Managing the Yin and Yang of Hyperkalemia and MRAs in Heart Failure Barry Greenberg M.D. Distinguished Professor of Medicine Director, Advanced Heart Failure Treatement Program University of California, San Diego La Jolla, CA
ACC/AHA Guideline Recommendations for Treating Stage C HFrEF HFrEF Stage C NYHA Class I IV Treatment: Class I, LOE A ACEI or ARB AND Beta Blocker For all volume overload, NYHA class II-IV patients For persistently symptomatic African Americans, NYHA class III-IV For NYHA class II-IV patients. Provided estimated creatinine >30 ml/min and K+ <5.0 meq/dl Add Add Add Class I, LOE C Loop Diuretics Class I, LOE A Hydral-Nitrates Class I, LOE A Aldosterone Antagonist Yancy C et al, Circulation 2013
PARADIGM-HF: Primary Endpoint of CV Death or HF Hospitalization Cumulative Probability 1.0 0.6 0.5 0.4 0.3 0.2 0.1 Number needed to treat = 21 HR 0.80 (95% CI, 0.73 0.87), p<0.001 Enalapril 1117 events (26.5%) Sac/Val 914 events (21.8%) 20% Number at Risk Sac/Val Enalapril 0 0 180 360 540 720 900 1080 Days since Randomization 4187 4212 3922 3883 3663 3579 3018 2922 2257 2123 1544 1488 896 853 1260 249 236 Sac/Val = Sacubitril/Valsartan; HR = hazard ratio. McMurray JJV, et al. N Engl J Med. 2014;371:993-1004.
Effect of Combined Neurohormonal Agents on Survival in HF Heather Burnett et al. Circ Heart Fail. 2017;10:e003529
Use of GDMT in HFrEF Results of the CHAMP-HF Registry
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.
Trials With Aldosterone Antagonist Primary Endpoint: All-Cause Mortality Trial Placebo Aldosterone Hazard Log-rank Antagonist Ratio P Value EPHESUS Post-MI RALES Advanced HF 554/3,319 478/3,313.85 (.75,.96).008 386/841 284/822.70 <.001 (.60,.82) EMPHASIS Milder HF 356/1373 249/1364.76 (.62,.93).008 Pitt B. N Engl J Med. 2003;348:1309-1321. Pitt B. N Engl J Med. 1999;341:709-717. Zannad F, et al. N Engl J Med. 2011;364:11-21
Hyperkalemia and the RALES Study Publication of RALES sparked an increase in prescriptions for spironolactone Also a parallel increase in hospital admissions and death from hyperkalemia Spironolactone prescription rate (per 1000 patients) Rate of admission for hyperkalemia (per 1000 patients) 160 140 120 100 80 60 40 20 0 12 10 8 6 4 2 0 Online release of RALES 1994 1996 1998 1999 2000 2001 Study year Online release of RALES 1994 1996 1998 1999 2000 2001 Study year Adapted from: Juurlink DN, et al. N Engl J Med. 2004;351:543-551.
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.
Hyperkalemia Was Common in PARADIGM-HF Patients Excluded Due to Elevated K + Levels During Run-in Period Veils Number of Patients with Elevated K + Due to Treatment McMurray et al., NEJM. 2014.
Hyperkalemia Is a Major Reason for MRA Discontinuation 134 HF patients followed in a Portuguese HF clinic Spironolactone use in patients with scr 2.5 mg/dl and K + 5 meq/l 25% of patients withdrew from spironolactone therapy (19/76) 30 Reason for spironolactone suspension (%) Hyperkalemia Renal function decline Gynecomastia Other % of Patients 20 10 17.1 0 Discontinuation DC of MRA of MRA *Severe hyperkalemia ( 6 meq/l) occurred in 7 patients who withdrew from spironolactone therapy (9.2%). Lopes RJ, et al. Clin Cardiol. 2008; 31:509-513.
Admitted 2011-2013 with Worsening of Chronic HF (n=1250) <1 Year Follow Up (n=806) >1 year Follow-Up (n=444) Not Candidates for MRA Based on Inclusion/ Exclusion Criteria (n=173) Fulfilled Criteria for MRA Use (n=271) No MRA on Admission (n=210) MRA on Admission (n=61) Discharged without MRA (n=164) MRA Initiated at DC (n=46) MRA Maintained during Hospitalization (n=59) MRA Discontinued (n=2) Receiving an MRA at Time of Hospital Discharge (n=105)
A (+) ON MRA (n=70) DC with MRA (n=105) (-) OFF MRA (n=35) (+) ON MRA (n = 70) MRA Tx to discharge, LVAD or OHT Without interruption With 1 or fewer drug discontinuations and tolerated therapy for > 180 days (6 months) 15 10 5 0 All-Cause Hospitalizations p = 0.0010 + - 10 8 6 4 2 0 Cardiovascular Hospitalizations p = 0.0032 + - (-) OFF MRA (n = 35) 2 or more discontinuations 1 discontinuation without restart and tx duration < 180 days (6 months) 8 6 4 2 0 Heart Failure Hospitalizations p = 0.0019 + - (+) ON MRA (-) OFF MRA Episodes of Hyperkalemia/Patient 2.5 2.0 1.5 1.0 0.5 0.0 p = 0.0006 + - Percent Survival (%) 100 50 Survival p < 0.02 0 0 500 1000 1500 2000 Days (+) ON MRA (-) OFF MRA
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% 0% 12.7% Control 23.5% CKD Stage 3a 33.0% CKD Stage 3b 47.7% 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).
Association Between Renal Function and Hyperkalemia in HF Patients Shah KB et al, Volume 46, Issue 5, 2005, 845 849
Serum Potassium Levels and Outcome in Acute Heart Failure (Data from the PROTECT Trial) Tromp J et al. JACC: 119; 290-296, 2017
Changes in RAAS Inhibitor Dose In Response to Hyperkalemia Among Patients on RAAS Inhibitor at Maximum Dose Percent of Hyperkalemia Events 75% 60% 45% 30% 15% 0% Maintained Dose Down-titrated Dose Discontinued 52% 38% 22% 16% Mild Hyperkalemia (Potassium 5.1-5.4 meq/l) 41% (23,556 events) (11,608 events) 47% 26% 21% Moderate-to-Severe Hyperkalemia Epstein M et al. Am J Manag Care. 2015;21:S212-S220
Percent Mortality by Prior RAAS Inhibitor Dose Epstein M et al. Am J Manag Care. 2015;21:S212-S220 40% Maximum Dose Submaximum Dose Discontinued 30% 30.1% 27. % Patients 20% 10% 9.8% 22.4% 20. 13.7% 13.1% 11.0% 10. 8.2% 5.0% 4.1% 0% CKD Stages 3-4 (N = 43,288 total patients across dose categories) Heart Failure (N = 20,529 total patients across dose categories) Diabetes (N = 79,087 total patients across dose categories) Total Population (N = 201,655 total patients across dose categories)
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.
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]) Modified from Palmer BF. N Engl J Med. 2004;351(6):585-59
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.
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 Kayexalate RAASi reduction Warnings related to serious gastrointestinal (GI) adverse events Precaution related to sodium Limiting the prescription of drugs known to be effective in these populations
Low K+ Diet Is the First Step in Chronic Management, but Compliance Is Difficult PotassiumRich Foods
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
Hyperkalemia in Heart Failure Unmet need for a safe and effective chronic therapy for prevention and treatment of hyperkalemia in HF patients on ACE-I, ARBs, MRA, and ARNI therapies.
New Drugs for Hyperkalemia Patiromer ZS-9 Ca 2+ Gut Lumen K+ Na + Colon Upper/Lower GI
Characteristics of New Potassium Binding Agents Characteristic Patiromer Zirconium Cyclosilicate (ZS-9) GI Absorption Non-absorbable Non-absorbable Molecular structure Organic polymer crystalline inorganic cation exchange compound Mechanism of Action Ca-K exchange Na-K exchange Relative K Affinity - 25-fold > Na Site of Action Colon Upper/Lower GI tract K selectivity relative to SPSS - 120-fold Onset of [K]p lowering 7 hours 2 hours
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 Overall Population* Baseline K + [Mean (SD)]: 5.31 meq/l (0.57) (n=90) 5.74 meq/l (0.40) (n=147) 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) -1.01-1.2-1.4-1.23 (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.
Effect of Discontinuing Patiromer Median Change in Serum K + (meq/l) 1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0.0 + 0.72 meq/l Placebo (n=52) = 0.72 meq/l p < 0.001 0.0 meq/l VELTASSA (n=55) 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% 62% 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
ZS-9 Lowers 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. Current treatments for hyperkalemia have limitations. Both patiromer and ZS-9 are newly available agents that are safe and effective to treat hyperkalemia. Use of these new agents are likely to become important adjuncts to heart failure therapy.