Summary of Educational Need & Gap Analysis
Hyperkalemia, defined as a potassium level of >5.0 mEq/L1 is a frequent and potentially life-threatening complication in patients with chronic kidney disease (CKD), diabetes, and heart failure (HF).1,2,3,4 Patients who experience hyperkalemia are asymptomatic until their potassium reaches critical levels.5 Regular monitoring for hyperkalemia is necessary; however, the development of abrupt hyperkalemia precipitated by acute renal failure, addition of medication, or even dietary indiscretion, is a potential concern.5
Research has shown that patients with heart failure and chronic kidney disease benefit from medications that result in inhibition of the renin-angiotensin-aldosterone system (RAASi).6,7 Unfortunately, hyperkalemia is a common limiting side effect of RAASi medications.8 Patients are frequently taken off of these medications at the first sign of mild to moderate hyperkalemia, or may never be started on them in the first place due to the potential concern for hyperkalemia.9
Treatment of hyperkalemia has remained essentially unchanged over the last 50 years,10 and acute treatment has largely focused on the intracellular transfer of potassium, which provides only transient benefit.5,11,12 Chronically, loop or thiazide diuretics can control mild hyperkalemia in CKD patients.1 Cation exchange resins such as sodium polystyrene sulfonate remove potassium via the gastrointestinal tract, but are relatively slow-acting and, when combined with sorbitol, can rarely cause intestinal necrosis or colonic perforation.1,5 Hemodialysis has remained the definitive treatment to acutely treat severe hyperkalemia in the setting of renal failure.5 Two novel agents have recently been developed for the acute treatment of hyperkalemia.1
Cardiologists frequently encounter hyperkalemia as a complication of the diseases they treat, comorbidities in their patient population, and the medications used in their patient population.3 There is a need for continuing education in the area of hyperkalemia given the new treatment options that are available and that will soon become available. Given our experience in live updates and online content for cardiologists, <<Client>> is pursuing development of a Cardiology Update series on the topic of hyperkalemia. We also propose the information be presented in a series of symposia at several specialty heart failure conferences with cardiologists and allied health professionals in attendance.
|Title of Initiative
|Identification, Treatment, and Long-term Management of Hyperkalemia: Novel Therapies to Induce and Maintain Normokalemia|
|Cardiologists and Allied Health professionals|
Identified Gaps in Practice
Several gaps in knowledge and/or clinical practice have been identified and are outlined below to support the need for the proposed educational series. Learning objectives for each gap will guide content development and clarify educational goals of this series.
Gap 1: Clinicians may not recognize the morbidity and mortality associated with even mild to moderate hyperkalemia.
Acker and colleagues reported that physicians treat hyperkalemia as per the current standard of care noly 39% of the time.13 However, the presence hyperkalemia has been shown to significantly increase mortality within 1 day (P <.001)2 and at 30, 90, and 365 days (P <.0001).14 Treatment of hyperkalemia with reductions of at least 1 mEq/L has been shown to effectively reduce the mortality risk.14 Increased mortality is largely tied to increase in cardiac arrhythmias such as ventricular fibrillation and resultant sudden cardiac death, but hyperkalemia is also associated with weakness and fatigue, respiratory depression, and neuromuscular blockade.5,15,16,17,18 Other risk factors of mortality in moderate to severe hyperkalemia are increasing age, anion gap metabolic acidosis, hypertension, and coronary artery disease.15
Learning Objective 1: Clinicians will be able to outline the various short-term and long-term risks of hyperkalemia in their patient population as well as the benefits of achieving normokalemia.
Gap 2: Clinicians may underestimate the frequency of hyperkalemia.
It has been estimated the hyperkalemia occurs in 1.1 to 10 of each 10 hospitalized patients.13 However, patients with advanced cardiac and kidney disease are often excluded from clinical trials, and complications and/or side effects are closely monitored.19 The Randomized Aldactone Evaluation (RALES) study showed the incidence of hyperkalemia to be as low as 2% in patients with heart failure and serum creatinine <2.5 mg/dL who were prescribed an aldosterone antagonist in addition to angiotensin converting enzyme inhibitors (ACEIs).20 However, real-world data has shown the incidence of hyperkalemia to be as high as 24% in clinical practice.21 In patients with documented CKD, the incidence of hyperkalemia in the setting of aldosterone antagonist therapy rose even further, to 35% in patients with creatinine level of ≥1.5 mg/dL and 63% in patients with baseline creatinine of ≥2.5 mg/dL.22 High rates of hyperkalemia also occurred in patients treated with ACEIs (20.4%) and angiotensin receptor blockers (ARBs) (31%).8
Learning Objective 2: Clinicians will be able to estimate the rates of hyperkalemia in various patient populations, including those receiving renin-angiotensin-aldosterone system medications, and optimally monitor patients.
Gap 3: Clinicians may underestimate how many eligible patients are excluded from RAASi therapy due to the risk of or presence of hyperkalemia.
Chronic kidney disease and certain medications are the two main factors increasing patients’ risk of developing hyperkalemia.13 RAAS inhibitors, while providing long-term benefit in patients with chronic kidney disease and proteinuria, diabetic nephropathy, and systolic heart failure,4 often cause or exacerbate hyperkalemia. These medications, which include ACEIs, ARBs, and aldosterone antagonists, are commonly withheld or withdrawn due to concerns for hyperkalemia.8,23 In an observational analysis of 12,565 patients who were eligible for aldosterone antagonist therapy, only 32.5% received this therapy at discharge according to the recommended guidelines.9 “The development of hyperkalemia poses a therapeutic dilemma, since the patients at highest risk for this complication are the same patients who derive the greatest cardiovascular benefit from these drugs.”23 Methods to increase use of these medications in this at-risk population include close monitoring of potassium levels; assessment and discontinuation of other medications that might reduce potassium clearance, such as NSAIDs; and reduction of dietary potassium.23
Learning Objective 3: Clinicians will be able to list absolute and relative contraindications to RAASi therapy for patient populations at particularly high risk of hyperkalemia as well as strategies for introducing and titrating these medications.
Gap 4: Clinicians may not be aware of new drugs that have recently been approved or are pending approval for acute and long-term management of hyperkalemia in at-risk populations.
Sodium zirconium cyclosilicate (SZC) and patiromer are two novel therapies for the management of acute and chronic hyperkalemia that have recently emerged on the healthcare landscape.1 They both offer the potential for acute and long-term management of hyperkalemia in patients with heart failure and CKD.1 Initial study results have shown effects lasting beyond the initial treatment phase with maintenance dosing, even in patients receiving RAASi therapy.24 SZC and patiromer are the first new medications to be developed for the treatment of hyperkalemia in more than 50 years.10
Sodium zirconium cyclosilicate:
Sodium zirconium cyclosilicate (SZC) is currently pending FDA approval. It is a novel therapy for hyperkalemia that works by exchanging potassium for sodium and hydrogen in the digestive tract.4 SZC is insoluble and highly selective for potassium over other electrolytes. It acts to trap and eliminate potassium in the gastrointestinal tract.25 A study showed significant potassium lowering effects within the first hour of SZC administration in clinical trials.12 Median time to normokalemia was 2.2 hours.26 Gastrointestinal side effect occurred at a similar frequency in treatment and placebo groups. There was a slight increase in peripheral edema and hypokalemia with SZC, but these complications were not severe or unmanageable.12
A double-blinded, phase 3 trial of SZC was conducted across 65 centers in the US, Australia, and South Africa from 2012 to 2013, with results published in the New England Journal of Medicine January 2015. A total of 753 patients with potassium levels between 5.0 and 6.5 mmol/L were initially randomized to receive either placebo or a dose of SZC at 1.25 g, 2.5 g, 5 g, or 10 g, three times daily for 48 hours. Potassium levels were then assessed, and patients receiving the 2.5 g, 5 g, and 10 g doses had statistically significant decreases in their serum potassium levels compared with placebo at 48 hours (P <.001 for all). A maintenance phase of once daily dosing from days 3 to 14 showed that daily doses of 5 g and 10 g maintained normokalemia in patients compared with placebo (P <.01). Adverse events were not significantly different between treatment and placebo groups, and the most common side effect in both groups was diarrhea.4
The HARMONIZE trial was a phase 3, randomized study evaluating the effect of SZC on potassium levels in patients with hyperkalemia (≥5.1 mEq/L) during 28 days of therapy. During the initial open-label phase, all patients received 10 g of SZC 3 times daily for 48 hours. Of 258 patients, 237 (98%) became normokalemic in 48 hours and were randomized to receive one of 3 maintenance doses daily for 28 days: 5 g (n = 45), 10 g (n = 51), or 15 g (n = 56), or placebo (n = 85). Mean potassium reduction in the first 48 hours was 1.1 mEq/L, and median time until potassium reached normal levels was 2.2 hours. The primary end point of mean serum potassium level between 8–29 days was significantly improved with all doses of SZC compared with placebo (P <.001 for all doses), with increased effects noted with higher doses. The side effect profile was similar to placebo, with the notable exception of increased peripheral edema (at 15 g) and hypokalemia (at 10 g and 15 g) with SZC. Results were published in JAMA December 2014.11
Both studies included patients with CKD (66-74.5%), diabetes (59.9-66%), heart failure (36-39.8%), and patients receiving RAASi (66.7-70%) therapy.4,11
Results of a phase 2 trial evaluating safety and efficacy of SZC in 90 patients with CKD and hyperkalemia were published in 2015 in Kidney International. Investigators found that at doses of 3 g and 10 g three times daily, potassium was significantly reduced compared with placebo. This effect was sustained for 3.5 days after the last dose. SZC was well tolerated, with no serious adverse events.27
Studies are ongoing to investigate the safety and efficacy of SZC over a 12-month time frame of initial treatment followed by maintenance dosing.28,29
“ZS-9 shows promise in the acute treatment of hyperkalemia and may make it possible to avoid or postpone the most effective therapy, emergency hemodialysis.”30 It also shows promise in limiting adjustment and discontinuation of RAASi therapy.26
Patiromer works by binding potassium in the colon, thereby effecting a decrease in serum potassium levels.1 It was recently approved by the FDA in October 2015 for the treatment of hyperkalemia. Trials have shown that treatment with patiromer resulted in a significant improvement in potassium levels compared with placebo, as early as 48 hours after treatment administration.31 This effect appears to be sustained with maintenance therapy.
The PEARL-HF trial, published in the European Heart Journal in 2011, studied the effects of patiromer in lowering potassium and maintaining normokalemia in 105 patients with heart failure and a history of hyperkalemia or CKD over a 30-day time period while introducing and titrating spironolactone. Patiromer treatment significantly lowered serum potassium levels (P <.001) and the incidence of hyperkalemia (P = .015) as compared with controls. At the end of the study, a higher percentage of patients were reported to be on 50 mg spironolactone daily with patiromer therapy vs control (P = .019).32
The OPAL-HK trial studied the effects of patiromer on potassium levels of 237 patients with CKD who were on RAASi therapy and had mild to moderate hyperkalemia (5.1 to <6.5 mmol/L). Results showed normal potassium levels in 76% of patients receiving patiromer (4.2 g or 8.4 g twice daily) at 4 weeks, and this effect was sustained in 85% of these patients with maintenance therapy over an additional 4 weeks, compared with only 40% of patients receiving placebo (P <.001 for the maintenance phase). Main side effects were constipation (11%) and hypokalemia (3%).33
The AMETHYST-DN trial was a phase 2 trial evaluating the use of patiromer (4.2 g to 16.8 g twice daily) in 306 patients with mild to moderate hyperkalemia. At 4 weeks, all doses of patiromer were associated with a significant decrease in potassium compared with starting levels (P <.001), which was sustained throughout 52 weeks of maintenance therapy. Common side effects were hypomagnesemia (7.2%), mild to moderate constipation (6.3%), and hypokalemia (5.6%).31
Patiromer currently has a black box warning that states it cannot be taken within 6 hours of other medications due to concern for decreased absorption. Another trial investigating the effects of dosing patiromer with and without food is currently under way.34
“Patiromer is effective in decreasing serum potassium, preventing recurrence of hyperkalemia, and reducing RAASi discontinuation.”10
Patients with chronic heart and kidney disease are at risk for developing hyperkalemia due to their disease processes as well as from treatment with ACEIs, ARBs, and aldosterone antagonists, all of which are medications known to provide long-term benefit in this patient population.1,2,3,4,6,7,8 Therefore, the acute and chronic management of hyperkalemia is a vital skill for physicians who care for these patients.
As the first new medications for the treatment of hyperkalemia in over 50 years,10 SZC and patiromer offer the potential to chronically control potassium levels in patients who have clinical indications for RAASi therapy and a have high risk of hyperkalemia.24 There is a need to educate cardiologists and primary care physicians on these new treatments that are available or will soon become available to treat and prevent hyperkalemia, thereby optimizing the benefit of RAASi therapy.
|Cardiology Update Series: Hyperkalemia||CME 4.0|
|7:00-7:45 AM||Registration & Continental Breakfast|
|7:45-8:00 AM||Welcome & Opening Remarks|
|8:00-9:00 AM||Review of Etiology, Pathophysiology, and Current Treatment of Hyperkalemia||1.0|
|9:00-10:00 AM||How Chronic Heart and Kidney Disease Contribute to Hyperkalemia: Disease Processes and Treatments||1.0|
|10:30-11:30 AM||Effect of Hyperkalemia on Ability to Use Guideline-Directed Therapy for Patients with Heart Failure and Chronic Kidney Disease||1.0|
|11:30 AM-12:30 PM||Novel Therapies for the Acute and Chronic Treatment of Hyperkalemia in the Setting of RAAS Inhibition||1.0|
Javed Butler, MD, MPH, Stony Brook, NY
Division Chief, Cardiology, Stony Brook University School of Medicine
Professor, Department of Medicine, Stony Brook University School of Medicine
Co-Director, Heart Institute, Stony Brook University School of Medicine
Steven N. Fishbane, MD, Manhasset, NY
Chief of Division of Medicine, Kidney Diseases and Hypertension, Long Island Jewish Medical Center
Chief of Division of Medicine, Kidney Diseases and Hypertension, North Shore University Hospital
Paul J. Hauptman, MD, St. Louis, MO
Professor of Internal Medicine, Division of Cardiology, St. Louis University School of Medicine
Assistant Dean, Clinical and Translational Research, St. Louis University School of Medicine
Bruce Spinowitz, MD, Flushing, NY
Clinical Professor of Medicine, Weill Medical College of Cornell University
Vice Chairman, Department of Medicine, New York Presbyterian Hospital Queens
Associate Director of Nephrology, New York Presbyterian Hospital Queens
- Ingelfinger JR. A New Era for the Treatment of Hyperkalemia? N Eng J Med. 2015;372(3):275-7.
- 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):1156-62.
- Kovesdy, CP. Management of hyperkalemia in chronic kidney disease. Nat Rev Nephrol. 2014;(10)11:653-62.
- Packham DK, Rasmussen HS, Lavin PT, et al. Sodium Zirconium Cyclosilicate in Hyperkalemia. N Engl J Med. 2015;372(3):222-31.
- Weiner ID, Wingo CS. Hyperkalemia: A Potential Silent Killer. J Am Soc Nephrol. 1998;9(8):1535-43.
- Cohn JN, Tognoni G. Valsartan Heart Failure Trial Investigators. Randomized trial of the angiotensin receptor blocker, valsartan, in chronic heart failure. N Eng J Med. 2001;345(23):1667-75.
- Massie BM, Armstrong PW, Cleland JG, et al. Toleration of high doses of angiotensin converting enzyme inhibitors in patients with chronic heart failure: Results from the Atlas trial. Arch Intern Med. 2001;161(2):165-71.
- Sadjadi SA, McMillan JI, Jaipaul N, et al. A comparative study of the prevalence of hyperkalemia with the use of angiotensin-converting enzymes inhibitors versus angiotensin receptor blockers. Ther Clin Risk Manag. 2009;5:547-52.
- Albert NM, Yaney CW, Liang L, et al. Use of Aldosterone Antagonists in Heart Failure. JAMA. 2009;302(15):1658-65.
- Montaperto AG, Gandhi MA, Gashlin LZ, et al. Patiromer: a clinical review. Curr Med Res Opin. 2016;32(1):155-64.
- 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.
- Packham DK, Kosiborod M. Pharmacodynamics and pharmacokinetics of sodium zirconium cyclosilicate [ZS-9] in the treatment of hyperkalemia. Expert Opin Drug Metab Toxicol. 2016;12(5):567-73.
- Acker CG, Johnson JP, Palevsky PM, et al. Hyperkalemia in Hospitalized Patients: Causes, Adequacy of Treatment, and Results of an Attempt to Improve Physician Compliance With Published Therapy Guidelines. Arch Intern Med. 1998;158(8):917-24.
- McMahon GM, Mendu ML, Gibbons FK, et al. Association between hyperkalemia at critical care initiation and mortality. Intensive Care Med. 2012;38(11):1834-42.
- Afzal B, Mehmood A, Shahbaz S, et al. Predictors of Outcome in Patients Presenting with Moderate to Severe Hyperkalemia. Emergency Med. 2013;4(1):169-71.
- Freeman SJ, Fale AD. Muscular paralysis and ventilator failure caused by hyperkalaemia. Br J Anaesth. 1993;70(2):226-7.
- Nyirenda MJ, Tang JI, Padfield PL, et al. Hyperkalaemia. BMJ. 2009;339:b4114.
- Pun PH, Smarz TR, Honeycutt EF, et al. Chronic kidney disease is associated with increased risk of sudden cardiac death among patients with coronary artery disease. Kidney Int. 2009;76(6):652-8.
- Dunn JD, Benton WW, Orozco-Torrentera E, et al. The Burden of Hyperkalemia in Patients With Cardiovascular and Renal Disease. American Journal of Managed Care website. http://www.ajmc.com/journals/supplement/2015/a577_nov15_hyperkalemia/a577_nov15_hyperkalemia. Published online November 30 2015. Accessed June 6 2016.
- 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(10):709-17
- Bozkurt B, Agoston I, Knowlton AA. Complications of inappropriate use of spironolactone in heart failure: when an old medicine spirals out of new guidelines. J Am Coll Cardiol. 2003;41(2):211-4.
- Shah KB, Rao K, Sawyer R, et al. The adequacy of laboratory monitoring in patients treated with spironolactone for congestive heart failure. J Am Coll Cardiol. 2005;46(5):845-9.
- Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med. 2004;351(6):585-92.
- Schaefer JA, Gales MA. Potassium-Binding Agents to Facilitate Renin-Angiotensin-Aldosterone System Inhibitor Therapy. Ann Pharmacother. Published online March 23 2016. Accessed May 30 2016.
- Stavros F, Yang A, Leon A, et al. Characterization of structure and function of ZS-9, a K+ selective ion trap. PLOS ONE website. http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0114686. Published December 22 2014. Accessed June 6 2016.
- Anker SD, Kosiborod M, Zannad F, et al. 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(10):1050-6.
- Ash SR, Singh B, Lavin PT, et al. 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 International. 2015;88(2):404-11.
- Open-label Safety and Efficacy of Sodium Zirconium Cyclosilicate for up to 12 Months. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/study/NCT02163499. Updated May 19, 2016. Accessed June 8, 2016.
- Open-label Safety & Efficacy of ZS (Sodium Zirconium Cyclosilicate)10g qd to Extend Study ZS-004 in Hyperkalemia. ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/NCT02107092. Updated May 5, 2016. Accessed June 8, 2016.
- Sterns RH, Grieff M, Bernstein PL. Treatment of hyperkalemia: something old, something new. Kidney International. 2016;(89)3:546–54.
- 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)151-61.
- 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;32(7):820-8.
- 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)211-21.
- Patiromer With or Without Food for the Treatment of Hyperkalemia (TOURMALINE). ClinicalTrials.gov website. https://clinicaltrials.gov/ct2/show/study/NCT02694744. Updated June 3 2016. Accessed June 9 2016.