New Approaches for Treating Hyperkalemia: Why, When and How? 24 th Annual San Diego Heart Failure Symposium June 1-2, 2018 La Jolla, CA Barry Greenberg, MD Distinguished Professor of Medicine Director, Advanced Heart Failure Treatment Program University of California, San Diego
Case Presentation 55 y/o male with known ischemic CM and EF of 0.20 admitted for worsening HF symptoms over past 4 weeks. Hx of CAD with stents in LAD and LCX and VT arrest treated with ICD. Markedly limited due to DOE and fatigue. Current meds: carvedilol 3.125 mg bid, ASA 81 mg, clopidogrel 75 mg, atorvastatin 40 mg, NTG SL prn.
Physical Examination BP 126/84, HR 101, RR 16, SpO2 96% GEN: no acute distress Lungs: clear to auscultation, no wheezing Cards: RRR, S3 present and Gr I-II/VI apical systolic murmur, JVP 15 cm Ext: 2+ edema, warm
Treatment and Hospital Course Patient is started on bumetanide 1 mg IV twice daily and he loses 15 lbs over the next 5 days. Feels much better but still volume overloaded on examination. Lisinopril 2.5 mg bid is added to his regimen and gradually uptitrated to 7.5 mg bid over the next few days. What are the next steps to consider? -uptitrate beta blocker -uptitrate ACEI -switch to sacubitril-valsartan -add aldosterone blocking agent
2013 AHA/ACC/HFSA Guidelines I IIa IIb III Aldosterone receptor antagonists are recommended in patients with NYHA class II-IV, LVEF of 35%,to reduce morbidity and mortality. Yancy CW, et al. J Am Coll Cardiol. 2013;62(16):e147-239.
Labs Na 138 K 5.5 Cl 101 Cr 1.42 Ca 9.6 WBC 7.4 Hgb 14 Plt 187 BNP 463
Serum Potassium Levels and Outcome in Acute Heart Failure (Data from the PROTECT Trial) Tromp J et al. JACC: 119; 290-296, 2017
2013 AHA/ACC/HFSA Guidelines I IIa IIb III Creatinine should be 2.5 mg/dl in men or 2.0 mg/dl in women (or egfr>30 ml/min/1.73m2) and potassium should be less than 5.0 meq/l. Careful monitoring of potassium, renal function, and diuretic dosing should be performed at initiation and closely followed thereafter to minimize risk of hyperkalemia and renal insufficiency. Yancy CW, et al. J Am Coll Cardiol. 2013;62(16):e147-239.
Hyperkalemia Prevalence Incidence and prevalence of hyperkalemia unknown 1 1 10% of hospitalized patients 1 Up to 11% of outpatients on ACE inhibitor at a VA outpatient clinic 2,3 CKD most common predisposing factor 3 Frequency in CKD population is as high as 40-50% 4 Comorbid conditions and accompanying treatments contribute to increased risk 3,4 Heart failure (HF) Type 2 diabetes mellitus (T2DM) Advanced age Use of RAAS inhibitors 1. Tamargo J, et al. Discov Med. 2014;18(100):249-254. 2. Reardon LC, MacPherson DS. Arch Intern Med. 1998;158:26 32. 3. Einhorn LM, et al. Arch Intern Med. 2009;169(12):1156-1162. 4. Kovesdy CP. Nat Rev Nephrol. 2014;10(11):653-62.
Hyperkalemia May Be a Recurrent Condition Assessment of Hyperkalemia Recurrence for Patients with Serum K + 5.5 meq/l 100% A retrospective analysis of a national cohort Percent Patients 75% 50% 25% 53% 47% More than 2 million medical records of >245,000 veterans* 70 individuals (0.21%) had more than 20 episodes in 1 year 0% 1 >1 Hyperkalemia Events *That had 1 hospitalization and 1 serum potassium value measured and recorded during either an inpatient or outpatient visit Einhorn LM, et al. Arch Intern Med. 2009;169(12):1156-1162.
2016 ACC/AHA/HFSA Heart Failure Guideline Update Pharmacological Treatment for Stage C HFrEF ARNI = angiotensin receptor blocker and neprilysin inhibitor; COR = class of recommendation; LOE = level of evidence. Yancy CW, et al. J Am Coll Cardiol. 2013;62(16):e147-239.
Hyperkalemia Prevalence Increases as Kidney Function Declines 5-Year Database Prevalence of Hyperkalemia * in Patients 65 Years Percent Patients with Hyperkalemia 60% 50% 40% 30% 20% 10% 12.7% 23.5% 33.0% 47.7% 0% Control CKD Stage 3a CKD Stage 3b CKD Stage 4 (egfr 45-59) (egfr 30-44) (egfr 15-29) *Hyperkalemia defined as highest reported potassium value 5.1 meq/l in 2008-2012 Based on analysis of 1.63 million persons aged 65 years with potassium readings on 2 dates (2008-2012), with >1 K + value between 2.5 and 10 meq/l during 2008-2012. Control population composed of patients 65 years without CKD stages 2-5, heart failure, diabetes, or end-stage renal disease (ESRD).
Drug-Induced Hyperkalemia Medications Associated with Hyperkalemia ACEi s, ARB s and sacubitril-valsartan combination K + -sparing diuretics, spironolactone Bactrim (trimethoprim), pentamidine NSAIDs Beta blocker (both non-selective and B2 selective) Heparin Digoxin (supratherapetuic levels) Succinylcholine (intubation in ICU, Surgery)* Calcineurin inhibitors (cyclosporine, tacrolimus [FK506]) *High risk patients include patients with neuromuscular disorders, myopathies, prolonged use of muscle relaxants, muscle trauma or inflammation, thermal trauma, disease atrophy, and severe infection; ACEi = angiotensin converting enzyme inhibitors; ARB = angiotensin receptor blocker; NSAID = non-steroidal anti-inflammatory drugs; ICU = intensive care unit Palmer BF. N Engl J Med. 2004;351(6):585-592.
The Addition of MRA to RAS Therapy Increases Hyperkalemia ( 6.0) Risk in HF Patients Hyperkalemia with spironolactone in Real-world vs Clinical-trial HF patients 14 12 Clinical trials Real-world 12 % of Patients 10 8 6 4 2 2 2.5 6 0 RALES EMPHASIS Shah 2005 Bozkurt 2003 1 2 3 4 N=822 N=1,336 N=840 N=104 1. Pitt B, Zannad F, Remme WJ, et al. N Engl J Med. 1999;341(10):709-717. 2. Zannad F. N Engl J Med. 2011;364:11-21. 3. Shah KB, et al. J Am Coll Cardiol. 2005;46(5):845-849. 4. Bozkurt B, et al. J Am Coll Cardiol. 2003;41(2):211-214.
MRA-Eligible HF Patients Are Undertreated: Get With the Guidelines HF Registry Among 12,565 patients eligible for aldosterone antagonist therapy, 4,087 (32.5%) received an aldosterone antagonist at discharge; there was a modest increase in treatment from 28% to 34% during the study period 100 Aldosterone Antagonist Prescriptions (%) 80 60 40 20 0 1-2 2005 3-4 1-2 2006 Quarter 3-4 1-2 2007 3-4 No. of patients 1,098 1,965 2,613 2,727 2,593 1,569 Albert NM, et al. JAMA. 2009;302(15):1658-1665.
Long-Term Hyperkalemia Management Strategies Strategy Limitation Dietary K + restriction of 40-60 mmol/day Potassium is common ingredient in many foods Restricts consumption of healthy foods Low K + diet often expensive RAASi reduction Limiting the prescription of drugs known to be effective in these populations Kayexalate Warnings related to serious gastrointestinal (GI) adverse events Precaution related to sodium
KAYEXALATE (Sodium Polystyrene Sulfonate) Is Not the Answer Can cause colonic necrosis (particularly when used with sorbitol). Should not be used in patients who do not have normal bowel function or in patients who are at risk of developing constipation or impaction. Administration presents patient with obligatory salt and water load (e.g. each g of SPS contains 100 mg of Na+ and the average daily dose of SPS is 15-60 g/day FDA: Food and Drug Administration References: http://www.fda.gov/safety/medwatch/safetyinformation/ucm186845.htm accessed 12/10/2014 Kayexalate PI December 2010. Sterns 2010; J Am Soc Nephrol 21: 733 735, 2010.; Kayexalate is a registered trademark of Sanofi Aventis
Patiromer (VELTASSA) Oral Suspension Patiromer Electron Microscopy Image Free-flowing powder of small, spherical beads (~100 µm) 1 Active moiety, patiromer, is nonabsorbed 1,2 Calcium (rather than sodium) is exchanged for potassium 1,2 Site of action is the gastrointestinal tract, mainly in the lumen of the colon where 1 - K + is the most abundant cation - Residence time of the polymer is the longest 1. Bushinsky DA, et al. Poster presented at: ASN Kidney Week 2014; Philadelphia, PA; November 11-16, 2014; Poster SA-PO153. 2. Weir MR, et al. N Engl J Med. 2015;372(3):211-221.
OPAL-HK Part A: 4-week Treatment Phase (Single-Blind) Subjects with CKD* on RAASi (n=243) Baseline Part A Starting Patiromer Dose 8.4g per day (total daily dose) (n=92) Baseline serum K + 5.1-<5.5 meq/l (Mild Hyperkalemia) 16.8g per day (total daily dose) (n=151) Baseline serum K + 5.5-<6.5 meq/l (Moderate/Severe Hyperkalemia) Primary endpoint: Mean change in serum potassium from Baseline to Week 4 Secondary endpoint: Proportion of patients with serum potassium level of 3.8 meq/l to < 5.1 meq/l at Week 4 Week 4 Part A All patients were on stable dose of at least one RAAS inhibiting agents *estimated glomerular filtration rate 15-60 ml/min/1.73m 2 dose titrated as needed to maintain target serum K+ 3.8 meq/l to < 5.1 meq/l 1. VELTASSA [package insert]. Redwood City, CA. Relypsa, Inc. 2015. 2. Weir M, et al. N Engl J Med. 2015;372(3):211-21.
OPAL-HK Study Part A: Efficacy Results Primary Endpoint: Patiromer Starting Dose Baseline K + [Mean (SD)]: 5.31 meq/l (0.57) 5.74 meq/l (0.40) (n=90) (n=147) Overall Population* 5.58 meq/l (0.51) (n=237) Mild HK Moderate/Severe HK Total Change in Serum Potassium (meq/l) 0-0.2-0.4-0.6-0.8-1 -0.65 (95% CI -0.74, -0.55) -1.01 Secondary Efficacy Endpoint: 76% of subjects had serum K + in the target range (3.8 to <5.1 meq/l) at week 4-1.2-1.4-1.23 (95% CI -1.31, -1.16) (95% CI -1.07, -0.95) Weir M, et al. N Engl J Med. 2015;372(3):211-221.
OPAL-HK: Primary and Secondary Efficacy Endpoints Mean Serum K + (meq/l) Study included 243 patients with CKD who were taking a RAAS blocker Secondary Efficacy Endpoint: 76% of subjects had serum K + in the target range (3.8 to <5.1 meq/l) at week 4 Base-line Weir MR, et al. N Engl J Med. 2015;372(3):211-221.
Phase 3 Part B: Exploratory Endpoints 100% P<0.001* P<0.001* Proportion of Subjects (%) 80% 60% 40% 20% 0% 16% Requiring any adjustment of RAASi (ie, down-titration or discontinuation) or patiromer dose increase due to hyperkalemia at any time during Part B 44% 94% Receiving any dose of a RAASi at the end of Part B Placebo Patiromer Weir MR, et al. N Engl J Med. 2015;372(3):211-221.
Mean Change in Serum Potassium Mean (95% CI) Serum Potassium (meq/l) Over 1 Year (AMETHYST-DN) Mean (95% CI) Serum Potassium over 52 weeks N= 301 (start of study) Study Visit (week) Baseline Serum K + 5.0 5.5 meq/l Baseline Serum K + 5.5 6.0 meq/l BL 2 4 6 8 12 16 20 24 28 32 36 40 44 48 52 14 28 Follow-Up (day) N= 173 (study end) Bakris GL, et al. JAMA 2015;314(2):151-161.
Patiromer: Adverse Reactions The most common adverse reactions (incidence 2%) are: Constipation (7.2%) Hypomagnesemia (5.3%) Diarrhea (4.8%) Nausea (2.3%) Abdominal discomfort (2.0%) Flatulence (2.0%) Mild to moderate hypersensitivity reactions were reported in 0.3% of patients treated with patiromer and included edema of the lips
Patiromer: Dosing and Administration Summary Dosing: Dose Titration: 8.4 grams of patiromer once daily (recommended starting dose) Administer at least 3 hours before or after other oral meds Monitor serum potassium and increase or decrease dose as necessary Up-titrate based on serum potassium level at 1-week or longer intervals, in increments of 8.4 grams. Maximum dose of 25.2 grams once daily Administration: Storage: Taken as oral suspension once a day with food Do not heat, add to heated foods or liquids or take in its dry form Store in the refrigerator at 2 C to 8 C (36 F to 46 F)* Use within 3 months if stored at room temperature (25 C ± 2 C [77 F ± 4 F])*
ZS-9: A Novel First-in-Class Inorganic Crystalline Compound Designed Specifically to Trap K + Adapted from: Stavros F, et al. PLoS One. 2014;9(12):e114686.
In Vitro, ZS-9 is More Selective for Potassium than Kayexalate (SPS) Adapted from: Stravos et al. PLOSONE 2014
Effect of Sodium Zirconium Cyclosilicate on K+ in Hyperkalemic Patients Kosiborod M, et al. JAMA. 2014;312(21):2223-2233.
Mean Serum Potassium Levels Over 48 Hours With ZS-9 Serum Potassium Levels During the Open-Label Phase (48 Hours)A, Mean serum potassium levels over time in patients treated during the open-label phase with zirconium cyclosilicate, 10 g, 3 times daily for 48 hours. B, Mean serum potassium levels at 0 and 48 hours across prespecified subgroups of chronic kidney disease (CKD) (by patient history and by estimated glomerular filtration rate [egfr] <60 ml/min/1.73 m 2 ), heart failure, diabetes mellitus, concomitant renin-angiotensin-aldosterone system inhibitor (RAASi) use, and baseline potassium levels. Error bars indicate 95% confidence intervals; shaded region, normal potassium range. 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.
Dose-Dependent Serum K+ Reduction Over 48 Hours in HF Patients on RAASi Source: El-Shahawy M, et al. Oral Presentation During a Late-Breaking Clinical Trial Session at the Heart Failure Society of America (HFSA) 18th Annual Scientific Meeting, Sep 15, 2014,
New Therapies For Hyperkalemia Hyperkalemia is common in patients with HF, CKD and/or diabetes. High levels of potassium may lead to dose reduction or discontinuation of RAAS inhibitors. There are problems with current treatments for hyperkalemia. New agents that are safe and effective to treat hyperkalemia are (patiromer) or will be (ZS-9) available. Use of these new agents are likely to become important adjuncts to heart failure therapy.