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
Matthieu.legrand@ucsf.edu
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)
that binds potassium and increases potassium excretion1
Patiromer Electron microscopy image2
*eGFR 15 to <60 mL/min/m2;
†Dose adjusted as needed by treating physician1.Weir MR et al. N Engl J Med 2015;372:211–21; 2.
Part B: Randomized withdrawal phase
(n=107)
Part A: Treatment phase
Week 4 Part B primary endpoint
Patients with CKD* on RAASi (n=243)
Week 8 Part B secondary endpoints
Patiromer† continued RAASi (n=55) Placebo continued RAASi (n=52) Serum K+ 5.5–<6.5 mEq/L: patiromer 8.4 g BID (n=151) Serum K+ 5.1–<5.5 mEq/L: patiromer 4.2 g BID (n=92)
R
Week 4 Part A primary endpoint
Overall –1.01
(95% CI: –1.07, –0.95)
P<0.001
Weir MR et al. N Engl J Med 2015;372:211–21
4.0 4.2 4.4 4.6 4.8 5.0 5.2 5.4 5.6 5.8 6.0 Mean serum K+ (mEq/L)
Mild HK Moderate/severe HK Overall
Baseline Week 4 Week 2
Secondary efficacy endpoint
Change from baseline in serum K+ (mEq/L)
Primary efficacy endpoint
–1.4 –1.0 –0.4 –0.2 –1.2 0.0 –0.8 –0.6
Mild HK –0.65
(95% CI: –0.74, –0.55)
Moderate/ severe HK –1.23
(95% CI: –1.31, –1.16)
76% of patients had serum potassium in the target range (3.8–<5.1 mmol/L) at week 4
Day 3
*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
Weir MR et al. N Engl J Med 2015;372:211–21
62 44 16 94 20 40 60 80 100 Placebo Patiromer
RAASi dose adjustment/ patiromer increase* Any RAASi dose† Proportion of patients (%)
P<0.001 P<0.001
AEs, n (%) Patiromer (n=243) Any 114 (47) Constipation 26 (11) Diarrhoea 8 (3) Hypomagnesaemia 8 (3) Nausea 8 (3) Anaemia 7 (3) Chronic renal failure 7 (3) Serious AEs† 3 (1)
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 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
Weir MR et al. N Engl J Med 2015;372:211–21
Part A: Initial treatment phase*
Events are listed if they occurred in at least 3% of patients
Part B: Randomized withdrawal phase*
Events are listed if they occurred in at least 4% of patients in the patiromer group
AEs, n (%) Placebo (n=52) Patiromer (n=55) Any 26 (50) 26 (47) Headache 4 (8) 2 (4) Supraventricular extrasystoles 1 (2) 2 (4) Constipation 2 (4) Diarrhoea 2 (4) Nausea 2 (4) Serious AEs† 1 (2)
Day 15 Day 28
*No patiromer dose titration
Pitt B et al. Eur Heart J 2011;32(7):820–8
Spironolactone 50 mg QD if serum K+ >3.5 to ≤5.1 mEq/L Spironolactone 25 mg QD Placebo n=49 Patiromer 25.2 g/day* n=56
R
Chronic HF, aged ≥18 years, clinically indicated to receive spironolactone and serum potassium >4.3–5.1 mEq/L, and either of:
(n=120)
*versus placebo LS, least squares
Pitt B et al. Eur Heart J 2011;32(7):820–8
14
P<0.01*
Patiromer
Spironolactone increased to 50 mg QD on day 15 if serum K+ ≤5.1 Spironolactone initiated at 25 mg QD
3 LS mean serum K+ (mEq/L) Day 4.1 4.3 4.5 4.7 4.9 5.1 7 21 28 Placebo
P<0.001* P<0.001*P<0.001* P<0.001* P<0.001*
17
Pitt B et al. Eur Heart J 2011;32(7):820–8
Placebo (n=49) Patiromer (n=55) P-value Total, n (%) 36 (74) 50 (91) 0.019
Patients able to titrate up spironolactone dose to 50 mg daily
– 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 Placebo (withdraw patiromer) Patiromer continued
Treatment phase (double blinded)
Run-in Phase (single blinded, up to 12 weeks)
RNi
RNi
R
the past 12 months leading to reduction of discoinuat ion
Subjects must also meet the following criteria at Screening:
within 12 months
Day 1/ Baseline Day 3 Week 1 Week 2 Week 6 Week 18 Every 3-month visits EoS visit Event driven
Potassium assessment visit (within 2 weeks of patiromer/placebo discontinuation) and/or Follow-up phone call (at least 2 weeks after the Eos visit)
ClinicalTrials.gov identifier: NCT03888066
– Time to first occurrence of CV death or CV hospitalization
ZS-9, sodium zirconium cyclosilicate
selective cation-exchange polymer in the gastrointestinal tract1
ZS-9 Structure of ZS-92
Oxygen atoms Zirconium atoms Silicon atoms
Duodenum Jejunum Ileum Colon/Rectum Exit
K+
Duodenum Jejunum Ileum Colon/Rectum Exit
Duodenum Jejunum Ileum Colon/Rectum Exit
Duodenum Jejunum Ileum Colon/Rectum Exit
Packham DK et al. N Engl J Med 2015;372:222–31
Packham DK et al. N Engl J Med 2015;372:222–31
Packham DK et al. N Engl J Med 2015;372:222–31
Packham DK et al. N Engl J Med 2015;372:222–31
Potassium levels during the maintenance phase
QD, once daily; R, randomization; TID, three times daily
Days 3–30
ZS-9 15 g QD (n=56) Placebo QD (n=85) ZS-9 5 g QD (n=45) ZS-9 10 g QD (n=51)
Days 1–2
Open-label phase: ZS-9 10 g TID (n=258) Screening: K+ ≥5.1 Achieved K+ 3.5–5.0
Up to 11 months
Open-label extension: ZS-9 10 g QD (n=123)
Kosiborod M et al JAMA 2015;312:2223–33
Kosiborod M et al JAMA 2015;312:2223–33
Placebo ZS-9 10 g QD ZS-9 5 g QD ZS-9 15 g QD
Mean serum K+ (mEq/L)
4.0 4.2 4.6 5.0 5.2 4.4 5.4 4.8 1
Study day
3 5 7 9 11 13 15 17 19 21 23 25 27 29 Number of patients: Placebo ZS-9 5 g QD ZS-9 10 g QD ZS-9 15 g QD 82 45 50 54 81 45 49 54 81 45 50 54 80 44 47 53 80 44 47 52 78 43 47 51 77 43 45 51 74 42 45 51 73 39 38 43
*Occurring in ≥5% of patients in any group AEs, adverse events; URTI, upper respiratory tract infection
Kosiborod M et al JAMA 2015;312:2223–33
AEs* during the randomized phase, n (%) Placebo (n=85) ZS-9 5 g QD (n=45) ZS-9 10 g QD (n=51) ZS-9 15 g QD (n=56) Any event 27 (32) 24 (53) 15 (29) 25 (45) Anaemia 0 (0) 0 (0) 0 (0) 3 (5) Constipation 6 (7) 0 (0) 1 (2) 1 (2) Oedema 2 (2) 1 (2) 3 (6) 8 (14) Hypokalaemia (all) 0 (0) 0 (0) 5 (10) 6 (11) Hypokalaemia (reported as an AE) 0 (0) 0 (0) 0 (0) 1 (2) Nasopharyngitis 1 (1) 0 (0) 0 (0) 3 (5) URTI 1 (1) 3 (7) 1 (2) 1 (2)
Fishbane al, JASN 30: 1723–1733, 2019.
Rossignol P, EHJ suppl, 2019
Vs Inclusion Exclusion criteria https://clinicaltrials.gov/ct2/show/results/NCT03337477
https://clinicaltrials.gov/ct2/show/results/NCT03337477
Hyperkalemia (K+>5.5 mml/L)
Insulin + glucose i.v. AND Nebulized 𝛄-2 agonist AND/OR
Hypertonic sodium bicarbonate i.v metabolic acidosis - pH≤7.2.
Nebulized 𝛄-2 agonist AND/OR Insulin + glucose i.v. AND
Hypertonic sodium bicarbonate i.v if metabolic acidosis - pH≤7.2.
cell membrane stabilization
Intracellular K+ shift
Discontinue oral and parenteral potassium supplements NO
K-related Changes on ECG?
YES
Exclude pseudohyperkalemia
Ca gluconate IV
Hypertonic sodium*
ESKD?
YES
K+>6.0 mml/L?
NO YES
Potassium binders**
Dépret, F. et al, Ann. Intensive Care 9, 32 (2019)
Hyperkalemia (K+>5.5 mml/L)
NO Insulin + glucose i.v. AND Nebulized 𝛄-2 agonist AND/OR
Hypertonic sodium bicarbonate i.v metabolic acidosis - pH≤7.2.
Nebulized 𝛄-2 agonist AND/OR Insulin + glucose i.v. AND
Hypertonic sodium bicarbonate i.v if metabolic acidosis - pH≤7.2.
YES
cell membrane stabilization
Intracellular K+ shift
K+ excretion/removal
Reconsider treatment leading to hyperkalemia Discontinue oral and parenteral potassium supplements
RRT
NO
K-related Changes on ECG?
YES
NO Exclude pseudohyperkalemia
Ca gluconate IV
Hypertonic sodium*
i.v. loop diuretics#
if no urinary tract obstruction AND Congested patient
NO
Oliguria?
(AKI or CKD)
Check serum K+ level: Decreasing?
ESKD?
NO YES
Follow-up
Treat the cause & optimize hemodynamics and ventilation
YES
Renal response?
YES
K+>6.0 mml/L?
NO YES
Potassium binders**
Dépret, F. et al, Ann. Intensive Care 9, 32 (2019)
Serum potassium concentration of more than 6 mmol/liter Serum potassium concentration of more than 5.5 mmol/liter despite medical treatment pH below 7.15 in a context of pure metabolicacidosis (PaCO2 below35 mmHg) or in a context of mixed acidosis with PaCO2 of 50 mmHg or more without possibilityof increasingalveolar ventilation Acute pulmonary edema due to fluid overload responsible for severe hypoxemia requiringoxygen flow rate of more than 5 l/min to maintain an SpO2 of more than 95% or requiringan FiO2 greater than 50% in patients alreadyon invasive or non-invasive mechanical ventilation and despite diuretic therapy
9 patients (4%) in the delayed-strategy group had severe hyperkalemia (with a median potassium level of 7.0 mmol per liter [interquartile range, 6.7 to 7.3]), whereas no patients in the early- strategy group had hyperkalemia (P=0.03)
De Nicola L et al, J Am Soc Nephrol 11(12):2337–2343, 2000
Sortie dialysat Entrée dialysat Entrée sang Sortie sang effluent
(du patient) (vers patient) High Concentration Low concentration Blood Dialysate
K+ Dialysate 0 meq/L K+ Dialysate 2 meq/L
Dialysate flow (ml/min)
Blood flow (ml/min)
Hemodialysis