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1 Disclaimer This slide deck in its original and unaltered format is for educational purposes and is current for the date of this live symposium. All materials contained herein reflect the views of the faculty, and not those of Creative Educational Concepts, Inc. or the commercial supporter(s). Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for specific patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient s conditions and possible contraindications on dangers in use, review or any applicable manufacturer s product information, and comparison with recommendations of other authorities. Usage Rights: This slide deck is provided for educational purposes and individual slides may be used for personal, non commercial presentations only if the content and references remain unchanged. No part of this slide deck may be published or distributed in print or electronic format without prior written permission from Creative Educational Concepts, Inc. Additional terms and conditions may apply. 1

2 Learning Objectives Examine the prevalence of and risk factors for hyperkalemia, its pathophysiologic consequences, and associated prognosis across healthcare settings Compare and contrast mechanisms of action, efficacy, and safety data for current and emerging pharmacologic treatment options for the management of hyperkalemia Using a case based approach, develop management strategies the pharmacist can employ to effectively prevent and manage hyperkalemia in acute and chronic care settings Hyperkalemia 101 Epidemiology, Pathophysiology, and Clinical Significance Kristy N. Greene, PharmD, BCPS, BCCCP Clinical Pharmacist Specialist Department of Pharmaceutical Services Emory University Hospital Midtown Atlanta, Georgia 2

3 Agenda Define hyperkalemia and associated frequencies Discuss pathophysiology of hyperkalemia and electrocardiogram (ECG) related changes Provide an overview of the clinical significance of hyperkalemia in patients with normal renal function and chronic kidney disease (CKD) Review the role of the renin angiotensin aldosterone system (RAAS) in contributions to hyperkalemia Hyperkalemia Common electrolyte abnormality that has the potential to be life threatening due to cardiac disturbances Frequently occurring in patients with CKD and end stage renal disease (ESRD) Defined as serum potassium above normal reference range (3 5 meq/l) Consequences: 67,000 ED visits and >40,000 hospitalizations in 2011 Medicare hospital charges: ~$697 million ED, emergency department. Einhorn LM, et al. Arch Intern Med. 2009; KDOQI. Am J Kidney Dis. 2004; 3

4 Potassium Homeostasis Imbalance between intracellular and extracellular compartments leads to neuromuscular and cardiovascular disturbances. McDonough A, Youn J. Physiology Hyperkalemia Frequencies General population: 2% 3% CKD: 40% 50% Kidney transplant recipients: 44% 73% Relative risk increase with dual RAASi: 55% RAASi, renin angiotensin aldosterone system inhibitor. Kovesdy CP. Nat Rev Nephrol. 2014; Kovesdy CP. Kidney Int Suppl

5 Major Predictors of Hyperkalemia Renal insufficiency or CKD Diabetes mellitus (DM) Cardiovascular disease (congestive heart failure [CHF], hypertension [HTN]) RAASi usage with increased risk in those with CHF, CKD, DM, HTN DM Hyporeninemic hypoaldosteronism Insulin deficiency Hypertonicity Anemia Dietary modifications Metabolic acidosis CKD Redistribution Kidney transplantation Tubulointerstitial disease Decreased GFR Decreased secretion Hyperkalemia Increased intake Decreased GFR Decreased urine flow Beta 2 agonists RAAS inhibitors Spironolactone/ eplerenone AKI CVD Tissue injury Digitalis Heparin AKI, acute kidney injury; CVD, cardiovascular disease; GFR, glomerular filtration rate. Kovesdy CP. Rev Endocr Metab Disord. 2017; Weir MR, Rolfe M. Clin J Am Soc Nephrol Acute vs Chronic Hyperkalemia Acute Abnormal release of potassium from cells Often due to acid base imbalances, hemolytic states, and trauma Chronic Due to impairment of potassium excretion >1 episode/year requiring chronic management Alvo M, Warnock DG. West J Med. 1984; Einhorn LM, et al. Arch Intern Med

6 Pathogenesis of Hyperkalemia Potassium >5.5 mmol/l Repeat samples if factitious hyperkalemia suspected GFR <15 ml/min/1.73m 2 GFR >15 ml/min/1.73m 2 Decreased renal potassium excretion Increased potassium load Aldosterone low Aldosterone high Acute renal failure Chronic renal failure Drugs Supplementation (oral/iv) Potassium rich diet Blood transfusion Tumor lysis/hemolysis Renin low Renin normal Renin high Post renal transplant Obstructive uropathy Sickle cell nephropathy Drugs PHA type 1/type 2 Type 1 RTA IV, intravenous; PHA, pseudohypoaldosteronism; RTA, renal tubular acidosis. Hyporeninemic hypoaldosteronism in: Interstitial nephritis Obstructive uropathies Drugs Diabetic nephropathy Primary hypoaldosteronism Congenital adrenal hyperplasia Drugs Addison s/congenital adrenal hypoplasia Lehnhardt A, Kemper MJ. Pediatr Nephrol Medication related Sources of Hyperkalemia Causes Drugs that promote transmembrane potassium shift Drugs that affect aldosterone secretion Agent or Medication Nonselective beta blockers (eg, propranolol, labetalol, carvedilol), digoxin intoxication, mannitol ACE inhibitors (eg, benazepril, lisinopril), direct renin inhibitors (eg, aliskiren), NSAIDs and COX 2 inhibitors (eg, ibuprofen, celecoxib), calcineurin inhibitors (cyclosporine, tacrolimus), heparin Drugs that cause tubular resistance to action of aldosterone Agents that contain potassium Other Aldosterone antagonists (eg, spironolactone, eplerenone) and other potassium sparing diuretics (eg, amiloride, triamterene), trimethoprim, pentamidine, heparin Salt substitutes and alternatives, penicillin G, stored blood products Succinylcholine, herbal supplements ACE, angiotensin converting enzyme; COX 2, cyclooxygenase 2; NSAIDs, nonsteroidal anti inflammatory drugs. Ben Salem C, et al. Drug Saf

7 Hyperkalemia related Mortality Risk in CKD vs Normal Renal Function Potassium level, meq/l < and < P value Population Odds Ratio None Stage 3 Stage 4 Stage 5 Severity of CKD <0.001 <0.05 Potassium 5.5 to 5.9 AND 6.0 Stage 5 with normokalemia vs reference group Einhorn LM, et al. Arch Intern Med All Cause Mortality Associated with Serum Potassium Levels in Non Dialysis Dependent Patients with CKD (n= 1227) Hayes J, et al. Nephron Clin Pract. 2012; Dunn JD, et al. Am J Med

8 Renin Angiotensin Aldosterone System (RAAS) Renin Inhibitors ACE inhibitors Renin ACE AGT ANGI Angiotensin receptor blockers (ARBs) ANGII Aldosterone receptor antagonists AGT AGT, angiotensinogen; ANGI, angiotensin I; ANGII, angiotensin II; K +, potassium ion. Tubule K + secretion Na + and Cl reabsorption Intravascular volume Blood pressure Adapted from Breyer MD, Susztak K. Nat Rev Drug Discov Hyperkalemia Associated with RAASi Use in CKD Trial No of Patients Hyperkalemia Definition (mmol/l) Incidence (%) J LIGHT (2004) 58 > AASK (2009) 417 > RENAAL (2001) ; ; 38.4 NEPHRON D (2013) 1448 >6 or need for ED visit, hospitalization, or dialysis 4.4 (losartan + placebo); 9.9 (losartan + lisinopril) Benazepril in advanced CKD IDNT (2001) 579 > AASK, African American Study of Kidney Disease and Hypertension; J LIGHT, Japanese Losartan Therapy Intended for the Global Renal Protection in Hypertensive Patients; NEPHRON D, Veterans Affairs Nephropathy in Diabetes; RENAAL, Reduction of Endpoints in NIDDM (noninsulin dependent diabetes mellitus) with the Angiotensin II Antagonist Losartan; IDNT, Irbesartan Diabetic Nephropathy Trial. Kovesdy CP. Nat Rev Nephrol

9 Electrocardiogram Changes Electrocardiographic Features of Hyperkalemia Serum potassium Major change (mmol/l) Tall peaked T waves Loss of P waves Widening of QRS complexes Sine wave, ventricular arrhythmias, asystole QRS, principle deflection in ECG. Diercks DB, et al. J Emerg Med. 2004; Slovis C, Jenkins R. BMJ Hyperkalemia in Hospitalized Patients No of ECGs Performed Potassium Concentration (meq/l) Absence of Potassiumrelated ECG Changes (%) Fordjour KN, et al Acker CG, et al Fordjour KN, et al. Am J Med Sci. 2014; Acker CG, et al. Arch Intern Med

10 Mean Pretreatment Potassium Concentration Prompting Acute Treatment Average Pre Potassium (meq/l) % % 7% 1% 0% Number of Therapies Fordjour KN, et al. Am J Med Sci % 70% 60% 50% 40% 30% 20% 10% Percent of Patients When to Treat? Elevated potassium 5 in the presence of the following Clinical symptoms (frank muscle paralysis, dyspnea, palpitations, chest pain, nausea/vomiting, paresthesias) AND/OR Presence of ECG related changes 10

11 Interventions for Acute Hyperkalemia Treatment Calcium chloride 10% Calcium gluconate 10% 6.8 mmol of calcium corresponding to 10 ml of calcium chloride or 30 ml of calcium gluconate Sodium bicarbonate mmol Regular insulin 10 units Albuterol mg aerosol Furosemide 40 mg or equivalent dose of other loop diuretic Cation exchange resins g Dialysis Route of Administration Intravenous Onset of action, duration of effect 1 3 min, min Mechanism Membrane potential stabilization Intravenous 5 10 min, ~2 hours Redistribution Intravenous 30 min, 4 6 hours Redistribution Nebulized 30 min, 2 4 hours Redistribution Intravenous Oral or rectal (with or without sorbitol) Hemodialysis Varies, Until diuresis present or longer Excretion 1 2 hours, 4 6 hours Excretion Within minutes, Until end of dialysis or longer depending on ongoing potassium intake or cellular redistribution Removal Kovesdy CP. Nat Rev Nephrol Correcting K+ Examining Current and Emerging Treatment Options Darren W. Grabe, BS, PharmD Associate Professor of Pharmacy Practice Chair, Department of Pharmacy Practice School of Pharmacy and Pharmaceutical Sciences Albany College of Pharmacy and Health Sciences Albany, New York 11

12 Hyperkalemia Treatment Timeline 1950s 1960s 1970s 1980s 1990s 2000s 2010s Sodium polystyrene sulfonate (6/1958) Furosemide (7/1966) Medicare Kidney Disease Entitlement (1972) Bumetanide (2/1983) Torsemide (8/1993) Patiromer (10/2015) ZS 9 (5/2018) New options lead to revisiting treatment algorithms for hyperkalemia FDA Prescribing Information. Review of Current Guidance Hyperkalemia defined as >5 meq/l Potassium binders Sodium polystyrene sulfonate Mechanism: Cation exchange resin (Na) Onset of action: 1 2 hours Patiromer Mechanism: Cation exchange resin (Ca) Onset of action: 7 hours Sodium zirconium cyclosilicate Mechanism: Cation exchange resin (Na + H) Onset of action: 1 hour Georgianos PI, Agarwal R. Kidney Int. 2018; FDA Prescribing Information. 12

13 Monitoring ACEIs and ARBs Check SCr and K +. Start ACEI or ARB at appropriate initial dose for indication, age, renal/liver function, volume status. Check SCr and K + within 1 2 weeks of initiation or dose increase. Consider waiting up to 4 weeks if no renal or hyperkalemia risk factors. SCr stable and K + <5.5 meq/l: increase dose, if appropriate. Repeat labs in 3 4 weeks. Stable SCr. Repeat labs in 1 2 weeks (more often if renal function poor or K + >4.5 meq/l), or when patient condition or meds change. SCr increased <30% and K + <5.5 meq/l: repeat labs in 2 3 weeks. SCr <30% above baseline and K + <5.5 meq/l. SCr increased 30% to <50% (but by 1 mg/dl) and K + <5.5 meq/l: cut dose in half and recheck every 5 7 days until stable. Ensure hydration. Stop NSAIDs. Assess K + sources. SCr still 30% above baseline after 4 weeks, or K meq/l, or SCr increased by >1mg/dL, discontinue. K meq/l or SCr increased by >1 mg/dl or by 50%, discontinue. Ensure hydration. Stop NSAIDs. Consider bilateral renal artery stenosis if SCr increased by 50%. ACEI, angiotensin converting enzyme inhibitor; SCr, serum creatinine. Adapted from: McDowell SE, et al. J R Soc Med. 2013; Schmidt M, et al. BMJ Open. 2017; Nurko S. Cleve Clin J Med Management of Hyperkalemia 13

14 Actions Taken after Hyperkalemia Action K >5 meq/l K >5.5 meq/l Control ED visit 1.2% 3.1% 0.7% Repeat serum K measurement 18.4% 44.3% 0.0% Rx SPS 0.7% 4.7% 0.0% Rx/Incr diuretic 5.6% 9.2% 2.5% D/C ACEI or ARB 10.5% 24.3% 4.8% Decr ACEI or ARB 2.6% 4.8% 1.2% D/C K sparing diuretic 23% 48.5% 7.5% Decr K sparing diuretic 1.4% 1.1% 0.5% D/C, discontinuation; Decr, decrease; Incr, increase; Rx, prescribe; SPS, sodium polystyrene sulfonate. Chang AR, et al. Hypertension Management of Hyperkalemia CPS, calcium polystyrene sulfonate; RCT, randomized controlled trial. Palaka E, et al. Int J Clin Pract

15 Current Therapies Management of Chronic Hyperkalemia Sodium polystyrene sulfonate (SPS) Patiromer calcium sorbitex (patiromer) Sodium zirconium cyclosilicate (ZS 9) Sodium Polystyrene Sulfonate Benzene, diethenyl polymer, with ethenylbenzene, sulfonated, sodium salt Contraindications Hypokalemia, hypersensitivity to polystyrene sulfonate resins, obstructive bowel disease Neonates with reduced gut motility, oral administration in neonates Administration Oral Rectal (enema) Available as Powder, suspension, enema Suspension in either water or sorbitol (33%) Store at 25 C (77 F) Average daily adult dose of resin: 15 g to 60 g Administer 15 g 1 to 4 times daily FDA Prescribing Information. 15

16 Efficacy of Sodium Polystyrene Sulfonate Approval based on study of 32 patients Hyperkalemia, azotemia, hemodialysis not yet available Serum potassium decreased by 1 meq/l (orally) and 0.8 meq/l (rectally) in 24 hours Duration days Oral dose ranged from 10 g three times a week to 60 g/day Rectal dose ranged from 10 g/day to 160 g/day Scherr L, et al. N Engl J Med Efficacy of Sodium Polystyrene Sulfonate Approval based on study of 32 patients Retrospective analysis of 138 patients Oral dose ranged from g Suspension with sorbitol administered Mean change in Serum potassium was 0.14 meq/l compared to control Mean change in serum potassium level (mmol/l) Control (n=66) Treatment (n=66) (B) Matched P=0.026 Scherr L, et al. N Engl J Med. 1961; Batterink J, et al. Can J Hosp Pharm

17 Efficacy of Sodium Polystyrene Sulfonate Approval based on study of 32 patients Retrospective analysis of 138 patients Prospective analysis of 6 hemodialysis patients No effect on serum potassium Group Serum Potassium Concentration (meq/l) Hour 0 Hour 4 Hour 8 Hour 12 Placebo Resin alone Resin + Sorbitol meq/l Resin alone 0 hours 12 hours Sorbitol + resin 0 hours 12 hours Scherr L, et al. N Engl J Med. 1961; Batterink J, et al. Can J Hosp Pharm. 2015; Gruy Kapral C, et al. J Am Soc Nephrol Efficacy of Sodium Polystyrene Sulfonate Approval based on study of 32 patients Retrospective analysis of 138 patients Prospective analysis of 6 hemodialysis patients Prospective, randomized, single blind study 97 patients with CKD, treated with SPS for 3 days Reduction in serum potassium (1.5 meq/l) at day 3 Significant rate of adverse effects (GI, incr. BP) BP, blood pressure; GI, gastrointestinal. Scherr L, et al. N Engl J Med. 1961; Batterink J, et al. Can J Hosp Pharm. 2015; Gruy Kapral C, et al. J Am Soc Nephrol. 1998; Nasir K, Ahmad A. J Ayub Med Coll Abbottadad

18 Efficacy of Sodium Polystyrene Sulfonate Approval based on study of 32 patients Retrospective analysis of 138 patients Prospective analysis of 6 hemodialysis patients Prospective, randomized, single blind study Prospective, randomized, double blind, placebo controlled trial 33 patients with CKD mean egfr ~20 ml/min/1.73m 2 mean potassium ~5.2 meq/l Daily dose of 30 grams sodium polystyrene sulfonate mixed with water SPS greater reduction in serum potassium at day 7 (1 meq/l) Increased rate of adverse effects Small sample size Scherr L, et al. N Engl J Med. 1961; Batterink J, et al. Can J Hosp Pharm. 2015; Gruy Kapral C, et al. J Am Soc Nephrol. 1998; Nasir K, Ahmad A. J Ayub Med Coll Abbottadad. 2014; Lepage L, et al. Clin J Am Soc Nephrol Concerns Regarding Sodium Polystyrene Sulfonate No rigorous clinical trials to determine efficacy and safety Takes several hours for reduction in serum potassium Questionable utility in emergent hyperkalemia Variable efficacy when not combined with sorbitol Significant safety concerns Drug interactions FDA Prescribing Information; Batterink J, et al. Can J Hosp Pharm. 2015; Berlyne GM, et al. Lancet

19 Incidence of Colonic Necrosis with SPS Retrospective study (n=752) 0.3% overall incidence in SPS group 1.8% post operative incidence No cases in control group Retrospective cohort 0.14% vs 0.07% Preparation with 33% sorbitol Systematic review 30 reports (58 cases) 41 preparations with sorbitol 17 preparations without sorbitol Retrospective chart review 0.4% overall incidence Gerstman BB, et al. Am J Kid Dis. 1992; Watson MA, et al. Am J Kid Dis. 2012; Harel Z, et al. Am J Med. 2013; Hagan AE, et al. Clin Nephrol Sodium Polystyrene Sulfonate Drug Interactions FDA Drug Safety Communication: FDA recommends separating dosing of potassiumlowering drug sodium polystyrene sulfonate from all other oral drugs. Prescribers and patients should consider separating SPS dosing from other medications taken by mouth by at least 3 hours Reduction in quetiapine levels Reduction in lithium absorption Reduction in iron absorption Hoge RH, et al. J Clin Pharm Ther. 2015; O Connor TA, et al. Ann Emerg Med. 1996; FDA Prescribing Information; 19

20 Patiromer Calcium Sorbitex (Patiromer) Potassium exchange resin Non absorbed, non degradable Primary effect in colon Contains sorbitol (50% of weight) Available as 8.4 g, 16.8 g, 25.2 g powder packets Specific instructions on preparing dose at home Must be refrigerated, stable for 3 months at room temperature Take with or without food Starting dose 8.4 g once daily Titrate weekly FDA Prescribing Information. Patiromer Calcium Sorbitex (Patiromer) 5.4 Patiromer without food Patiromer with food 5.2 Serum K +, meq/l BL Day 3 Week 1 Week 2 Week 1 Week 2 PwoF, n= PwF, n= Pergola P, et al. Am J Nephrol

21 AMETHYST DN Efficacy of Patiromer Trial Comments Results Dose finding, safety + efficacy Diabetes mellitus + CKD (stages 3 and 4) Hyperkalemic Receiving RAASi 52 weeks All patients on ACEI/ARB/combo Majority on spironolactone Effective for mild and moderate hyperkalemia Serum K maintained for 52 weeks; increased 3 days after discontinuation OPAL HK PEARL HF Safety + efficacy CKD (stages 3 + 4) Hyperkalemic Receiving RAASi 2 phases, 4 weeks + 8 weeks Safety, efficacy, tolerability Chronic HF Indication for spironolactone Hyperkalemic CKD + HF therapy (RAASi) 4 week trial All patients on ACEI/ARB/combo Effective for mild/mod/severe hyperkalemia Constipation most common ADR (11%) Incidence of hyperkalemia lower in treatment group Additional benefit seen in those with CKD and HF GI related ADRs occurred in 21% of participants ADR, adverse drug reaction; HF, heart failure. Bakris GL, et al. JAMA. 2015; Weir MR, et al. N Engl J Med. 2015; Pitt B, et al. Eur Heart J AMETHYST DN Trial Serum Potassium Levels Bakris GL, et al. JAMA

22 OPAL HK Trial Serum Potassium Levels Weir MR, et al. N Engl J Med Adverse Events While on Patiromer in 2% of Subjects Adverse Event Overall N=243 All, n (%) Subjects Reporting 1 AE 114 (47%) Constipation 26 (11%) Diarrhea 8 (3%) Hypomagnesaemia 8 (3%) Nausea 8 (3%) Anemia 7(3%) Chronic renal failure 7(3%) 1 Serious adverse event 3 (1%) Weir MR, et al. N Engl J Med

23 OPAL HK Implications for RAAS Inhibition Proportion of Patients, % Effect on Concomitant RAAS Inhibitor Therapy Placebo (n=52) Requiring Any Adjustment of RAASi (i.e., downtitration or discontinuation) Due to Hyperkalemia at Any Time During Part B Patiromer (n=55) Receiving Any Dose of a RAASi at the End of Part B Weir M, et al. N Engl J Med Additional Benefit of Patiromer Measure Mild Hyperkalemia Mod/Sev Hyperkalemia Overall Serum aldosterone (ng/dl) 1.81 ± ± ±0.47 Systolic BP (mmhg) 5.40 ± ± ±1.17 Diastolic BP (mmhg) 3.34 ± ± ±0.77 All values adjusted for concomitant antihypertensive use in initial treatment phase Weir MR, et al. Kidney Int

24 PEARL HF Trial Serum Potassium Levels Pitt B, et al. Eur Heart J Patiromer Drug Interactions >50% Interaction 30% 50% Interaction <30% Interaction In vitro binding studies as part of FDA requirement 28 drugs tested 50% of tested drugs were bound by patiromer Amlodipine Cinacalcet Ciprofloxacin Levothyroxine Quinidine Trimethoprim Clopidogrel Lithium Metoprolol Verapamil Warfarin Allopurinol Amoxicillin Apixaban Aspirin Atorvastatin Cephalexin Digoxin Glipizide Lisinopril Phenytoin Rivaroxaban Spironolactone Valsartan Weir MR, et al. Kidney Int

25 Patiromer Drug Interactions In vitro binding studies as part of FDA requirement 28 drugs tested 50% of tested drugs were bound by patiromer In vivo studies conducted to further answer question 12 medications studied Low risk of drug drug interactions with other oral medications Administer other oral medications at least 3 hours before or 3 hours after Drugs Evaluated Amlodipine Cinacalcet Ciprofloxacin* Clopidogrel Furosemide Levothyroxine* Lithium Metformin* Metoprolol Trimethoprim Verapamil Warfarin *Patiromer decreased systemic exposure of these medications Weir MR, et al. Kidney Int Sodium Zirconium Cyclosilicate Non absorbed, non degradable, inorganic cation exchange resin Non absorbed, non degradable Crystalline lattice structure, traps K+ throughout intestine Exchanges Na+ and H+ for K+ Preferentially traps monovalent cations Available as 5 g, 10 g, powder packets Mix with water Take with or without food Starting dose 10 grams three times daily for up to 48 hours Maintenance dose 5 grams every other day to 15 g daily Titrate weekly FDA Prescribing Information. 25

26 Efficacy of Sodium Zirconium Cyclosilicate Trial Comments Results HARMONIZE Phase 3, randomized, doubleblind, placebo controlled trial Persistent hyperkalemia Randomized to placebo or 3 different ZS 9 doses (5 g, 10 g, 15 g daily) 48 hour open label phase n=258 Those achieving normokalemia randomized to 28 day study n=237 Majority patients on RAASi Majority with CKD Effective for mild and moderate hyperkalemia Adverse events comparable to placebo Edema noted in higher doses Packham DK, et al. Phase 3, randomized, twostage, double blind, placebo controlled Stage 3 CKD with hyperkalemia Serum K, meq/l Dose ranging study 753 patients randomized to receive ZS g, 2.5 g, 5 g, or 10 g 72% attained normal serum K Steepest decline in first 48 hours Adverse events similar to those of placebo, primarily GI in nature HARMONIZE = Hyperkalemia Randomized Intervention Multi Dose ZS 9 Maintenance. Kosiborod M, et al. JAMA. 2014; Packham DK, et al. New Engl J Med Randomized Phase Mean Potassium Levels Over Time Kosiborod M, et al. JAMA

27 Efficacy of Sodium Zirconium Cyclosilicate Kosiborod M, et al. JAMA Efficacy of Sodium Zirconium Cyclosilicate Kosiborod M, et al. JAMA

28 Efficacy of Sodium Zirconium Cyclosilicate 5.4 Placebo (N=158) ZS 9, 5 g (N=157) ZS 9, 10 g (N=157) Dose P<0.05 Serum Potassium (mmol/l) Hour Packham DK, et al. New Engl J Med Safety and Tolerability Tolerability profile comparable to placebo No treatment related serious adverse events Numerically lower rates of GI AEs with ZS 9 vs placebo PBO ZS 5 g ZS 10 g ZS 15 g 12 (14%) 3 (7%) 1 (2%) 5 (9%) Edema numerically higher in ZS 9 15 g dose PBO ZS 5 g ZS 10 g ZS 15 g Reported AE 2 (2%) 1 (2%) 3 (6%) 8 (14%) Needed Treatment Adjusted 2/2 0/1 0/3 5/8 7 out of 14 edema patients did not require treatment 13 out of 14 edema patients had peripheral edema only and successfully completed the study Hypokalemia higher in ZS 9 10 g and 15 g dose groups PBO ZS 5 g ZS 10 g ZS 15 g Hypokalemia 0 (0%) 0 (0%) 5 (10) 6 (11%) Adverse Event 0 (0%) 0 (0%) 0 (0%) 1 (2%) PBO, placebo. All cases mild ( meq/l) and resolved with dose adjustments Kosiborod M, et al. JAMA

29 Safety of Sodium Zirconium Cyclosilicate Adverse Effects Open label Phase Placebo ZS 9 (10 g/d) N=258 No. (%) N=85 No. (%) 5g N=45 No. (%) 10 g N=51 No. (%) 15 g N=56 No. (%) Any event 20 (7.8) 27 (31.8) 24 (53.3) 15 (29.4) 25 (44.6) Constipation 2 (0.8) 6 (7.1) 0 1 (2.0) 1 (1.8) Edema* 0 2 (2.4) 1 (2.2) 3 (5.9) 8 (14.3) Hypokalemia (9.8) 6 (10.7) *Including generalized and peripheral edema. Kosiborod M, et al. JAMA Sodium Zirconium Cyclosilicate Drug Interactions In vitro studies 39 drugs tested 23 demonstrated measurable interaction Primary interaction mechanism related to ZS 9 s potential to transiently increase gastric ph In vivo studies 9 of the 23 drugs demonstrating in vitro interaction were subsequently tested in vivo Amlodipine, atorvastatin, clopidogrel, dabigatran, furosemide, glipizide, levothyroxine, losartan, warfarin FDA Prescribing Information. 29

30 Sodium Zirconium Cyclosilicate Drug Interactions An increase in systemic exposure was seen with weak acids Furosemide Atorvastatin Conversely, a decrease in systemic exposure was observed for weak bases Dabigatran 3 drugs demonstrated no measurable change in systemic exposure Losartan Glipizide Levothyroxine FDA Prescribing Information. Integration of New Binders into Clinical Practice Palaka E, et al. Int J Clin Pract

31 Conclusions Chronic hyperkalemia can be managed with sodium polystyrene sulfonate, patiromer or sodium zirconium cyclosilicate Sodium polystyrene sulfonate is often combined with sorbitol and exchanges sodium for potassium Patiromer is a spherical product which contains sorbitol and exchanges calcium for potassium Sodium zirconium cyclosilicate exchanges sodium and hydrogen ions for potassium The efficacy of sodium polystyrene sulfonate is unclear with few controlled studies which have variable results The efficacy of patiromer is well studied in a variety of populations The efficacy of sodium zirconium cyclosilicate is well studied in a variety of populations The safety data regarding sodium polystyrene sulfonate raises significant concern Patiromer is generally well tolerated with attention needed to GI disturbances and reduction in magnesium levels Sodium zirconium cyclosilicate is well tolerated with limited GI disturbances but attention is needed to the development of edema Case based Challenges in Hyperkalemia Management Katherine E. DiPalo, PharmD, BCACP, BCGP Director, Heart Failure Readmissions Reduction Program Montefiore Medical Center Bronx, New York 31

32 Agenda Describe strategies to initiate and optimize RAAS inhibitor therapy in heart failure patients with chronic hyperkalemia Review monitoring guidelines for safe use Discuss care integration and team approach to improve patient outcomes Highlight patient education resources Hyperkalemia Fact vs Fiction Fact Hyperkalemia is a common cause of RAAS inhibitor downtitration and discontinuation in patients with heart failure Heart failure patients, especially with comorbidities, such as diabetes and CKD, are at highrisk for hyperkalemia Fiction Previous occurrence of hyperkalemia is an absolute contraindication to subsequent RAAS inhibition Sodium polystyrene sulfonate (SPS) is safe and effective in the management of recurrent hyperkalemia KDOQI. Am J Kidney Dis. 2004; Palmer BF. N Engl J Med

33 Management of Chronic Hyperkalemia before Era of New K + Binders Assess renal function Prescribe low K + diet Titrate or discontinue RAASi Prescribe diuretic therapy KDOQI. Am J Kidney Dis. 2004; Palmer BF. N Engl J Med Limitations of Long term Hyperkalemia Management Strategies Treatment Focuses on Diet Changes, Removal of Therapies That Increase Serum K +, and SPS RAASi reduction SPS 2 Dietary K + restriction of meq/day Limiting the dose of or discontinuing treatment with drugs known to be effective in these populations 1 Warnings related to serious GI AEs and colonic necrosis Precaution related to Na + K + is a common ingredient in many foods 3 Restricts consumption of healthy foods (eg, the DASH Diet) 3 Low K + diet often expensive 4 AE, adverse event; DASH, Dietary Approaches to Stop Hypertension. 1 KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl. 2013; 2 SPS Prescribing Information; _EBB_Potassium.pdf; 4 Drewnowski A, et al. J Hum Hypertens

34 FP is a 69 year old Italian male referred to the outpatient HF team after 2 recent hospitalizations for acute decompensated HF Hyperkalemia documented in EMR as an allergy to ACE inhibitors Patient Case The Grey Zone Past Medical History Labs Vitals Medications Hypertension Heart failure with reduced ejection fraction NYHA Class III EF 25% s/p AICD Chronic kidney disease stage 3A Diabetes mellitus Osteoarthritis Serum creatinine: 1.6 mg/dl Estimated GFR: 45 ml/min/m 2 Potassium: 4.9 meq/l NT probnp: 4500 pg/ml Digoxin level: 0.4 ng/ml BP: 144/96 mmhg HR: 76/minute AICD, automated implantable cardioverter defibrillator; BID, twice daily; EMR, electronic medical record; HR, heart rate; NT probnp, N terminal prohormone of brain natriuretic peptide; s/p, status post; TID, three times daily. Carvedilol 12.5 mg BID Hydralazine 25 mg TID Isosorbide dinitrate 20 mg TID Naproxen 500 mg BID as needed Digoxin 125 mcg daily Torsemide 40 mg BID Hyperkalemia is a Complex Clinical Challenge Aging reduces renal function Comorbidities (CKD, diabetes, HF) places patients at high risk of hyperkalemia Comorbidities require therapy (RAAS inhibitor) that increases risk of hyperkalemia Discontinuing therapy places patients at risk of CV events CV, cardiovascular. 34

35 ACCF/AHA Guidelines for RAAS Inhibition C/I, contraindication; COR, Class of Recommendation; CRT, cardiac resynchronization therapy; CRT D, CRT defibrillator; Dx, diagnosis; GDMT, guideline directed medical therapy; ICD, implantable cardioverter defibrillator; LBBB, left bundle branch block; LVAD, left ventricular assist device; LVEF, left ventricular ejection fraction; NSR, normal sinus rhythm. Yancy CW, et al. J Am Coll Cardiol Balancing RAAS Inhibitor Use and Potassium Level Chronic Management Challenges RAAS inhibitors: ACE inhibitors, ARBs, aldosterone blockers 1,2 Guidelines recommended (ACCF/AHA and HFSA) Proven outcomes benefit in HF Potential risks of RAAS inhibitor therapy Risk of increased serum potassium 1,2 Utilization limited by risk of hyperkalemia 1,3 Up to 65% of patients with HF are suboptimally dosed 3 Resolve the competing issue (hyperkalemia) so patients can remain on appropriate drugs that lower mortality ACCF, American College of Cardiology Foundation; AHA, American Heart Association; HFSA, Heart Failure Society of America. 1 Heart Failure Society of America, et al. J Card Fail. 2010; 2 Yancy CW, et al. Circulation. 2013; 3 Epstein M, et al. Am J Manag Care

36 KDOQI Guidelines Monitoring of Serum Potassium before Initiating RAASi Therapy The KDOQI guidelines recommend the following before initiating ACE inhibitor or ARB treatment in patients with CKD for management of blood pressure: No intervention if baseline serum potassium level is 4.5 meq/l Dietary counseling if serum potassium level is meq/l Dietary counseling and initiation of potassium lowering medications and ARB or ACE inhibitor if serum potassium level is meq/l Immediate initiation of potassium lowering medications before initiating ACE inhibitor or ARB if serum potassium level is >5.5 meq/l KDOQI, Kidney Disease Outcomes Quality Initiative. KDOQI. Am J Kidney Dis Dietary Management of Hyperkalemia Dietary K + restriction Recommended to less than 2.4 g/day in patients with stage III or higher CKD Patients at risk for hyperkalemia should receive comprehensive dietary K + education DASH diet Overall effects of DASH diet seem beneficial Patients with CKD or diabetes mellitus may be at increased risk for hyperkalemia and its consequences Pitt B, et al. Hypertension

37 Counsel Patients to Avoid Foods High in K + Food Portion K + Content, mg Beans black, canned ½ cup 903 Beans lima, canned 1 cup 987 Brussels sprouts frozen, boiled 1 cup 446 Clams moisture cooked 19 small 665 Guacamole with tomatoes ½ cup 458 Lentils boiled 1 cup 731 Mango 1 medium 564 Milk coconut 8 fl oz 497 Orange juice 8 oz 496 Oysters raw 6 medium 504 Plantain cooked 1 cup 716 Potato baked 1 medium 926 Raisins 1 cup 1086 Spinach frozen, boiled 1 cup 574 Tomato paste, canned, no added salt 6 oz aakp nutrition counter reference kidney patient electronic download/. Review for Medications That May Cause Increase in Serum Potassium Levels ACE inhibitors Aliskiren Amiloride Angiotensin II receptor blockers Azole antifungals (eg, ketoconazole, fluconazole, itraconazole) Beta blockers Cyclosporine Digoxin Drospirenone Eplerenone and finerenone Heparin and its derivatives Herbal remedies (eg, alfalfa, dandelion, hawthorn berries, horsetail, milkweed, nettle, noni juice, Siberian gensing) Hyperosmolar solutions (eg, mannitol glucose) Intravenous cationic amino acids NSAIDs Pentamidine Spironolactone Suxamethonium Tacrolimus Triamterene Trimethoprim and its combinations Weiner ID, et al. Comprehensive Clinical Nephrology. 2010; Palmer BF. N Engl J Med

38 The Art of Prior Authorization Receive approval before prescribing Use electronic prior authorization (epa) CoverMyMeds Standardize request letter Refer to HF guidelines Highlight safety and efficacy concerns with formulary alternatives (SPS) Check for copay assistance Manufacturer Patient Access Network ACCF/AHA Guidance on Serum Potassium Monitoring in Patients with HF Who Are Taking a RAAS Inhibitor Intervention ACE inhibitor Potassium Monitoring Recommendation Assess within 1 to 2 weeks of initiation of therapy and periodically thereafter Especially in patients with preexisting hypotension, hyponatremia, diabetes mellitus, or azotemia, or in those taking potassium supplements ARB Assess within 1 to 2 weeks after initiation and follow closely after changes in dose Yancy CW, et al. J Am Coll Cardiol

39 The Grey Zone 1 Week Later After dietary counseling, discontinuation of naproxen and digoxin, and pre authorization for patiromer, enalapril 5 mg BID initiated FP reports feeling great with the following labs and vitals during clinic visit Labs Vitals Meds Serum crea nine: 1.5 mg/dl 1.7 mg/dl Estimated GFR: 45 ml/min/m 2 40 ml/min/m 2 Potassium: 4.9 meq/l 5.3 meq/l NT probnp: 4500 pg/ml 2700 pg/ml BP: 144/96 mmhg 132/84 mmhg HR: 76/min 74/min Carvedilol 12.5 mg BID Hydralazine 25 mg TID Isosorbide dinitrate 20 mg TID Enalapril 5 mg BID Torsemide 40 mg BID Guidelines Recommend RAAS Inhibitor Dose Modifications with Increasing Serum K + Most Conservative NICE 1 Do not start RAAS inhibitor if serum K + >5.0 meq/l HFSA HF 2 MRA not recommended if serum K + >5.0 meq/l ACC/AHA HF 3 MRA not recommended if serum K + >5.0 meq/l ESC HFA 4 /K/DOQI 5 Reduce dose of or stop ACE inhibitor/ ARB, MRA if serum K + >5.5 meq/l Most Aggressive NICE 1 Stop RAAS inhibitor if serum K + >6.0 meq/l ACC, American College of Cardiology; ESC, European Society of Cardiology; HFA, Heart Failure Association; NICE, National Institute for Health and Care Excellence Heart Failure Society of America, et al. J Card Fail. 2010; 3 Yancy CW, et al. Circulation. 2013; 4 McMurray JJ, et al. Eur Heart J. 2012; 5 KDOQI. Am J Kidney Dis

40 Nearly Half of Patients on Maximum Dose of RAAS Inhibitor Had Down Titrated or Discontinued Therapy after a Hyperkalemia Event Mild Hyperkalemia K meq/l (23,556 events) Moderate to Severe Hyperkalemia K meq/l (11,608 events) Maintained dose, % Downtitrated, % Discontinued, % Epstein M, et al. Am J Manag Care Sodium Polystyrene Sulfonate (SPS) In use since the early 1960s Approved before current era of evidence based medicine Minimal efficacy data Safety Risk of acute bowel necrosis, hypernatremia, constipation, diarrhea, and GI intolerance Reports of highly fatal upper and lower GI transmural necrosis with SPS combined with 70% sorbitol Occurs in 0.1% to 0.3% of patients FDA Prescribing Information; Kovesdy CP. Am J Med. 2015; Harel Z, et al. Am J Med

41 OPAL HK Phase 3 Study Part B Effect on Concomitant RAAS Inhibitor Therapy Proportion of Patients, % Placebo (n=52) Requiring Any Adjustment of RAASi (i.e., downtitration or discontinuation) Due to Hyperkalemia at Any Time During Part B Patiromer (n=55) Receiving Any Dose of a RAASi at the End of Part B Weir MR, et al. N Engl J Med Sodium Zirconium Cyclosilicate Treatment Effect in Patients with HF Receiving Maximal, Submaximal, or No RAAS Inhibitor Therapy Maximal RAAS Inhibitor Submaximal RAAS Inhibitor Not Taking RAAS Inhibitor Patients Achieving Normokalemia, % Time, h Sodium zirconium cyclosilicate restored normokalemia regardless of presence or intensity of RAAS inhibitor therapy at baseline. Kosiborod M, et al. Circulation

42 A New Approach to the Grey Zone Novel potassium binders: patiromer and sodium zirconium cyclosilicate Effective in treating hyperkalemia Well tolerated Safety and efficacy data for up to 1 year Facilitate optimal dosing of RAAS inhibitor therapy Decrease ED and urgent care visits Reduce the rate of hospitalization Reduce cost of care Alleviate fear of taking/prescribing RAAS inhibitor therapy Liberalize patient diet and improve quality of life Sarwar CM, et al. J Am Coll Cardiol The Grey Zone 2 Weeks Later With prior authorization already obtained patiromer 8.4 g/day is immediately started FP reports no taste, no problems and repeats blood work 5 days later Labs Vitals Medications Serum crea nine: 1.5 mg/dl 1.7 mg/dl 1.7 mg/dl Estimated GFR: 45 ml/min/m 2 40 ml/min/m 2 40 ml/min/m 2 Potassium: 4.9 meq/l 5.3 meq/l 4.6 meq/l Magnesium: 2.0 meq/l NT probnp: 4500 pg/ml 2700 pg/ml 2500 pg/ml BP: 144/96 mmhg 132/84 mmhg 130/82 mmhg HR: 76/min 74/min 76/min Carvedilol 12.5 mg BID Hydralazine 25 mg TID Isosorbide dinitrate 20 mg TID Enalapril 5 mg BID Patiromer 8.4 g daily Torsemide 40 mg BID 42

43 New and Emerging K + Binders Efficacy and Safety Patiromer OPAL HK AEs include mild to moderate constipation (11%) and hypokalemia (3%) Mean Serum Potassium (mmol/l) Day 3 Baseline Week 1 Overall Week 2 Mild hyperkalemia Moderate to severe hyperkalemia Week 3 Week 4 Weir MR, et al. N Engl J Med New and Emerging K + Binders Efficacy and Safety ZS 9 HARMONIZE Proportion of patients with mean serum K + <5.1 meq/l during days 8 29 AEs include edema (2% to 14%) and hypokalemia (0% to 11%) Patients, % P<0.001 vs placebo 15 g ZS 10 g ZS 5 g ZS Placebo 46 Kosiborod M, et al. JAMA

44 ATLAS Low vs High Dose Lisinopril on Morbidity/Mortality in HF % of Patients With ADE Hyperkalemia 7 Worsening renal function Low dose: 2.5 to 5.0 mg/d (n=1596) High dose: 32.5 to 35 mg/d (n=1568) ADE, adverse drug event. Packer M, et al. Circulation HEAAL Low vs High Dose Losartan on Morbidity/Mortality in HF % of Patients With ADE Hyperkalemia 4.7 Worsening renal function Low dose: 50 mg/d (n=1919) High dose: 150 mg/d (n=1927) Konstam MA, et al. Lancet

45 PARADIGM HF Hyperkalemia Development during Study Elevated Serum Potassium Patients, % Sacubitril/Valsartan (n=4187) sk+ >5.5 mmol/l sk+ >6.0 mmol/l Enalapril (n=4212) sk +, serum potassium. McMurray JJ, et al. N Engl J Med Spironolactone Causes Hyperkalemia in a Dose Dependent Fashion 25 K mmol/l Hyperkalemia, % Placebo 12.5 mg 25 mg 50 mg 75 mg Spironolactone Optimal dosing of MRA in HF is limited by hyperkalemia The RALES Investigators. Am J Cardiol

46 Patients, % Higher Incidence of Hyperkalemia with MRAs in the Real World 2 RALES (N=822) Incidence of severe hyperkalemia ( 6 meq/l) Incidence Clinical Trials of Severe Hyperkalemia ( 6.0 meq/l) Real World EMPHASIS (N=1336) 6 Shah 2005 (N=840)* Real World 12 Bozkurt 2003 (N=104) *Out of a total of 840 patients enrolled, 551 patients with follow up laboratory values determined. 1 Pitt B, et al. N Engl J Med. 1999; 2 Zannad F, et al. N Engl J Med. 2011; 3 Shah KB, et al. J Am Coll Cardiol. 2005; 4 Bozkurt B, et al. J Am Coll Cardiol ACCF/AHA Guidelines for MRA Dosing MRA Dosing MRAs egfr 50 ml/min/1.73 m 2 egfr ml/min/1.73 m 2 Eplerenone Spironolactone Initial: 25 mg daily Maintenance: 50 mg daily Initial: mg daily Maintenance: 25 mg daily or 25 mg twice daily Initial: 25 mg once every other day Maintenance: 25 mg daily Initial: 12.5 mg daily or 12.5 mg once every other day Maintenance: mg daily Intervention Aldosterone Receptor Antagonist egfr, estimated glomerular filtration rate. Potassium Monitoring Recommendation Recheck within 2 to 3 days and again at 7 days after initiation Subsequent monitoring should occur at least monthly for the first 3 mo and every 3 mo thereafter Addition or increase in dosage of ACEIs or ARBs should trigger a new cycle of monitoring Yancey C, et al. Circulation

47 Hyperkalemia A Fluid Continuum of Decisions Chronic treatment choices become more challenging In clinical practice, patients can be stable, but if something common happens, such as dehydration, renal function goes down and potassium goes up However, drugs don t work if we don t prescribe them! Some drug is better than none Potassium binders can be titrated to effect Rastergar A, et al. Postgrad Med J The Interprofessional Approach Multidisciplinary process involving Cardiologists, nephrologists, primary care providers, case managers, pharmacists, nurses, nutritionists Communication is crucial Between inpatient and ambulatory settings Between specialties Between providers and patients Education is key Low potassium diet Consider ethnic preferences and dietary influences Offer options for real life scenarios Potassium binders Administration to avoid DDIs Adherence and rebound hyperkalemia DDI, drug drug interaction. 47

48 Patient Resources _EBB_Potassium.pdf. Patient Resources (continued) _EBB_Potassium.pdf; information/kidney disease/chronic kidney disease ckd/eating nutrition. 48

49 Getting Out of the Grey Zone With novel potassium binders (patiromer and sodium zirconium cyclosilicate) hyperkalemia may be less of a factor, and Patients will have more freedom to eat a healthy diet to improve their quality of life Provider fear of prescribing RAAS inhibitor therapy may be alleviated RAAS inhibitor therapy may be initiated and optimally dosed Patients will receive guideline directed medical therapy that will reduce hospitalizations and decrease morbidity and mortality Abbreviations ACC: American College of Cardiology ACCF: American College of Cardiology Foundation ACE: angiotensin converting enzyme ACEI: angiotensin converting enzyme inhibitor ADE: adverse drug event ADR: adverse drug reaction AE: adverse event AGT: angiotensinogen AHA: American Heart Association AICD: automated implantable cardioverter defibrillator AKI: acute kidney injury ANGII: angiotensin II ARB: angiotensin receptor blocker BID: twice daily BP: blood pressure CHF: congestive heart failure C/I: contraindication COR: class of recommendation COX 2: cyclooxygenase 2 CRT: cardiac resynchronization therapy CRT D: cardiac resynchronization therapy defibrillator CV: cardiovascular D/C: discontinuation 49

50 Abbreviations DDI: drug drug interaction Decr: decrease DASH: dietary approaches to stop hypertension DM: diabetes mellitus Dx: diagnosis ECG: electrocardiogram ED: emergency department egfr: estimated glomerular filtration rate EMR: electronic medical record epa: electronic prior authorization FDA: Food and Drug Administration ESC: European Society of Cardiology ESRD: end stage renal disease GDMT: guideline directed medical therapy GFR: glomerular filtration rate GI: gastrointestinal HF: heart failure HFA: Heart Failure Association HFH: heart failure hospitalization HFSA: Heart Failure Society of America HR: heart rate HTN: hypertension ICD: International Classification of Diseases, or implantable cardioverter defibrillator Incr: increase IV: intravenous K+: potassium ion Abbreviations KDOQI: Kidney Disease Outcomes Quality QRS: principal deflection in ECG Initiative RAAS: renin angiotensin aldosterone system LBBB: left bundle branch block RAASi: renin angiotensin aldosterone system LVAD: left ventricular assist device inhibitor LVEF: left ventricular ejection fraction RCT:randomizedcontrolledtrial MRA: mineralocorticoid receptor antagonist RTA: renal tubular acidosis NICE: National Institute for Health and Care Rx: prescribe Excellence sk+: serum potassium NSAID: non steroidal anti inflammatory drug s/p: status post NSR: normal sinus rhythm SPS: sodium polystyrene sulfonate NT probnp: N terminal prohormone of brain SCr: serum creatinine natriuretic peptide TID: three times daily PBO: placebo PHA: pseudohypoaldosteronism 50

51 Notes 51

52 AAKP Nutrition Counter: A Reference for Kidney Patients. American Association of Kidney Patients website aakp nutrition counter reference kidney patient electronic download/. Accessed November 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): Agency for Healthcare Research and Quality. Healthcare Cost and Utilization Project. AHRQ website. Accessed November Alvo M, Warnock DG. Hyperkalemia. West J Med. 1984;141(5): 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): Batterink J, Lin J, Au Yeung SH, et al. Effectiveness of sodium polystyrene sulfonate for short term treatment of hyperkalemia. Can J Hosp Pharm. 2015;68(4): Ben Salem C, Badreddine A, Fathallah N, et al. Drug induced hyperkalemia. Drug Saf. 2014;37(9): Berlyne GM, Janabi K, Shaw AB, et al. Treatment of hyperkalemia with a calcium resin. Lancet. 1966;1(7430): 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): Breyer MD, Susztak K. The next generation of therapeutics for chronic kidney disease. Nat Rev Drug Discov. 2016;15(8): Center for Drug Evaluation and Research. Final risk evaluation and mitigation strategy (REMS) review: Veltassa. October 21, FDA website. Accessed November Chaitman M, Dixit D, Bridgeman MB. Potassium binding agents for the clinical management of hyperkalemia. P&T. 2016;41(1): Chang AR, Sang Y, Leddy J, et al. Antihypertensive medications and the prevalence of hyperkalemia in a large health system. Hypertension. 2016;67(6): Choi HY, Ha SK. Potassium balances in maintenance hemodialysis. Electrolyte Blood Press. 2013;11(1):9 16. Chronic kidney disease in adults: assessment and management clinical guideline. The National Institute for Health and Care Excellence (NICE) website. January Accessed November Diercks DB, Shumaik GM, Harrigan RA, et al. Electrocardiographic manifestations: electrolyte abnormalities. J Emerg Med. 2004;27(2): Dunn JD, Benton WW, Orozco Torrentera E, et al. The burden of hyperkalemia in patients with cardiovascular and renal disease. Am J Manag Care. 2015;21(15 Suppl):s307 s315.

53 Elliott W, Chan J. Patiromer for oral suspension (Veltassa). March 1, Relias Media website. patiromer for oral suspension veltassa. Accessed November 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): 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(11 Suppl):S212 S220. 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: Fordjour KN, Walton T, Doran JJ. Management of hyperkalemia in hospitalized patients. Am J Med Sci. 2014;347(2): Georgianos PI, Agarwal R. Revisiting RAAS blockade in CKD with newer potassium binding drugs. Kidney Int. 2018;93: 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): Gruy Kapral C, Emmett M, Santa Ana CA, et al. Effect of single dose resin cathartic therapy on serum potassium concentration in patients with end stage renal disease. J Am Soc Nephrol. 1998;9(10): Hagan AE, Farrington CA, Wall GC, et al. Sodium polystyrene sulfonate for the treatment of acute hyperkalemia: a retrospective study. Clin Nephrol. 2016;85(1): Harel Z, Harel S, Shah PS, et al. Gastrointestinal adverse events with sodium polystyrene sulfonate (Kayexalate) use: a systematic review. Am J Med. 2013;126(3):264:e9 e24. Hayes J, Kalantar Zadeh K, Lu JL, et al. Association of hypo and hyperkalemia with disease progression and mortality in males with chronic kidney disease: the role of race. Nephron Clin Pract. 2012;120(1):c8 c16. Heart Failure Society of America; Lindenfeld J, Albert NM, Boehmer JP, et al. HFSA 2010 Comprehensive Heart Failure Practice Guideline. J Card Fail. 2010;16(6):e1 e194. Hoge RH, Arbouw ME, Radstake SD, et al. Subtherapeutic serum quetiapine concentrations after absorption inhibition by binding resins: a case report. J Clin Pharm Ther. 2015;40(3): If you need to limit potassium. National Kidney Foundation website _EBB_Potassium.pdf. Accessed November KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl. 2013;(3)1. Kidney Disease Outcomes Quality Initiative (K/DOQI). K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis. 2004;43(5 Suppl 1):S1 S290. 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(9704): 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):