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Authors: Kathy Tang, PharmD, BCPS and Kristin Watson, PharmD, BCPS-AQ Cardiology
Patiromer (Veltassaâ) and sodium zirconium cyclosilicate are novel potassium-lowering agents that have recently garnered attention for the management of hyperkalemia and reducing the risk of hyperkalemia associated with some medications used in the management of heart failure with reduced ejection fraction (HFrEF). Guideline-directed medical therapy for HFrEF includes several classes of renin-angiotensin-aldosterone-system (RAAS) inhibitors—angiotensin converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), and aldosterone antagonists—all of which can cause hyperkalemia. In practice, these therapies are generally discontinued or dose-reduced if serum potassium concentrations exceed 5.5 mEq/L.1 Hyperkalemia can develop in 10 to 15% of outpatients receiving RAAS inhibitor therapy.2,3 The rate of death associated with hyperkalemia has been reported to be as high as 2 in 1,000 among those receiving an aldosterone antagonist.4
Both patiromer and sodium zirconium cyclosilicate are non-absorbable cation exchange polymers that decrease serum potassium by binding to potassium in the gastrointestinal tract and increasing fecal excretion.5,6,7 In 2015, patiromer was approved by the FDA for the management of hyperkalemia, but not in emergent situations due to its delayed onset of action.5 Sodium zirconium cyclosilicate is not yet FDA approved; a New Drug Application was re-submitted in October 2016.8
Patiromer’s efficacy in patients with hyperkalemia and diabetic kidney disease was demonstrated in AMETHYST-DN, a phase 2, multicenter, randomized clinical trial.9 A significant decrease in serum potassium concentrations was observed after 4 weeks of treatment and continued through 52 weeks. Diabetic kidney disease was defined as type 2 diabetes with an estimated glomerular filtration rate (eGFR) of 15-60 mL/min/1.73 m2. Use of an ACEI, ARB, or both were required for at least 28 days before enrollment. Patients were randomized to one of three doses of patiromer, after a 4-week run-in period, based on baseline potassium. Those with mild hyperkalemia (potassium 5.0 – 5.5 mEq/L) received patiromer 8.4 g, 16.8 g, or 25.2 g twice daily and those in the moderate hyperkalemia group (potassium 5.5 – 6.0 mEq/L), received 16.8 g, 25.2 g, or 33.6 g twice daily. The initial dose was continued for 8 weeks. Patients then entered the maintenance phase where therapy could be increased or decreased over the next 44 weeks based on serum potassium concentrations. At week 4, patiromer significantly reduced serum potassium concentrations across all dose groups (see Table 1). Reductions in potassium were first observed at 48 hours after patiromer initiation, confirming the delayed onset of effect. Overall, the most common treatment-related adverse effects were hypomagnesemia (7.2%), mild-moderate constipation (6.3%), and diarrhea (2.7%). Hypokalemia (potassium < 3.5 mEq/L) leading to discontinuation of patiromer occurred in 9.2% patients; there were no serious adverse events resulting from hypokalemia.
|Table 1 Change in potassium concentrations after 4 weeks of patiromer|
|Mild Hyperkalemia||Moderate Hyperkalemia|
|Patiromer Daily Dose||Baseline K+||Mean K+ Reduction||Patiromer Dose||Baseline K+||Mean K+ Reduction|
|8.4 g||5.1||0.35||16.8 g||5.7||0.87|
|16.8 g||5.2||0.51||25.2 g||5.7||0.97|
|25.2 g||5.1||0.55||33.6 g||5.6||0.92|
K+= serum potassium concentration
P <0.001 for all changes versus baseline according to starting dose groups
Sodium zirconium cyclosilicate was evaluated in adult ambulatory patients with two consecutive serum potassium concentrations ≥ 5.1 mEq/L in HARMONIZE, a phase 3, randomized, double-blind trial. Patients requiring hemodialysis were excluded.7 All participants received open-label zirconium cyclosilicate 10 g three times daily for 48 hours. Patients were then randomized to zirconium cyclosilicate 5 g, 10 g, 15 g, or placebo daily for 28 days. During the open-label period, serum potassium was reduced by 1.1 mEq/L and potassium concentrations normalized (potassium < 5.1 mEq/L) in 98% of patients at 48 hours. During the randomization phase (days 8-29), there was a significant reduction in mean serum potassium concentrations – 5.53 mEq/L to 4.8 mEq/L in the 5 g group, 5.58 mEq/L to 4.5 mEq/L in the 10 g group, 5.55 mEq/L to 4.4 mEq/L in the 15 g group, and 5.55 mEq/L to 5.1 mEq/L in the placebo group. No major treatment-related adverse events were observed. Edema was more common in the zirconium cyclosilicate 15 g group (14% vs. 2% in the 5 g group, 6% in the 10 g group, and 2% in the placebo group). Hypokalemia, defined as potassium concentration < 3.5 mEq/L, was more common in the zirconium cyclosilicate 10 g and 15 g groups (none in the placebo and 5 g groups, 10% in the 10 g group, vs. 11% in the 15 g group). All cases of hypokalemia resolved after the dose of the study drug was reduced.
Given trials demonstrating the efficacy of these novel hyperkalemic agents, what might be their role in managing hyperkalemia when initiating, continuing, or dose-titrating medications in HFrEF that have been shown to decrease mortality and hospitalizations?
The effect of patiromer on reducing serum potassium in patients with heart failure and chronic kidney disease was first explored in PEARL-HF.10 PEARL-HF included patients with chronic heart failure (mean left ventricular ejection fraction (LVEF) 40-41%), an indication for spironolactone, and a serum potassium of 4.3 – 5.1 mEq/L. In addition, patients also had to have either 1) chronic kidney disease (eGFR <60 mL/min) and use of ACEI, ARB, and/or or beta-blocker or 2) a documented history of hyperkalemia leading to discontinuation of a RAAS agent or beta-blocker. In this prospective, double-blind study, patients were initiated on spironolactone 25 mg daily and randomized to receive placebo or patiromer 15 g BID, with standardized titration of spironolactone to 50 mg at two weeks based on serum potassium. After four weeks, patients receiving patiromer had significantly lower serum potassium compared to those receiving placebo (difference of 0.45 mEq/L. p<0.001). Significantly more patients in the patiromer group were able to have spironolactone titrated to 50 mg daily (50% vs. 36%, p=0.019). The most common adverse events were GI-related and occurred more frequently in the patiromer group compared with placebo, such as flatulence (7% vs. none), diarrhea (5% vs. 2%), and constipation (5% vs. none). A statistically significant decrease in magnesium was observed in the patiromer group compared to placebo (24% v. 2%, p=0.001) but no increase in arrhythmias was observed.
Use of patiromer in heart failure was also evaluated in a pre-specified analysis of the OPAL-HK trial.11 OPAL-HK included patients with a serum potassium of 5.1 – 6.5 mEq/L with stage 3 or 4 chronic kidney disease (eGFR of 15-60 mL/min/1.73 m2) who had been receiving a RAAS inhibitor for 28 days or more. There was a 4-week run-in period in which patients received 4.2 g or 8.4 g BID based on their baseline potassium. Patients were randomized to either continue patiromer or switch to placebo. It is unknown whether patients with HFrEF and/or heart failure with preserved ejection fraction were included as LVEF was not reported. The use of ACEI and ARB was similar in the heart failure (n=102) and non-heart failure (n=141) groups. However, more patients in the heart failure group were receiving an aldosterone antagonist (20% v. 1%). During the initial 4-week treatment phase, patiromer significantly reduced serum potassium from baseline in patients with heart failure by 1.06 mEq/L (p<0.001) and those without heart failure by 0.98 mEq/L (p<0.001). In the randomized 4-week withdrawal phase, continuation of patiromer reduced the proportion of patients with heart failure who developed recurrent hyperkalemia (8% in HF, compared to 52% with placebo, p<0.001). A mean change in serum potassium of 0.10 mEq/L was observed in the continuation group and 0.74 mEq/L in the placebo group, indicating that patiromer use was necessary to prevent the return of hyperkalemia (p<0.001).
Though OPAL-HK demonstrated the efficacy of patiromer at reducing serum potassium, its impact on clinical outcomes (i.e., by allowing the continuation of RAAS inhibitor therapy) has yet to be determined. Many of the landmark trials looking at medical therapies in HFrEF excluded patients with an elevated potassium concentration, as seen in Table 2. While the acceptable potassium concentrations for enrollment varied, it should be appreciated that patients with increased baseline serum potassium were excluded.
|Table 2. Sample of studies evaluating patients with heart failure with an exclusion criterion based on serum potassium12-16|
|Trial||Serum Potassium Exclusion Criteria|
|CHARM-Overall: Effects of candesartan on mortality and morbidity in patients with chronic heart failure||K > 5.5 mEq/L|
|HEAAL: Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure||K > 5.7 mEq/L|
|RALES: The effect of spironolactone on morbidity and mortality in severe heart failure||K > 5.0 mEq/L|
|EMPHASIS-HF: Eplerenone in patients with systolic heart failure and mild symptoms||K > 5.0 mEq/L|
|PARADIGM-HF: Angiotensin–neprilysin inhibition versus enalapril in heart failure||K > 5.2 mEq/L|
CHARM = Candesartan in heart failure – assessment of mortality and morbidity trial; EMPHASIS-HF = Eplerenone in patients with systolic heart failure and mild symptoms trial; HEAAL = Heart failure endpoint of angiotensin II antagonist losartan study; PARADIGM-HF = Prospective comparison of ARNI [angiotensin receptor–neprilysin inhibitor] with ACEI [angiotensin-converting–enzyme inhibitor] to determine impact on global mortality and morbidity in heart failure trial; RALES = Randomized aldactone evaluation study
If patiromer and sodium zirconium cyclosilicate can reduce serum potassium to a concentration where RAAS inhibitors can be initiated or titrated, can the results of the landmark HFrEF trials be applied to these patients? We cannot rule out that patients with higher baseline serum potassium may have different physiology than populations studied in landmark trials and thus it is unknown whether RAAS inhibitors might exert the same benefits.
Among other considerations is the cost-benefit of adding an antihyperkalemic agent. Currently, patiromer has a wholesale price of $142.80 for four 8.4 g doses, which corresponds to $35.70 for a daily initial recommended dose of 8.4 g and a monthly cost of $1,071. Higher doses would result in higher cost. Based on the results of OPAL-HK, a cost-benefit analysis of patiromer would have to include both initial treatment as well as continuation. Importantly, whether a benefit is even conferred by patiromer in patients with HFrEF remains unknown.
When hyperkalemia occurs in setting of RAAS therapy, evaluate for other potential causes (e.g., potassium supplementation, salt substitutes, and other medications that increase potassium). The dose of RAAS inhibitor therapies should be reduced or discontinued based on the severity of hyperkalemia (i.e., based on serum potassium concentrations and/or electrocardiographic changes), the patient’s clinical status (e.g., renal function) and timing of initiation or dose-titration of RAAS inhibitor therapy. When appropriate, recommend discontinuing or dose-reducing aldosterone antagonist therapy prior to adjusting other RAAS agents.
Although patiromer and sodium zirconium cyclosilicate reduce serum potassium concentrations, their role in increasing the initiation, continuation, or up-titration of standard HFrEF therapies has not been shown and they should not be routinely recommended for this use, especially given the costs of therapy and availability of alternative management strategies.
Kristin Watson, PharmD, BCPS-AQ Cardiology
Kathy Tang, PharmD, BCPS
- Yancy CW, Jessup M, Bozkurt B, et al; American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 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 Oct 15;62(16):e147-239.
- Reardon LC, Macpherson DS. Hyperkalemia in outpatients using angiotensin-converting enzyme inhibitors. How much should we worry? Arch Intern Med 1998;158:26-32.
- McMurray JJV, Packer M, Desai AS et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Eng J Med. 2014;371:993-1004.
- Juurlink DN, Mamdani MM, Lee DS et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Eng J Med 2004;351:543-51.
- Veltassa (patiromer) package insert. Redwood City, CA. Relypsa, Inc. 2016 November.
- Linder KE, Krawczynski MA, Laskey D. Sodium Zirconium Cyclosilicate (ZS-9): A Novel Agent for the Treatment of Hyperkalemia. Pharmacotherapy 2016 Aug;36(8):923-33.
- Kosiborod M, Rasmussen HS, Lavin P et al. Effect of sodium zirconium cyclosilicate on potassium lowering for 28 days among outpatients with hyperkalemia: the HARMONIZE randomized clinical trial. JAMA. 2014;312(21):2223-33.
- FDA accepts for review New Drug Application for sodium zirconium cyclosilicate (ZS-9) for the treatment of hyperkalaemia. (2016, October 18). Retrieved February 23, 2017, from https://www.astrazeneca.com/media-centre/press-releases/2016/fda-accepts-for-review-new-drug-application-for-sodium-zirconium-18102016.html
- Bakris GL, Pitt B, Weir MR et al. Effect of patiromer on serum potassium level in patients with hyperkalemia and diabetic kidney disease: the AMETHYST-DN randomized clinical trial. JAMA 2015 Jul 14;314(2):151-61.
- Pitt B, Anker SD, Bushinsky DA et al. 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 Heart J. 2011 Apr;32(7):820-8.
- Pitt B, Bakris GL, Bushinsky DA et al. 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 Oct;17(10):1057-65.
- Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003;363:759-66.
- Konstam, MA, Neaton JD, Dickstein K, et al. Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial Lancet 2009:374:1840-1848.
- Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Eng J Med. 1999;341:709-17.
- Zannad F, McMurray JJV, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Eng J Med. 2011;364(1):11-21.
- McMurray JJV, Packer, M, Desai AS. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Eng J Med. 2014;371:993-1004.
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