Conflict of interest

Hyperkalemia in Heart and Kidney patients: Rescue is here Wajeh Qunibi, MD, FACP Professor of Medicine University of Texas Health Science Center San Antonio, TX CARDIORENAL CONNECTION April 28, 2017 Conflict of interest Research grant from ZS Pharma

Objectives Discuss the prevalence of hyperkalemia in heart and kidney patients Discuss novel agents for treatment of hyperkalemia Challenges in Hyperkalemia studies Definition of hyperkalemia Serum [K+] > 5.0 meq/l > 5.5 meq/l > 6.0 meq/l Hemolyzed specimens Prevalence varies with level of GFR in different studies Outcomes of hyperkalemia by serum K+ level: Short-term vs long-term outcomes EKG changes

Prevalence of Hyperkalemia (serum K > 5.0 meq/l) HK is in the general population: < 1% of normal healthy adults 2.6% of emergency department visits 1-10% of hospital admissions Prevalence significantly higher in CKD: 7.7% to 83% Patients at highest risk for HK are those taking RAASi with CKD stage 3 or greater who also have DM, HF or both. Use of renin angiotensin aldosterone system (RAAS) inhibitors contribute to hyperkalemia in 35-75% of all cases Source: 1Jain et al, 2012; 2McMahon et al, 2012; 3Makani et al, 2013; 4Takaichi et al, 2007; 5Fondjour et al, 2012. Drugs blocking the Renin Angiotensin Aldosterone System causing hyperkalemia due to decreased renal K excretion Direct renin inhibitors Palmer. NEJM 2004

Risk of Hyperkalemia (K+ > 5.5 meq/l) in non-diabetic hypertensive patients with CKD receiving RAASi by baseline GFR in the AASK Trial N = 1094 nondiabetic adults with hypertensive CKD from AASK FU = 3.0 to 6.4 years Weinberg et al. Arch I Med 2009 Incidence of Hyperkalemia ( 5.5) in Veterans with and without CKD % of patients Retrospective analysis of 245,808 inpatient and outpatient veterans (with at least 1 hospitalization and 1 serum K+ record in 2004-2005) 80 70 60 50 40 30 20 10 0 8.9 20.7 42.1 56.7 No CKD Stage 3 Stage 4 Stage 5 15,485/174,935* 11,958/57,798* 3,516/8,351* 2,678/4,724* *Number of patients with hyperkalemia divided by number of patients in each respective cohort. Of the 66 259 hyperkalemic events (3.2% of records), more occurred as inpatient events [52.7%]) than as outpatient events (47.3%) Einhorn LM, et al. Arch Intern Med. 2009;169(12):1156-1162.

Incidence of Hyperkalemia ( 5.5) in Veterans with and without CKD by RAASi use 40% 41% 30% % of patients 20% 10% 5.3% 8.7% 18% No RAASi RAASi 0% No RAASi RAASi No CKD CKD Einhorn LM, et al. Arch Intern Med. 2009;169(12):1156-1162. Hyperkalemia associated RAAS inhibitor use in selected clinical trials in patients with CKD

Increased Rate of Hospitalization in HF Patients on MRAs after the publication of Randomized Aldactone Evaluation Study (RALES) in 1999 30% reduction in mortality Spironolactone prescriptions Pitt et al. NEJM 1999 Hospital admission for hyperkalemia In-Hospital mortality from hyperkalemia Juurlink et al. NEJM 2004 Hyperkalemia in a cohort of patients with newly diagnosed heart failure N = 19,194 patients with newly diagnosed HF Age: 1 89 years HK identified in 11.3% of patients during follow-up of 3.9 years Risk factors for HK: Renal failure Type II diabetes Valvular heart disease Use of potassium-sparing diuretics ACE inhibitors Trimethoprim Non-steroidal anti-inflammatory drugs Drug combinations. The risk was highest within the first month of medication use Michel et al. European Journal of Heart Failure (2015) 17, 205 213

Hyperkalemia in Heart Failure patients increases as Renal Function declines particularly in MRA-treated patients Chaudry et al. JACC 68, Issue 14, 2016, 1575 1589 WRF: Worsening renal function HK is more frequent in stage 3 diabetic CKD patients than in non-diabetic CKD patients Loutradis et al. Am J Nephrol 2015;42:351 360 180 patients with CKD 180 patients with CKD HK defined as K+ > 5.0 meq/l

Increased mortality risk within 1 day of moderate (Serum K 5.5 and <6.0) and severe ( 6.0 meq/l) hyperkalemia Einhorn et al. Arch I Med 2009 The reference group: Patients with K+ <5.5 meq/l) and no CKD Study cohort: 245,808 patients from VA 2,103,422 K records 70,873 (28.8%) had CKD 66% on ACEI/ARB 50% had DM 2.4% od patients died within 1 day Graded In-Hospital mortality increase with higher serum K+ level particularly in ND-CKD patients Grodzinsky et al. Am J Med 129, Issue 8, 2016, 858 865

In hospital mortality based on number of hyperkalemia in events in CKD patients with AMI Grodzinsky et al. Am J Med 129, Issue 8, 2016, 858 865 Serum Potassium Levels and Mortality in Acute Myocardial Infarction 38 689 patients with confirmed AMI U-shaped relationship between mean post-admission serum K+ level and in-hospital mortality Lowest mortality observed with post-admission serum K+ levels between 3.5 and <4.5 meq/l Goyal et al. JAMA. 2012;307(2):157-164

Associations between serum potassium (K+) (meq/l) and mortality in ND-CKD patients Jiacong Luo et al. CJASN 2016;11:90-100 n=55,266 egfr < 60 Median FU = 2.76 years EKG changes of hyperkalemia are insensitive in guiding therapy in stable patients 242 hospitalized patients All had hyperkalemia ([K+] > 6.0 meq/l) 77% had Renal failure 63 % due to drugs causing HK 49% had hyperglycemia Mean serum [K+] was 6.5±0.6 meq/l EKG changes of hyperkalemia: 46% had any EKG changes suggestive of hyperkalemia Only 36% had peaked T wave Prevalence of ECG changes was independent of the severity of hyperkalemia Acker et al. Arch I Med 1998

Treatment of Hyperkalemia Standard approach: Low K diet (2-3 grams/day) Assessment of renal function Review medications and discontinue RAAS inhibitors/ other offending agents (may not be desirable) Correction of metabolic acidosis Treatment of hyperglycemia Enhance urinary excretion: Loop diuretics Mineralocorticoid stimulation: Fludrocortisone (begins to work within 3 hours) but has potent Na retaining action Enhance intestinal K+ excretion by use of potassium binders: Sodium polystyrene sulfonate (Kayexalate) Patiromer ZS-9 Acute Treatment of Hyperkalemia Therapeutic agent Mechanism of action Onset of action Duration of effect IV calcium gluconate Insulin B2-adrenergic agonist (Albuterol) Antagonizes effects of K+ on cardiac muscle membrane Promotes uptake of K+ by cells Promotes uptake of K+ by cells 1-3 min 30-60 min 30 min 4-6 hours 30 min 2-4 hours Hemodialysis Removal of K from body Immediate > 3 hours

Enhance intestinal K+ excretion by use of potassium binders Potassium Concentration in the Intestine Na (meq/l) K (meq/l) 140 140 110 80 15 6 8 10 meq of K +,* = Duodenum Jejunum Ileum Colon 22.5 1,2 4.5 1,2 16 1,3 * Based on estimated volume of 1.5L, 0.75L, 0.25L, and 0.2L in the duodenum, jejunum, ileum, and colon respectively 2,3 2 1,2 1. Fordtran. Fed Proc. 1967. 2. Fordtran et al., Am J Dig. 1966. 3. http://en.wikibooks.org/wiki/medical_physiology/gastrointestinal_physiology/secretions Sodium Polystyrene sulfonate (Kayexalate) Approved by FDA in 1958 Efficacy not tested in RCTs Given orally or rectally with or without sorbitol Exchanges Na for K, Ca, Mg, and NH4 in the colon Most effective in distal colon and rectum GI side effects: anorexia, nausea, vomiting, diarrhea May cause colonic obstruction, necrosis, and perforation Necrosis may be caused by sorbitol 2009: FDA issued warning against using SPS with 70% sorbitol A premixed suspension of SPS in 33% sorbitol, the only preparation stocked by many hospital pharmacies is commonly used Sterns et al. CJASN 2010

33 European ambulatory patients with CKD and mild hyperkalemia (5.0 5.9 meq/l) Randomized to 30 g/day SPS without sorbitol for 7 days or placebo SPS superior to placebo in reducing serum K+ level (mean difference: 1.04 meq/l) GI and electrolyte side effects more common in SPS group Lepage et al. CJASN 2015 Kayexalate Combined with Sorbitol Reports Colonic Necrosis with SPS Crystals Watson et al. AJKD 2012 SPS prescribed to 2,194 inpatients 82 inpatient colonic necrosis cases were identified. 3 received oral SPS in 33% sorbitol 30 or fewer days before colonic necrosis Incidence of colonic necrosis: 0.14% in those prescribed SPS versus 0.07% in those not prescribed SPS

Sodium Polystyrene sulfonate is non-selective and has greater affinity for Ca & Mg than K Kayexalate (SPS) Ion Binding Potassium, Calcium, and Magnesium Concentration Ratio (1:1:1) 59 Selectivity Ratio* 0.2 18 24 K+ Ca2+ Mg2+ *Selectivity Ratio = [K+] / [Ca+2] + [Mg+2] **Exchange capacity of Ca2+ and Mg2+ was below the set detection limit of 0.05 meq/g; therefore, 0.05 meq/g assumed for calculation purposes. Singh et al., ASH Poster Presentation. 2014. A New Era for the Treatment of Hyperkalemia 2 new oral drugs to prevent and treat hyperkalemia have been studied in clinical trials: Patiromer sorbitex calcium (RLY5016S-Veltassa) Sodium zirconium cyclosilicate (ZS-9) Trials indicate that both compounds are effective and safe for treatment of hyperkalemia

Patiromer Calcium Nonabsorbable synthetic polymer Consists of smooth spherical beads 100 μm in diameter Administered orally as powder suspended in water Does not swell when exposed to water Does not require a laxative to reach the distal colon Binds K+ in exchange for Ca and Mg in distal colon Recommended starting dose 8.4 g/d Can increase dose by 8.4 g/d at weekly intervals. Max dose 25.2 g/d Approved by the FDA in October 2015. Efficacy and safety of Patiromer on serum K+ levels in patients with chronic heart failure receiving standard therapy and spironolactone (Placebo) (Patiromer) Pitt et al. Eur Ht J 2011 (Patiromer) Double-blind Placebo-controlled trial N = 120 patients with HF 1/3 rd had DM; egfr 80 All on RAASi or BB Patiromer ( 15 g orally bid) or placebo for 4 weeks All patients started on Spironolactone

Initial Treatment Phase: Mean change in serum K+ was -1.01 meq/l from baseline to week 4 243 patients with CKD treated with RAASi had serum K+ levels of 5.1 to <6.5 meq/l Patiromer given twice daily (plus low K+ diet with continuation of RAASi) 2-phase study: initial and maintenance phases. Weir M, et al. NEJM. 2015;372:211-221 Randomized Withdrawal Phase: During 8 weeks, 94% of patients in patiromer group continued RAASi versus 44% in placebo. Also 60% of the placebo group had recurrence of hyperkalemia (>5.5 meq/ l) vs 15% in patiromer group Weir M, et al. NEJM. 2015;372:211-221 107 patients were enrolled in the second phase Median change in K+ was lower in patiromer group (0 versus 0.72mEq/l

Patiromer (4.2-16.8 g bid) resulted in significant decreases in serum K+ level after 4 weeks of treatment, lasting through 52 weeks in diabetic CKD patients with mild or moderate Hyperkalemia Phase 2 study Enrolled 306 stages 3 and 4 CKD (15 60 ml/min/1.73m2) patients with T2DM using RAAS blockers Randomized to doses of patiromer according to their baseline K+ level (no placebo group) Bakris et al. JAMA 2015 Mild HK: >5.0-5.5 meq/l 4.2 g bid...0.35 meq/l 8.4 g bid...0.51 12.6 g bid...0.55 Moderate HK:>5.5-<6.0mEq/L 8.4 g bid...0.87 12.6 g bid...0.97 16.8 g bid...0.92 Most common Adverse Effect of Patiromer

Phase 1 study: The first statistically significant serum potassium decline occurred at 7h of Patiromer treatment in CKD patients with hyperkalemia on RAASi -0.21 meq/l -0.75 meq/l Bushinsky et al. KI 2015 FDA approval in October 2015 FDA approved patiromer in October 2015 with 2 warnings: Patiromer should not be used as an emergency treatment for life-threatening hyperkalemia because of its delayed onset of action Patients should take Patiromer at least 6 hours before or after other oral medications FDA updated statement on Nov 27, 2016: FDA removed the Boxed Warning Regarding Drug-Drug Interactions The updated label recommends patients take Patiromer at least 3 hours before or after other oral medications (not the 6-hour separation time)

ZS-9: Sodium Zirconium Cyclosilicate ZS-9 is an inorganic, nonabsorbable crystalline compound Exchanges Na+ for K+ in the intestine. Has specific pore size for K+ and NH4+ Highly selective for K+ and NH4+ ions, which are nearly identical in size ZS-9 binds K+ throughout the intestine ZS-9 is insoluble, neither systemically absorbed nor metabolized As ZS-9 can bind NH4+, it can result in an increase in serum bicarbonate. ZS-9 In vitro ion exchange Capacity and Specificity Selectivity ratio SPS: 18/59+24 = 0.2 ZS-9: 96/2+2 = 24 24/0.2 = 120 SPS is more selective for Ca2+ than K+ ZS-9 is 24 times more selective for K+ than Ca2+ and Mg2+ ZS-9 is 120 times more selective for K+ than SPS ZS-9 has 9 times K+ binding capacity than SPS

Overview of ZS-9 Clinical Trials 750 To date, almost 2000 patients were enrolled in various clinical trials with ZS-9 *POC: Proof of Concept ZS Pharma R&D- NYC, 2014 Mean K+ levels in patients who received ZS-9 three times daily, as compared with placebo, were significantly reduced at most time points Two-stage, double-blind, phase 3 trial 753 patients (CKD, HF, DM, RAASi) K+ 5.0-6.5 meq/l Randomly assigned to ZS-9 (1.25 g, 2.5 g, 5 g, or 10 g) or placebo 3x daily for 48 hours (Acute phase). NK patients entered maintenance phase. 72% achieved NK (3.5 4.9mEq/l) at 48 hours were randomly assigned to ZS-9 (as their initial dose) or placebo once daily on days 3 to 14 Packham et al. NEJM Nov 2014

HARMONIZE Trial: Mean serum K+ levels over time 258 Patients treated during the open-label phase with ZS 10 g 3 times daily for 48 hours then randomized for 28 days 10 g ZS-9 thrice daily for 6 doses K+ 5.6 meq/l K+ 4.5 meq/l During open-label phase with ZS 10 g 3 times daily for 48 hours, serum K+ was reduced by 1.1 meq/l 258 patients 66% had GFR < 60 70% were on RAASi 36% had HF 66% had DM Kosiborod et al. JAMA 2014 Patients achieving normokalemia (K+: 3.5-5.0 meq/l) randomized to ZS 5, 10 or 15 g/day or placebo for 28 days Mean serum K+: 4.8 on ZS 5 g/d 4.5 on Zs 10 g/d 4.4 on ZS 15 g/d 5.1 on Placebo Mean Serum K+ level over 52-Week Long Term Phase Acute Phase 10 g TID for 1-3 days Maintenance Phase NK patients: 5g/d for 52 week Serum Potassium (meq/l) N = 751 patients

ZS-9 given as 10 g significantly reduced the serum K+ level within 1 hour in patients with baseline serum K + 6.0 meq/l Baseline Serum K+ (meq/l) Time (Hour) Subgroup of 45 patients with serum K+ 6 mmol/l (6.1 to 7.2 meq/l) who participated in 2 controlled trials Kosiborod et al. NEJM 2015 * p-value <0.0001 43 Adverse Events (n=684) 44

Conclusions Hyperkalemia is common in cardiac and CKD patients: Associated with increased risk of death Prevents use of cardiorenal protective agents (RAASi) Current approach is reactive waiting for hyperkalemia to develop before intervention Potential of newer treatment agents: More effective Allow continued use of cardiorenal protective agents (RAASi) Possible preventive use in CKD/ESRD patients Have less serious adverse effects Thank You