Abstract
Background
Chronic heart failure (CHF) is a growing epidemic. The cornerstone of pharmacological therapy in CHF patients with reduced ejection fraction (HFrEF) is the inhibition of the renin–angiotensin–aldosterone system (RAAS). One of the adverse effects of RAAS blockade is the development of hyperkalaemia, which often limits the optimization of recommended, Class I treatments. In this context, potassium binders patiromer or sodium zirconium cyclosilicate (ZS-9) provide an opportunity to optimize the pharmacological management of these patients.
Case summary
We present a case report illustrating our real-life experience using the potassium-binder patiromer in a patient with HFrEF, in whom recurrent hyperkalaemia (up to 6.3 mmol/L with low doses of enalapril) was preventing titration of RAAS inhibition therapies. Use of patiromer allowed re-introducing ramipril (subsequently switched to sacubitril/valsartan) and eplerenone. Serum potassium levels remained normal with patiromer 16.8 g/24 h, and the patient’s tolerance to patiromer was excellent.
Discussion
In patients with HFrEF and recurrent hyperkalaemia, optimal RAAS inhibition is often discontinued. In this context, novel potassium binders such as patiromer or ZS-9 have been shown to be effective in lowering potassium and maintaining normokalaemia, with a good safety profile and patient tolerance, all of which make them promising alternative options. Our preliminary experience suggests that patiromer may be a helpful and well-tolerated treatment option, which may aid in achieving optimal RAAS inhibition in HFrEF patients with recurrent hyperkalaemia. Registries of HFrEF patients will help better understand whether therapies such as patiromer have prognostic benefits through facilitating optimal RAAS blockade.
Keywords: Case report, Chronic heart failure, Heart failure, Hyperkalaemia, Patiromer, Potassium
Learning points
Hyperkalaemia may prevent the optimization of therapy in patients with chronic heart failure (CHF) impacting prognosis.
Calcium/sodium polystyrene sulphonates, a common treatment to avoid recurrent hyperkalaemia in clinical practice in Europe, has a lack of evidence in its efficacy and is associated with side effects.
New potassium binders such as patiromer or zirconium cyclosilicate can be an important treatment option to avoid hyperkalaemia in patients with chronic conditions as CHF and chronic kidney disease.
Introduction
Chronic heart failure (CHF) is a growing public health problem.1 Around half of the patients with CHF have a left ventricular ejection fraction (LVEF) below 40%—so-called ‘heart failure with reduced ejection fraction’ (HFrEF).2,3 A major cornerstone of medical therapy in these patients is the inhibition of the renin–angiotensin–aldosterone system (RAAS).2,3 An undesirable effects of RAAS blockade is the development of hyperkalaemia (defined as serum potassium levels > 5.0 mmol/L),4 a condition which often prevents optimizing Class I pharmacotherapies such as angiotensin-converting enzyme inhibitors (ACEIs)5 or mineralocorticoid receptor antagonists (MRAs),6 a failure which is likely to have prognostic implications.4
In this context, novel treatments for hyperkalaemia such as patiromer or sodium zirconium cyclosilicate (ZS-9) provide an opportunity to ameliorate this issue.4,7,8 These potassium binders have been recently approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA) (FDA approval in 2015 and EMA approval in 2017 for patiromer use, and both FDA and EMA approvals for ZS-9 use in 2018).9 Nevertheless, the real-world experience with these therapies is currently limited.
Timeline
| June 2017 | Discharge after acute heart failure hospitalization. Follow-up in multidisciplinary chronic care management programme |
| July 2017 | Enalapril 10 mg + eplerenone 25 mg |
| August 2017 | Enalapril + eplerenone discontinuation [Potassium (K+) 6.3 mmol/L] |
| September 2017 | Ramipril 1.25 mg |
| October 2017 | Ramipril discontinuation (K+ 6.1 mmol/L) |
| November–December 2017 | Hospital admission due to acute heart failure |
| December 2017 | Discharge after acute heart failure hospitalization. Ramipril 2.5 mg + patiromer 8.4 g |
| January 2018 | Ramipril 2.5 mg + patiromer 16.8g (K+ 5.4 mmol/L) |
| February 2018 | Ramipril 5 mg + patiromer 16.8 g |
| March 2018 | Ramipril 5 mg + eplerenone 12.5 mg + patiromer 16.8 g |
| April 2018 | Ramipril 5 mg + eplerenone 25 mg + patiromer 16.8 g |
| May 2018 | Ramipril discontinuation Sacubitril/valsartan 24/26 mg + eplerenone 25 mg + patiromer 16.8 g |
Case presentation
We present a 74-year-old Caucasian male with a history of Type 2 diabetes mellitus, hypertension, hypercholesterolaemia, former tobacco use, chronic pulmonary obstructive disease, and chronic kidney disease (CKD) Stage 3 [baseline estimated glomerular filtration rate (eGFR) ranging 40–50 mL/min]. Relevant cardiac history included atrial fibrillation and ischaemic heart disease with an acute myocardial infarction (AMI) in 2009; the angiography showed coronary disease: chronic total occlusion of the right coronary artery and severe stenosis of the proximal left anterior descending artery, treated percutaneously with a drug-eluting stent.
After the AMI, the patient’s LVEF was <40%, and he developed HFrEF. He presented several acute decompensations requiring hospital admissions between 2011 and July 2017. In the latter admission, echocardiography showed a dilated left ventricle (end-diastolic volume: 67 mL/m2), LVEF 34%, moderate functional mitral regurgitation, normal right ventricle without pulmonary hypertension. A stress echocardiography was performed, showing no ischaemia and no significant worsening of mitral regurgitation. The patient was discharged in a New York Heart Association (NYHA) functional Class IIb, with suboptimal medical therapy.
It was then when the patient began follow-up in the multidisciplinary CHF management programme, which included intensive health education, and careful pharmacological titration. During follow-up, low doses of an ACEI (enalapril), a beta-blocker (nebivolol), and MRA (eplerenone) were initiated sequentially, as per current clinical practice guidelines.
Up-titration of beta-blockers up to 10 mg/day was successfully achieved after 2 months. The same did not occur with enalapril and eplerenone: both had to be discontinued 2 weeks after initiating eplerenone due to deterioration of renal function and hyperkalaemia (eGFR 30 mL/min, K + 6.3 mmol/L). There were no clinical manifestations, no significant arrhythmias and both T wave and the QRS complex remained unaltered in the electrocardiogram. Blood tests showed a recovery of renal function and potassium levels 1 week after (eGFR 39 mL/min, K + 4.9 mmol/L). A few weeks later, in a second attempt to use ACEIs, low doses of ramipril (1.25 mg/24 h) were initiated. Despite the very low dose, K+ levels raised again up to 6.1 mmol/L (eGFR unchanged). Ramipril was discontinued, and the patient was once again questioned about dietary habits, with no evidence of intake of potassium-rich foods, supplements, or other preventable causes of hyperkalaemia.
To facilitate further attempts to optimally inhibit the RAAS, calcium polystyrene sulphonate was introduced. Nevertheless, the patient spontaneously abandoned treatment due to self-reported gastric intolerance. During this period, the patient suffered a new acute decompensation of CHF in the context of a respiratory infection, leading to acute pulmonary oedema.
Certain that was unable to achieve optimal RAAS inhibition due to recurrent hyperkalaemia, we requested special permission to use patiromer, a potassium binder which had not been commercialized in Europe by then. After discharge (eGFR 50 mL/min, K + 4.6 mmol/L) patiromer 8.4 g/24 h and ramipril 2.5 mg/24 h were initiated simultaneously. The laboratory tests 3 days later showed serum potassium levels of 5.4 mmol/L, eGFR 53 mL/min. Ramipril was maintained, and the dose of patiromer was doubled (16.8 g/24 h); subsequent blood test showed serum potassium levels back to normal (4.9 mmol/L). Ramipril was then up-titrated to 5 mg/24 h, without evidence of hyperkalaemia in the subsequent controls. MRAs were then reintroduced. First, 12.5 mg/24 h of eplerenone, potassium levels being persistently <5 mmol/L, followed by up-titration to 25 mg/24 h. The patient’s subjective tolerance was excellent, and blood tests consistently showed stable eGFRs and potassium levels.
Given the persistent NYHA Class IIb, during follow-up, ramipril was replaced by an angiotensin receptor blocker neprilysin inhibitor (sacubitril/valsartan 24/26 mg), with no recurrence of significant hyperkalaemia. There were no substantial differences in renal function or electrolytes before and after patiromer initiation, except potassium levels. Creatinine and eGFR levels ranged 130–150 µmol/L and 40–50 mL/min, respectively, and phosphate levels ranged 1.1–1.2 mmol/L. Magnessemia ranged 0.6–0.7 mmol/L, i.e. compatible with mild hypomagnesemia, which was present before patiromer initiation and was not worsened by therapy. It has not been possible to further up-titrate RAAS inhibitors due to arterial hypotension (persistent asymptomatic systolic blood pressure below 90 mmHg). The patient is now in NYHA Class IIa and has had no recent decompensations.
After 3 months under optimal medical therapy, follow-up echocardiography has recently been performed, showing no significant changes: the left ventricle remained dilated, with an LVEF of 35%. The patient will soon receive an implantable cardioverter-defibrillator.
Discussion
We present a case report illustrating the real-life use of potassium-binder patiromer in a patient with HFrEF and recurrent hyperkalaemia, which precluded optimal RAAS inhibition. In these patients, clinical practice guidelines recommend looking for reversible causes (diet, supplements, drugs) and correcting them.2–4 Lowering or discontinuation of RAAS inhibitors is recommended when potassium levels are >5.5 mmol/L.2–4
Although clinical experience with potassium binders in patients with CHF and CKD is accumulated for calcium/sodium polystyrene sulphonate, clinical trial evidence on its efficacy is lacking and its prolonged use may be associated with severe side effects, such as bowel necrosis.10,11 Also, patient tolerance is usually poor, mainly due to gastrointestinal symptoms. In this context, novel potassium binders such as patiromer and ZS-9, both of which have been shown to be effective in lowering potassium and maintaining normokalaemia in patients with CHF, CKD, and hyperkalaemia, with a good safety profile and patient tolerance,7,8 appear as promising alternative options.12
Patiromer is an oral non-absorbed polymer, which exchanges calcium and K+ in the colon, resulting in increased K+ excretion. Drug–drug interactions are uncommon, and there are no significant systemic side effects. The most frequent include gastrointestinal symptoms (i.e. diarrhoea, constipation) and non-serious electrolyte abnormalities (i.e. hypomagnesaemia). Sodium zirconium cyclosilicate is an inorganic cation that eliminates excess potassium in the gastrointestinal tract. In clinical trials, the short-term safety profile of ZS-9 seems similar to placebo; studies with longer follow-up are needed. In a recent review of potassium binders among CKD, there were encouraging outcomes in maintaining normokalaemia and RAAS inhibitors in patients with eGFR between 15 and 60 mL/min. There are also some positive real-world data in patients in haemodialysis under patiromer.11
Our preliminary experience suggests that patiromer may be a helpful treatment to achieve optimal RAAS inhibition, preventing hyperkalaemia and enabling up-titration of Class IA drugs in CHF patients. Large registries of HFrEF patients will help better characterize the effectiveness of these novel therapies, as well as identify the subgroups of patients most likely to benefit.
Lead author biography

Dr Josep Comín-Colet has born in Barcelona in 1968. Studied Medicine and Surgery in Barcelona University, Internal Medicine Resident in the UK, and Cardiology specialist training at the Hospital of Bellvitge (Barcelona) between 1996 and 2001. Great expertise in Heart Failure, he developed the Heart Failure Program at the Hospital del Mar (University Hospital in Barcelona, Spain). Doctor in Medicine (PhD) at the Autonomous University of Barcelona. Currently, Director of the South Metropolitan Barcelona Integrated Heart Failure Program and Clinical Director of the Community Heart Failure Unit and Head of the Chronic Heart Failure Section at the Department of Cardiology, Bellvitge University Hospital, Hospitalet de Llobregat (Barcelona, Spain).
Supplementary material
Supplementary material is available at European Heart Journal - Case Reports online.
Supplementary Material
Acknowledgements
We would like to thank Dr Alberto Garay, Dr Lidia Alcoberro, Dr Pedro Moliner, Encarnación Hidalgo (RN) and Esther Calero (RN) as part of our team, and also Dr Miguel Cainzos-Achirica for his critical review of the present report. We also thank CERCA Programme for institutional support.
Slide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.
Consent: The author/s confirm that written consent for submission and publication of this case report including image(s) and associated text has been obtained from the patient in line with COPE guidance.
Conflict of interest: J.C.-C. has received speaker fees from Vifor Pharma. All other authors declared no conflict of interest.
References
- 1. Benjamin EJ, Blaha MJ, Chiuve SE, Cushman M, Das SR, Deo R, de Ferranti SD, Floyd J, Fornage M, Gillespie C, Isasi CR, Jiménez MC, Jordan LC, Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Mackey RH, Matsushita K, Mozaffarian D, Mussolino ME, Nasir K, Neumar RW, Palaniappan L, Pandey DK, Thiagarajan RR, Reeves MJ, Ritchey M, Rodriguez CJ, Roth GA, Rosamond WD, Sasson C, Towfighi A, Tsao CW, Turner MB, Virani SS, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2017 update: a report from the American Heart Association. Circulation 2017;135:e146–e603. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P.. 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;37:2129–2200. [DOI] [PubMed] [Google Scholar]
- 3. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Colvin MM, Drazner MH, Filippatos GS, Fonarow GC, Givertz MM, Hollenberg SM, Lindenfeld J, Masoudi FA, McBride PE, Peterson PN, Stevenson LW, Westlake C.. 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Failure Society of America. Circulation 2017;136:e137–e161. [DOI] [PubMed] [Google Scholar]
- 4. Rosano GMC, Tamargo J, Kjeldsen KP, Lainscak M, Agewall S, Anker SD, Ceconi C, Coats A, Drexel H, Filippatos G, Kaski JC, Lund L, Niessner A, Ponikowski P, Savarese G, Schmidt TA, Seferovic P, Wassmann S, Walther T, Lewis BS, Expert consensus document on the management of hyperkalaemia in patients with cardiovascular disease treated with renin angiotensin aldosterone system inhibitors: coordinated by the working group on cardiovascular pharmacotherapy of The European Society Of Cardiology. Eur Heart J Cardiovasc Pharmacother 2018;4:180–188. [DOI] [PubMed] [Google Scholar]
- 5. Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN.. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med. 1991;325:293–302. [DOI] [PubMed] [Google Scholar]
- 6. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11–21.21073363 [Google Scholar]
- 7. Pitt B, Bakris GL, Bushinsky DA, Garza D, Mayo MR, Stasiv Y, Christ-Schmidt H, Berman L, Weir MR.. Effect of patiromer on reducing serum potassium and preventing recurrent hyperkalaemia in patients with heart failure and chronic kidney disease on RAAS inhibitors. Eur J Heart Fail 2015;17:1057–1065. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Anker SD, Kosiborod M, Zannad F, Piña IL, McCullough PA, Filippatos G, van der Meer P, Ponikowski P, Rasmussen HS, Lavin PT, Singh B, Yang A, Deedwania P.. Maintenance of serum potassium with sodium zirconium cyclosilicate (ZS-9) in heart failure patients: results from a phase 3 randomized, double-blind, placebo-controlled trial. Eur J Heart Fail 2015;17:1050–1056. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Rossignol P. A new area for the management of hyperkalaemia with potassium binders: clinical use in nephrology. Eur Heart J Suppl 2019;21:A48–A54. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Sterns RH, Rojas M, Bernstein P, Chennupati S.. Ion-exchange resins for the treatment of hyperkalemia: are they safe and effective? J Am Soc Nephrol 2010;21:733–735. [DOI] [PubMed] [Google Scholar]
- 11. Pitt B, Bushinsky DA, Kitzman DW, Ruschitzka F, Metra M, Filippatos G, Rossignol P, Du Mond C, Garza D, Berman L, Lainscak M; on behalf of the Patiromer-204 Investigators. Evaluation of an individualized dose titration regimen of patiromer to prevent hyperkalaemia in patients with heart failure and chronic kidney disease. ESC Heart Fail 2018;5:257–266. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Palmer BF. Potassium binders for hyperkalemia in chronic kidney disease-diet, renin-angiotensin-aldosterone system inhibitor therapy, and hemodialysis. Mayo Clin Proc 2019;95:339–354. [DOI] [PubMed] [Google Scholar]
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