Discontinuing renin-angiotensin system inhibitors after incident hyperkalemia and clinical outcomes: target trial emulation

Although renin-angiotensin system inhibitors (RASi) are the mainstay in the management of heart failure with reduced ejection fraction, chronic kidney disease, and other cardiovascular conditions, they are often discontinued due to hyperkalemia. The prognostic impact of discontinuing RASi after developing hyperkalemia remains uncertain. Using a target trial framework based on the cloning, censoring, and weighting method, we compared discontinuing RASi after incident hyperkalemia with continuing RASi. We identified 2305 patients with an estimated glomerular filtration rate (eGFR) of ≥10 ml/min/1.73 m² who developed hyperkalemia (serum potassium levels ≥5.5 mEq/L) while on RASi in the Osaka Consortium for Kidney Disease Research (OCKR) database. The primary outcome was a composite of initiation of kidney replacement therapy, a ≥50% decline in eGFR, or reaching eGFR <5 ml/min/1.73 m². Secondary outcomes included all-cause death and severe hyperkalemia (serum potassium levels ≥6.5 mEq/L). The mean (standard deviation) age and eGFR were 68 (14) years and 29 (17) mL/min/1.73 m², respectively. After developing hyperkalemia, 346 (15%) discontinued RASi. Discontinuing RASi was associated with a 16% [95% confidence interval 2-33%] higher hazard of mortality than continuing RASi while the composite kidney outcome did not differ between groups (adjusted hazard ratio [HR] 1.01 [0.81-1.26]). Severe hyperkalemia occurred less frequently in those who discontinued RASi than those who continued RASi (adjusted HR 0.83 [0.69, 0.99]). RASi discontinuation after incident hyperkalemia was associated with higher mortality despite a lower risk of severe hyperkalemia. It was not related to kidney outcome. Appropriate clinical decision-making regarding RASi discontinuation may depend on the clinical context.