Elsevier

American Heart Journal

Volume 188, June 2017, Pages 99-108
American Heart Journal

Clinical Investigation
True rate of mineralocorticoid receptor antagonists-related hyperkalemia in placebo-controlled trials: A meta-analysis

https://doi.org/10.1016/j.ahj.2017.03.011Get rights and content

Background

Mineralocorticoid receptor antagonists (MRA) improve survival in heart failure with reduced ejection fraction but are often underused, mostly due to concerns of hyperkalemia. Because hyperkalemia occurs also on placebo, we aimed to determine the truly MRA-related rate of hyperkalemia.

Methods

We performed a meta-analysis including randomized, placebo-controlled trials reporting hyperkalemia on MRAs in patients after myocardial infarction or with chronic heart failure. We evaluated the truly MRA-related rate of hyperkalemia that represents hyperkalemia on MRA, corrected for hyperkalemia on placebo (Pla), according to the equation: True MRA (%) = (MRA (%) − Pla (%))/MRA (%).

Results

A total number of 16,065 patients from 7 trials were analyzed. Hyperkalemia was more frequently observed on MRA (9.3%) vs placebo (4.3%) (risk ratio 2.17, 95% CI 1.92-2.45, P < .0001). Truly MRA-related hyperkalemia was 54%, whereas 46% were non–MRA related. In trials using eplerenone, hyperkalemia was documented in 5.0% on eplerenone and in 2.6% on placebo (P < .0001). In spironolactone trials, hyperkalemia was documented in 17.5% and in 7.5% of patients on placebo (P = .0001). Hypokalemia occurred less frequently in patients on MRA (9.3%) compared with placebo (14.8%) (risk ratio 0.58, CI 0.47-0.72, P < .0001).

Conclusion

This meta-analysis shows that in clinical trials, 54% of hyperkalemia cases were specifically related to the MRA treatment and 46% to other reasons. Therefore, non–MRA-related rises in potassium levels might be underestimated and should be rigorously explored before cessation of the evidence-based therapy with MRAs.

Section snippets

Study protocol

The meta-analysis is in accordance with the PRISMA statement for meta-analysis.19 The primary analysis was carried out according to a predefined protocol. We included articles reporting hyperkalemia and/or hypokalemia as adverse effects of MRA therapy in randomized, placebo-controlled studies in patients with arterial hypertension, coronary heart disease, and heart failure. Trials included had to have a minimum of 100 patients in each arm and follow-up of at least 4 weeks. Only trials with the

Results

Initially, we identified 682 potentially appropriate trials. After reviewing the titles and abstracts, 665 trials were excluded. The main reasons for exclusion were that MRA was not the primary objective of investigation, lack of randomization or placebo-group, small number of analyzed patients, and evaluation of the effect of MRA in other clinical settings we found not appropriate (ie, patients with nephropathy). From 17 further reviewed trials, 8 trials did not met the predefined study

Discussion

The key findings of this study were that about half of the cases of hyperkalemia in patients on MRA in clinical trials are specifically related to MRA treatment, whereas the other half were MRA unrelated. These results were similar for spironolactone and eplerenone in patients after myocardial infarction or with CHF. Furthermore, MRA treatment reduced the occurrence of hypokalemia.

Conclusion

In contrast to the general perception, this meta-analysis shows that almost 50% of hyperkalemia cases are not related to MRA treatment. Without downplaying the risk of MRA-related hyperkalemia, it is clinically relevant to exclude other causes of high potassium levels before withdrawal the MRA medication to avoid undertreatment with a well-proven beneficial heart failure drug.

Conflict of interest

All authors have no conflict of interest to declare.

Acknowledgements

D.V. acquired the data, conceived and designed the research, performed statistical analysis, drafted the manuscript, and made critical revision for key intellectual content. A.N.V. drafted the manuscript. D.L. and M.B. conceived and designed the research, drafted the manuscript, and made critical revision for key intellectual content. S.W. made critical revision of the statistic used in this analysis. P.B. made critical revision for key intellectual content.

References (45)

  • P. Ponikowski et al.

    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 Heart J

    (2016)
  • B. Pitt et al.

    Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction

    N Engl J Med

    (2003)
  • M.R. Weir et al.

    Potassium homeostasis and renin-angiotensin-aldosterone system inhibitors

    Clin J Am Soc Nephrol

    (2010)
  • M.L. Krogager et al.

    Short-term mortality risk of serum potassium levels in hypertension: a retrospective analysis of nationwide registry data

    Eur Heart J

    (2016)
  • N.M. Albert et al.

    Use of aldosterone antagonists in heart failure

    JAMA

    (2009)
  • G.C. Fonarow et al.

    Heart failure care in the outpatient cardiology practice setting: findings from IMPROVE HF

    Circ Heart Fail

    (2008)
  • M.S. Nieminen et al.

    EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population

    Eur Heart J

    (2006)
  • W. von Scheidt et al.

    Characteristics, management modalities and outcome in chronic systolic heart failure patients treated in tertiary care centers: results from the EVIdence based TreAtment in Heart Failure (EVITA-HF) registry

    Clin Res Cardiol

    (2014)
  • U. Tebbe et al.

    Registry in Germany focusing on level-specific and evidence-based decision finding in the treatment of heart failure: REFLECT-HF

    Clin Res Cardiol

    (2014)
  • P. Rossignol et al.

    Impact of eplerenone on cardiovascular outcomes in heart failure patients with hypokalaemia

    Eur J Heart Fail

    (2016)
  • D. Moher et al.

    Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement

    Ann Intern Med

    (2009)
  • K.L. Chin et al.

    The treatment gap in patients with chronic systolic heart failure: a systematic review of evidence-based prescribing in practice

    Heart Fail Rev

    (2016)
  • Cited by (50)

    • Real world comparison of spironolactone and eplerenone in patients with heart failure

      2022, European Journal of Internal Medicine
      Citation Excerpt :

      Sexual side effects like dysmenorrhea in women and gynaecomastia in men are relatively frequent with spironolactone but rarely seen with eplerenone, and may constitute a barrier for treatment adherence in a real world setting. Moreover, the incidence of hyperkalaemia appears to be lower in patients treated with eplerenone than in patients treated with spironolactone [19], a fact that might be explained by the longer half-life of the first drug [5]. In our study, the cumulative rate of drug suspension for any cause and drug suspension due to side effects were higher in patients treated with spironolactone than in patients treated with eplerenone; being this result mostly driven by a higher incidence of gynaecomastia in the first group.

    • Mineralcorticoid receptor blockers in chronic kidney disease

      2021, Nefrologia
      Citation Excerpt :

      Aldosterone stimulates colonic K+ secretion through BK channels, secretion that is inhibited by spironolactone.129,130 The association of aldosterone antagonists with ACEI or ARA2 contributes to hyperkalemia, but in these patients there may also concur other causes of elevated serum K+.131 Given the occurrence of hyperkalemia in subjects who receive RAAS blockers for processes in which they have shown benefit, frequently the dose has to be reduced or even suppressed.

    • Patients with acute heart failure treated with the CARRESS-HF diuretic protocol in association with canrenoate potassium: Tolerance of high doses of canrenoate potassium

      2020, Archives of Cardiovascular Diseases
      Citation Excerpt :

      More specifically, there was no case of hyperkalaemia with potassium canrenoate, even among patients with kalaemia > 5.0 mM at admission or with severe impaired renal function, despite theoretical contraindication. HF guidelines recommend avoiding MRAs only in patients with an estimated glomerular filtration rate < 30 mL/min or serum potassium concentration > 5.0 mmol/L [18–21]. However, even in this fragile population, the results of the present observational study suggest that MRA treatment could be possible, with close clinical and laboratory monitoring of hospitalized patients and the short-term use of intravenous MRAs.

    View all citing articles on Scopus
    1

    These two authors contributed equally to this work.

    View full text