Time-dependent survival effectiveness of Sacubitril/Valsartan and Gliflozins in heart failure with reduced ejection fraction after cardiac resynchronization therapy

Abstract Time-dependent Survival Effectiveness of Sacubitril/Valsartan and Gliflozins in Cardiac Resynchronization Therapy Recipients Aims Robust evidence validating the long-term efficacy of Sacubitril/valsartan (ARNi), gliflozins (SGLT2i), and cardiac resynchronization therapy (CRT) combination remains scarce and data suggesting a synergistic advantage of these drugs alongside CRT have not considered their time-varying administration, leading to the well-known immortal bias, since only patients with longer initial survival could commence these treatments (Panel A in the Figure). This single-center longitudinal cohort study aimed to examine survival impacts of ARNi and SGLT2i in HFrEF patients after CRT implantation. Methods 183 HFrEF patients consecutively admitted for CRT implantation between January 2015 and August 2022 were included. To account for patients who started or discontinued ARNi and/or SGLT2i at different time points during the study period, guided by the gradual emergence of scientific evidence (Panel B), an adapted Kaplan-Meier survival function and Cox regression models were constructed, updating the patient’s status to compare mortality rates during off-therapy with on-therapy periods. Results Of the 183 patients enrolled (81% men; median [IQR] age at CRT implantation: 67.2 [60.8-75.5] years), 62 were already receiving the drugs at the enrollment. During a median follow-up (CI 95%) of 7.1 (6.6-8.1) years, an additional 54 ARNi and 68 SGLT2i were prescribed, resulting in a total of 33, 13 and 78 patients in ARNi, SGLT2i and both drugs, respectively (Panel B). In total, 73 (40%) patients died, with 54 (30%) deaths related to HFrEF. Specifically, 37 occurred in no drugs group (total person-years:525) and 17 in ARNi/SGLT2i recipients (total person-years: 413). Time-dependent Cox regression analysis revealed a significant reduction in HF-related mortality risk associated with ARNi use, also confirmed after adjusting for confounders (HR 0.5 [CI 95%, 0.2-0.9; p=0.029]). To corroborate sacubitril/valsartan efficacy irrespective of the timing of prescription, as sensitivity analysis we compared only patients who started ARNi concomitantly or after CRT implantation, vs no drugs group: remarkably, Cox regression models showed a comparable reduction in HF-related mortality risk (HR 0.3, CI 95% 0.1-0-6, p=004; and HR 0.4, CI 95% 0.2-0.8, p=0.02, respectively). Prescribing SGLT2i did not affect survival, although the shorter periods of patients in gliflozins compared to ARNi or no drugs groups (p<0.001) requires cautious interpretation of these data. 1-year response to CRT remained the strongest predictor of lower mortality (p<0.001) (Panel C). Conclusions Using appropriate time-dependent analysis, ARNi improved survival regardless of whether prescribed at the time of CRT or during follow-up. Further studies are needed to conclusively determine the role of gliflozins in this setting of patients (Panel D).