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Joseph F. Dasta, M.Sc., FCCM, FCCPProfessor Emeritus The Ohio State University College of PharmacyAdjunct Professor The University of Texas College of Pharmacy

Faculty DisclosuresFaculty Disclosures

Joseph F. Dasta, M.Sc., FCCM, FCCPProfessor Emeritus The Ohio State University College of PharmacyAdjunct Professor The University of Texas College of Pharmacy

Disclosures

Consultant, Otsuka America Pharmaceutical

All conflicts have been resolved through peer review.

Learning ObjectivesLearning Objectives

• Describe the risk factors, risk stratification and treatment options for hospitalized patients with hyponatremia

• Explain new data on treatment options, current guidelines and goals of therapy to improveguidelines and goals of therapy to improve outcomes in patients with hyponatremia

• Review institutional protocols and the role of the health-system pharmacist in the management of hyponatremia

Hyponatremia: Definition

Serum [Na+], mEq/L

<125 125‐134 135‐144Severe 

hyponatremia Mild hyponatremia Normonatremia

• Commonly defined as serum sodium concentration ([Na+]) <135 mEq/L, but cut‐off values vary

• Generally considered a disorder of water rather than a disorder of salt

• Results from increased water retention

• When considering hyponatremia, think of edemaVerbalis JG, et al. Am J Med 2007;120:S1-S21

Incidence of Hyponatremia in Acute Hospital Care

Incidence of Hyponatremia by Serum [Na+], mEq/L

<116 <126 <136

Hawkins RC. Clin Chim Acta. 2003;337(1-2):169-172.

6 6 36

Present on admission 0.5% 2.5% 28.2%

Hospital-acquired 0.7% 3.7% 14.4%

TOTAL 1.2% 6.2% 42.6%

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[Na+]  <135  mEq/L 

(n=12,562)

[Na+] 130‐134 mEq/L

(n=10,469)

[Na+] 125‐129 mEq/L (n=1591)

[Na+] 120‐124 mEq/L (n=353)

[Na+] <120 mEq/L(n=149)

Multivariable‐adjusted hazard ratio in‐hospital mortality

1.47(1.33‐1.62)

1.37(1.23‐1.52)

2.01(1.64‐2.45)

1.67(1.09‐2.56)

1.46(0.73‐2.91)

Mortality Associated with Hyponatremia

Mortality Associated with Hyponatremia

Multivariable‐adjusted hazard ratio 1‐year mortality

1.38 (1.32‐1.46)

1.35 (1.28‐1.43)

1.53 (1.36‐1.71)

1.78 (1.44‐2.21)

1.03 (0.68‐1.56)

Multivariable‐adjusted hazard ratio 5‐year mortality

1.25 (1.21‐1.30)

1.24 (1.19‐1.29)

1.33 (1.23‐1.44)

1.29 (1.09‐1.53)

1.09 (0.84‐1.41)

Waikar et al. Am J Med. 2009;122(9):857-865.

Hyponatremia:Persistent, Acquired, Resolved

Hyponatremia:Persistent, Acquired, Resolved

Waikar et al. Am J Med. 2009;122(9):857-865.

• Mortality was highest in patients with persistent or acquired hyponatremia and lower in those with hyponatremia that resolved

• Mortality was lowest in those with normonatremia

Annual Cost of Hyponatremia in the United States

• Prevalence‐based cost‐of‐illness study– Included information from databases, published literature, 

and expert physician panel• Low and high scenarios were estimated and 

incorporated in a cost‐of‐illness model• Results (estimates)

– Prevalence of 3.2 to 6.1 million persons annually– 1 million hospitalizations annually with a principal or 

secondary diagnosis of hyponatremia• 58‐67% of patients had a longer length of stay due to symptomatic hyponatremia

– Direct costs of $1.6 to $3.6 billion annually

Boscoe A et al. Cost Eff Resour Alloc. 2006; 4:10.

Economic Impact of HyponatremiaEconomic Impact of Hyponatremia

Callahan et al. Postgraduate Med. 2009;121(2):186-191.

Hyponatremia inPatients with Pneumonia

• Commercial database (2004‐2005)– 39 hospitals – 7965 patients with pneumonia– 8% were hyponatremic (serum sodium <135 mEq/L)

Zilberberg MD et al. BMC Pulm Med. 2008; 8:16.

Variable

Serum Sodium

p ValueNormal

(n = 7316)Hyponatremia

(n = 649)Mechanical ventilation (%) 2.3 3.9 0.014Mean LOS in ICU (days) 5.3 6.3 0.07Median hospital costs (in 2005 $) 5732 7086 0.001

$1324 median increase in hospital costs (range $98 –2682) in 2005 dollars

Hyponatremia in HF• Nearly 1 million hospitalizations for HF occur annually in the United 

States (7 million HF patients in the U.S.)– Most are related to worsening systemic congestion– Use of diuretics, the mainstay therapy for congestion, contributes to 

electrolyte abnormalities and worsening renal function

• Hyponatremia is common in patients with cardiac disease‐ 20% ‐ 28% of patients hospitalized with HF had concomitant 

hyponatremia

• Hyponatremia concomitant with CHF significantly increases hospital LOS (P=.0001)

CHF = congestive heart failure. Gheorghiade M, et al. JAMA. 2004;291(16):1963-1971. Cleland JG, et al. Eur Heart J. 2003;24(5): 442-463. Crook MA, et al. Ann Clin Biochem. 1999;36(Pt 2):158-162. Gheorghiade M, et al. Circulation. 2003;107(21):2690-2696. Krumholz HM, et al. Am J Manag Care. 1999;5(6):715-723.

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P < .0001Admission Serum Sodium

[Na+] < 135 mEq/L

[Na+] ≥ 135 mEq/L

Hyponatremia in Heart FailureHyponatremia in Heart Failure45

40

35

30

25

34.8

42.5

1. Gheorghiade et al. Eur Heart J. 2007;28:980-988. 2. Gheorghiade et al. Arch Intern Med. 2007;167:1998-2005. 3. Gheorghiade et al. JAMA. 2004;291(16):1963-1971. 4. Klein et al. Circulation. 2005;111:2451-2460.

P < .0001

In-Hospital Mortality (%)

Post-Discharge Mortality (%)

Death or RehospitalizationSince Discharge (%)

20

15

10

5

0

P < .0001

6.4 5.5

LOS (days)

P < .0001

6.0 3.27.1

12.4

Neurohormonal Activation in Heart Failure

Baroreceptor dysfunction

↓ Afferent inhibitory signals

Vasomotor center

↑ Sympathetic nervous system activity

↑ Renin secretion

↑ Vasopressin secretion

↑ Angiotension II

↓ Limb blood flow

↓ Renal blood flow↑ Aldosterone

↑ Sodium reabsorption↑ H2O reabsorption

KC1

Vasopressin Affects in Heart Failure

BRAIN

Supraoptic Paraventricular

neuronsneurons

Pituitary, posterior

lobe

Angiotension II hyperosmolality + Vasopressin - Baroreceptors natriuretic

peptides

Inhibition of renin secretion

Renal H2O reabsorpitonVasoconstrictionIncreased arterial

barorecptor sensitivity

Prevalence of sodium disturbances in cirrhosis

Prevalence of sodium disturbances in cirrhosis

27.9

35.1

25

30

35

40

%

4.4

11.1

15.8

4.51.3

0

5

10

15

20

</=120 121-125 126-130 131-135 136-140 141-145 >145

serum sodium (mEq/L)

Adapted from P.Angeli et al. Hepatology 2006; 44:1535-1542

Hyponatremia Mortality Impact in Cirrhosis

• Liver Transplant candidates in the VA system, 97-03 (n= 507)—Hepatitis C (68%), EtOH (67%)—MELD 16.2 + 6.7—Hyponatremia (<130 mEq/L): 31%—Persistent Ascites/Hydrothorax: 38%

• Predictors of 6 month mortality

Odds Ratio p

MELD 1.25 (1.16-1.35) <0.001

Na < 135 mEq/L 2.76 (1.31-5.81) 0.008

Persistent Ascites 2.72 (1.31-5.71) 0.008

Heuman DM, et al. Hepatology. 2004;40(4):802-10.

• Predictors of 6-month mortality

Increased Risk of Falls with “Asymptomatic” Hyponatremia

Group n Falls Odds Ratio

Adjusted Odds Ratio*

9.45 67.43“Asymptomatic”Chronic

Hyponatremia 122 21.3%9.45

(2.64-34.09)p <.001

67.43 (7.48-607.42)

p <.001

Normonatremic controls 244 5.35% 1.00 1.00

*adjusted for age, sex and covariates

Adapted from: Renneboog B, et al. Am J Med. 2006;119(1): 71. e1-8.

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Hyponatremia & Gait Stability

Serum [Na+] = 124 mEq/L Serum [Na+] = 135 mEq/L

Serum [Na+] = 139 mEq/LSerum [Na+] = 130 mEq/L

Reprinted from Renneboog B et al. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med. 2006;199:71.e1-71.e8. ©2006, with permission from Elsevier.

Serum [Na+] = 124 mEq/L Serum [Na+] = 135 mEq/L

Pathophysiologic Mechanism ofMechanism of 

Water and Salt Balance

Hyponatremia Classification

Dilutional Hyponatremia

Total body sodium near normalTotal body water increased

Depletional Hyponatremia

Hypovolemic

CawleyMJ. Ann Pharmacother. 2007; 41:840‐50.

Euvolemic(no edema)

SIADHHypothyroidism

Secondary adrenal

insufficiency

Hypervolemic(edema)

Heart failureCirrhosisNephroticsyndrome

Sodium lostTotal body water reduced

Diarrhea PancreatitisVomiting Diuretic excessBurns Renal salt

wastingTrauma Primary adrenal

insufficiency

Common Medications Associated with SIADH

Medications CategoryCaptopril, enalapril ACE inhibitor

Amiodarone Antiarrhythmic

Carbamazepine Anticonvulsant

Clozapine, chlorpromazine, flupnenazine, haloperidol Antipsychotic

Theophylline Bronchodilator

Carboplatin cisplatin cyclophosphamide ifosfamideCarboplatin, cisplatin, cyclophosphamide, ifosfamide, vinblastine, vincristine Chemotherapeutic

Amiloride/hydrochlorothiazide, chlorothiazide, furosemide, indapamide Diuretic

“Ecstasy” (3,4,methylenedioxymethamphetamine [MDMA]), nicotine Recreational

Citalopram, duloxetine, fluoxetine, paroxetine, sertraline, venlafaxine SSRI

Chloropropamide, glibenclamide, glimepiride, glipizide Sulfonylurea

Amitryptyline Tricyclic antidepressant

Desmopressin acetate (DDAVP), oxytocin Vasopressin analogue

Diagnostic Algorithm for Hyponatremia

Assessment of volume status

HypovolemiaTotal body water ↓Total body Na+ ↓ ↓

Euvolemia (no edema)Total body water ↑Total body Na+ ↔

HypovolemiaTotal body water ↑ ↑

Total body Na+ ↑

U[Na+] >20 mEq/L U[Na+] <20 mEq/L U[Na+] >20 mEq/L U[Na+] >20 mEq/L U[Na+] <20 mEq/L

Renal LossesDiuretic excessMineral corticoid

deficiencySalt-losing

deficiencyBicarbonaturia with

renal tubal acidosis and metabolic alkalosis

KetonuriaOsmotic diuresis

Extrarenal LossesVomitingDiarrheaThird spacing of

fluidsBurnsPancreatitisTrauma

GlucocorticoiddeficiencyHypothyroidismSIADH secretionDrug-induced stress

Acute or chronicrenal failure

Nephrotic syndromeCirrhosisCardiac failure

SIADH = syndrome of inappropriate antidiuretic hormone. Adapted from Kumar S, Beri T. Diseases of water metabolism. In: Berl T, Bonventre JV, eds. Atlas of Diseases of the Kidney. Vol. 1. Philadelphia, PA: Current Medicine, Inc; 1999:1.1-1.22.

Legend: ↑ increase; ↑ ↑ greater increase; ↓ decrease; ↓ ↓ greater decrease; ↔ no change

[Na+] q [Na+] q [Na+] q [Na+] q [Na+] q

AVP Release and Sites of ActionAnxiety and stress (V1)

Myocyte hypertrophy (V1)

Posterior pituitaryAVP release

Blood:Platelet aggregation (V1)Von Willebrand factor (V2)

Body fluid:Water retention (V2)

Vascular tone:Vasoconstriction (V1)

Vasodilation (V2)

Glycogenolysis (V1)

AVP = arginine vasopressin.Adapted from Ferguson JW, et al. Clin Sci (Lond). 2003;105(1):1-8.

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AVP Regulates Water andElectrolyte Balance

10 -

5 -

Thirst

asm

a AV

PWater excess

Plasma osmolality decreases

(<280 mOsm/kg)

Water deficit

Plasma osmolality increases

(>280 mOsm/kg)

0 -|

280|

290|

300|

310

Pla

Plasma Osmolality (mOsm/kg)

( g)

Plasma AVP declines

Renal water excretion Plasma osmolality normalizes (285-295 mOsm/kg)

( g)

Plasma AVP rises

Renal water excretion

Kumar S, Beri T. Diseases of water metabolism. in: Berl T, Bonventre JV, eds. Atlas of Diseases of the Kidney. Vol. 1. Philadelphia, PA: Current Medicine, Inc; 1999:1.1-1.22. Robertson GL, et al. Am J Med. 1982;72(2):339-353. Rossi NF, et al. Crit Care Clin. 1987;3(4):759-777.

Vasopressin Levels Inappropriately Elevated in Patients with SIADH

Zerbe R et al. Vasopressin function in the syndrome of inappropriate antidiuresis. Annu Rev Med. 1980;31:315-327. Annual Review of Medicine.Copyright 1980 by Annual Reviews, Inc. Reproduced with permission of Annual Reviews, Inc.

AVP Regulation of Water Reabsorption from Renal Tubular Cells

Collecting du

AVP

H2O

Exocytic insertionAMP

ATPAQP2GTP

(Gs)

Vasa

rect

a Collecting Duct CellAQP3

AQP = aquaporin; GTP = guanine nucleotide binding protein; ATP = adenosine triphosphate; cAMP = cyclic adenosine monophosphate; PKA = protein kinase A.Mayinger B, et al. Exp Clin Endocrinol Diabetes. 1999;107(3):157-165.

uctAVPAVP V2

receptor

Basolateral membrane

Luminal membrane

H2OAQP2

insertioncAMP

PKA

Recyclingvesicle

Endocytic retrieval

(Gs)

AQP4

Symptomatic Hyponatremia: Neurological ManifestationsSymptomatic Hyponatremia: Neurological Manifestations

• Headache• Irritability• Nausea/Vomiting• Mental Slowing

ChronicMental Slowing

• Confusion/Delerium • Disorientation• Stupor/Coma• Convulsions• Respiratory Arrest

Acute

Risk Stratification

• Acute vs. Chronic– Acute = less than 48 hours in duration

• Concerned about neurologic sequellae – Osmotic differential between brain and blood– Brain swelling

– Chronic = greater than 48 hours in duration• Symptoms may be more modest

– Brain has time to adapt

• Duration of hyponatremia– How aggressive?– How fast?

Sodium and the BrainSodium and the Brain

+ +++

Na+ moves from high concentrations to low

Water follows Na+

Time-dependent

+ +

+

+

+

+

++ ++

++

++

++

BRAIN EDEMA

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+++

Na+ moves from high concentrations to low

Water follows Na+

Implications for treatment

Sodium and the BrainSodium and the Brain

++

+ ++

++

Rapid fluid shifts out of the brain: OSMOTIC DEMYELINATION SYNDROME (ODS)

How Aggressive? How Fast?How Aggressive? How Fast?

LEVEL 2 - MODERATE SYMPTOMS: nausea confusion disorientation

LEVEL 3 - SEVERE SYMPTOMS:vomiting, seizures, obtundation,respiratory distress, coma

Emergency!Correct RAPIDLY

LEVEL 1 - NO OR MINIMAL SYMPTOMS:headache, irritability, inability to concentrate, altered mood, depression

nausea, confusion, disorientation, altered mental status

OK to correct more slowly

• Raise [Na+] by <8-12 mEq in the 1st 24 hrs

• Raise [Na+] by <18 -24 mEq in the 1st 48 hrs

• Symptomatic: 1 mEq/L/h until neurologic symptoms resolve or [Na+] >120 mEq/L

Serum Sodium Safe Rate of CorrectionSerum Sodium Safe Rate of Correction

or [Na ] 120 mEq/L

— Slow rate of correction once symptoms resolve or Na+ 120-130 mEq/L

Verbalis JG et al. Am J Med. 2007;120:S1-S21.Kumar S et al. In: Atlas of Diseases of the Kidney. 1999:1.1-1.21.Adrogue HJ et al. N Engl J Med. 2000;342:1581-1589.

Approaches to Management

• Traditional: add to the numerator

Sodium

Total Body WaterSerum Sodium =

• More rational approach: subtract from the denominator– Diuretic vs. aquaretic– Fluid restriction

• Assumes it is inexpensive 

Prospective Observational Hyponatremia Registry*

• Goals– Describe clinical and laboratory data in patients either admitted with hyponatremia or occurring during hospitalizationG i i i ht i t h i th i b i d i– Gain insight into how various therapies are being used in hospital settings

– Quantify resources used in real‐world setting

• Experience through September 2011– Is first study to evaluate current practices– Enrolled 1487 patients (target of 2500 in US)

Dasta J et al. ACCP Annual Meeting; 2011 Oct 18. Poster 95E.

*Includes hospitals in U.S. and outside U.S.

Current Treatment StrategiesAGENT LIMITATIONS

Fluid restriction • Slow to correct over days (1-2 mEq/L/day)

• Poorly tolerated due to thirst

• Should not be used with high AVP level and urine osmolality

•Consider pharmacy implications of “Reduce input to 1200 ml/d”Diuretics • Allows relaxation of fluid restriction

• Potential for ototoxicity, volume depletion, and K+ and Mg+

depletion

Demeclocycline • Not FDA approved for hyponatremia

• Slow to correct over days

• Nephrotoxic in cirrhosis and heart failure

Oral Sodium Chloride

• Nausea and vomiting

• Rarely can give large enough dose to be effective

• No data

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Current Treatment Strategies

AGENT LIMITATIONS

Isotonic saline • Ineffective in dilutional hyponatremia

• Should not be used in setting of edema

• No safety data

• Complex calculations• Complex calculations

Hypertonic saline • No consensus regarding appropriate infusion rates

• Overcorrection can cause osmotic demyelination syndrome

• Should not be used in setting of edema

• No safety data

• Complex calculations and risk of over correction

ICU Patient Example: Total Daily VolumeSignificant volume from IV drugs

Medications mL/dayNorepinephrine 8 mg/250 mL IV at 10 micrograms/minute 450

Vancomycin 1 gram in 250 mL IVPB Q24H 250

Piperacillin/Tazobactam 2.25 grams in 50 mL IVPB Q6H 200

Lorazepam 50 mg/250 mL IV at 5mg/hour 600

38

p g g

Azithromycin 500 mg in 250mL IVPB QAM 250

Normal saline 1000 mL IV at 100 mL/hour 2,400

Insulin aspart low-dose correction scale SQ Q4H -

Ipratropium/albuterol 2.5/0.5mg in 3 mL NEBULIZER Q6H -

Famotidine 20 mg in 50 mL IVPB QAM 50

Heparin 5000 UNITS/1 mL SUBCUTAENOUSLY Q8H -

TOTAL FLUID: 4,200

• When to consider using HTS– Symptomatic hyponatremia (seizure, coma)– Acute severe hyponatremia (<24 hr, <120 mEq/L)– Hyponatremia worsening on 0.9% NaCl– Induced hypernatremic states

• Use equations to calculate rate/duration

The Role of Hypertonic SalineThe Role of Hypertonic Saline

• Use equations to calculate rate/duration—Medication safety issues?

– Adrogué‐Madias formula, used to predict rise in [Na+] after HTS, may underestimate correction rate, increasing risk for inadvertent overcorrection

– 10% rate of overcorrection; Higher risk for overcorrection when Na+ < 120 mEq/L

1. Zietse R et al. NDT Plus. 2009;2(Suppl 3): iii12–iii19.2. Fall PJ. Postgrad Med. 2000;107:75-82.

Newest Option for Hyponatremia:Vasopressin Antagonists

Non‐peptide AVP receptor antagonists

Conivaptan Lixivaptan Satavaptan Tolvaptan

Receptor V1a/V2 V2 V2 V2

Route of administration IV Oral Oral Oral

Urine volume ↑ ↑ ↑ ↑Urine volume ↑ ↑ ↑ ↑

Urine osmolality ↓ ↓ ↓ ↓

Na+ excretion/24 hrs ↔

↔ low dose↑ high dose

↔ ↔

Lee CR, et al. Am Heart J 2003;146:9-18.FDA Approved

CONIVAPTAN

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Conivaptan: Pivotal Phase III Trial• R, MC, DB, PC

– n = 84 patients 

• Loading dose followed by 4 day continuous infusion– Placebo– Conivaptan 40mg/day– Conivaptan 80mg/dayConivaptan 80mg/day

• Primary endpoint– ∆ in serum sodium from baseline (AUC)

• Secondary endpoints– Time from 1st dose to sodium > 4mEq/L– Time sodium > 4mEq/L from baseline– Number patients with > 6mEq/L increase in sodium or normal (>135mEq/L)

Zeltser D, et al. Am J Nephrol 2007;27:447-57.

Sodium ResponseSodium Response

From Zeltser D et al. Am J Nephrol. 2007;27:447-457.

Aquaresis with ConivaptanAquaresis with Conivaptan

2500

2000

1500

VAPRISOL 40 mg/d

Placebo

EWC

(mL)

Day 1/Hour 24

Day 2/Hour 24

Day 4/Hour 24

Data on file. Astellas Pharma US, Inc.

1000

500

0

ResultsEndpoint Placebo

N = 29Con 40mg IV

N = 29Con 80mg IV

N = 26∆ in baseline Na AUC, mean (SE), mEq*h/L

12.9 (61.2) 490.9 (56.8) † 716.6 (60.4) †

Time 1st dose to Na> 4mEq/L from BL,

median hrs (95% CI)

NE 23.7 (95%CI 10.0, 24.0) †

23.4 (95%CI 6.0, 24.0) †

Total time Na above BL 14 2 (5 25) 53 2 (5 17) † 72 7 (5 43) †Total time Na above BL, mean (SE), h

14.2 (5.25) 53.2 (5.17) † 72.7 (5.43) †

Change in Na from BL to end of treatment,mean (SE), mEq/L

0.8 (0.80) 6.3 (0.74) † 9.4 (0.79) †

Increase Na > 6mEq/L or > 135mEq/L,n (%)

6 (20.7%) 20 (69.0%) † 23 (88.5%) †

† p < 0.001, NE = not estimable Zeltser D, et al. Am J Nephrol 2007;27:447-57.

Conivaptan: open label extension study

a+ ] (m

Eq/L

)

130

135

140Conivaptan 20 mg/d (n=11)Conivaptan 40 mg/d (n=93)

Conivaptan Study day

0 5 15 30 35

Mea

n se

rum

[Na

0

125

130

120

10 20 25

Conivaptan hydrochloride injection.Prescribing information; February 2006.

Conivaptan Adverse Events

Placebo (n=29)

Con 40 mg (n=29)

Con 80 mg (n=26)

Phlebitis 6.9% 24.1% 30.8%Hypotension 6.9% 13.8% 19.2%Postural Hypotension 0% 13.8% 3.8%I j ti Sit

Zeltser D, et al. Am J Nephrology. 2007; 27: 447-457.

Injection Site Inflammation 0% 6.9% 11.5%

Pyrexia 0% 10.3% 7.7%Hyperkalemia 3.4% 0%Injection-site Thrombosis 0% 10.3% 0%

Overcorrection 0% 6.9% 7.7%

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Special Populations: Neurology

Series n Dosing Timing 6mEq/L Rise Safety

#1 22 Bolus + Infusion

24 hrs 86%

24h post D/C =

No excessive correction5 pts with

2 retrospective case series, neuro ICU patients

24h post D/C = 47%

5 pts with phlebitis

#2 24 Bolus only* 72 hrs Single Bolus:56%

Double Bolus:52%

1 pt with excessive correction

No phlebitis

*Concomitant 1.25% or 2% saline permitted Wright, et al. Neurocritical Care 2009;11:6-13

Murphy T, et al. Neurocritical Care 2009;11:14-19

Acute Hyponatremia: Neuro ICU Results

Murphy et alN=24

Wright et alN=22

Baseline [Na+] 131.4 + 3.0 130.5

Peak [Na+] within 8 hours 137.1 + 2.8 140.4

[Na+] change from baseline 6.31 + 3.0 9.9

> 4 mEq/L change by 8 hours 12/16 (75%)

> 6 mEq/L change by 8 hours 9/16 (56%) 19/22 (86%)

Correct >135 mEq/L by 8 hours 12/16 (75%) 130.5

TOLVAPTAN

SALT – 1 and SALT – 2

• Two MC, R, DB, PC trials– Tolvaptan 15 mg (increased to 30 – 60 mg)– Placebo 

• Primary Endpoints:

Study of Ascending Levels of Tolvaptan in Hyponatremia

• Primary Endpoints:– ∆ in AUC for the serum Na+ concentration 

• Baseline to day 4 • Baseline to day 30

Schrier RW, et al. NEJM. 2006; 355(20):2099 -2112.

SALT – 1 Results

Endpoint Placebon = 103

Tolvaptann = 103

p-value

All Patients: Day 4 0.25 ± 2.08 3.62 ± 2.68 < 0.001

All Patients: Day 30 1.66 ± 3.59 6.22 ± 4.10 < 0.001

Mild (130 135 l/L) D 4 0 32 ± 2 27 2 52 ± 1 95 0 001

AUC for serum Na+ (mmol/L)

Mild (130 – 135 mmol/L): Day 4 - 0.32 ± 2.27 2.52 ± 1.95 < 0.001

Mild (130 – 135 mmol/L): Day 30 0.68 ± 2.78 3.87 ± 3.01 < 0.001

Marked (< 130 mmol/L): Day 4 0.76 ± 1.77 4.56 ± 2.88 < 0.001

Marked (< 130 mmol/L): Day 30 2.54 ± 4.01 8.24 ± 3.84 < 0.001

SALT – 2 Data not shown but similar

Note: Na+ concentration similar to placeob within 5 days of D/C

Schrier RW, et al. NEJM. 2006; 355(20):2099 -2112.

SALT – 1 and SALT – 2 (continued)SALT – 1 and SALT – 2 (continued)

Schrier RW et al. N Engl J Med. 2006;355:2099-2112.

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10

SALTWATER Open-Label ExtensionSALTWATER Open-Label Extension Special Populations: Heart Failure

• R, DB, PC, MC• Patients:

—Hospitalized for HF, EF < 40%, HF symptoms— Not required to have HYPONATREMIA

EVEREST TRIALS: Short-term

• Treatment— Tolvaptan 30 mg daily— Placebo

• Primary Endpoint— Global clinical status and body weight

• Discharge or 7 days

Gheorghiade M, et al. JAMA 2007;297:1332-43.

Special Populations: Heart Failure

• Extension of short term trials

• Minimum 60 day treatment (median = 9.9 mos)– Tolvaptan/Placebo

• On top of standard HF therapy

EVEREST TRIALS: Long-term

• Primary Endpoint– All‐cause mortality

• Superiority/Non‐inferiority

– Composite: CV death or hospitalization for HF• Superiority 

• Secondary Endpoint– Δ in dyspnea, body weight, edema

Konstam MA, et al. JAMA 2007;297:1319-31.

Special Populations: Heart Failure

The Endpoints

Short – term results– Global clinical status and body weight

• Improvement with tolvaptan

Long term results

EVEREST TRIALS: Results

Long – term results– All‐cause mortality

• No difference– Composite: CV death or hospitalization for HF

• No difference– Δ in dyspnea, body weight, edema

• Improvement with tolvaptan

Konstam MA, et al. JAMA 2007;297:1319-31

Gheorghiade M, et al. JAMA 2007;297:1332-43

Recent Research in Economics

Recent Research in Economics

of Hyponatremia Management

of Hyponatremia Management

Tolvaptan: Practical Considerations• Indicated for symptomatic hyponatremia

– < 125mEq/L– Unresponsive to correction with fluid restriction– In‐hospital initiation

• Administered by oral route once daily15 mg/30 mg/60 mg– 15 mg/30 mg/60 mg

• Contraindication: Co‐administration with potent CYP3A4 enzyme inhibitors– ketoconazole, itraconazole, indinivar

• Patients should be encouraged to drink when thirsty

• Co‐administration with hypertonic saline: NR

Tolvaptan [package insert]; 2009.

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11

Tolvaptan Adverse Effects

SALT studies• No osmotic demyelination• Excessive Na+ correction = 1.8%

EVEREST• Thirst• Polyuria• Pollakiuria• Hypernatremia

Meta‐analysis of 11 randomized controlled trials in 1094 patients

ange

(mEq

/L)

8

65.70

Net

(Na)

Ser

um C

ha

4

2

Time (days)1 2 3 4

Jaber BL, et al. Am J Med. 2011; 27: 447-57

5 300

3.30

4.204.40

4.90 4.60

No trials 10 10 10 11 5 2

No. participants 1018 1018 1018 1094 258 448

Safety Analysis of VRAsAdverse Event No. Trials Summary Odds

RatioP value

Overly rapid correction of hyponatremia (high dose)*

Development of hypernatremia (high dose)*

Postural hypotension

9 (995)

6 (719)

4 (236)

3.03 (1.82-5.05)

7.75 (2.77-21.65)

2.17 (1.03-4.56)

<0.001

<0.001

0.04yp ( ) ( )Hypotension 6 (807) 1.21 (0.71-2.08) 0.48Thirst 3 (558) 3.25 (1.87-5.63) <0.001Nausea 4 (556) 1.32 (0.69-2.50) 0.40Headache 3 (522) 1.02 (0.53-1.96) 0.94Renal impairment 5 (689) 2.64 (0.80-8.79) 0.11Infusion site phlebitis 1 (84) 4.22 (1.59-11.22) 0.004Death 6 (733) 0.67 (0.38-1.18) 0.17

Jaber BL, et al. Am J Med. 2011; 27: 447-57 *No reported cases of ODS

LEVEL 2 - MODERATE SYMPTOMS: nausea, confusion,

LEVEL 3 - SEVERE SYMPTOMS:vomiting, seizures, obtundation,respiratory distress, coma

Hyponatremia Treatment OptionsHyponatremia Treatment Options

Vasopressin Antagonist or Hypertonic Saline***

Hypertonic Saline

LEVEL 1 - NO OR MINIMAL SYMPTOMS: headache, irritability, inability to concentrate, altered mood, depression

disorientation, altered mental status

Fluid restrictionConsider vasopressin antagonist or hypertonic saline if…•Unable to tolerate fluid restriction or failure of fluid restriction

•Need for rapid correction of Na+

Hypertonic Saline

***Vasopressin antagonists may be preferred if volume overloaded

Community-Acquired

Hyponatremia*(37.9%)

Hospital Aggravated

Hyponatremia†

(5.7%)

Hospital-Acquired

Hyponatremia‡

(38.2%)

53,236 adult patients admitted to an academic medical center

Hyponatremia Treatment OptionsHyponatremia Treatment Options

Wald R et al. Arch Intern Med. 2010;170:294-302.

OR for in-hospital mortality 1.52 2.30 1.66

Adjusted increasein LOS 14% 40% 64%

OR for discharge to short- or long-term care facility

1.12 1.73 1.64

Pharmacist Roles and ResponsibilitiesPharmacist Roles and Responsibilities

• Monitor for hyponatremia• Consider drug related causes• Educate clinicians on hyponatremia• Participate in clinical decision making• Participate in formulary decision making• Be the catalyst for protocol development• Ensure optimal management of hyponatremia