Risk of hyperkalemia from renin-angiotensin-aldosterone system inhibitors and factors associated with treatment discontinuities in a real-world population

Abstract

Background: Hyperkalemia rates in renin-angiotensin-aldosterone system (RAAS) inhibitor users, and factors associated with treatment interruptions and cessations, have not been explored in a large, population-wide database.

Methods: RAAS inhibitor users were identified in the linked UK Clinical Practice Research Datalink-Hospital Episodes Statistics data set, 2009-15. Treatment interruptions (no active prescription followed by reappearance) and cessations were determined. Hyperkalemia (serum K+>5.5 mmol/L) rates were calculated and factors associated with interruptions and cessations modeled using time-varying Cox regression, including hyperkalemia (as a time-dependent variable).

Results: Among 434 027 RAAS inhibitor users, the hyperkalemia rate was 1.30 (95% confidence interval 1.28-1.32) per 100 patient-years. Of 73.7% of patients who experienced off-treatment periods, 57.6% experienced interruption only, 7.5% cessation only and 8.6% both. Within 1 year of initiating RAAS inhibitor treatment, approximately one-third of the patients experienced interruption or cessation. Hazard ratios for patients with severe hyperkalemia were 1.10 (10.5-1.16) for interruptions and 3.37 (3.25-3.50) for cessation. Compared with no chronic kidney disease (CKD), risk of interruption was 1.20 (1.16-1.25) and 1.57 (1.44-1.72) for Stages 4 and 5, respectively, and of cessation was 2.20 (2.07-2.33) and 2.87 (2.56-3.22). Risk of interruption increased for patients with heart failure or diabetes [1.04 (1.02-1.05); 1.13 (1.12-1.14), respectively] but the risk of cessation decreased [0.85 (0.82-0.87); 0.92 (0.90-0.94)].

Conclusions: Risk of RAAS inhibitor interruption and cessation increased as CKD stage progressed. Efforts targeting reasons for interruptions and, especially, cessations, such as hyperkalemia prevention, could decrease off-treatment periods for patients who would otherwise benefit, such as those with CKD, heart failure or diabetes.

Keywords: CKD; angiotensin II; diabetes mellitus; epidemiology; hyperkalemia.