Stopping Renin-Angiotensin System Inhibitors in Patients with Advanced CKD and Risk of Adverse Outcomes: A Nationwide Study

Edouard L. Fu; Marie Evans; Catherine M. Clase; Laurie A. Tomlinson; Merel van Diepen; Friedo W. Dekker; Juan J. Carrero

doi:10.1681/ASN.2020050682

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Visual Abstract

Significance Statement

Whether renin-angiotensin system (RAS) inhibition is safe and effective in patients with advanced CKD is unknown. Single-center studies suggest there is improved kidney function after stopping RAS inhibition and possible delay in initiating kidney replacement therapy (KRT), but large prospective studies assessing cardiovascular and kidney outcomes are lacking. In this nationwide study of 10,254 Swedish patients with advanced CKD on RAS inhibitor therapy and under routine care by nephrologists, discontinuing this treatment associated with increases in the 5-year absolute risks of mortality and major adverse cardiovascular events—13.6% and 11.9%, respectively—but an 8.3% decrease in absolute risk of initiating KRT. These findings caution against routine discontinuation of RAS inhibitor therapy in such patients and suggest cardiovascular risk and risk of KRT be considered in decisions about stopping RAS inhibitor therapy.

Abstract

Background It is unknown whether stopping renin-angiotensin system (RAS) inhibitor therapy in patients with advanced CKD affects outcomes.

Methods We studied patients referred to nephrologist care, listed on the Swedish Renal Registry during 2007–2017, who developed advanced CKD (eGFR<30 ml/min per 1.73 m²) while on RAS inhibitor therapy. Using target trial emulation techniques on the basis of cloning, censoring, and weighting, we compared the risks of stopping within 6 months and remaining off treatment versus continuing RAS inhibitor therapy. These included risks of subsequent 5-year all-cause mortality, major adverse cardiovascular events, and initiation of kidney replacement therapy (KRT).

Results Of 10,254 prevalent RAS inhibitor users (median age 72 years, 36% female) with new-onset eGFR <30 ml/min per 1.73 m², 1553 (15%) stopped RAS inhibitor therapy within 6 months. Median eGFR was 23 ml/min per 1.73 m². Compared with continuing RAS inhibition, stopping this therapy was associated with a higher absolute 5-year risk of death (40.9% versus 54.5%) and major adverse cardiovascular events (47.6% versus 59.5%), but with a lower risk of KRT (36.1% versus 27.9%); these corresponded to absolute risk differences of 13.6 events per 100 patients, 11.9 events per 100 patients, and −8.3 events per 100 patients, respectively. Results were consistent whether patients stopped RAS inhibition at higher or lower eGFR, across prespecified subgroups, after adjustment and stratification for albuminuria and potassium, and when modeling RAS inhibition as a time-dependent exposure using a marginal structural model.

Conclusions In this nationwide observational study of people with advanced CKD, stopping RAS inhibition was associated with higher absolute risks of mortality and major adverse cardiovascular events, but also with a lower absolute risk of initiating KRT.

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