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Improving the Management of Hyperkalemia
Biff F. Palmer, M.D.Professor of Internal MedicineUniversity of Texas Southwestern Medical CenterDallas, Texas
Hyperkalemia: Epidemiology, Pathophysiology, and Clinical Consequences
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Distribution of Total Body K+
Muscle: 2,700 mEq
Liver: 250 mEq
Erythrocytes: 250 mEq
Bone: 300 mEq
Intracellular Fluid3,500 mEq (140-150 mEq/L)
Extracellular fluid70 mEq (3.5-5.5 mEq/L)
K+ Gradient Sets Cell Voltage
Regulation of K+ Homeostasis
ICF3,500 mEq
(140-150 mEq/L)
ECF70 mEq
(3.5-5.5 mEq/L)
Intake100 mEq
Renal excretion90 mEq
GI excretion10 mEq
Cell Shift
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Epidemiology of Hyperkalemia
• Incidence as high as 40%-55% in patients with CKD
• Even in specialized CKD clinics, the incidence is as high as 55%
Einhorn LM, et al. Arch Intern Med. 2009;169:1156-1162. Hayes J, et al. Nephron Clin Pract. 2012;120:c8-c16. Sarafidis PA, et al. Clin J Am Soc Nephrol. 2012;7:1234-1241.
Does the development of hyperkalemia have prognostic significance?
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Einhorn LM, et al. Arch Intern Med. 2009;169:1156-1162.
Serum Potassium (mEq/L)
1-day mortality rate 6-17 times higher in patients with K+
≥5.5 mEq/L than in those with K+
< 5.5 mEq/L
< 5.5 > 5.5 and < 6.0 > 6.0
Ratio compared to < 5.5 1.0 6.2 16.7
Mortality Rate Within 1 Day of a Hyperkalemia Event
1-D
ay M
ort
alit
y R
ate
Differential Diagnosis of Hyperkalemia
• Pseudohyperkalemia
• Excess K+ intake
• Cell shifts
• Impaired renal excretion
• Only cause of sustained hyperkalemia
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Seasonal Pseudohyperkalemia
Samples taken over 2 years from general practice, inpatient samples unaffected
Sinclair D, et al. J Clin Pathol. 2003;56:385-387.
Differential Diagnosis of Hyperkalemia
• Pseudohyperkalemia
• Excess K+ intake
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Excess Intake
• Salt substitutes
• Large amounts of juice
• Coconut juice (44.3 mmol/L)
• Orange juice (51-yo-man with K+ of 9 mEq/L, drank 2.5 L daily, 1,125 mEq/d for 3 wks)
• Noni juice
• River bed clay (100 mEq/100 g clay)
• Burnt match heads (cautopyreiophagia)
• Bananas:
– 15 yo with K+ of 6.1 mEq/L ingesting 20/d
Palmer BF, Sterns RH. Neph SAP. 2009;8. Sterns RH, Palmer BF. NephSAP: 2007;6.
Differential Diagnosis of Hyperkalemia
• Pseudohyperkalemia
• Excess K+ intake
• Cell shifts
• Impaired renal excretion
• Only cause of sustained hyperkalemia
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Impaired Renal K+ Excretion
• Primary decrease in mineralocorticoid activity
Renin
IMPAIRED RELEASEOF RENIN
NSAIDsBeta Blockers
Cyclosporine, TacrolimusDiabetesElderly
Angiotensin I Angiotensin II
Aldosterone
Na+
Na+
K+
K+LUMEN
Afferent Arteriole
Juxtaglomerularcells
AdrenalGland
Collecting Duct(principal cell)
Palmer BF. N Engl J Med .2004;351:585-592.
Primary Decrease in Mineralocorticoid Activity
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Change in PRA and Aldosterone with Na+ Restriction in Young vs Elderly
Plasma Renin Activity (ng/100 mL/3h) Plasma Aldosterone (ng/100 mL)
Na+ Intake (mEq/24h) Na+ Intake (mEq/24h)
Weidmann P, et al. Kidney Int. 1975;8:325-333.
K+ Infusion: Blunted Rise in Serum Aldosterone in Elderly vs Young
Ald
oste
rone
(pg
/mL)
Time (min)
KCl (0.05 mEq/kg wt over 45 minutes)
Mulkerrin E, et al. J Am Soc Nephrol. 1995.;6:1459-1462
Similar basal levels and increase in serum K+ during infusion
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Primary Decrease in Mineralocorticoid Activity
Renin
IMPAIRED RELEASEOF RENIN
NSAIDsBeta Blockers
Cyclosporine, TacrolimusDiabetesElderly
Angiotensin I Angiotensin II
ANGIOTENSIN-CONVERTING ENZYME
INHIBITORS
ANGIOTENSINRECEPTOR BLOCKERS
Aldosterone
Na+
Na+
K+
K+LUMEN
Afferent Arteriole
Juxtaglomerularcells
AdrenalGland
Collecting Duct(principal cell)
DIRECT RENININHIBITOR
Palmer BF. N Engl J Med. 2004;351:585-592.
Renin
IMPAIRED RELEASEOF RENIN
NSAIDsBeta Blockers
Cyclosporine, TacrolimusDiabetesElderly
Angiotensin I Angiotensin II
ANGIOTENSIN-CONVERTING ENZYME
INHIBITORS
ANGIOTENSINRECEPTOR BLOCKERS
Aldosterone
IMPAIREDALDOSTERONEMETABOLISM
Adrenal DiseaseHeparin
Ketoconazole
Na+
K+
K+LUMEN
Afferent Arteriole
Juxtaglomerularcells
AdrenalGland
Collecting Duct(principal cell)
Primary Decrease in Mineralocorticoid Activity
DIRECT RENININHIBITOR
Palmer BF. N Engl J Med. 2004;351:585-592.
Na+
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Renin
IMPAIRED RELEASEOF RENIN
NSAIDsBeta Blockers
Cyclosporine, TacrolimusDiabetesElderly
Angiotensin I Angiotensin II
ANGIOTENSIN-CONVERTING ENZYME
INHIBITORS
ANGIOTENSINRECEPTOR BLOCKERS
Aldosterone
IMPAIREDALDOSTERONEMETABOLISM
Adrenal DiseaseHeparin
Ketoconazole
Na+
K+
K+
ALDOSTERONERECEPTORBLOCKERS
SpironolactoneEplerenone
Drospirenone
LUMEN
Afferent Arteriole
Juxtaglomerularcells
AdrenalGland
Collecting Duct(principal cell)
Primary Decrease in Mineralocorticoid Activity
DIRECT RENININHIBITOR
Palmer BF. N Engl J Med. 2004;351:585-592.
Na+
Renin
IMPAIRED RELEASEOF RENIN
NSAIDsBeta Blockers
Cyclosporine, TacrolimusDiabetesElderly
Angiotensin I Angiotensin II
ANGIOTENSIN-CONVERTING ENZYME
INHIBITORS
ANGIOTENSINRECEPTOR BLOCKERS
Aldosterone
IMPAIREDALDOSTERONEMETABOLISM
Adrenal DiseaseHeparin
Ketoconazole
SODIUM CHANNELBLOCKERS
AmilorideTriamterene
TrimethoprimPentamidine
Na+
K+
K+
ALDOSTERONERECEPTORBLOCKERS
SpironolactoneEplerenone
Drospirenone
LUMEN
Afferent Arteriole
Juxtaglomerularcells
AdrenalGland
Collecting Duct(principal cell)
Primary Decrease in Mineralocorticoid Activity
DIRECT RENININHIBITOR
Palmer BF. N Engl J Med. 2004;351:585-592.
Na+
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Impaired Renal K+ Excretion
• Primary decrease in mineralocorticoid activity
• Primary decrease in distal Na+ delivery
Primary Decrease in Distal Na+
Delivery
• Oliguric acute renal failure
• Acute glomerulonephritis
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Impaired Renal K+ Excretion
• Primary decrease in mineralocorticoid activity
• Primary decrease in distal Na+ delivery
• Abnormal cortical collecting duct
Abnormal Collecting Duct
• Drugs
• Tubulointerstitial nephritis
• Urinary obstruction
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What are the clinical consequencesof hyperkalemia?
Clinical Consequences of Hyperkalemia
• Cardiac toxicity
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Poor Sensitivity and Specificity of ECG as Diagnostic Test for Hyperkalemia
• In 127 patients with serum K+ between 6-9.3 mEq/L, only 46% of ECGs noted to have changes1
• In 90 cases, only 24 noted to have characteristic T- wave changes as read by a cardiologist2
• Only 1/14 who presented with arrhythmias or arrest had strict criteria
Potassium quintiles by presence of strict criteria for ECG changes
1Acker CG, et al. Arch Intern Med. 1998;158:917-924. 2Montague BT, et al. Clin J Am Soc Nephrol. 2008;3:324-330.
Clinical Consequences of Hyperkalemia
• Cardiac toxicity
• Muscle weakness
• Impaired renal acidification
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Hyperkalemia
NH4+
Medullaryaccumulation
NH4+NH4
+
H+
NH3
NH3
H+
NH3
H+
H+
H+
H+
UpH = 5.0Net acid excretion reduced
Metabolic Acidosis in CKD
Metabolic Acidosis
Increased ammoniagenesis in remaining nephrons
Increased endothelinComplement activation
Tubulointerstitial renal disease
Chen W, Abramowitz MK. BMC Nephrol. 2014;15:55.
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Summary
• Hyperkalemia is common in CKD patients and in those with conditions that disrupt the renin-angiotensin-aldosterone system
• Hyperkalemic events are associated with worse outcomes– Cardiac events
– Muscle weakness
– Impaired acidification
• Strategies to limit development of hyperkalemia would be of clinical utility
Hyperkalemia Management: Current Challenges and Evolving Perspectives
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RAASi Promotes Kidney‐Saving and
Life‐Saving Benefits in Patients With CKD,
Heart Failure, or Diabetes Mellitus
CKD, chronic kidney disease; RAASi, renin-angiotensin-aldosterone system inhibitor.
RALES/EMPHASIS‐HF: MRAs Improved Survival in Patients With HF
HF, heart failure; MRAs, mineralocorticoid receptor antagonists.Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, Palensky J, Wittes J. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999;341(10):709-717.
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Hyperkalemia Is a Common Complication
in Patients With Heart Failure Receiving
Mineralocorticoid Receptor Antagonists
Hospitalizations for Hyperkalemia Spiked in Heart Failure Patients After Publication of RALES
Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, Redelmeier DA. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med. 2004;351(6):543-551.
Online releaseof RALES
Rate of hospital admission for hyperkalemia among patients recently hospitalized
for heart failure who were receiving ACEi
Rat
e o
f A
dm
issi
on
fo
r H
yper
kale
mia
(p
er 1
,000
pat
ien
ts)
Study Year
1994
10
12
14
8
6
4
2
0
1995 1996 1997 1998 1999 2000 2001
The yellow lines and 95% CIs beginning in 1999 represent the projected rates of hospital admissions for hyperkalemia.
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Hyperkalemia Is a Major Reason for Discontinuation of MRA• 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)
HF, heart failure; MRA, mineralocorticoid receptor antagonist; sCR, serum creatinineLopes RJ, et al. Clin Cardiol. 2008;31:509-513.
% of Patien
ts
*Severe hyperkalemia (≥6 mEq/L) occurred in 7 patients who withdrew from spironolactone therapy (9.2%).
Reason for spironolactone suspension (%)
Discontinuation of MRA
Entresto (LCZ696) is approved by FDA
• Combination of the ARB valsartan and neprilysin inhibitor
• Indicated to reduce the risk of cardiovascular death and hospitalization for heart failure patients with chronic heart failure (CHF) (NYHA class II-IV) and reduced ejection fraction
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Hyperkalemia Will Remain an Issue With LCZ‐696PARADIGM Heart Failure Study
•PARADIGM‐HF selected a population at low risk for hyperkalemia prior to randomization
–Excluded patients with eGFR <30 mL/min/1.73 m2
–Excluded patients with serum potassium level of more than 5.2 mmol/L at screening (or more than 5.4 mmol/L at randomization)
•Hyperkalemia rates remained high in all patients despite carefully selected population
–>5.5 mmol/L: 16.1% LCZ‐696 versus 17.3% ACEi (P = .15)
–>6.0 mmol/L: 4.3% LCZ‐696 versus 5.6% ACEi (P = .007)
eGFR, estimated glomerular filtration rate; HF, heart failure. McMurray J, et.al. N Engl J Med. 2014;371(11):993-1004.
Hyperkalemia versus RAASi: The Catch‐22 of Managing Diseases That Benefit From RAASi Therapy
Prescribe RAASi and
Accept Presence of
Hyperkalemia?
RAASi, renin-angiotensin-aldosterone system inhibitor.
Avoid/Discontinue
Proven RAASi
Therapies?
CATCH‐22
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Hyperkalemia Is a Leading Reason for Not Starting RAASiand the Major Reason for Discontinuation of RAASi in CKD
• 279 patients with CKD followed up for a mean of 22 months
• Baseline mean eGFR was 33.3 mL/min/1.73m2 and the serum K+ was 4.73 mEq/L
Yildrim T, et al. Ren Fail. 2012;34(9):1095-1099.
(80 patients) (51 patients)
% of Patients
CKD, chronic kidney disease; eGFR, estimated glomerular filtration rate; RAASi, renin-angiotensin-aldosterone system inhibitor.
Current Guidelines Tend to Lessen the Use of
Full Recommended Doses of Renin‐
Angiotensin‐Aldosterone System Inhibitors
Because of Concerns Related to Hyperkalemia
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Guidelines Recommend RAASi Modifications at Various Serum K+ Levels
Serum K+ Threshold Before Change in RAASi Guideline Recommendation
>6.0
>5.5
>5.0
ACA/AHA HFa:Maintain MRA 4.0‐5.0
ACC/AHA,a ESC HF,b K/DOQIf:Reduce dose of/stop ACEi/ARB, AA if >5.5
HFSA HFc: MRA not recommended >5.0
NICEe:Stop RAASi if >6.0
NICEe: don’t start RAASi if >5.0
KDIGO Guidelines do not provide
recommendationsd
K/DOQIf: don’t start RAASi if > 5.0
MRA, mineralocorticoid receptor antagonist; RAASi, renin-angiotensin-aldosterone inhibitor.a. Yancy CW, et al. J Am Coll Cardiol. 2013;62(16):e147-239. b. McMurray JJ, et al. Eur Heart J. 2012;33(14):1787-1847.c. Heart Failure Society of America, Lindenfeld J, et al. J Card Fail. 2010;16(6):e1-e194. d. KDIGO Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int Suppl. 2013;3(1). e. National Institute for Health and Care Excellence (NICE) [UK]. 2008. http://www.nice.org.uk/CG73. f. http://www.kidney.org/professionals/kdoqi/guidelines_bp/guide_11.htm#table131.
Serum K
+ (m
Eq/L)
Hyperkalemia Prevents Use of Guideline‐Recommended RAASi Therapy to Delay Progression to ESRD
Kidney Disease Outcomes Quality Initiative, Guideline 11: Use of ACEis and ARBs in CKD
• In general, highest tolerated doses of ACEior ARB (RAASi) are recommended
• If hyperkalemia develops, reduce dose of ACEi or ARB and/or discontinue the ACEior ARB
Optimal dose25%
Untreated/can’t tolerate
33%
Suboptimal dose42%
RAASi treatmentin CKD*
~90% of nephrologists: hyperkalemia is top concern with use of RAASi medication**
ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CKD, chronic kidney disease; ESRD, end-stage renal disease; RAASi, renin-angiotensin-aldosterone system inhibitor.
*Estimates based on data adapted from Treatment Algorithm Quantitative Study, June 2013, N = 386. **Primary market research, April 2012.
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Therapies To Treat Acute Hyperkalemia
aModified from Weisberg LS. Crit Care Med. 2008;36(12):3246-3251. bModified from Floege J, Johnson RJ, Feehally J, eds. Comprehensive Clinical Nephrology. St.Louis, MO: Mosby; 2010. cBallantyne F 3rd, Davis LD, Reynolds EW Jr. Am J Physiol. 1975;229(4):935-940.MOA, mechanism of action; CPS, calcium polystyrene sulfonate; SPS, sodium polystyrene sulfonate.
Calcium gluconate salt↓ threshold poten al of cardiac myocytesa
InsulinActivates the Na+/K+‐ATPase pumpa
β‐adrenoceptor agonists
Sodium bicarbonateAlkalinizes the urine, thereby enhancing urinary K+ excretiona
Loop diureticsEnhance urinary K+ excretionb
SPS/CPSEnhance K+ removal through the colonc
HemodialysisRemoval of K+ from blooda
Membrane Stabilizationa,b K+ Redistributiona,b K + Eliminationa,b
Sodium Polystyrene Sulfonate:Limited Data to Substantiate Efficacy
aSterns RH, Rojas M, Bernstein P, Chennupati S. J Am Soc Nephrol. 2010;21(5):733-735. bKayaxelate PI 2010. cKamel KS, Schreiber M. Nephrol Dial Transplant. 2012;27(12):4294-4297. dGruy-Kapral C, Emmett M, Santa Ana CA, Porter JL, Fordtran JS, Fine KD. J Am Soc Nephrol. 1998;9(10):1924-1930.FDA, US Food and Drug Administration; SPS, sodium polystyrene sulfonate.
“…no convincing evidence that SPS increases fecal K+ losses in experimental animals or humans and no evidence that adding sorbitol
to the resin increases its effectiveness...”a
FDA approved in 1958, before well‐controlled studies were requireda
• Indicated for the treatment of hyperkalemiab
There is concern that kayexalate may not be effective without osmoticallyactive amounts of sorbitolc,d
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WARNINGSIntestinal Necrosis
• Cases of intestinal necrosis, which may be fatal, and other serious gastrointestinal adverse events (bleeding, ischemic colitis, perforation) have been reported in association with kayexalate use
• The majority of these cases reported the concomitant use of sorbitol
• Risk factors for gastrointestinal adverse events were present in many of the cases, including prematurity, history of intestinal disease or surgery, hypovolemia, and renal insufficiency and failure
• Concomitant administration of sorbitol is not recommended
FDA Issued Warning on Sodium Polystyrene Sulfonate in September 2009
Kayexalate Prescribing Information. December 2010. www,fda.gov/Safety/MedWatch/SafetyInformation/ucm186845.htm. FDA, US Food and Drug Administration.
Necrosis (62%), Ulceration (48%), Perforation (9%), and SPS crystals (90%)a
Histopathology of SPS‐Related GI Injury
Hematoxylin and eosin stain (original magnification ×40)
SPS crystals within the ulcer and on the surfaceb
aHarel Z, Harel S, Shah PS, Wald R, Perl J, Bell CM. Am J Med. 2013;126(3):264.e9-24. bBomback AS, Woosley JT, Kshirsagar AV. Am J Emerg Med. 2009 Jul;27(6):753.e1-2.GI, gastointestinal; SPS, sodium polystyrene sulfonate.
Base of an ulcer that shows necrotic debrisreplacing the intestinal mucosab
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Patiromer (RLY5016) Is a Polymer That Binds Potassium in the Colon
• Patiromer is a nonabsorbed K+
binding polymer
• Patiromer binds K+ in colon
• Patiromer acts as a “sink” to increase colonic K+ excretion
Patiromer (RLY5016)
Buysse JM, et al. Future Cardiol. 20128:17-28.GFR, glomerular filtration rate; RAAS, renin-angiotensin-aldosterone system.
Hyperkalemia is most commonly caused by chronic kidney disease, or the use of RAAS blockade drugs that limit urinary K+ excretion and increase serum K+ level
Hyperkalemia
Patiromer in Patients With Kidney Disease and Hyperkalemia Receiving RAAS Inhibitors (OPAL‐HK)
• Patients with CKD on RAAS inhibitors (n = 243) with hyperkalemia (5.1‐6.5 mEq/L) were assigned to receive patiromer (4.2 or 8.4 g twice daily) for 4 weeks
• Eligible patients (n = 107) included those with baseline K+ of 5.5‐6.4 mEq/L in whom the K+ level decreased to 3.8‐5.0 mEq/L entered an 8‐week randomized withdrawal phase in which they were randomized to continue patiromer or switch to placebo.
Weir MR, et al. N Engl J Med. 2015;372:211-221.CKD, chronic kidney disease; RAAS, renin-angiotensin-aldosterone system.
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Patiromer Titrated Dose
Potassium 5.5 ‐ <6.5
Potassium 5.1 ‐ <5.5
Part ASingle‐Blind,Uncontrolled
n = 243
Part BRandomized Withdrawal,
Single‐Blind, Placebo‐Controlled
n = 107
4 Weeks
Part B PrimaryEndpoint:Between‐Group Difference in Serum Potassium at Week 4
Subjects with CKD andon RAAS inhibitors
Responders with Part A Baseline Potassium 5.5‐6.4
Patiromer +RAAS Inhibitor
Placebo +RAAS Inhibitor
8 Weeks
Part A Primary Endpoint:Change from Baseline in Mean Serum Potassium
Weir MR, et al. N Engl J Med. 2015;372:211-221.CKD, chronic kidney disease; RAAS, renin-angiotensin-aldosterone system.
Phase 3 Trial Design
Pivotal Phase 3 Trial – Part A Results
Weir MR, et al. N Engl J Med. 2015;372:211-221.
Baseline Week 4Week 2
Dose Group 1−0.65
DoseGroup 2−1.23
AllSubjects−1.01
P<0.001
Part A Primary Efficacy Endpoint:Mean Change from Baseline to Part A Week 4 (All Subjects)
Week 1 Week 3Day 2
P < .001
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* Or earlier time point if subject first had serum potassium <3.8 mEq/L or ≥5.5 mEq/L
Weir MR, et al. N Engl J Med. 2015;372:211-221.
Placebo Patiromer
Est
imat
ed M
edia
n C
han
ge
fro
m P
art
B
Bas
elin
e in
Ser
um
Po
tass
ium
(m
Eq
/L)
∆ = 0.72 mEq/L
P <0.001
Estimated Median Change from Part B Baseline 0.00 mEq/L0.72 mEq/L
Pivotal Phase 3 Trial – Part B ResultsPart B Primary Efficacy Endpoint: Difference Between Groups in the Median Change in Serum Potassium from Part B Baseline to Part B Week 4*
Pro
port
ion
With
Rec
urre
nt
Hyp
erka
lem
ia
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
AW4/BBL BW1 BW2 BW3 BW4 BW5 BW6 BW7 BW8
52 46 38 31 29 23 16 12 4
55 53 48 47 44 39 38 38 29
Study Week
Subjects without recurrent hyperkalemia at any time before, and at, the study visit and still on study drug
PlaceboPatiromer
Time to First Recurrent Hyperkalemia Event During Phase 3 Part B
Weeks 1-4* Recurrent Hyperkalemia = Serum
Potassium ≥5.5 mEq/L
Weeks 5-8 Recurrent Hyperkalemia = Serum
Potassium ≥5.1 mEq/L
* Part B Weeks 1-4 = Primary Efficacy Outcome Period
Weir MR, et al. N Engl J Med. 2015;372:211-221.
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Adverse Events During the Safety Follow‐up Period for That Phase
Weir MR, et al. N Engl J Med. 2015;372:211-221.
Adverse Events During the Randomized Withdrawal Phase and Through the Safety Follow‐up Period for That Phase
Adverse Event Patients(N = 52)
Patiromer(N = 55)
≥1 Adverse event 26 (50) 26 (47)
Headache 4 (8) 2 (4)
Supraventricular extrasystoles 1 (2) 2 (4)
Constipation 0 2 (4)
Diarrhea 0 2 (4)
Nausea 0 2 (4)
≥1 Serious adverse event 1 (2) 0
All data presented as n (%).
Responses to Patiromerwere sustained over 52 weeks (AMETHYST‐DN Randomized Clinical Trial)
J Am Med Assoc 2015;314(2):151‐161
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Patiromer (Veltassa) is approved by FDA and indicated for the treatment of hyperkalemia
Valtassa binds to many orally administered medications, which could decrease their absorption and reduce their effectiveness, administer other oral medications at least 6 hours before or 6 hours after Valtassa
FDA Safety Alert
FDA is requiring the Kayexalate manufacturer to conduct studies to investigate Kayexalate’s potential to bind to other medications administered by mouth
Prescribers and patients should consider separating Kayexalate dosing from other medications taken by mouth by at least 6 hours
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ZS‐9: A novel, selective K+ binder
ZS‐9 Properties
• Microporous zirconium silicate compound
• Insoluble, highly stable• 9.3x more K+ binding capacity than
Kayexalate® • >125x more selective for K+ than
Kayexalate®
HARMONIZE Trial
• Multicenter, randomized, double‐blind, placebo‐controlled trial evaluating zirconium cyclosilicate (ZS‐9) 3 times daily in an initial 48‐hour open label phase (n = 258)
• Patients (n = 237) achieving normokalemia (3.5‐5.0 mEq/L) were randomized to once‐daily ZS‐9, 5 g (n = 45), 10 g (n = 51) or 15 g (n = 56), or placebo (n = 85) daily for 28 days.
Kosiborod M, et al. JAMA. 2014;312(21):2223-2233.
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HARMONIZE Trial
Participants with comorbidity in open label phase:
Kosiborod M, et al. JAMA. 2014;312(21):2223-2233.CHF, congestive heart failure; DM, diabetes mellitus; RAASi, renin-angiotensin aldosterone inhibitor.
CHF 36.4%
DM 65.9%
RAASi 69.8%
Serum Potassium Levels During the Open‐Label Phase (48 hours)
Kosiborod M, et al. JAMA. 2014;312(21):2223-2233.
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Serum Potassium Levels During the Open‐Label Phase (48 hours)
Kosiborod M, et al. JAMA. 2014;312(21):2223-2233.
Serum Potassium Levels During the Randomized Phase (Days 8–29) According to Study Group
Kosiborod M, et al. JAMA. 2014;312(21):2223-2233.
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Serum Potassium Levels During the Randomized Phase (Days 8–29) According to Study Group
Kosiborod M, et al. JAMA. 2014;312(21):2223-2233.
Sodium Zirconium Cyclosilicate in Hyperkalemia
• Multicenter, two‐stage double blind trial
• Patients (n = 754) with hyperkalemia randomly assigned to receive ZS‐9 (1.25 g, 2.5 g, 5 g, or 10 g) or placebo 3 times daily for 48 hours.
• Patients achieving normokalemia (3.5–4.9 mEq/L) were randomly assigned to ZS‐9 or placebo once daily from days 3 through 11.
Packham DK, et al. N Engl J Med. 2015;372:222-231.
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Packham DK, et al. N Engl J Med. 2015;372:222-231.
Potassium Levels During the Study
Rev CV Med 16 140 2015