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Hyperkalemia in new-onset HFrEF patients receiving guideline-directed medical therapies
Literature - Henrysson J, Thunström E, Chen X, et al. - ESC Heart Fail. 2022 Sep 25 [Online ahead of print]. doi: 10.1002/ehf2.14137

Introduction and methods


Despite improvement in the treatment of patients with HFrEF, the 5-year survival rate after hospitalization in this group is still only 25% [1]. One of the underlying reasons is suboptimal clinical implementation of guideline-directed medical therapies (GDMTs), such as MRAs. Although the 2016 ESC Guidelines on HF recommend MRAs as part of the first-line therapy for HFrEF patients [2], these drugs are often not prescribed, underdosed, or discontinued due to adverse events [3-6].

Potential reasons for the underuse of MRAs are hyperkalemia and worsening renal function [7,8]. However, the reported incidence of hyperkalemia in MRA-treated patients varies and is too low to explain the proportion of undertreated patients.

Aim of the study

The study aim was to investigate the incidence and magnitude of documented hyperkalemia and the expected risk of hyperkalemia in HFrEF patients at baseline (i.e., time of HFrEF diagnosis) and during optimal uptitration of GDMTs in a real-world setting.


This was a retrospective observational analysis of the medical records of 630 patients who had been hospitalized for new-onset HFrEF at the Sahlgrenska University Hospital in Gothenburg, Sweden from January 2016 through December 2019. The study was conducted in the fall of 2020 (mean observation time: 13.4 months; SD: 29.12). During the study period, potassium binders were not used in clinical practice at the three hospitals affiliated with the Sahlgrenska University Hospital.

According to the 2016 ESC Guidelines, all newly diagnosed HFrEF patients must go through maximum uptitration of ACEi/ARB beta-blocker, and MRA within 6 months after the diagnosis [2]. Therefore, study patients were divided into 4 groups based on potentially receiving MRA treatment within the first 6 months: (1) those who never received an MRA, (2) those who needed an MRA dose reduction, (3) those who needed MRA discontinuation, and (4) those on stable MRA treatment. Potassium levels (in serum or plasma) were assessed at baseline, and the highest potassium level during the 6 months after baseline was also recorded. The expected risk of hyperkalemia included an overall assessment based on previous studies [9].

In an exploratory analysis, all-cause mortality of patients not treated with MRA was compared with that of matched (for age, sex, and comorbidities) patients treated with MRA from the Swedish Heart Failure Registry, a nationwide HF registry implemented in Sweden in 2003 [10].

Main results

Incidence of documented hyperkalemia and expected hyperkalemia risk at baseline and follow-up

  • In the entire study population, hyperkalemia (potassium: ≥5.0 mmol/L) was seen in 37 patients (5.9%) at baseline and in 154 patients (24.4%) after 6 months of initiation or uptitration of GDMTs (+414%; P<0.0001).
  • The incidence of hyperkalemia increased from 6.0% at baseline to 28.0% at 6 months (+467%) in group 1 (n=268; 42.5% of total study population), from 6.8% to 54.5% (+801%) in group 2 (n=44; 7.0%), from 8.8% to 50.9% (+578%) in group 3 (n=57; 9.0%), and from 5.0% to 10.7% (+214%) in group 4 (n=261; 41.4%) (all P<0.0001 ).
  • Overall, the incidence of borderline hyperkalemia (potassium: 4.8–4.9 mmol/L) increased from 9.0% at baseline to 12.1% at 6 months (+134%); in group 1, it increased from 7.5% to 15.3% (+204%).
  • In the study population as a whole, the expected risk of hyperkalemia increased from 0.3% at baseline to 0.8% at 6 months (+267%); there were no significant differences in this risk between the 4 MRA groups at baseline nor at 6 months.

//Hypokalemia/normokalemia at baseline and hyperkalemia at follow-up//

  • At baseline, 536 of the 630 patients (85.1%) had hypokalemia (potassium:<3.5 mmol/L) or normokalemia (potassium: <4.8 mmol/L).
  • At 6 months, the proportions of patients with hypokalemia/normokalemia were 27.3% in group 2, 33.3% in group 3, and 70.9% in group 4.
  • In the MRA-naïve group (group 1), 87.5% of the patients had hypokalemia/normokalemia at baseline; this proportion had decreased to 47.8% at 6 months.
  • Of the group 1–patients with hypokalemia/normokalemia at baseline (87.5%), 16.7% had borderline hyperkalemia 6 months later, 22.4% had mild hyperkalemia (potassium: 5.0–5.4 mmol/L), 5.7% had moderate hyperkalemia (potassium: 5.5–5.9 mmol/L), and 0.9% had severe hyperkalemia (potassium: ≥6.0 mmol/L).

//Exploratory analysis of all-cause mortality after 1 year//

  • During the observation period, 14.2% of the patients in group 1 died, 27.2% in group 2, 17.5% in group 3, and 9.6% in group 4 (P=0.009).
  • Lack of MRA use was associated with a higher risk of 1-year all-cause mortality.
  • Univariate Cox regression analysis showed no increased mortality risk for patients with mild hyperkalemia (hazard ratio (HR): 1.206; 95%CI: 0.914–1.590) and those with moderate hyperkalemia (HR: 0.859; 95%CI: 0.271–2.729).


In a retrospective analysis of an observational cohort, the incidence of hyperkalemia increased from 6% at the time of the HFrEF diagnosis to 24% during uptitration of GDMTs in 6 months. During this time, the expected risk of hyperkalemia increased 2.7-fold. However, after the 6 months, less than 50% of the HFrEF patients were on MRA treatment. The incidence and magnitude of hyperkalemia did vary considerably between different clinical phenotypes.

Based on their results, the authors believe that physicians might be reluctant to prescribe MRAs to HFrEF patients when they believe the hyperkalemia risk is high based on their clinical experience. “Our data should help clinicians estimate the ‘real and potential’ risk of hyperkalemia and, most importantly, provide tailored therapy to HF patients by treating them with GDMT while preventing hyperkalemia, either by increasing the use of ARNI and SGLT2 inhibitors, which may moderate the risk of hyperkalemia, or by adding a potassium binder in those with a higher risk of hyperkalemia.”


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2. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al., Authors/Task Force Members; Document Reviewers. 2016 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016; 18: 891–975.

3. Thorvaldsen T, Benson L, Dahlström U, Edner M, Lund LH. Use of evidence-based therapy and survival in heart failure in Sweden 2003-2012. Eur J Heart Fail. 2016; 18: 503–511.

4. Ferreira JP, Rossignol P, Machu JL, Sharma A, Girerd N, Anker SD, et al. Mineralocorticoid receptor antagonist pattern of use in heart failure with reduced ejection fraction: Findings from BIOSTAT-CHF. Eur J Heart Fail. 2017; 19: 1284–1293.

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6. Trevisan M, de Deco P, Xu H, Evans M, Lindholm B, Bellocco R, et al. Incidence, predictors and clinical management of hyperkalaemia in new users of mineralocorticoid receptor antagonists. Eur J Heart Fail. 2018; 20: 1217–1226. Erratum in: Eur J Heart Fail. 2019; 21: 540.

7. Swedberg K, Kjekshus J. Effects of enalapril on mortality in severe congestive heart failure: Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). Am J Cardiol. 1988; 62: 60A–66A.

8. Martens P, Kooij J, Maessen L, Dauw J, Dupont M, Mullens W. The importance of developing hyperkalaemia in heart failure during long-term follow-up. Acta Cardiol. 2020; 8: 1–9.

9. Thomsen RW, Nicolaisen SK, Hasvold P, Sanchez RG, Pedersen L, Adelborg K, et al. Elevated potassium levels in patients with chronic kidney disease: Occurrence, risk factors and clinical outcomes-A Danish population-based cohort study. Nephrol Dial Transplant. 2018; 33: 1610–1620.

10. Savarese G, Carrero JJ, Pitt B, Anker SD, Rosano GMC, Dahlström U, et al. Factors associated with underuse of mineralocorticoid receptor antagonists in heart failure with reduced ejection fraction: An analysis of 11 215 patients from the Swedish heart failure registry. Eur J Heart Fail. 2018; 20: 1326–1334.

Find this article online at ESC Heart Fail.

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