Risk of Hyperkalemia With Mineralocorticoid Receptor Antagonists

Study Questions:

What is the risk of hyperkalemia associated with use of mineralocorticoid receptor antagonists (MRAs) for patients with heart failure and reduced ejection fraction (HFrEF) treated with sacubitril/valsartan in comparison with enalapril?


The PARADIGM-HF (Prospective Comparison of ARNI With an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial randomly assigned 8,399 patients with chronic HF, New York Heart Association class II-IV symptoms, and a left ventricular EF of 40% or less to treatment with enalapril 10 mg twice daily or sacubitril/valsartan 97/103 mg twice daily (previously known as LCZ696 [200 mg twice daily]) in addition to guideline-directed medical therapy. Use of MRAs was encouraged, but left to the discretion of study investigators. Serum potassium level was measured at every study visit. The incidence of hyperkalemia (potassium level >5.5 mEq/L) and severe hyperkalemia (potassium level >6.0 mEq/L) among patients treated or not treated with an MRA at baseline and the risk of subsequent hyperkalemia for those newly treated with an MRA during study follow-up were defined in time-updated Cox proportional hazards models. Analyses were conducted between August 1 and October 15, 2016. The main outcomes of interest were incident hyperkalemia and severe hyperkalemia.


In comparison with the 3,728 patients (44.4% of enrolled participants [21.6% female]) not taking an MRA at baseline, the 4,671 patients (55.6% [22.0% female]) taking an MRA tended to be younger, with a lower EF, lower systolic blood pressure, and more advanced HF symptoms. Among those taking an MRA at baseline, the overall rates of hyperkalemia were similar between treatment groups, but severe hyperkalemia was more common in patients randomly assigned to enalapril than to sacubitril/valsartan (3.1 vs. 2.2 per 100 patient-years; hazard ratio [HR], 1.37; 95% confidence interval [CI], 1.06-1.76; p = 0.02). In analyses including patients who newly started taking MRAs during the PARADIGM-HF trial, severe hyperkalemia remained more common in those randomly assigned to enalapril than to those randomly assigned to sacubitril/valsartan (3.3 vs 2.3 per 100 patient-years; HR, 1.43; 95% CI, 1.13-1.81; p = 0.003).


The authors concluded that among MRA-treated patients with symptomatic HFrEF, severe hyperkalemia is more likely during treatment with enalapril than with sacubitril/valsartan.


These data from a secondary analysis of the PARADIGM-HF trial suggest that neprilysin inhibition may attenuate the risk of hyperkalemia when MRAs are combined with other inhibitors of the renin-angiotensin-aldosterone system in patients with HF. It would seem that the use of sacubitril/valsartan instead of enalapril among eligible patients with HFrEF may increase the ability to use MRAs safely. It should be noted that randomization in the PARADIGM-HF trial was not stratified according to MRA use and there were no reliable data available regarding MRA dosing or adherence over the course of the study, so these findings need additional prospective validation.

Clinical Topics: Heart Failure and Cardiomyopathies, Acute Heart Failure, Heart Failure and Cardiac Biomarkers

Keywords: AHA Annual Scientific Sessions, Blood Pressure, Enalapril, Heart Failure, Hyperkalemia, Mineralocorticoid Receptor Antagonists, Neprilysin, Potassium, Renin-Angiotensin System, Risk Assessment, Stroke Volume, Treatment Outcome

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