Clinical InvestigationTrue rate of mineralocorticoid receptor antagonists-related hyperkalemia in placebo-controlled trials: A meta-analysis
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)
- et al.
The mineralocorticoid receptor promotes fibrotic remodeling in atrial fibrillation
J Biol Chem
(2014) - et al.
2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines
J Am Coll Cardiol
(2013) - et al.
Temporal trends and predictors in the use of aldosterone antagonists post–acute myocardial infarction
J Am Coll Cardiol
(2013) - et al.
Aldosterone receptor antagonist use after myocardial infarction. Data from the REICIAM registry
Rev Esp Cardiol
(2011) - et al.
Systematic review of genuine versus spurious side-effects of beta-blockers in heart failure using placebo control: recommendations for patient information
Int J Cardiol
(2013) - et al.
The adequacy of laboratory monitoring in patients treated with spironolactone for congestive heart failure
J Am Coll Cardiol
(2005) Aldosterone in congestive heart failure
N Engl J Med
(2001)- et al.
Extrarenal effects of aldosterone
Curr Opin Nephrol Hypertens
(2012) - et al.
Eplerenone in patients with systolic heart failure and mild symptoms
N Engl J Med
(2011) - et al.
The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators
N Engl J Med
(1999)
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
Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction
N Engl J Med
Potassium homeostasis and renin-angiotensin-aldosterone system inhibitors
Clin J Am Soc Nephrol
Short-term mortality risk of serum potassium levels in hypertension: a retrospective analysis of nationwide registry data
Eur Heart J
Use of aldosterone antagonists in heart failure
JAMA
Heart failure care in the outpatient cardiology practice setting: findings from IMPROVE HF
Circ Heart Fail
EuroHeart Failure Survey II (EHFS II): a survey on hospitalized acute heart failure patients: description of population
Eur Heart J
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
Registry in Germany focusing on level-specific and evidence-based decision finding in the treatment of heart failure: REFLECT-HF
Clin Res Cardiol
Impact of eplerenone on cardiovascular outcomes in heart failure patients with hypokalaemia
Eur J Heart Fail
Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement
Ann Intern Med
The treatment gap in patients with chronic systolic heart failure: a systematic review of evidence-based prescribing in practice
Heart Fail Rev
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2021, NefrologiaCitation 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.
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2020, Archives of Cardiovascular DiseasesCitation 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.
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These two authors contributed equally to this work.