New Agents for Treating Hyperkalemia - Can They Help Us Improve Outcomes in HF?

Transcription

1 New Agents for Treating Hyperkalemia - Can They Help Us Improve Outcomes in HF? 19 th Annual San Diego Heart Failure Symposium for Primary Care Physicians January 11-12, 2019 La Jolla, CA Barry Greenberg M.D. Distinguished Professor of Medicine Director, Advanced Heart Failure Treatement Program University of California, San Diego La Jolla, CA

2 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

3 Trials With Mineralicorticoid Receptor Antagonists Primary Endpoint: All-Cause Mortality Trial Placebo Aldosterone Hazard Log-rank Antagonist Ratio P Value EPHESUS Post-MI RALES Advanced HF 554/3, /3, (.75,.96) / / <.001 (.60,.82) EMPHASIS Milder HF 356/ / (.62,.93).008 Pitt B. N Engl J Med. 2003;348: Pitt B. N Engl J Med. 1999;341: Zannad F, et al. N Engl J Med. 2011;364:11-21

4 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) Online release of RALES Study year Online release of RALES Study year Adapted from: Juurlink DN, et al. N Engl J Med. 2004;351:

5 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 Clinical trials Real-world 12 % of Patients RALES EMPHASIS Shah 2005 Bozkurt N=822 N=1,336 N=840 N= Pitt B, Zannad F, Remme WJ, et al. N Engl J Med. 1999;341(10): Zannad F. N Engl J Med. 2011;364: Shah KB, et al. J Am Coll Cardiol. 2005;46(5): Bozkurt B, et al. J Am Coll Cardiol. 2003;41(2):

6 Use of GDMT in HFrEF Results of the CHAMP-HF Registry

7 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

8 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 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:

9 Admitted 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) Discharged without MRA (n=164) Fulfilled Criteria for MRA Use (n=271) Only 105 of 271 (39%) Eligible Patients Were Taking an MRA on Admission MRA at Hospital Discharge (n=61) No MRA on Admission (n=210) 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)

10 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) All-Cause Hospitalizations p = Cardiovascular Hospitalizations p = (-) OFF MRA (n = 35) 2 or more discontinuations 1 discontinuation without restart and tx duration < 180 days (6 months) Heart Failure Hospitalizations p = (+) ON MRA (-) OFF MRA Episodes of Hyperkalemia/Patient p = Percent Survival (%) Survival p < Days (+) ON MRA (-) OFF MRA

11 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) All-Cause Hospitalizations (-) OFF MRA (n = 35) 2 or more discontinuations 1 discontinuation without restart and tx duration < 180 days (6 months) Stopping an MRA is associated with worse outcomes 10 8 p including = increased p = mortality Cardiovascular Hospitalizations Heart Failure Hospitalizations p = (+) ON MRA (-) OFF MRA Episodes of Hyperkalemia/Patient p = Percent Survival (%) p < 0.02 Survival Days (+) ON MRA (-) OFF MRA

12 Association Between Renal Function and Hyperkalemia in HF Patients Shah KB et al, JCF Volume 46, Issue 5, 2005,

13 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

14 Long-Term Hyperkalemia Management Strategies Strategy Limitation Dietary K + restriction of 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

15 Low K+ Diet Is the First Step in Chronic Management, but Compliance Is Difficult PotassiumRich Foods

16 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 g/day. FDA: Food and Drug Administration References: accessed 12/10/2014 Kayexalate PI December Sterns 2010; J Am Soc Nephrol 21: , 2010.; Kayexalate is a registered trademark of Sanofi Aventis

17 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 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

18 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)

19 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.

20 New Drugs for Hyperkalemia Patiromer ZS-9 Ca 2+ Gut Lumen K+ Na + Colon Upper/Lower GI

21 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 fold Onset of [K]p lowering 7 hours 2 hours

22 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 <5.5 meq/l (Mild Hyperkalemia) 16.8g per day (total daily dose) (n=151) Baseline serum K <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 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 Weir M, et al. N Engl J Med. 2015;372(3):

23 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) (95% CI -0.74, -0.55) (95% CI -1.31, -1.16) (95% CI -1.07, -0.95) Weir M, et al. N Engl J Med. 2015;372(3):

24 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):

25 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):

26 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 meq/l Baseline Serum K meq/l BL Follow-Up (day) N= 173 (study end) Bakris GL, et al. JAMA 2015;314(2):

27 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

28 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):e

29 In Vitro, ZS-9 is More Selective for Potassium than Kayexalate (SPS) Adapted from: Stravos et al. PLOSONE 2014

30 ZS-9 Lowers K + in Hyperkalemic Patients Kosiborod M, et al. JAMA. 2014;312(21):

31 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):

32 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,

33 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.