARNi or SGLT2i group and 66 of 121 (54.5%) in the no treatment group were classified as responders (p = 0.006). In multivariable analysis, ARNi/SGLT2i use was an independent predictor of CRT response (odds ratio, 5.38; CI 95%, 2-16.2; p = 0.001). At mid-term follow-up (median time [interquartile range, IQR] 40.6 [25.2; 58.3] months), 61 patients started to assume these drugs. NYHA functional class improved in 23 (37.7%) patients and decreased in only 2 (3.3%) in ARNi/SGLT2i patients vs 13 (33.3%) in no treatment group (p < 0.001). ARNi and SGLT2i improved significantly also the Δ LVEF, with a median [IQR] increase of 4 [2; 8] % compared to the no treatment group - 1.8 [-4; 0.2] % (p < 0.001) and were independently associated with a NYHA functional class II or I at long-term (hazard ratio [HR], 3.67; CI 95%, 1.37-10.2; p < 0.001). Their estimated effectiveness was consistent over the entire follow-up period (Schoenfeld residuals test, p = 0.10), although without reaching statistical significance effects on cardiovascular survival (HR, 0.61; CI 95%, 0.25-1.50; p = 0.22). CONCLUSIONS The ARNi and SGLT2i treatment in CRT patients improves the clinical and echocardiographic response at 12-month and long-term follow-up, independently from the time of initiation. These drugs also confer benefit on survival, however further studies are needed to confirm these data. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial This trial is a retrospective study and it was not registered. ### Funding Statement Dr. Giuseppe Ammirati received a grant from the CardioPath Ph.D. programme. Non external funding was received for any aspect of the submitted work. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Not Applicable The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Institutional Ethics Committee Carlo Romano of Federico II University of Naples. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Not Applicable I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Not Applicable I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Not Applicable The data that support the findings of this study are available from the corresponding author upon reasonable request. The corresponding author has full access to all the data in the study and takes responsibility for its integrity and the data analysis. * ARNi : Angiotensin receptor-neprilysin inhibitor COPD : Chronic obstructive pulmonary disease CRT : Cardiac resynchronization therapy HF : Heart failure HFrEF : Heart failure and reduced ejection fraction ICM : Ischemic cardiomyopathy LVEF : Left ventricular ejection fraction LVESV : Left ventricular end-systolic volume NICM : Non-ischemic cardiomyopathy SGLT2i : Sodium-glucose co-transporter 2 inhibitors