Impact of renin-angiotensin system inhibitors discontinuation in advanced chronic kidney disease: a target trial emulation

BACKGROUND: Renin-angiotensin system (RAS) inhibitors are a cornerstone of cardiovascular and kidney risk modification in chronic kidney disease (CKD). Yet, they are often discontinued in advanced CKD to limit adverse effects or to delay kidney replacement therapy (KRT). METHODS: From the CKD-Renal Epidemiology and Information Network prospective cohort study, we selected participants with an estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m² and treated with RAS inhibitors. We performed a target trial emulation with parametric g-formula to compare two strategies: to discontinue or to continue RAS inhibitors. Models were adjusted for sociodemographics, clinical and laboratory characteristics, and drug prescriptions. Outcomes were the composite of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure, i.e. major cardiovascular events (MACE), and KRT initiation. RESULTS: Among the 1434 patients included (median age 68 years, median eGFR 25 ml/min/1.73 m², 35% women), 386 (27%) discontinued RAS inhibitors over a median follow-up of 35 months. Very few events related to adverse drug reactions were reported in the 3 months preceding RAS inhibitor discontinuation (n = 23), but their incidence over this period was ∼13-fold higher than that during the entire follow-up. The 3-year adjusted relative risk of MACE associated to discontinuing RAS inhibitors, compared to continuing, was 2.02 (95% Confidence interval (CI), 1.62-2.47), and that of KRT initiation, 1.34 (95% CI, 1.14-1.60). DISCUSSION: RAS inhibitor discontinuation was strongly associated with MACE and KRT risks, major causes of morbidity, and mortality in advanced CKD. Our findings, consistent with prior data, suggest the risk-benefit balance favors continued use with close monitoring.