Risk of Hyperkalemia in Patients with Heart Failure Treated with Spironolactone in Combination with Sacubitril/Valsartan vs. Renin–Angiotensin System Inhibitors

We aimed to compare the risk of hyperkalemia in patients with heart failure initiating spironolactone while receiving sacubitril/valsartan vs. those initiating while on a RASi in a real‐world clinical setting among a heterogeneous population. We conducted a new‐user, active comparator cohort study of patients with heart failure initiating spironolactone from April 1, 2016, to July 31, 2024, using a large national commercial insurance database. Patients were classified as RASi users (continuous ACEi/ARB use ≥30 days prior to and including spironolactone initiation) or ARNI users (continuous sacubitril/valsartan use over the same period). Propensity score based fine‐stratification weighting was used for confounding control. Outcomes included hyperkalemia (serum potassium >5.5 mmol/L) and severe hyperkalemia (>6 mmol/L), assessed over a maximum follow‐up of 180 days. About 57,926 patients initiated spironolactone: 8,589 while on ARNI (mean age: 70.6 years, 39.5% female) and 49,337 while on RASi (mean age: 72.8 years, 48.6% female). Incidence rates (95% confidence intervals) for hyperkalemia were lower among ARNI users (9.44 (8.46, 10.51) vs. 12.55 (12.07, 13.04) per 100 person‐years), corresponding to a weighted rate difference of −1.20 (−1.74, −0.60) events per 100 person‐years. Adjusted hazard ratios (95% CI) were 0.89 (0.79–1.01) for hyperkalemia and 0.74 (0.57–0.95) for severe hyperkalemia. Findings were consistent across subgroups. Initiation of spironolactone among patients with heart failure receiving sacubitril/valsartan was associated with a lower risk of severe hyperkalemia, compared with RASi use. This study expands upon previous findings suggesting the risk of hyperkalemia when using MRAs may be mitigated through the substitution of sacubitril/valsartan for RASi.