SGLT2i with ARNi versus RASi in heart failure with reduced ejection fraction: Improved survival and reduced...

The management of heart failure with reduced ejection fraction (HFrEF) has advanced with the introduction of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and angiotensin receptor-neprilysin inhibitors (ARNi). However, direct comparisons between combination therapies using SGLT2i plus ARNi versus SGLT2i plus conventional renin-angiotensin system inhibitors (RASi) remain limited.

This retrospective cohort study included 2985 HFrEF patients receiving SGLT2i with either ARNi (n = 1542) or RASi (n = 1443) between 2016 and 2022. Inverse probability of treatment weighting was applied to balance baseline characteristics. The primary outcomes included all-cause mortality, cardiovascular death, heart failure hospitalization (HFH), and renal function decline.

Over a median follow-up of 1.1 years, SGLT2i + ARNi was associated with significantly lower all-cause mortality compared to SGLT2i + RASi [hazard ratio (HR): 0.81; 95 % confidence interval (CI): 0.67-0.97]. Risk of cardiovascular death (HR: 0.95; 95 % CI: 0.85-1.0), HFH (subdistribution HR: 0.95; 95 % CI: 0.85-1.06), and renal function decline (subdistribution HR: 0.96; 95 % CI: 0.82-1.13) were comparable between groups. The incidence of hyperkalemia was significantly lower with SGLT2i + ARNi (subdistribution HR: 0.38; 95 % CI: 0.27-0.54). Subgroup analysis revealed a more pronounced survival benefit of SGLT2i + ARNi among patients without heart failure hospitalization in the prior year (HR = 0.58 vs. 0.87; p for interaction = 0.041).

Among patients with HFrEF receiving SGLT2i therapy, concomitant use of ARNi was associated with a significant reduction in all-cause mortality, comparable cardiovascular and renal outcomes, and a lower risk of hyperkalemia compared to RASi. These findings support the preferential use of ARNi over RASi as background therapy in SGLT2i-treated HFrEF patients.