Updated Evidence of Hyperkalemia Occurrence: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

OBJECTIVES: To provide updated evidence of serum potassium changes in patients treated with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) taken concomitantly with spironolactone compared to ACEI/ARB therapy alone.

METHODS: A search of PubMed, Embase, Scopus, and Web of Science identified studies including patients receiving both spironolactone and ACEI or ARB therapy compared to ACEI/ARB therapy alone. Mean differences of serum potassium change over time were calculated for each study to estimate an average treatment effect using random effects models. Heterogeneity was assessed using Cochran's Q and I2. Uncertainty was reported using a prediction interval. Statistical analyses were performed using R, version 4.2.2.

RESULTS: Of the initial articles identified, 24 randomized controlled studies were included in the meta-analysis, including 752 patients receiving spironolactone (20-50mg) plus ACEI/ARB and 728 patients receiving ACEI/ARB alone. Patients receiving spironolactone and ACEI/ARB had a mean serum potassium concentration that was 0.27 mEq/L higher (95% CI, 0.17-0.37 mEq/L) than those receiving ACEI/ARB alone. Heterogeneity was high across studies (tau²: 0.0480, [0.0226 to 0.1025]; I²: 96.8% [96.0% to 97.4%]; Q statistic= 719.84, p-value < 0.0001. A predicted interval of -0.20 to 0.74 was calculated to help clinicians interpret the value of the treatment effect. A second analysis of 20 studies including 574 patients receiving 25 mg of spironolactone plus ACEI/ARB and 564 patients receiving ACEI/ARB alone showed a larger mean difference in potassium concentration of 0.30 mEq/L (95% CI, 0.18 to 0.41 mEq/L); the heterogeneity was also high (tau²: 0.0521, [0.024 to 0.129]; I²:96.6% [95.6% to 97.3%], and the prediction interval was -0.20 to 0.79.

CONCLUSIONS: Patients treated with spironolactone and ACEI/ARB have higher mean serum potassium concentrations than those receiving ACEI/ARB therapy alone. We recommend that serum potassium and renal function be monitored in patients starting combination therapy to avoid potential hyperkalemia.