Rapid Renin Angiotensin Aldosterone System inhibitor optimisation in patients with chronic kidney disease and heart failure with reduced ejection fraction using potassium binder: a randomised, double-blinded, placebo-controlled trial

Abstract Renin-angiotensin-aldosterone inhibitors (RAASi) improve outcomes in patients with heart failure with reduced ejection fraction (HFrEF), but their use is often limited by hyperkalaemia in chronic kidney disease (CKD) patients. This double-blind, placebo-controlled, randomised trial evaluated whether sodium zirconium cyclosilicate (SZC) enables RAASi up-titration in HFrEF patients with CKD stages 3–5 and serum potassium of 5.0–5.5 mmol/L over 14 weeks. The primary binary outcome was defined as achieving the target dose of RAAS inhibition therapy without reaching hyperkalaemia (serum potassium ≥5.6 mmol/L) over 14 weeks or otherwise. Participants ( n = 112) were randomised 1:1 to receive sodium zirconium cyclosilicate (SZC) or placebo. The per-protocol (PP) analyses included 43 out of 53 (81%) in the SZC arm and 53 out of 59 participants (90%) in the placebo arm; the intention-to-treat (ITT) analyses included all 112. At the end of the trial, 24 of 43 participants (56%) in the SZC group achieved the target RAASi dose without developing hyperkalaemia compared with 15 of 53 patients (28%) in the placebo group (PP analysis, p = 0.006, ITT analysis, p = 0.007,). Participants in the SZC group were 3 times more likely to reach the target dose without reaching potassium 5.6 mmol/L (OR = 3.16; 95% CI 1.35–7.39; p = 0.008) than in the placebo group (ITT analysis). No significant differences in adverse events between the two groups were observed. SZC appears to safely support rapid RAASi optimisation in HFrEF patients with CKD. This trial was funded by AstraZeneca via Externally Sponsored Scientific Research grant ESR-19-20174. Trial Registration: Clinicaltrials.gov NCT05004363 and EudraCT number 2020-002946-18.