Hyperkalemia-related discontinuation of renin-angiotensin-aldosterone system inhibitors and clinical outcomes in CKD: a population-based cohort study

Rationale & Objective — Renin-Angiotensin-Aldosterone system inhibitors (RAASi) are evidence-based therapies that slow the progression of Chronic Kidney Disease (CKD) but can cause hyperkalemia. We aimed to evaluate the association of discontinuing RAASi’s after an episode of hyperkalemia and clinical outcomes in patients with CKD.

Study Design — Retrospective cohort study.

Setting and Participants — Adults in Manitoba (7,200) and Ontario, Canada (n=71,290) with an episode of de novo RAASi-related hyperkalemia (serum potassium ≥ 5.5 mmol/L) and CKD.

Exposure — RAASi prescription.

Outcomes — The primary outcome was all-cause mortality. Secondary outcomes were cardiovascular (CV) mortality, fatal and non-fatal CV events, dialysis initiation and a negative control outcome (cataract surgery).

Analytical approach — Cox proportional hazards models examined the association of RAASi continuation (vs. discontinuation) and outcomes using intention to treat approach. Sensitivity analyses included time-dependent, dose-dependent, and propensity matched analyses.

Results — The mean potassium and mean eGFR were 5.8 mEq/L and 41 ml/min/1.73m 2 in Manitoba and 5.7 mEq/L and 41 ml/min/1.73m 2 in Ontario. RAASi discontinuation was associated with a higher risk of all-cause mortality [hazard ratio (HR) 1.32, 95% CI: 1.22-1.41 in Manitoba, and HR: 1.47, 95% CI: 1.41-1.52 in Ontario] and cardiovascular mortality [HR: 1.28, 95% CI: 1.13-1.44 in Manitoba, and HR: 1.32, 95% CI: 1.25-1.39 in Ontario]. RAASi discontinuation was associated with an increased risk of dialysis initiation in both cohorts (Manitoba: HR, 1.26 [95% CI, 0.89-1.78] and Ontario HR, 1.11 [95% CI, 1.08-1.16]).

Limitations — Retrospective study and residual confounding.

Conclusions — RAASi discontinuation is associated with higher mortality and cardiovascular events compared to continuation among patients with hyperkalemia and CKD. Strategies to maintain RAASi treatment after an episode of hyperkalemia may improve clinical outcomes in the CKD population.