The development of new potassium binding agents has increased interest in the field of hyperkalaemia management. This was the topic of a Vifor-sponsored satellite symposium at the meeting entitled ‘Enabling and optimising renin-angiotensin-aldosterone system inhibitor therapy in cardio-renal patients through hyperkalaemia management’.
Presenters included cardiologists, Professors Michael Boehm (University of the Saarland, Homburg, Saarland, Germany) and Stefan Anker (University Medical Center Göttingen, Göttingen, Germany) and nephrologist, Matthew Weir (University of Maryland Medical Centre, Baltimore, Maryland, USA). Their presentations are summarised below.
The addition of mineralocorticoid receptor antagonists (MRAs) to angiotensin converting enzyme (ACE) inhibition or receptor blockade (ARB) has been shown in randomised-controlled trials to improve morbidity and mortality in patients with heart failure.1,2
In the EMPHASIS-HF study, the addition of eplerenone in patients with heart failure (New York Heart Association Class II) with an ejection fraction of <35% produced a 37% risk reduction in cardiovascular death or hospitalisation.3 However, a significant barrier to the use of renin-angiotensin-aldosterone system inhibitors (RAASi) and their appropriate uptitration has been the risk of hyperkalaemia.
Data from the EMPHASIS-HF (Eplereonone in Patients with Systolic Heart Failure and Mild Symptoms) and EPHESUS (Eplerenone, a Selective Aldosterone Blocker, in Patients with Left Ventricular Dysfunction after Myocardial Infarction) studies estimate 11.8% of patients have a potassium concentration of ≥5.5 mmol/L, whilst 5.5% reach ≥6.0 mmol/L respectively.2,3 Furthermore, whilst patients with pre-existing chronic kidney disease (CKD) may in fact derive the greatest benefit given their increased cardiovascular risk, the incidence of hyperkalaemia increases with reduced creatinine clearance and the addition of a MRA to an ACE inhibitor/ARB increases hyperkalaemia 3.7-fold in diabetic nephropathy.4 Given that real-world studies suggest that actual rates of hyperkalaemia exceed estimates from clinical trials, strategies to reduce this risk are urgently needed.5
A potential solution are potassium binders. Patiromer, a potassium binder approved by the US Food and Drug Administration and more recently in the European Union, was shown in the OPAL-HF study to significantly reduce potassium concentration, whilst on cessation serum potassium subsequently rose.6 A dose-titration study performed over one year (AMETHYST-DN [Effect of Patiromer on Serum Potassium Level in Patients With Hyperkalaemia and Diabetic Kidney Disease]) also showed good efficacy and a double-blind placebo-controlled randomised controlled trial (PEARL-HF [Prevention of Hyperkalaemia in Patients with Heart Failure using a Novel Polymeric Potassium Binder, RLY5016]) showed significant reductions of serum potassium from baseline concentrations, enabling a higher proportion of patients to take spironolactone 50 mg/day compared to placebo.7,8 Not only did fewer patients become hyperkalaemic on spironolactone but fewer also stopped RAASi whilst on patiromer. Furthermore, serum potassium was significantly reduced seven hours after the initial dose. On the other hand, existing potassium binders e.g. sodium polystyrene sulfonate, although its onset is unknown, is generally thought to act within hours to days and has not been evaluated in randomised trials.
Another potassium binder has been undergoing clinical trials with promising results. ZQ-9 (sodium zirconium cyclosilicate) allows selective potassium binding in exchange for sodium and hydrogen. Results from phase II and III double-blinded randomised controlled trials have shown rapid reductions (between one to four hours) in severe hyperkalaemia (baseline potassium concentration ≥6.0 mEq/L) and demonstrated dose-dependent effects – the HARMONIZE trial, an international multi-centre phase III study across 44 sites showed that doses of 5 g, 10 g and 15 g were able to dose-dependently reduce serum potassium over one month.9,10 More recent data has shown long-term safety and efficacy over 12 months’ duration.
Whilst the effects of potassium binders are promising, their adverse effects must be considered. A major limitation of sodium polystyrene sulfonate is its poor tolerability due to gastrointestinal side-effects, hypokalaemia, electrolyte disturbance and colonic necrosis. Patiromer and ZQ-9, while having similar but milder adverse effects, are better tolerated.9
Nevertheless, patiromer is most commonly associated with hypomagnesaemia (9%), worsening CKD (9%), worsening hypertension (8%), diarrhoea (6%) and constipation (6%). Adverse effects of ZQ-9 were also common (occurring in 53.4% of patients), most frequently worsening hypertension (8.2%), peripheral oedema (7.6%) and constipation (5%). Oedema was also observed more commonly with higher doses of ZQ-9 (e.g. 15 g). Whereas no drug interactions have been found with ZQ-9 to date, patiromer must be taken three hours apart from other oral drugs.
In summary, studies have shown that novel potassium binders are effective and well tolerated, being able to treat chronic hyperkalaemia in patients with CKD and heart failure. Importantly, they may act as enabling drugs, allowing initiation and uptitration of RAASi to provide patients with the degree of benefit shown in clinical trials to date, whilst on the other hand, they can reduce the risk of hyperkalaemia, a concern that often faces the prescribing physician.
There is a significant clinical need for adequate control of hyperkalaemia given that large US database studies have shown that after moderate-to-severe hyperkalaemia events, 21% of patients down-titrate and 27% discontinue RAASi after a single moderate-to-severe hyperkalaemia event.11
Such novel potassium binders may represent a solution. Further work is needed however and hard outcomes, beyond serum potassium concentration, such as mortality and morbidity remain to be investigated.
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References
1. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709–17. https://doi.org/10.1056/NEJM199909023411001
2. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309–21. https://doi.org/10.1056/NEJMoa030207
3. Zannad F, McMurray JJV, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11–21. https://doi.org/10.1056/NEJMoa1009492
4. Sun LJ, Sun YN, Shan JP et al. Effects of mineralocorticoid receptor antagonists on the progression of diabetic nephropathy. J Diabetes Investig 2017;8:609–18. https://doi.org/10.1111/jdi.12629
5. Weir MR. Renin-angiotensin-aldosterone system inhibitor therapy benefit and challenges in cardio-renal patients. Presentation at the European Society of Cardiology Congress 2017, August 27th 2017, Barcelona, Spain. http://congress365.escardio.org/Presentation/155303?_ga=2.6527414.54513265.1507742133-139500263.1507742133#.Wd5R54ZrzJw
6. Weir MR, Bakris GL, OPAL-HK Investigators et al. Patiromer in patients with kidney disease and hyperkalaemia receiving RAAS inhibitors. N Engl J Med 2015;372:211–21. https://doi.org/10.1056/NEJMoa1410853
7. Pitt B, Anker SD, Bushinsky DA, Evaluation of the efficacy and safety of RLY5016, a polymeric potassium binder, in a double-blind, placebo-controlled study in patients with chronic heart failure (the PEARL-HF) trial. Eur H J 2011;32:820–8 https://doi.org/10.1093/eurheartj/ehq502
8. Bakris GL, Pitt B, Weir MR. Effect of patiromer on serum potassium level in patients with hyperkalaemia and diabetic kidney disease: The AMETHYST-DN randomized clinical Trial. JAMA 2015;314:151–61 https://doi.org/10.1001/jama.2015.7446
9. Anker SD. Changing the treatment paradigm of hyperkalaemia management to enable RAASi therapy. Presentation at the European Society of Cardiology Congress 2017, August 27th 2017, Barcelona, Spain. http://congress365.escardio.org/Presentation/155304?_ga=2.174928806.54513265.1507742133-139500263.1507742133#.Wd8wpIZrxcA
10. Kosiborod M, Rasmussen HS, Lavin P, et al. Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalaemia: the HARMONIZE randomized clinical trial. JAMA 2014;312:2223–33 https://doi.org/10.1001/jama.2014.15688
11. Epstein M, Reaven NL, Funk SE, et al. Evaluation of the treatment gap between clinical guidelines and the utilization of renin-angiotensin-aldosterone system inhibitors. Am J Manag Care 2015;21:S212–20 http://www.ajmc.com/journals/supplement/2015/A579_Sep15_RAASi/A579_Sep15_RAASi_Epstein_S212/
