Therapeutic challenges: Treatment of Hyperkalemia Matthieu Legrand - PowerPoint PPT Presentation

Therapeutic challenges: Treatment of Hyperkalemia Matthieu Legrand MD, PhD Matthieu.legrand@ucsf.edu Department of Anesthesioloy, Peri-operative Care and Critical Care University of California, San Francisco INI-CRCT network

COI/financial support • French ministry of health • Lecture fees Baxter & Fresenius • Consulting fees Novartis • Research support (biomarkers dosages) from Sphingotec

Conclusions • Patiromer and ZS9: – Allow maintenance on RASSi – Consistent results in controlling sK – Data lacking in acute settings even if rapid decrease in sK+ suggested • RRT – Medical treatment first – Diffusion and convection have different impact on extra corporal K + flux

Aronson et al , J Am Soc Nephrol 22: 1981–1989, 2011

Dépret, F. et al, Ann. Intensive Care 9, 32 (2019)

TREATMENT OF HYPERKALEMIA Patiromer (FDA approved in 2015, EMA approved in July 2017) Sodium zirconium cyclosilicate (SZC) (EMA approved April 2018and FDA approved May 2018)

RAASi enablement by patiromer in initially hyperkalaemic or normokalaemic patients at risk to develop hyperkalaemia • OPAL-HK • PEARL-HF • AMBER • DIAMOND: ongoing CV outcome trial

Properties of patiromer Electron microscopy image 2 Patiromer • Organic potassium binder 1 • Orally administered 1 • Non-absorbed 1 • Calcium-exchange polymer that binds potassium and increases potassium excretion 1 1. Buysse J et al . Future Cardiol 2012;8:17–28; 2. Cope J et al . Presented at : American Society of Nephrology Renal Week; Denver, CO; Nov 16–21, 2010. Poster F-PO1616

Patiromer K+ Ca² + Patiromer Patiromer Patiromer

Patiromer Ca² + K+ Ca² + Patiromer Patiromer Patiromer

Patiromer Ca² + K+ Ca² + K+ Patiromer Patiromer Patiromer

OPAL-HK: Phase III, 2-part, single-blind withdrawal study Part A: Treatment phase Part B: Randomized withdrawal phase Serum K + 5.1–<5.5 mEq/L: patiromer 4.2 g BID Patients with (n=92) CKD* on Patiromer † RAASi Serum K + 3.8–<5.1 mEq/L continued RAASi • Serum K + 5.5–<6.5 mEq/L: (n=243) (n=55) Still on patiromer • R patiromer 8.4 g BID Still on RAASi • Placebo (n=151) (n=107) continued RAASi (n=52) Week 4 Week 4 Week 8 Part A Part B Part B primary primary secondary endpoint endpoint endpoints 1. Weir MR et al . N Engl J Med 2015;372:211–21; 2. *eGFR 15 to <60 mL/min/m 2 ; † Dose adjusted as needed by treating physician

OPAL-HK (Part A): Primary and secondary efficacy endpoints Primary efficacy endpoint Secondary efficacy endpoint Change from baseline in serum K+ (mEq/L) 6.0 Mild HK Moderate/severe HK Overall 0.0 5.8 Overall Mild HK Moderate/ 76% of patients had serum –0.2 –1.01 5.6 –0.65 severe HK potassium in the target Mean serum K + (mEq/L) (95% CI: (95% CI: –1.23 range –0.4 –1.07, –0.95) 5.4 –0.74, –0.55) (95% CI: (3.8–<5.1 mmol/L) at –1.31, –1.16) –0.6 5.2 week 4 5.0 –0.8 4.8 –1.0 Day 3 P <0.001 4.6 –1.2 4.4 –1.4 4.2 4.0 Baseline Week 2 Week 4 Weir MR et al . N Engl J Med 2015;372:211–21

OPAL-HK (Part B): Exploratory endpoints – statistically significant results P <0.001 100 Placebo Patiromer 94 Proportion of patients (%) 80 P <0.001 60 62 40 44 20 16 0 Any RAASi dose † RAASi dose adjustment/ patiromer increase * Weir MR et al . N Engl J Med 2015;372:211–21 *Requiring any adjustment of RAASi (ie down-titration or discontinuation) or patiromer dose increase due to hyperkalaemia at any time during Part B; † Receiving any dose of a RAASi at the end of Part B

OPAL-HK: Most common AEs Part A: Initial treatment phase* Part B: Randomized withdrawal phase* Patiromer Placebo Patiromer AEs, n (%) AEs, n (%) (n=243) (n=52) (n=55) Any 114 (47) Any 26 (50) 26 (47) Constipation 26 (11) Headache 4 (8) 2 (4) Diarrhoea 8 (3) Supraventricular 1 (2) 2 (4) extrasystoles Hypomagnesaemia 8 (3) Constipation 0 2 (4) Nausea 8 (3) Diarrhoea 0 2 (4) Anaemia 7 (3) Nausea 0 2 (4) Chronic renal failure 7 (3) Serious AEs † 3 (1) Serious AEs † 1 (2) 0 Events are listed if they occurred in at least 3% of patients Events are listed if they occurred in at least 4% of patients in the patiromer group During the initial treatment phase and through its follow-up period, the incidence of hypokalaemia (serum potassium level <3.5 mmol/L) was 3.0%; *Including safety follow-up period for that Weir MR et al . N Engl J Med 2015;372:211–21 phase, which was 1–2 weeks after discontinuation of the study drug; † All SAEs are included; none were considered related to the study drug. SAE, serious adverse events

PEARL-HF: Phase II, double-blind study in HF patients at high risk for HK and initiating spironolactone Chronic HF, aged ≥18 years, clinically indicated to receive spironolactone and serum potassium >4.3–5.1 mEq/L, and either of: • CKD (eGFR <60 mL/min) and on ≥1 RAASi (ACEi, ARB) or β-blocker • Documented hyperkalaemia that led to discontinuation of RAASi or β-blocker within 6 months (n=120) R Spironolactone 25 mg QD Patiromer Placebo 25.2 g/day* Day 15 n=49 n=56 Spironolactone 50 mg QD if serum K+ >3.5 to ≤5.1 mEq/L Day 28 *No patiromer dose titration Pitt B et al . Eur Heart J 2011;32(7):820–8

PEARL-HF: Primary endpoint Spironolactone Spironolactone increased initiated at 25 mg QD to 50 mg QD on day 15 if serum K + on day 1 ≤5.1 Placebo Patiromer 5.1 LS mean serum K + 4.9 (mEq/L) 4.7 4.5 P <0.01* P <0.001* P <0.001* P <0.001* 4.3 P <0.001* P <0.001* 4.1 3 17 0 7 14 21 28 Day *versus placebo Pitt B et al . Eur Heart J 2011;32(7):820–8 LS, least squares

PEARL-HF: Up-titration of spironolactone Patients able to titrate up spironolactone dose to 50 mg daily Placebo Patiromer P -value (n=49) (n=55) Total, n (%) 36 (74) 50 (91) 0.019 Pitt B et al . Eur Heart J 2011;32(7):820–8

Lancet. 2019 At week 12, 98 (66%) of 148 patients in the placebo group and 126 (86%) of 147 patients in the patiromer group remained on spironolactone (between-group difference 19·5%, 95% CI 10·0-29·0; p<0·0001)

Patiromer for the Management of Hyperkalemia in Subjects Receiving RAASi Medications for the Treatment of Heart Failure (DIAMOND) • Design Multinational, multicentre (2388 participants) – Double-blind, placebo-controlled, randomised withdrawal, parallel group study – Run-in phase (maximum 12 weeks) followed by treatment phase (at least 6 months per subject) – Patiromer 1 packet/day with possible dose adjustments (from 0 up to 3 packets/day) versus placebo – Run-in Phase Treatment phase (double blinded) (single blinded, up to 12 weeks) Patiromer continued sK + >5.0 mEq/L Initiate patiromer • • Optimize ACEi/ARB/A RNi • On RAASi • Initiate/optimize MRA • R sK + ≤5.0 mEq/L • • Initiate patiromer History of hyperkalaemia in • • Optimize ACEi/ARB/A RNi the past 12 months leading • Initiate/optimize MRA to reduction of discoinuat ion Placebo (withdraw patiromer) of RAASi EoS visit Day 1/ Day 3 Week 1 Week 2 Week 6 Week 18 Subjects must also meet the following Event driven Baseline criteria at Screening: Every 3-month visits HFrEF (LVEF <40%) • eGRF ≥30 mL/min/1.73 m² • Hospitalization for HF (or equivalent) • Potassium assessment visit (within 2 weeks of within 12 months patiromer/placebo discontinuation) and/or Primary outcome • Follow-up phone call (at least 2 weeks after the Eos visit) – Time to first occurrence of CV death or CV hospitalization ClinicalTrials.gov identifier: NCT03888066

Properties of ZS-9 Structure of ZS-9 2 ZS-9 • Inorganic potassium binder 1 • Orally administered 1 • Non-absorbed 1 • Sodium-based potassium- selective cation-exchange polymer in the gastrointestinal tract 1 Oxygen atoms Zirconium atoms Silicon atoms 1. Ash SR et al. Kidney Int 2015;88:404–11; 2. Stavros F et al. PLoS One 2014;9:e114686 ZS-9, sodium zirconium cyclosilicate

ZS-9, sodium zirconium cyclosilicate K + Duodenum Jejunum Ileum Colon/Rectum Exit

ZS-9, sodium zirconium cyclosilicate Duodenum Jejunum Ileum Colon/Rectum Exit

ZS-9, sodium zirconium cyclosilicate Duodenum Jejunum Ileum Colon/Rectum Exit

ZS-9, sodium zirconium cyclosilicate Duodenum Jejunum Ileum Colon/Rectum Exit

Packham DK et al . N Engl J Med 2015;372:222–31 ZS-9: ZS-003 Phase III study

Initiation phase At 48 hours, there were absolute mean reductions of - 0.46 mmol per liter (95% confidence interval [CI], − 0.53 to − 0.39) in the 2.5-g group, - 0.54 mmol per liter (95% CI, − 0.62 to − 0.47) in the 5-g group, - 0.73 mmol per liter (95% CI, − 0.82 to − 0.65) in the 10-g group, -0.25 mmol per liter (95% CI, − 0.32 to − 0.19) in the placebo group (P<0.001 for all comparisons). Packham DK et al . N Engl J Med 2015;372:222–31

Initiation phase The mean reduction from baseline at 1 hour after the first 10-g dose of ZS-9 was 0.11 mmol per liter (95% CI, − 0.17 to − 0.05), as compared with an increase of 0.01 mmol per liter (95% CI, − 0.05 to 0.07) in the placebo group (P=0.009) Packham DK et al . N Engl J Med 2015;372:222–31

ZS-9: ZS-003 Phase III study Potassium levels during the maintenance phase Packham DK et al . N Engl J Med 2015;372:222–31