- Email: [email protected]
Patiromer for Hyperkalemia in Diabetic CKD: A New Kid on the Block
In the Literature Patiromer for Hyperkalemia in Diabetic CKD: A New Kid on the Block Commentary on 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;314(2):151-161.
P
ersons with chronic kidney disease (CKD), diabetes, or heart failure treated with reninangiotensin-aldosterone system (RAAS)-blocking agents are at an increased risk for hyperkalemia.1-4 Although mild to moderate hyperkalemia (serum potassium, 5.0-6.0 mEq/L) is often asymptomatic, severe hyperkalemia (serum potassium . 6.0 mEq/L) can cause cardiac arrhythmias and death.1 Hyperkalemia also limits use of RAAS-blocking agents, which have heart- and kidney-protective effects. Treatment of hyperkalemia involves dietary potassium restriction, discontinuation of RAAS-blocking agents, and use of potassium-binding cation-exchange polymers to enhance gut elimination. Sodium polystyrene sulfonate, until recently the only available exchange resin, is associated with constipation when ingested in powder format, but with diarrhea when premixed with sorbitol. Sodium polystyrene sulfonate–sorbitol enemas can cause colonic necrosis and perforation in settings of decreased gut motility5,6 and critical illness.7,8 The past 2 years have witnessed the emergence of new cation-exchange polymers to treat hyperkalemia in ambulatory settings.9-11
WHAT DOES THIS IMPORTANT STUDY SHOW? In a recent issue of JAMA, the AMETHYST-DN (Patiromer in the Treatment of Hyperkalemia in Patients With Hypertension and Diabetic Nephropathy) trial reports the effects of a new potassium-binding polymer, patiromer (patiromer sorbitex calcium), administered in ambulatory settings to patients with type 2 diabetes with an estimated glomerular filtration rate (eGFR) , 60 mL/min/1.73 m2 and hyperkalemia.12 For this phase 2, multicenter, open-label, dose-ranging, randomized trial, 306 patients of white ethnicity receiving an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), or both were enrolled. The study included a 4week run-in, an 8-week treatment, a 44-week maintenance, and a 4-week post-therapy surveillance phase. Two cohorts of patients without hyperkalemia using an ACE inhibitor, an ARB, or both were enrolled, and spironolactone (25-50 mg once daily) was added to achieve a target blood pressure , 130/80 mm Hg. A third cohort with mild to moderate hyperkalemia (serum potassium, 5.0-6.0 mEq/L) was also enrolled without adding spironolactone. Overall, 222 participants with mild hyperkalemia (serum potassium, 5.1-5.5 mEq/L) were randomly assigned to receive 8.4, Am J Kidney Dis. 2016;-(-):---
16.8, or 25.2 g of patiromer daily; 84 participants with moderate hyperkalemia were randomly assigned to receive 16.8, 25.2, or 33.6 g of patiromer daily. The starting dose was adjusted to achieve a serum potassium level # 5 mEq/L. Participants were counseled to maintain a low-potassium diet. Participants who did not become hyperkalemic and those with serum potassium levels . 6.0 mEq/L during the run-in phase were excluded. The primary efficacy end point was mean change in serum potassium level at week 4, and the primary safety end point was the frequency and severity of adverse events. Baseline characteristics were comparable among participants with mild and moderate hyperkalemia. Mean age was 66 years, and eGFR was 41 mL/min/1.73 m2. Nearly 28% had stage 4/5 CKD, 75% were receiving an ACE inhibitor or ARB, and 42% were receiving diuretics. Baseline serum potassium levels were 5.2 and 5.7 mEq/L in patients with mild and moderate hyperkalemia, respectively. There was a significant dose-dependent reduction in serum potassium levels in patients with mild hyperkalemia, ranging from 0.35 to 0.51 mEq/L, with escalating patiromer doses. A similar reduction was seen in patients with moderate hyperkalemia, with overall ranges of 0.87 to 0.97 mEq/L. Times required to lower serum potassium levels to ,5 mEq/L were 48 hours and 1 week in patients with mild and moderate hyperkalemia, respectively. Most participants maintained normokalemia during the maintenance phase. Serum potassium levels increased significantly within 3 days of entering the surveillance phase, reaching an increase of 0.39 to 0.48 mEq/L at 28 days. Hypomagnesemia (7.2%), constipation (4.6%), and diarrhea (2.7%) were the most common treatment-related adverse events. Serious adverse events were reported in 14.5%, but none was attributed to patiromer.
HOW DOES THIS STUDY COMPARE WITH PRIOR STUDIES? Sodium polystyrene sulfonate was first approved in 1958 prior to wide-scale clinical experience with its use. In 1961, Scherr et al13 administered 30 to 60 g of Address correspondence to Bertrand L. Jaber, Division of Nephrology, St. Elizabeth’s Medical Center, 736 Cambridge St, Boston, MA 02135. E-mail: [email protected] Ó 2016 by the National Kidney Foundation, Inc. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2016.01.001 1
Garimella and Jaber
sodium polystyrene sulfonate to 32 patients with kidney failure on a low-potassium diet. In 23 patients, serum potassium levels decreased by $0.4 mEq/L over 24 hours. Twenty-three oliguric patients also received 20% dextrose, 3 received insulin and glucose, and 5 received bicarbonate, while some also received cathartics. Another study compared sodium polystyrene sulfonate–sorbitol in 5 oliguric patients to sorbitol alone in 3 patients. A 1.4-mEq/L serum potassium level reduction was observed at 5 days in patients receiving sodium polystyrene sulfonate–sorbitol; those receiving sorbitol alone had a greater reduction of 1.7 mEq/L.14 In both studies, the small sample size, lack of randomization and appropriate control groups, and use of medication that confounded the effect of sodium polystyrene sulfonate were significant limitations. Importantly, neither study evaluated whether sodium polystyrene sulfonate could be used in patients taking RAAS-blocking agents or those with acute severe hyperkalemia requiring a rapid serum potassium level reduction. Sodium zirconium cyclosilicate (ZS Pharma, Inc) is a selective cation exchanger that entraps potassium in the gut in exchange for sodium and hydrogen. In patients with stage 3 CKD and hyperkalemia (serum potassium, 5.0-6.0 mEq/L), compared to placebo, sodium zirconium cyclosilicate resulted in a 0.92mEq/L serum potassium level decrease over 38 hours.15 A larger phase 3 randomized controlled trial of sodium zirconium cyclosilicate enrolled patients with serum potassium levels . 5.1 mEq/L.9 A total of 237 participants who achieved normokalemia while receiving 10 g of sodium zirconium cyclosilicate thrice daily were randomly assigned to receive 5, 10, or 15 g of sodium zirconium cyclosilicate once daily or placebo for 28 days. Sodium zirconium cyclosilicate decreased serum potassium levels from 5.6 to 4.5 mEq/L within 48 hours in 98% of patients, with a median normalization time of 2.2 hours. More patients remained normokalemic while receiving sodium zirconium cyclosilicate compared to placebo. Edema was the most common adverse event reported
with sodium zirconium cyclosilicate (2%-14%) and was dose dependent.9 In a third phase 3 placebocontrolled trial, 753 participants with serum potassium levels of 5.0 to 6.4 mEq/L were randomly assigned to receive either placebo or sodium zirconium cyclosilicate (1.25, 2.5, 5, or 10 g) thrice daily for 48 hours.16 Participants achieving normokalemia were then re–randomly assigned to receive their original sodium zirconium cyclosilicate dose or placebo once daily for 12 days. After 48 hours, there was a progressive dose-dependent serum potassium level reduction with escalating doses of sodium zirconium cyclosilicate, ranging from 0.46 to 0.73 mEq/L, compared to 0.25 mEq/L in the placebo group. For the rest of the study, serum potassium levels were maintained at 4.7 and 4.5 mEq/L in patients receiving 5 and 10 g of sodium zirconium cyclosilicate once daily compared to .5.0 mEq/L in the placebo group. Diarrhea was the most commonly reported adverse effect in the placebo and sodium zirconium cyclosilicate groups. Prior to the AMETHYST-DN trial publication,12 a smaller trial of 237 patients evaluated patiromer, 4.2 or 8.4 g, twice daily for mild and moderate hyperkalemia in persons with CKD receiving RAAS blockade.17 Serum potassium levels decreased by 0.65 and 1.23 mEq/L, respectively. Participants with moderate hyperkalemia were then randomly assigned to either placebo or their original patiromer dose. Compared to the placebo group that experienced a 0.72-mEq/L serum potassium level increase, patients receiving patiromer had no serum potassium level elevation at 8 weeks. Hyperkalemia recurrence was lower in the patiromer compared to placebo group. In another trial evaluating whether patiromer, 8.4 g, twice daily can rapidly correct hyperkalemia in patients with serum potassium levels of 5.9 mEq/L, a 0.2-mEq/L reduction was observed within 7 hours, reaching 0.75 mEq/L by 48 hours.10 In both studies, constipation was the most common side effect of patiromer. Table 1 provides a brief comparison of sodium polystyrene sulfonate, patiromer, and sodium zirconium cyclosilicate.
Table 1. Comparison of Potassium Binders
Type of compound Mechanism of action Route of administration Formulation Location of potassium binding
2
Sodium Polystyrene Sulfonate (SPS)
Patiromer Sorbitex Calcium (Patiromer)
Sodium Zirconium Cycosilicate
Nonabsorbed, organic polymer in a sorbitol base Nonspecific cation binding in exchange for sodium Oral or rectal Suspension in sorbitol or dissolvable powder Colon
Nonabsorbed, organic polymer and sorbitol complex Nonspecific cation binding in exchange for calcium Oral Oral suspension
Nonabsorbed, insoluble inorganic crystal Selective potassium binding in exchange for sodium and hydrogen Oral Oral suspension
Distal colon predominantly
Entire intestinal tract
Am J Kidney Dis. 2016;-(-):---
In the Literature
WHAT SHOULD CLINICIANS AND RESEARCHERS DO? On October 21, 2015, the US Food and Drug Administration (FDA) approved patiromer under the brand name of Veltassa (Relypsa, Inc) for the treatment of hyperkalemia in CKD, thus heralding the arrival of a new drug into a market that has been stagnant for decades. Patiromer is expected to become available in January 2016.18 No information is yet available regarding its projected costs. An important consideration is patiromer’s potential to bind to other medications in the gut, decreasing their absorption. The manufacturer recommends administering patiromer at least 6 hours apart from other medications.18 The FDA has since issued a drug safety communication mandating drug interaction studies with sodium polystyrene sulfonate.19 The use of patiromer in acute settings such as in patients with serum potassium levels . 6.5 mEq/L or those with electrocardiographic changes has not been evaluated. Although it has not been approved for use under these circumstances, if used off label, monotherapy with patiromer cannot be considered effective. Standard treatment with beta-adrenergic agonists, insulin, and glucose must be used to rapidly lower serum potassium levels. Although the landmark AMETHYST-DN trial led to the approval of patiromer to treat mild to moderate hyperkalemia, given the promising results with sodium zirconium cyclosilicate, head-to-head comparison of the 2 drugs is needed. Given the gastrointestinal side effects, unpleasant taste, and risk for colonic necrosis with sodium polystyrene sulfonate, its days as the primary treatment option for hyperkalemia are likely numbered. The emergence of patiromer as a novel potassium-binding drug from rigorous trials heralds a paradigm shift in treating hyperkalemia. When available, patiromer has the potential to facilitate the use of RAAS-blocking agents in patients with proteinuric CKD who stand to greatly benefit from their use. Pranav S. Garimella, MD, MPH Tufts Medical Center Boston, Massachusetts Bertrand L. Jaber, MD, MS St Elizabeth’s Medical Center Boston, Massachusetts
ACKNOWLEDGEMENTS Support: Dr Garimella is supported by National Institutes of Health training grant 5T32DK007777. Financial Disclosure: The authors declare that they have no relevant financial interests. Peer Review: Evaluated by the Deputy Editor and the Editor-inChief.
Am J Kidney Dis. 2016;-(-):---
REFERENCES 1. Einhorn LM, Zhan M, Hsu VD, et al. The frequency of hyperkalemia and its significance in chronic kidney disease. Arch Intern Med. 2009;169(12):1156-1162. 2. Desai AS, Swedberg K, McMurray JJ, et al. Incidence and predictors of hyperkalemia in patients with heart failure: an analysis of the CHARM Program. J Am Coll Cardiol. 2007;50(20):1959-1966. 3. Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med. 2004;351(6):543-551. 4. Susantitaphong P, Sewaralthahab K, Balk EM, Eiam-ong S, Madias NE, Jaber BL. Efficacy and safety of combined vs. single renin-angiotensin-aldosterone system blockade in chronic kidney disease: a meta-analysis. Am J Hypertens. 2013;26(3):424-441. 5. Gerstman BB, Kirkman R, Platt R. Intestinal necrosis associated with postoperative orally administered sodium polystyrene sulfonate in sorbitol. Am J Kidney Dis. 1992;20(2):159-161. 6. Wootton FT, Rhodes DF, Lee WM, Fitts CT. Colonic necrosis with Kayexalate-sorbitol enemas after renal transplantation. Ann Intern Med. 1989;111(11):947-949. 7. Rogers FB, Li SC. Acute colonic necrosis associated with sodium polystyrene sulfonate (Kayexalate) enemas in a critically ill patient: case report and review of the literature. J Trauma. 2001;51(2):395-397. 8. Cheng ES, Stringer KM, Pegg SP. Colonic necrosis and perforation following oral sodium polystyrene sulfonate (Resonium A/Kayexalate in a burn patient. Burns. 2002;28(2):189-190. 9. 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. 10. 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. 11. Packham DK, Rasmussen HS, Lavin PT, et al. Sodium zirconium cyclosilicate in hyperkalemia. N Engl J Med. 2015;372(3):222-231. 12. 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;314(2):151-161. 13. Scherr L, Ogden DA, Mead AW, Spritz N, Rubin AL. Management of hyperkalemia with a cation-exchange resin. N Engl J Med. 1961;264:115-119. 14. Flinn RB, Merrill JP, Welzant WR. Treatment of the oliguric patient with a new sodium-exchange resin and sorbitol; a preliminary report. N Engl J Med. 1961;264:111-115. 15. Ash SR, Singh B, Lavin PT, Stavros F, Rasmussen HS. A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, ZS-9, is safe and efficient. Kidney Int. 2015;88(2):404-411. 16. Packham DK, Rasmussen HS, Singh B. New agents for hyperkalemia. N Engl J Med. 2015;372(16):1571-1572. 17. Weir MR, Bakris GL, Bushinsky DA, et al. Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med. 2015;372(3):211-221. 18. Relypsa. Relypsa Announces FDA Approval of Veltassa(TM) (patiromer) for Oral Suspension for the Treatment of Hyperkalemia. http://investor.relypsa.com/releasedetail.cfm? releaseid5937821. Accessed October 26, 2015. 19. US Food and Drug Administration. FDA Drug Safety Communication: FDA requires drug interaction studies with potassium-lowering drug Kayexalate (sodium polystyrene sulfonate). Accessed, http://www. fda.gov/Drugs/DrugSafety/ucm468035.htm. October 30, 2015.
3
P
ersons with chronic kidney disease (CKD), diabetes, or heart failure treated with reninangiotensin-aldosterone system (RAAS)-blocking agents are at an increased risk for hyperkalemia.1-4 Although mild to moderate hyperkalemia (serum potassium, 5.0-6.0 mEq/L) is often asymptomatic, severe hyperkalemia (serum potassium . 6.0 mEq/L) can cause cardiac arrhythmias and death.1 Hyperkalemia also limits use of RAAS-blocking agents, which have heart- and kidney-protective effects. Treatment of hyperkalemia involves dietary potassium restriction, discontinuation of RAAS-blocking agents, and use of potassium-binding cation-exchange polymers to enhance gut elimination. Sodium polystyrene sulfonate, until recently the only available exchange resin, is associated with constipation when ingested in powder format, but with diarrhea when premixed with sorbitol. Sodium polystyrene sulfonate–sorbitol enemas can cause colonic necrosis and perforation in settings of decreased gut motility5,6 and critical illness.7,8 The past 2 years have witnessed the emergence of new cation-exchange polymers to treat hyperkalemia in ambulatory settings.9-11
WHAT DOES THIS IMPORTANT STUDY SHOW? In a recent issue of JAMA, the AMETHYST-DN (Patiromer in the Treatment of Hyperkalemia in Patients With Hypertension and Diabetic Nephropathy) trial reports the effects of a new potassium-binding polymer, patiromer (patiromer sorbitex calcium), administered in ambulatory settings to patients with type 2 diabetes with an estimated glomerular filtration rate (eGFR) , 60 mL/min/1.73 m2 and hyperkalemia.12 For this phase 2, multicenter, open-label, dose-ranging, randomized trial, 306 patients of white ethnicity receiving an angiotensin-converting enzyme (ACE) inhibitor, an angiotensin receptor blocker (ARB), or both were enrolled. The study included a 4week run-in, an 8-week treatment, a 44-week maintenance, and a 4-week post-therapy surveillance phase. Two cohorts of patients without hyperkalemia using an ACE inhibitor, an ARB, or both were enrolled, and spironolactone (25-50 mg once daily) was added to achieve a target blood pressure , 130/80 mm Hg. A third cohort with mild to moderate hyperkalemia (serum potassium, 5.0-6.0 mEq/L) was also enrolled without adding spironolactone. Overall, 222 participants with mild hyperkalemia (serum potassium, 5.1-5.5 mEq/L) were randomly assigned to receive 8.4, Am J Kidney Dis. 2016;-(-):---
16.8, or 25.2 g of patiromer daily; 84 participants with moderate hyperkalemia were randomly assigned to receive 16.8, 25.2, or 33.6 g of patiromer daily. The starting dose was adjusted to achieve a serum potassium level # 5 mEq/L. Participants were counseled to maintain a low-potassium diet. Participants who did not become hyperkalemic and those with serum potassium levels . 6.0 mEq/L during the run-in phase were excluded. The primary efficacy end point was mean change in serum potassium level at week 4, and the primary safety end point was the frequency and severity of adverse events. Baseline characteristics were comparable among participants with mild and moderate hyperkalemia. Mean age was 66 years, and eGFR was 41 mL/min/1.73 m2. Nearly 28% had stage 4/5 CKD, 75% were receiving an ACE inhibitor or ARB, and 42% were receiving diuretics. Baseline serum potassium levels were 5.2 and 5.7 mEq/L in patients with mild and moderate hyperkalemia, respectively. There was a significant dose-dependent reduction in serum potassium levels in patients with mild hyperkalemia, ranging from 0.35 to 0.51 mEq/L, with escalating patiromer doses. A similar reduction was seen in patients with moderate hyperkalemia, with overall ranges of 0.87 to 0.97 mEq/L. Times required to lower serum potassium levels to ,5 mEq/L were 48 hours and 1 week in patients with mild and moderate hyperkalemia, respectively. Most participants maintained normokalemia during the maintenance phase. Serum potassium levels increased significantly within 3 days of entering the surveillance phase, reaching an increase of 0.39 to 0.48 mEq/L at 28 days. Hypomagnesemia (7.2%), constipation (4.6%), and diarrhea (2.7%) were the most common treatment-related adverse events. Serious adverse events were reported in 14.5%, but none was attributed to patiromer.
HOW DOES THIS STUDY COMPARE WITH PRIOR STUDIES? Sodium polystyrene sulfonate was first approved in 1958 prior to wide-scale clinical experience with its use. In 1961, Scherr et al13 administered 30 to 60 g of Address correspondence to Bertrand L. Jaber, Division of Nephrology, St. Elizabeth’s Medical Center, 736 Cambridge St, Boston, MA 02135. E-mail: [email protected] Ó 2016 by the National Kidney Foundation, Inc. 0272-6386 http://dx.doi.org/10.1053/j.ajkd.2016.01.001 1
Garimella and Jaber
sodium polystyrene sulfonate to 32 patients with kidney failure on a low-potassium diet. In 23 patients, serum potassium levels decreased by $0.4 mEq/L over 24 hours. Twenty-three oliguric patients also received 20% dextrose, 3 received insulin and glucose, and 5 received bicarbonate, while some also received cathartics. Another study compared sodium polystyrene sulfonate–sorbitol in 5 oliguric patients to sorbitol alone in 3 patients. A 1.4-mEq/L serum potassium level reduction was observed at 5 days in patients receiving sodium polystyrene sulfonate–sorbitol; those receiving sorbitol alone had a greater reduction of 1.7 mEq/L.14 In both studies, the small sample size, lack of randomization and appropriate control groups, and use of medication that confounded the effect of sodium polystyrene sulfonate were significant limitations. Importantly, neither study evaluated whether sodium polystyrene sulfonate could be used in patients taking RAAS-blocking agents or those with acute severe hyperkalemia requiring a rapid serum potassium level reduction. Sodium zirconium cyclosilicate (ZS Pharma, Inc) is a selective cation exchanger that entraps potassium in the gut in exchange for sodium and hydrogen. In patients with stage 3 CKD and hyperkalemia (serum potassium, 5.0-6.0 mEq/L), compared to placebo, sodium zirconium cyclosilicate resulted in a 0.92mEq/L serum potassium level decrease over 38 hours.15 A larger phase 3 randomized controlled trial of sodium zirconium cyclosilicate enrolled patients with serum potassium levels . 5.1 mEq/L.9 A total of 237 participants who achieved normokalemia while receiving 10 g of sodium zirconium cyclosilicate thrice daily were randomly assigned to receive 5, 10, or 15 g of sodium zirconium cyclosilicate once daily or placebo for 28 days. Sodium zirconium cyclosilicate decreased serum potassium levels from 5.6 to 4.5 mEq/L within 48 hours in 98% of patients, with a median normalization time of 2.2 hours. More patients remained normokalemic while receiving sodium zirconium cyclosilicate compared to placebo. Edema was the most common adverse event reported
with sodium zirconium cyclosilicate (2%-14%) and was dose dependent.9 In a third phase 3 placebocontrolled trial, 753 participants with serum potassium levels of 5.0 to 6.4 mEq/L were randomly assigned to receive either placebo or sodium zirconium cyclosilicate (1.25, 2.5, 5, or 10 g) thrice daily for 48 hours.16 Participants achieving normokalemia were then re–randomly assigned to receive their original sodium zirconium cyclosilicate dose or placebo once daily for 12 days. After 48 hours, there was a progressive dose-dependent serum potassium level reduction with escalating doses of sodium zirconium cyclosilicate, ranging from 0.46 to 0.73 mEq/L, compared to 0.25 mEq/L in the placebo group. For the rest of the study, serum potassium levels were maintained at 4.7 and 4.5 mEq/L in patients receiving 5 and 10 g of sodium zirconium cyclosilicate once daily compared to .5.0 mEq/L in the placebo group. Diarrhea was the most commonly reported adverse effect in the placebo and sodium zirconium cyclosilicate groups. Prior to the AMETHYST-DN trial publication,12 a smaller trial of 237 patients evaluated patiromer, 4.2 or 8.4 g, twice daily for mild and moderate hyperkalemia in persons with CKD receiving RAAS blockade.17 Serum potassium levels decreased by 0.65 and 1.23 mEq/L, respectively. Participants with moderate hyperkalemia were then randomly assigned to either placebo or their original patiromer dose. Compared to the placebo group that experienced a 0.72-mEq/L serum potassium level increase, patients receiving patiromer had no serum potassium level elevation at 8 weeks. Hyperkalemia recurrence was lower in the patiromer compared to placebo group. In another trial evaluating whether patiromer, 8.4 g, twice daily can rapidly correct hyperkalemia in patients with serum potassium levels of 5.9 mEq/L, a 0.2-mEq/L reduction was observed within 7 hours, reaching 0.75 mEq/L by 48 hours.10 In both studies, constipation was the most common side effect of patiromer. Table 1 provides a brief comparison of sodium polystyrene sulfonate, patiromer, and sodium zirconium cyclosilicate.
Table 1. Comparison of Potassium Binders
Type of compound Mechanism of action Route of administration Formulation Location of potassium binding
2
Sodium Polystyrene Sulfonate (SPS)
Patiromer Sorbitex Calcium (Patiromer)
Sodium Zirconium Cycosilicate
Nonabsorbed, organic polymer in a sorbitol base Nonspecific cation binding in exchange for sodium Oral or rectal Suspension in sorbitol or dissolvable powder Colon
Nonabsorbed, organic polymer and sorbitol complex Nonspecific cation binding in exchange for calcium Oral Oral suspension
Nonabsorbed, insoluble inorganic crystal Selective potassium binding in exchange for sodium and hydrogen Oral Oral suspension
Distal colon predominantly
Entire intestinal tract
Am J Kidney Dis. 2016;-(-):---
In the Literature
WHAT SHOULD CLINICIANS AND RESEARCHERS DO? On October 21, 2015, the US Food and Drug Administration (FDA) approved patiromer under the brand name of Veltassa (Relypsa, Inc) for the treatment of hyperkalemia in CKD, thus heralding the arrival of a new drug into a market that has been stagnant for decades. Patiromer is expected to become available in January 2016.18 No information is yet available regarding its projected costs. An important consideration is patiromer’s potential to bind to other medications in the gut, decreasing their absorption. The manufacturer recommends administering patiromer at least 6 hours apart from other medications.18 The FDA has since issued a drug safety communication mandating drug interaction studies with sodium polystyrene sulfonate.19 The use of patiromer in acute settings such as in patients with serum potassium levels . 6.5 mEq/L or those with electrocardiographic changes has not been evaluated. Although it has not been approved for use under these circumstances, if used off label, monotherapy with patiromer cannot be considered effective. Standard treatment with beta-adrenergic agonists, insulin, and glucose must be used to rapidly lower serum potassium levels. Although the landmark AMETHYST-DN trial led to the approval of patiromer to treat mild to moderate hyperkalemia, given the promising results with sodium zirconium cyclosilicate, head-to-head comparison of the 2 drugs is needed. Given the gastrointestinal side effects, unpleasant taste, and risk for colonic necrosis with sodium polystyrene sulfonate, its days as the primary treatment option for hyperkalemia are likely numbered. The emergence of patiromer as a novel potassium-binding drug from rigorous trials heralds a paradigm shift in treating hyperkalemia. When available, patiromer has the potential to facilitate the use of RAAS-blocking agents in patients with proteinuric CKD who stand to greatly benefit from their use. Pranav S. Garimella, MD, MPH Tufts Medical Center Boston, Massachusetts Bertrand L. Jaber, MD, MS St Elizabeth’s Medical Center Boston, Massachusetts
ACKNOWLEDGEMENTS Support: Dr Garimella is supported by National Institutes of Health training grant 5T32DK007777. Financial Disclosure: The authors declare that they have no relevant financial interests. Peer Review: Evaluated by the Deputy Editor and the Editor-inChief.
Am J Kidney Dis. 2016;-(-):---
REFERENCES 1. Einhorn LM, Zhan M, Hsu VD, et al. The frequency of hyperkalemia and its significance in chronic kidney disease. Arch Intern Med. 2009;169(12):1156-1162. 2. Desai AS, Swedberg K, McMurray JJ, et al. Incidence and predictors of hyperkalemia in patients with heart failure: an analysis of the CHARM Program. J Am Coll Cardiol. 2007;50(20):1959-1966. 3. Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med. 2004;351(6):543-551. 4. Susantitaphong P, Sewaralthahab K, Balk EM, Eiam-ong S, Madias NE, Jaber BL. Efficacy and safety of combined vs. single renin-angiotensin-aldosterone system blockade in chronic kidney disease: a meta-analysis. Am J Hypertens. 2013;26(3):424-441. 5. Gerstman BB, Kirkman R, Platt R. Intestinal necrosis associated with postoperative orally administered sodium polystyrene sulfonate in sorbitol. Am J Kidney Dis. 1992;20(2):159-161. 6. Wootton FT, Rhodes DF, Lee WM, Fitts CT. Colonic necrosis with Kayexalate-sorbitol enemas after renal transplantation. Ann Intern Med. 1989;111(11):947-949. 7. Rogers FB, Li SC. Acute colonic necrosis associated with sodium polystyrene sulfonate (Kayexalate) enemas in a critically ill patient: case report and review of the literature. J Trauma. 2001;51(2):395-397. 8. Cheng ES, Stringer KM, Pegg SP. Colonic necrosis and perforation following oral sodium polystyrene sulfonate (Resonium A/Kayexalate in a burn patient. Burns. 2002;28(2):189-190. 9. 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. 10. 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. 11. Packham DK, Rasmussen HS, Lavin PT, et al. Sodium zirconium cyclosilicate in hyperkalemia. N Engl J Med. 2015;372(3):222-231. 12. 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;314(2):151-161. 13. Scherr L, Ogden DA, Mead AW, Spritz N, Rubin AL. Management of hyperkalemia with a cation-exchange resin. N Engl J Med. 1961;264:115-119. 14. Flinn RB, Merrill JP, Welzant WR. Treatment of the oliguric patient with a new sodium-exchange resin and sorbitol; a preliminary report. N Engl J Med. 1961;264:111-115. 15. Ash SR, Singh B, Lavin PT, Stavros F, Rasmussen HS. A phase 2 study on the treatment of hyperkalemia in patients with chronic kidney disease suggests that the selective potassium trap, ZS-9, is safe and efficient. Kidney Int. 2015;88(2):404-411. 16. Packham DK, Rasmussen HS, Singh B. New agents for hyperkalemia. N Engl J Med. 2015;372(16):1571-1572. 17. Weir MR, Bakris GL, Bushinsky DA, et al. Patiromer in patients with kidney disease and hyperkalemia receiving RAAS inhibitors. N Engl J Med. 2015;372(3):211-221. 18. Relypsa. Relypsa Announces FDA Approval of Veltassa(TM) (patiromer) for Oral Suspension for the Treatment of Hyperkalemia. http://investor.relypsa.com/releasedetail.cfm? releaseid5937821. Accessed October 26, 2015. 19. US Food and Drug Administration. FDA Drug Safety Communication: FDA requires drug interaction studies with potassium-lowering drug Kayexalate (sodium polystyrene sulfonate). Accessed, http://www. fda.gov/Drugs/DrugSafety/ucm468035.htm. October 30, 2015.
3