Hyperkalemia: Caught in a Bind?

Hyperkalemia, used to describe an elevated level of potassium in the blood, occurs when there is a disturbance in the balance between intake and elimination or a shift of potassium between the intracellular and extracellular spaces.

Eighty percent to 90% of potassium is eliminated renally. Therefore, patients with kidney disease are most at risk of developing hyperkalemia. The most severe consequence is ventricular fibrillation and sudden cardiac death. When electrocardiogram changes, such as peaked T waves, are present, hyperkalemia should be treated as a medical emergency. Treatment of severe hyperkalemia is focused on stabilizing the cardiac membrane, shifting potassium intracellularly, and eliminating potassium from total body stores.¹

New options for increasing the elimination of potassium have been approved in recent years. Previously, the only cation exchange resin available was sodium polystyrene sulfonate (SPS), which was approved in 1958, before manufacturers had to demonstrate both efficacy and safety.² Disadvantages of SPS include poor palatability, the rare but serious adverse effect of colonic necrosis, and the sodium content (1500 mg per 15 g of SPS), which may not be tolerated in patients with comorbidities such as edema, heart failure, and hypertension.³

Patiromer (Veltassa), approved in 2015, is a nonabsorbed polymer that binds potassium in the gastrointestinal (GI) tract. It is available as a powder that is mixed with water prior to administration. The starting dose is 8.4 g daily, which is increased weekly based on potassium levels to a maximum of 25.2 g daily.⁴

The potassium-lowering effect of patiromer depends on baseline potassium values and dose. In a study⁵ evaluating efficacy after 4 weeks of treatment, patients with baseline potassium values between 5.1 and 5.5 mEq/L had a mean reduction in potassium of —0.65 mEq/L, and those with a potassium level between 5.5 and 6.5 mEq/L had a mean reduction in potassium of –1.23 mEq/L. The average daily dose in these 2 groups was 12.8 and 21.4 g, respectively.

Another study⁶ assessed patiromer’s use in the treatment of acute hyperkalemia. There were 25 participants with a mean serum potassium level of 5.93 mEq/L. Patients received 8.4 g of patiromer twice a day for 4 doses. Seven hours after the first dose was given, the potassium level decreased by —0.21 mEq/L, but just 20% of patients had achieved a serum potassium level of less than 5.5 mEq/L. This percentage increased to 80% after 24 hours. Because off its delayed onset of action, patiromer should not be used as the sole agent to treat severe hyperkalemia.

Patiromer does not selectively bind potassium, and hypomagnesemia was reported in 5.3% to 9% of clinical trial participants. The most commonly reported adverse effects were constipation, nausea, vomiting, diarrhea, and flatulence. Patiromer binds to medications, so patients should be counseled to take other medications 3 hours before or 3 hours after taking their dose. Also, patiromer is heat sensitive and should not be microwaved or added to hot beverages.⁴

The newest cation exchange resin, sodium zirconium cyclosilicate (Lokelma), was approved in May 2018. It reduces potassium by exchanging sodium and hydrogen for potassium in the GI tract.⁷ It has a high affinity for potassium ions, unlike patiromer and SPS, and does not affect serum magnesium or calcium levels.⁸ Sodium zirconium cyclosilicate is a powder that needs to be mixed in water prior to administration. The approved dosing is 10 g 3 times a day for up to 48 hours. After this, the dose is decreased to 10 g once a day and then adjusted based on serum potassium levels.⁷

A greater response is seen with higher doses of sodium zirconium cyclosilicate and in patients with higher initial potassium levels. After patients received 10 g 3 times a day for 48 hours, potassium levels decreased by an average of —0.6 mEq/L in those with a baseline potassium level of 5.3 mEq/L or less and by –1.1 mEq/L in patients with a level greater than 5.5 mEq/L.⁹

One disadvantage of the formulation is the sodium content. A 5-g dose of sodium zirconium cyclosilicate contains about 400 mg of sodium.⁷ In patients on daily maintenance therapy, edema was seen in 2% of patients receiving the placebo, 2% receiving 5 g, 6% receiving 10 g, and 14% receiving 15 g.¹⁰

These new treatment options may be beneficial in patients who are unable to receive optimal treatment with renin-angiotensin-aldosterone system (RAAS) inhibitors. RAAS inhibitors play an important role in the treatment of chronic kidney disease and heart failure. Unfortunately, because of drug-induced hyperkalemia, many patients who could benefit from treatment with RAAS inhibitors are unable to take them. In general, patiromer and sodium zirconium cyclosilicate were well tolerated and effectively decreased and maintained potassium within normal range for an extended duration.

Staley Lawes, PharmD, BCPS, FISMP, is a medication safety officer in the pharmacy department of Hackensack Meridian Health in Edison, New Jersey.

References

• Weiner ID, Wingo CS. Hyperkalemia: a potential silent killer. J Am Soc Nephrol. 1998;9(8):1535-1543.
• Kefauver-Harris amendments revolutionized drug development. FDA website. www.fda.gov/ForConsumers/ConsumerUpdates/ucm322856.htm. Published October 10, 201 Accessed October 18, 2018.
• Kayexalate [prescribing information]. Bridgewater, NJ: Sanofi-Aventis; 2009. www.accessdata.fda.gov/drugsatfda_docs/label/2009/011287s022lbl.pdf. Accessed October 31, 2018.
• Veltassa [prescribing information]. Redwood City, CA: Relypsa Inc; 2018. veltassa.com/pi.pdf. Accessed October 31, 2018.
• Weir MR, Bakris GL, Bushinsky DA, et al; OPAL-HK Investigators. Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med. 2015;372(3):211-221. doi: 10.1056/NEJMoa1410853.
• Bushinsky DA, Williams GH, Pitt B, et al. Patiromer induces rapid and sustained potassium lowering in patients with chronic kidney disease and hyperkalemia. Kidney Int. 2015;88(6):1427-1433. doi: 10.1038/ki.2015.270.
• Lokelma [prescribing information]. Wilmington, DE: AstraZeneca; 2018. www.accessdata.fda.gov/drugsatfda_docs/label/2018/207078s000lbl.pdf. Accessed October 31, 2018.
• Beccari MV, Meaney CJ. Clinical utility of patiromer, sodium zirconium cyclosilicate, and sodium polystyrene sulfonate for the treatment of hyperkalemia: an evidence-based review. Core Evid. 2017;12:11-24. doi: 10.2147/CE.S129555.
• Packham DK, Rasmussen HS, Lavin PT, et al. Sodium zirconium cyclosilicate in hyperkalaemia. N Engl J Med. 2015;372(3):222-231. doi: 10.1056/NEJMoa1411487.
• 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):2223-2233. doi: 1001/jama.2014.15688.