Discontinuation of RAAS Inhibitors and Risk of Mortality in CKD

Patients with proteinuric chronic kidney disease (CKD) are commonly treated with renin-angiotensin-aldosterone system (RAAS) inhibitors, with well-established beneficial outcomes. Results of large, randomized trials have demonstrated that use RAAS inhibitors among patients with CKD is associated with kidney-protective and antiproteinuric effects, as well as a lowering of risk of cardiovascular disease. Guidelines recommend the use of RAAS inhibition as first-line treatment for patients with CKD.

RAAS inhibitors have also been shown to have an association with an increased risk of hyperkalemia, an independent risk factor for arrhythmias, mortality, and hospitalization. Patients likely to gain the potential renal and cardiovascular benefits from RAAS inhibitors are also at the highest risk for hyperkalemia.

At present, there is no standard of care for management of chronic hyperkalemia in patients with CKD.  Results of observational studies have identified discontinuation or dose reduction of RAAS inhibition as the most common management strategy in patients with chronic hyperkalemia.

Silvia J. Leon, MD, MSc, and colleagues conducted a retrospective cohort study to examine the risk of all-cause and cardiovascular mortality, fatal and nonfatal cardiovascular events, and initiation of dialysis with discontinuation of RAAS inhibitors in patients with CKD and hyperkalemia. Results were reported in the American Journal of Kidney Diseases [2022;80(2):164-173].

The study included adults in Manitoba, and Ontario, Canada. Eligible patients had an episode of de novo RAAS-related hyperkalemia, defined as serum potassium ≥5.5 mmol/L, and CKD. The study exposure was a prescription for an RAAS inhibitor. The primary outcome of interest was all-cause mortality. Secondary outcomes included cardiovascular mortality, fatal and nonfatal cardiovascular events, and initiation of dialysis.

The association between the continuation (vs discontinuation) and outcomes was examined using Cox proportional hazards models using intent to treat. Sensitivity analyses included time-dependent, dose-dependent, and propensity-matched analyses.

The Manitoba cohort included 8534 patients who met eligibility criteria. Ninety days after the hyperkalemia episode, a total of 7200 surviving patients were included in the analysis. In the Ontario cohort, 78 938 patients ≥66 years of age met inclusion criteria. Ninety days following the hyperkalemia episode, 71 290 were included in the analysis. In the Manitoba cohort, 24% of the patients experienced the hyperkalemia episode in the inpatient setting.

Mean age of participants in the Manitoba cohort was 72.39 years, and approximately 48% were female. Mean serum potassium was 5.84 mmol/L, and mean estimated glomerular filtration rate (eGFR) at baseline was 40.87 mL/min/1.73 m². In the Ontario cohort, mean age was 79.48 years, and 52% were female. Mean serum potassium was 5.75 mmol/L and mean eGFR was 41.16 mL/min/1.73 m².

In Manitoba, participants who discontinued RAAS inhibitors were older (74 vs 72 years; P<.001), had lower eGFR (39 vs 41 mL/min/1.73 m²; P<.001), and had higher serum potassium at baseline (5.90 vs 5.80 mmol/L; P<.001). Differences were similar in the Ontario cohort: those who discontinued RAAS inhibitors were older (80 vs 79 years), had lower eGFR (38 vs 41 mL/min/1.73 m²), and had higher serum potassium at baseline (5.85 vs 5.73 mmol/L).

In unadjusted analyses, compared with continuation of RAAS inhibitor, discontinuation was associated with a higher risk of all-cause mortality in both the Manitoba (hazard ratio [HR], 1.48; 95% CI, 1.38-1.58) and Ontario (HR, 1.78; 95% CI, 1.75-1.85) cohorts. The association remained in adjusted Cox proportional hazards regression models (Manitoba: adjusted HR [aHR], 1.32; 95% CI, 1.22-1.41; Ontario: aHR, 1.47; 95% CI, 1.41-1.52).

In both study cohorts, there was also an association between discontinuation of RAAS inhibitors and a 30% higher risk of cardiovascular mortality compared with continuation of RAAS inhibition (Manitoba: aHR, 1.28; 95% CI, 1.13-1.44; Ontario: aHR, 1.32; 95% CI, 1.25-1.39). Participants who discontinued use of RAAS inhibitors also had a higher risk of fatal and nonfatal cardiovascular events compared with those who continued RAAS inhibitor therapy (Manitoba: aHR, 1.17; 95% CI, 1.11-1.24; Ontario: aHR, 1.18; 95% CI, 1.15-1.22)

In both cohorts, the risk of dialysis initiation was greater among participants who discontinued RAAS inhibitor therapy compared with those who continued use of RAAS inhibitors (Manitoba: aHR, 1.65; 95% CI, 1.41-1.85; Ontario: aHR, 1.11; 95% CI, 1.08-1.16).

In analyses that utilized a time-dependent approach, results were similar. There were associations between RAAS inhibitor discontinuation and higher risk of all-cause and cardiovascular mortality, fatal and nonfatal cardiovascular events, and initiation of dialysis. In analyses in a subset of participants with serum potassium level of ≥5.8 mmol/L, there were associations between hyperkalemia and all-cause  mortality (aHR, 1.33; 95% CI, 1.20-1.48) and cardiovascular mortality (aHR, 1.30; 95% CI, 1.09-1.56).

In Cox regression models, with further adjustment for acute kidney injury and sepsis at baseline, the results were similar (all-cause mortality: aHR, 1.23; 95% CI, 1.20-1.39; cardiovascular mortality: aHR, 1.26; 95% CI, 1.12-1.42).

At the time of the hyperkalemia episode, ~35% of the Manitoba cohort and ~40% of the Ontario cohort were on the maximal RAAS dose. Of the participants on the maximal dose, 12.33% in the Manitoba cohort and 14.46 % in the Ontario cohort were down-titrated to a submaximal dose. Further, 32% of the Manitoba cohort and 11% of the Ontario cohort at a maximal dose at baseline discontinued use of an RAAS inhibitor.

Compared with a maximal dose of RAAS inhibitors, there were associations between submaximal dose use and increased all-cause mortality (Manitoba: HR, 1.24; 95% CI, 1.12-1.37; Ontario: HR, 1.11; 95% CI, 1.08-1.14).

The researchers cited some limitations to the study findings, including the observational design with retrospective cohorts, leading to the possibility of unmeasured confounders. In addition, because medications associated with hyperkalemia are commonly provided over the counter, it was not possible to fully capture their concomitant use. Finally, there were no data available on blood pressure measurements.

In conclusion, the authors said, “Our results demonstrate that continuation of RAAS inhibitors after an episode of hyperkalemia is associated with improved all-cause and cardiovascular event free survival in patients with CKD. Moreover, the maximal recommended dose was associated with a larger survival benefit than submaximal doses. Newer medications for the treatment of hyperkalemia may enable patients to continue their RAAS inhibitors after an episode of hyperkalemia.”

Takeaway Points

1. The most common management strategy for management of hyperkalemia in patients with chronic kidney disease (CKD) is discontinuation or dose reduction of renin-angiotensin-aldosterone system (RAAS) inhibitors.
2. Researchers reported results of a study designed to examine the association between discontinuation of RAAS inhibitors following an episode of hyperkalemia with clinical outcomes in patients with CKD.
3. There were associations between discontinuation and dose reduction of RAAS inhibitors and increased risk of all-cause mortality, cardiovascular mortality, and cardiovascular events compared with continuation.