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Hyponatremia: Obstacles and Opportunities for Clinical Pharmacists

© 2013 Paradigm Medical Communications, LLC, except where noted.

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© 2013 Paradigm Medical Communications, LLC

except where noted.

Hyponatremia

Obstacles and Opportunities for Clinical Pharmacists

Introduction of Case Study & The Pharmacist’s Role in Hyponatremia Management

The Pathophysiology of Hyponatremia

A Practical Approach to Hyponatremia Management: Conventional & Novel Therapies

Discussion and Q&A

Agenda

Hyponatremia: Signs, Symptoms, and Clinical Burden



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Case StudyHyponatremia in SIADH

� An 80-year-old woman was referred to the clinic for management of chronic hyponatremia

� Patient’s daughter explained that her mother’s symptoms had been getting increasingly worse, including

� Weakness and feeling “shaky”

� Unsteady gait and falls

� Memory problems

� Poor response to fluid restriction and loop diuretics

1

Case StudyHistory

� Chronic systolic heart failure

� DVT

� HTN

� Anemia

� Severe pulmonary HTN

� GERD

� COPD

� Insomnia

� Anxiety

� Social history

� Widow

� No alcohol, cigarette, drug use

� Lives at home with daughter

� No known drug allergies

� Family history

� Both patients had CAD

� Mother died from breast cancer

in her 80s

2CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; DVT, deep venous thrombosis,

GERD, gastroesophageal reflux disease; HTN, hypertension.



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Case StudyCurrent Medications

� Carvediol 25 mg bid

� Warfarin 5 mg qd

� Olmesartan 20 mg qd

� Rabeprazole 20 mg qd

� Tiotropium 18 µg inhaled qd

� Fluoxetine 10 mg qd

� Furosemide 20 mg qd

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Case StudyPhysical Exam

� Pleasant, alert, and oriented

� BP 122/68 mm Hg, HR 72 bpm, RR 18, temp: 97.4°F

� HEENT: moist mucous membranes, EOMI

� Neck: supple, no JVD, no bruits

� Chest: good air entry, clear to auscultation, no rales

� Heart: S1, S2, RRR, no rub

� Abdomen: soft, nontender, normal bowel sounds

� Extremities: no edema

� Musculoskeletal: muscle strength 5/5 all extremities, sensory intact to light touch, DTRs equal in biceps and patella bilaterally

DTR, deep tendon reflex; EOMI, extraocular movements intact; HEENT, heart, eyes, ears, nose, and throat;

HR, heart rate; JVD, jugular venous distension; RR, respiratory rate; RRR, regular rate and rhythm. 4



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Case StudyLaboratory Results

BUN, blood urea nitrogen; [Na+], serum sodium concentration; NT-proBNP, N-terminal prohormone of brain

natriuretic peptide; WNL, within normal limits. 5

2 wk prior to exam

Serum [Na+]: 121 mEq/L

Day of exam

Serum [Na+]: 128 mEq/L Creatinine: 1.1 mg/dL

Serum [K+]: 4.6 mEq/L Glucose: 78 mg/dL

Serum [Ca+]: 9.4 mEq/L Albumin: 4.5 g/dL

Uric acid: 3.6 mg/dL Liver function tests: WNL

BUN: 22 mg/dL NT-proBNP: 350 pg/mL

6 d after exam

Serum [Na+]: 121 mEq/L Urine osmolality: 254 mOsm/kg

Serum osmolality: 259 mOsm/kg

Many Roles of the Pharmacist

Monitor for hyponatremia development +

resolution

Consider a more pathophysiologic

approach to diagnosis and

treatment

Consider drug-related causes of

hyponatremia

Ensure appropriate monitoring for morbidities of hyponatremia

Ensure optimal management of hyponatremia

Participate in clinical decision

making

Participate in formulary decision making

and address cost-containment concerns

beyond acquisition costs

Educate clinicians on hyponatremia

Develop preventative hospital systems directed toward hyponatremia

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The Pathophysiology of Hyponatremia

Learning Objective

� Summarize the pathophysiology of hyponatremia with an appreciation for the role of vasopressin

Hyponatremia: Incidence

� Common definition: serum sodium concentration ([Na+) ≤135 mEq/L, but cut-off values vary

� Typically occurs due to excess body water diluting serum sodium as a result of excess vasopressin / AVP/ ADH

� Most common electrolyte disorder seen in clinical practice1-3

� Occurs in up to 3.2 to 6.1 million persons annually4

� Up to 15% of hospitalized patients, 24.5% of ICU patients5,6

� ≈ 1 million annual hospitalizations with 1° or 2° discharge diagnosis of hyponatremia4

� Incidence increases with age7

AVP, arginine vasopressin; ADH, antidiuretic hormone; ICU, intensive care unit.

1. Ellison DH et al. N Engl J Med. 2007;356: 2064-2072. 2. Verbalis JG et al. Am J Med. 2007;120:S1-S21. 3. Upadhyay A et al. Am J Med.

2006;119(7A):S30-S35. 4. Boscoe A et al. Cost Eff Resour Alloc. 2006;4:10. 5. Baylis PH. Int J Biochem Cell Biol. 2003;35:1495-1499.

6. Cawley M. Ann Pharmacother. 2007;41(5):840-850. 7. Hawkins RC. Clinica Chimica Acta. 2003;337:169-172. 8



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Hyponatremia: Underreported, Often Mismanaged

� Clinical lab values vsICD-9 codes 1999–2000

� 2632 cases of hyponatremia identified using lab data alone

� 66% did not have appropriate ICD-9 code� 94% of moderately hyponatremic

patients

� 87% of severely hyponatremic patients

� Review of 104 patients with serum [Na+] <125 mEq/L from 6-mo lab/chart data in large teaching hospital� 49% of diagnoses inconsistent

with clinical details

� 33% had “significant” management errors

Movig K et al. J Clin Epidemiol. 2003;56:530-535. 9

Reported cases of hyponatremia from databases represent

only 1/3 of cases

41

20

0

20

40

60

Management Errors Appropriate

Management

Mortality, %

Huda MS et al. Postgrad Med J. 2006;82:216-219.

Classification of Hyponatremia

Dilutional Hyponatremia

Total body water INCREASED

The most common type

SIADHHypothyroidismSecondary adrenal

insufficiency

Hypervolemic(edema)

Total body sodiumINCREASED

Heart failureCirrhosisNephrotic syndromeRenal failure

Depletional Hyponatremia

Total body water DECREASED

Hypovolemic

Total body sodium DECREASED

Diarrhea PancreatitisVomiting Diuretic useBurns Renal salt wastingTrauma Primary adrenal

insufficiency

Euvolemic(no edema)

Total body sodiumUNCHANGED

SIADH, syndrome of inappropriate antidiuretic hormone secretion.Cawley M. Ann Pharmacother. 2007;41(5):840-850. Cole CD et al. Neurosurg Focus. 2004;16(4):E9. 10



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Etiologies of Hypo-osmolarHyponatremia

CNS, central nervous system.Cole CD et al. Neurosurg Focus. 2004;16(4):E9. Verbalis JG et al. Am J Med. 2007;120:S1-S21. 11

Hypervolemia

Heart failure

Cirrhosis

Nephrotic

syndrome

Anaphylaxis

Renal failure

Sepsis

Pregnancy

Euvolemia

SIADH

• Tumors

• CNS disorders

• Drug-induced

• Pulmonary diseases

• Other

Glucocorticoid deficiency

Hypothyroidism

Primary polydipsia

Hypovolemia

Thiazide diuretics

Cerebral salt wasting

Mineralocorticoid deficiency

Salt-wasting nephropathy

Bicarbonaturia, glucosuria,

ketonuria

Gastrointestinal losses

Third space losses

Sweat losses

Most often a complication of other illnesses in which excess water accumulates in the body at a higher rate than can be excreted

Receptor-Mediated Effects of Arginine Vasopressin (AVP)

� Plasma osmolality (Posm) is regulated by thirst and release of AVP

� Also known as antidiuretic hormone (ADH)

Receptor

subtype Site(s) of action Activation effects

V1a

� Vascular smooth muscle cells1

� Platelets1

� Lymphocytes and monocytes1

� Liver1

� Vasoconstriction, myocardial stimulation1

� Platelet aggregation1

� Cytokine release2

� Glycogenolysis1

V1b� Anterior pituitary1 � Release of ACTH1

and β-endorphin3

V2� Renal collecting duct1

� Renal free water absorption1

1. Verbalis JG. J Mol Endocrinol. 2002;29(1):1-9.

2. Loxley HD et al. Neuroendocrinology. 1993;57:801-814.

3. Kjaer A. Acta Endocrinol. 1993;129:489-496. 12



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Pathophysiology of Hyponatremia

AQP2, aquaporin-2; cAMP, cyclic adenosine monophosphate; PKA, protein kinase A; V2, vasopressin-2.© Leiden University. From Dubois EA et al. Br J Clin Pharmacol. 2012;73(1):9-11.

� Increased AVP concentrations increase activity of V2 receptors in renal collecting ducts

� This activates synthesis of adenylate cyclase, cAMP, and PKA, enhancing expression of AQP2 channels

� AQP2 channels transport water molecules from collecting duct back into circulation, resulting in decreased Posm and reduced urine volume

� Na+ excretion continues, resulting in hyponatremia

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Dysregulation of Normal AVP Response Complicates Many Disease States

SAH, subarachnoid hemorrhage; TBI, traumatic brain injury.

1. Greenberg H. 2011. Available at: www.medscape.org/viewarticle/753199_transcript. Accessed May 1, 2013. 2. Goldsmith SR.

Am J Cardiol. 2005;95(suppl):14B-23B. 3. Porcel A et al. Arch Intern Med. 2002;162:323-328. 4. Nair V et al. Am J Nephrol.

2007;27:184-190. 5. Tang WW et al. Am J Med. 1993;94(2):169-174. 6. Agha A et al. J Clin Endocrinol Metab. 2004;89:5987-5992.

7. Speedy DB et al. Med Sci Sports Exerc. 1999;31:809-815.

During extreme exercise (marathons + triathlons), up to 29% of athletes develop hyponatremia.7

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Disease State

Prevalence of Hyponatremia in

Hospitalized Patients Mechanism

Heart failure (HF)1,2 ≈20% Neurohormonal activation

Cirrhosis3 35% Neurohormonal activation

Community-acquired pneumonia4 10%–28% SIADH ± reset osmostat

AIDS5 38% SIADH

Neurologic injury (TBI, SAH, infection, intracerebral hemorrhage, massive cerebral infarction, others)6

2.3%–36.6% SIADH, idiopathic



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CNS, central nervous system; MAOIs, monoamine oxidase inhibitors; TCAs, tricyclic antidepressants;

SSRIs, selective serotonin reuptake inhibitors.

1. Adrogué HJ. Am J Nephrol. 2005;25:240-249. 2. Liamis G et al. Am J Kidney Dis. 2008;52(1):144-153.

3. Fourlanos S et al. Aust Prescr. 2003;26:114-117. 15

Hyponatremia: Risk Factors

Drugs� Antidepressants

(TCAs, SSRIs, MAOIs)1,2

� Antiepileptics1

� Antihypertensives3

� Antipsychotics1

� Anticancer agents1

� Diuretics1

� NSAIDS3

� Opiate derivatives1

� Proton-pump inhibitors3

Miscellaneous conditions� Adrenal insufficiency1

� Cirrhosis1

� CNS impairment1

� Heart failure1

� Low body weight2

� SIADH3

� Surgery or injury1

� Very old age1

� Very young age1

Mechanisms of Drug-Induced Hyponatremia

Antidepressants

Antipsychotics

Antiepileptics

Antineoplastic agents

Opiates

Antidiabetic drugs

Antiepileptics

Antineoplastic agents

NSAIDs

Thiazide diuretics/indapamide

Amiloride

Loop diuretics

↑↑↑↑ Effect of AVP at renal tubule level

Altered Na / H2O homeostasis

↑↑↑↑ Hypothalamic production of AVP

Liamis G et al. Am J Kidney Dis. 2008;52(1):144-153. 16



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SSRI-Induced Hyponatremia

� 0.5%‒32% incidence1

� Most cases during first few weeks of therapy1

� Normal serum [Na+] usually achieved within 2 weeks following discontinuation of drug

� Risk factors

� Older age1,2

� Concomitant diuretic therapy1,2

� Low body weight2

� Baseline serum [Na+] <138 mEq/L2

171. Liamis G et al. Am J Kidney Dis. 2008;52(1):144-153. 2. Jacob S et al. Ann Pharmacother. 2006;40(9):1618-1622

Hyponatremia: Signs, Symptoms, and Clinical Burden

Learning Objective

� Identify the signs, symptoms, and clinical consequences of hyponatremia



11

Osteoporosis

and

fracturesHyponatremia

Consequences of Hyponatremia

Gait

disturbances

and falls

Neurologic

dysfunction and

decreased mental

function

Cerebral

edemaSeizures,

coma

Increased

mortality

risk

Increased

hospital

LOS

Increased

rate of ICU

admission

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Hyponatremia & Neurologic Dysfunction

*The SF-12 is a subset of the SF-36 Health Survey and has been shown to reproduce at least 90% of the variance in PCS-36 and MCS-36 in both general and patient populations.

Advisory Committee Meeting of the Cardiovascular and Renal Drugs Division of the US Food and Drug Administration. June 25, 2008.

Available at: www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4373b1-05.pdf. Accessed March 15, 2013. 20

SF-12* Mental Component Summary (MCS)

Depression



12

Correction of Hyponatremia Improves Mental Function

Mean change in MCS score from baseline

� Statistically greater mean improvement observed with tolvaptan than with placebo

� Clinically meaningful improvement in mentalfunction

21Advisory Committee Meeting of the Cardiovascular and Renal Drugs Division of the US Food and Drug Administration. June 25, 2008.

Available at: www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4373b1-05.pdf. Accessed March 15, 2013.

5.3

4.7

5.95.4

1.6

0.2

1.92.4

Total Cirrhosis CHF SIADH

MCS

Tolvaptan

Placebo

*P<.05

**

Hyponatremia, Gait Instability,& Falls

� Case-control study of 122 patients with asymptomatic chronic hyponatremia ([Na+] 126 ± 5 mEq/L), 244 matched controls

� Hyponatremic patients more often admitted for falls than controls (21.3% vs 5.3%; P <.001)

� Frequency of falls the same—regardless of level of hyponatremia

� Gait instability significantly increased in patients with chronic hyponatremia

� Attention errors increased 1.2-fold (P=.001) in hyponatremic patients compared with normal controls

� Comparable to increase observed after moderate alcohol intake in healthy volunteers

Renneboog B et al. Am J Med. 2006;119:71.e1-8. 22



13

Reprinted from Renneboog B et al. Mild chronic hyponatremia is associated with falls, unsteadiness,

and attention deficits. Am J Med. 2006;119:71.e1-8. © 2006, with permission from Elsevier.

Gait stability assessed in 16 hyponatremic patients ([Na+] 124-130 mEq/L)� Patients asked to walk on pressure mat� Skew from midline of path measured as length of walk

Correction of Hyponatremia Stabilizes Gait

Gait instability significantly increased in hyponatremia Gait stability normalized

Correctionof hyponatremia

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Hyponatremia & Fractures in Ambulatory Falls

� Case-control study of bone fractures after incidental fall1

� Patients presenting with falls and fractures had significantly higher incidence of hyponatremia (13.1%) than age-matched controls (3.9%)

� Hyponatremia drug-induced in 53% (36% diuretics, 17% SSRI),

� Hyponatremia due to SIADH in 37%

• Hyponatremia significantly associated with fracture (P=.01) 2

� Independent of age and gender2

� Even mild chronic hyponatremia increases fracture risk3

1. Gankam Kengne FG et al. Q J Med. 2008;101:583-588. 2. Sandhu HS et al. Int Urol Nephrol. 2009;41:733-737.

3. Hoorn EJ et al. J Bone Miner Res.. 2011;26(8):1822-1828. 4. Verbalis JG et al. J Bone Miner Res. 2010;25(3):554-563. 24

Bone quality should be assessed in all patients with chronic hyponatremia4



14

� 1-y study of 4123 patients (≥65 y) admitted to community hospital; 3.5% had admission serum [Na+]<130 mEq/L1

� Mortality increased as serum [Na+] decreased

� Admission hyponatremia significant predictor of in-hospital mortality (RR, 1.95; P<.006)

� Even mild hyponatremia is associated with increased in-hospital mortality2

� Mild hyponatremia also associated with increased mortality in an ambulatory setting3

Hyponatremia is an Independent Risk Factor for In-Hospital Mortality

8

15

19

0

5

10

15

20

>129

mEq/L

120-129

mEq/L

<120

mEq/L

Mortality, %1

RR, relative risk.1. Terzian C et al. J Gen Intern Med. 1994;9:89-91. 2. Waikar SS et al. Am J Med. 2009;122:857-865.

3. Gankam-Kengne F et al. Kidney Int. 2013;83(4):700-706. 25

Impact of Hyponatremia on Selected Hospital Outcomes

HN Cohort Non-HN Cohort P-Value

LOS, d 8.8 ± 10.3 7.7 ± 8.5 < .001

Hospital Admission Costs $15,281 ± $24,054 $13,439 ± $22,198 < .001

ICU LOS, d 5.5 ± 7.9 4.9 ± 7.1 < .001

ICU Costs $8525 ± $13,342 $7597 ± $12,695 < .001

Increased Chance of Hospital

Readmission 30 d Postdischarge15% < .0001

261. Amin A et al. J Hosp Med. 2012;7:634–639

� 558,815 hyponatremic (HN) patients selected from Premier Hospital Database from 1/1/07 to 3/31/10, matched to 558,815 non-HN control cohort using propensity score matching

� Differences in healthcare resource utilization, costs, and hospital readmissions between cohorts calculated using bivariate and multivariate statistics



15

Symptoms Correlate with Severity & Rate of Decline in Serum [Na+]1

� Asymptomatic presentation is common2

� May present with mild, nonspecific symptoms1

� Degree of symptomatology is surrogate for duration of hyponatremia1

� Symptoms from underlying disease process is also common1

Symptom

Respiratory arrest

Coma

Seizures

Delirium

Restlessness

Lethargy

Headache

Fatigue

Confusion

Nausea + vomiting

Asymptomatic

Increasing severity of

hyponatremia and rate of

[Na+] decline

271. Bagshaw SM et al. J Can Anesth.2009;56:151-167. 2. Ghali K. Cardiology. 2008;111:147-157.

Acute Versus Chronic Hyponatremia

� Life-threatening: usually ACUTE

� Symptomatic but less impaired: usually CHRONIC

28

Acute (≤48 h) Chronic (>48 h)

Symptoms include:

• Cerebral edema

• Seizures

• Increased mortality risk

Symptoms include:

• Nausea/vomiting

• Confusion or personality changes

• Neurologic dysfunction

• Gait disturbances

• Seizures (with very low serum [Na+] levels)

Rapid correction reverses cerebral

edema without sequelae

Rapid correction may cause brain dehydration

and osmotic demyelination syndrome (ODS)



16

H2O moves into brain along osmotic gradients,

causing symptomatic cerebral edema

Extracellular Na+

decreases byNa+ loss or H2O gain

29

Hypotonic state

Compensatory mechanism begins

Water gain

Cerebral swelling

When brain swelling >8%, it exceeds

skull capacity

Acute hyponatremia(≤48 h)

Chronic hyponatremia

(>48 h)

Gullans SR et al. Annu Rev Med. 1993;44:289-301. Verbalis JG. Endocrinol Nutr. 2010;57(Suppl 2):30-40.

Loss of electrolytes and osmolytes

decreases brain solute content

Brain edema is virtually absent

Herniation and death

Pathophysiology Adaptation

Acute Versus Chronic Hyponatremia

A Practical Approach to Hyponatremia Management:

Conventional and Novel Therapies

Learning Objective

� Describe appropriate pharmacologic strategies for managing hyponatremia



17

Treatment Overview

� Most important treatment factors� Severity of neurologic symptoms1,2

� Volume status1,2

� Acute vs chronic2,3

� Identify likely cause of hyponatremia1

� Principles to guide treatment� Weigh risks and benefits4

� Neurologic consequences can follow both failure to promptly treat and excessively rapid rate of correction3

� Even modest improvement in serum [Na+] have survival benefits5

� Monitor serum [Na+] frequently2,6

� Address underlying disease and stop offending medications1

311. Ellison DH et al. N Engl J Med. 2007;356:2064-2072. 2. Lien YH et al. Am J Med. 2007;120:653-658. 3. Ghali K. Cardiology.

2008;111:147-157. 4. Adrogue HJ et al. N Engl J Med. 2000;342:1581-1589. 5. Rossi J et al. Acute Card Care. 2007;9:82-86.

6. Vaidya C et al. Cleve Clin J Med. 2010;77(10):715-726.

Correct Serum [Na+] to Safe Level at Safe Rate

Insufficient correction1

Cerebral edema ODS

Too aggressive correction1

32

� Raise [Na+] by <8–12 mEq/L in 1st 24 h1-3

� Raise [Na+] by <18 mEq/L in 1st 48 h1

� Symptomatic: 1 mEq/L/h until neurologic symptoms resolve or [Na+] ≥120 mEq/L or a total magnitude correction of 18 mEq/L is achieved1,2

1. Verbalis JG et al. Am J Med. 2007;120:S1-S21. 2. Kumar S et al. In: Atlas of Diseases of the Kidney. 1999:1.1-1.21.

3. Adrogue HJ et al. N Engl J Med. 2000;342:1581-1589.



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Risks of Hyponatremia & Correction: A Balancing Act

Acute hyponatremia

Marked brain edema

Minimal brain volume

regulation

Chronic symptomatic hyponatremia

Some brain edema

Partial brain volume

regulation

Chronic asymptomatic hyponatremia

Minimal brain edema

Complete brain volume

regulation

Verbalis JG. Trends Endocrinol Metab. 1992;3(1):1-7.

Risks of

hyponatremia

Risks of

correction

33

Serum [Na+] =Na+

E + K+E

Body water

2. Subtract from

the denominator

1. Add to the

numerator

Na+E, exchangeable sodium; K+

E, exchangeable potassium.

Adrogue HJ et al. N Engl J Med. 2000;342:1581-1589. 34

Correcting Hyponatremia



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Case StudyReview

80-year-old woman with multiple medical problems including HF, HTN, GERD, COPD

� She has chronic hyponatremia (current [Na+] 121 mEq/L) and symptoms consistent with this diagnosis

� She has had a poor response to fluid restriction and a loop diuretic (furosemide)

� No evidence of fluid overload at this time

35

Case StudyEtiology

What is the most likely etiology of this patient’s hyponatremia?

A. Heart failure

B. Drug-induced (SSRI)

C. Pulmonary disease

D. Drug-induced (diuretic)

36



20

Case StudyNext Steps

What are the treatment considerations?

What are the treatment options?

A. Hypertonic saline infusion

B. Addition of NaCl tablets

C. AVP receptor antagonist

D. Fluid restriction to <1 L/d

37

Treatments for Hyponatremia

1. Goldsmith SR. Am J Cardiol. 2005;95(suppl):14B-23B. 2. Verbalis JG. Endocrinol Nutr. 2010;57(suppl 2):30-40. 3. Kumar S et al. In: Schrier RW et al (eds). Atlas of Diseases of the Kidney. Vol. 1. Philadelphia, PA: Current Medicine, Inc; 1999:1.1-1.22. 4. Rosner MH. Kidney Int. 2012;82(11):1154-1156. 5. Decaux G et al. Lancet. 2008;371:1624-1632. 38

Treatment1,2 Benefits Limitations

Saline infusion

• Rapid response in

symptomatic patients1

• Complex calculations1

• Not be used in edema-forming

disorders2

Fluid restriction• Inexpensive3 • Slow and limited response1,4

• Adherence concerns1,3

Demeclocycline

• No need to limit water intake3

• Targets excessive AVP1

• Slow response1,4

• Nephrotoxic in CHF and

cirrhosis1,3,4

Loop diuretics• Allows relaxation of fluid

restriction4

• May cause volume, K+ , + Mg+

depletion1

AVP receptor

antagonists

• Target excessive AVP4

• Aquaresis (solute-free urine

output)1,3

• Not to be used in hypovolemic

states5



21

The Role of Hypertonic Saline (HTS)

� Consider HTS (3% NaCl) when� Symptomatic hyponatremia (seizure, coma)1

� Acute severe hyponatremia (<24 h, <120 mEq/L)2

� Hyponatremia worsening on normal saline (0.9% NaCl) 3

� Induced hypernatremic states for prevention/treatment of cerebral edema4

� Discontinue HTS when serum [Na+] reaches 125–130 mEq/L3

� Exception: states of cerebral edema with Na+ augmentation

� Safety concerns: requires ICU monitoring2

� Adrogué-Madias formula, used to predict rise in [Na+] after HTS, may underestimate correction rate, increasing risk for inadvertent overcorrection1

� No randomized trials performed1

� HTS may or may not be combined with loop diuretic1

1. Zietse R et al. NDT Plus. 2009;2(Suppl 3): iii12–iii19. 2. Verbalis JG. Endocrinol Nutr. 2010;57(Supl. 2):30-40. 3. Adrogue HJ et al. N Engl J Med. 2000;342:1581-1589. 4. Murphy N et al. Hepatology. 2004;39(2):464-470. 39

Fluid Restriction

� Standard procedure: restrict fluid to <1 L/d1

� Slow rate of improvement2

� Poor patient adherence2

� Predictors of failure3

� High Uosm (>500 mOsm/kg H2O)

� Urine [Na+] and [K+] > serum [Na+]

� 24-h urine output <1,500 mL/d

� Increase in serum [Na+] <2 mEq/L in 24 h

� Not appropriate for hypovolemic hyponatremia4

40Uosm, urine osmolality.1. Goldsmith SR. Am J Cardiol. 2005;95(suppl):14B-23B. 2. Rosner MH. Kidney Int. 2012;82:1154–1156.3. Courtesy of Joseph G. Verbalis, MD. 4. Adrogue HJ et al. N Engl J Med. 2000;342:1581-1589.



22

Demeclocycline

� Causes nephrogenic form of diabetes insipidus, decreasing urine concentration even in presence of high plasma AVP levels

� Dose: 600 to 1,200 mg/d in divided doses� Takes several days to achieve maximal diuretic effects

� Wait 3–4 d before deciding to increase dose

� Can cause � Reversible azotemia

� Nephrotoxicity (especially in patients with cirrhosis)

� Monitor renal function on regular basis, discontinue if increasing azotemia

41Verbalis JG et al. Am J Med. 2007;120(11A):S1-S21.

Loop Diuretics

� Increase rate of urine flow, excretion of Na+ and Cl-1

� Allow relaxation of fluid restriction2

� Can be used in SIADH patients when fluid restriction alone is insufficient, taking care to avoid hypovolemiafrom diuretic-induced sodium losses3

� Can enhance free water excretion and help prevent volume overload in patients being treated with HTS for acute symptomatic hyponatremia4

� Potential for volume depletion, K+ and Mg2+ depletion, ototoxicity1,5

421. Goldsmith SR. Am J Cardiol. 2005;95(suppl):14B-23B. 2. Rosner MH. Kidney Int. 2012;82:1154–1156. 3. Goh KP et al. Am Fam

Physician. 2004;69:2387-2394. 4. Lauriat SM et al. J Am Soc Nephrol. 1997;8(10):1599-1607. 5. Kumar S et al. In: Schrier RW et al (eds). Atlas of Diseases of the Kidney. Vol. 1. Philadelphia, PA: Current Medicine, Inc; 1999:1.1-1.22.



23

The Vaptans: Overview

1. Decaux G et al. Lancet. 2008;371:1624-1632. 2. Hline SS et al. Ther Clin Risk Manag. 2008;4(2):315-326. 3. Verbalis JG. Cleve Clin J

Med. 2006;73(Suppl 3):S24-S33. 4. Zietse R et al. NDT Plus. 2009; 2(Suppl 3):iii12-19. 5. Ross E, Sigal SH. J Hosp Med. 2010;5(6):S8-S17.

6. Zmily HD et al. Int J Nephrol Renovas Dis. 2011;4:57-71. 7. Samsca (tolvaptan)[prescribing information]. Rockville, MD: Otsuka

America Pharmaceutical, Inc.; April 2013. 8. Lixivaptan. www.drugs.com/nda/lixivaptan_120913.htm. Accessed April 30, 2013. 43

Agent

Receptor

Selectivity/

Affinity Route

t1/2,

h

Urine

Volume

Urine

Osmolality FDA Status

Therapy

Duration

Conivaptan

Mixed (V1A+V2);1

V2 affinity 10××××that of V1A

2

IV1 3–81,2 ↑↑↑↑3,4 ↓↓↓↓3,4Approved

20055 4 d1

Tolvaptan

Selective for V2;3,4

V2 affinity 1.8××××native AVP;

V2 affinity 29××××that of V1A

Oral1 6–121,6 ↑↑↑↑3,4 ↓↓↓↓3,4Approved

20095 <30 d7

Lixivaptan V23,4 Oral1 7–101 ↑↑↑↑3,4 ↓↓↓↓3,4

Additional

data

requested8

NA

The Vaptans: Mechanism of Action

© Leiden University. From Dubois EA et al. Br J Clin Pharmacol. 2012;73(1):9-11.

� Vaptans block effects of AVP in the kidney

� This results in fewer AQP2

channels in the apical membrane

� Fewer water molecules are retained and more water is excreted in urine

� Posm eventually increases and normal plasma [Na+] achieved

44



24

Conivaptan Clinical Studies

� Double-blind, placebo-controlled, randomized, multicenter study of 84 patients with euvolemic/hypervolemic hyponatremia (serum [Na+] 115 to <130 mEq/L); all received fluid restriction ≤2 L/d1

� Conivaptan administered 20 mg loading dose (over 30 m) with 4-d continuous infusion of either 40 mg/d or 80 mg/d

� Mean increase in serum [Na+]from baseline significantly higher with conivaptan vs placeboat 24, 48, 72 h posttreatment

Conivaptan 80 mg: 8.1–8.8 mEq/L

Conivaptan 40 mg: 6.4–6.9 mEq/L

Placebo: 0.4–1.9 mEq/L

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

Reproduced with permission of S./KARGER AG in the format reuse in CME materials via Copyright Clearance Center.

Conivaptan Clinical Studies (continued)

� Mean free water clearance from baseline to treatment Days 1 + 2 significantly higher with conivaptan 40 + 80 mg/d than placebo (P<.001, P=.03)1

� Most common AEs: hypotension, postural hypotension, infusion site inflammation, pyrexia, hyperkalemia (no ODS)1

� In an open-label extension trial, mean serum [Na+] was maintained over time2

AE, adverse event. 1. Zeltser D et al. Am J Nephrol. 2007;27:447-457.

2. VAPRISOL (conivaptan hydrochloride injection)

[prescribing information]. Deerfield, Ill: Astellas

Pharma US, Inc.; October 2012. 46120

125

130

135

140

Baseline Day 11 Day 34

Mean

seru

m [

Na+

], m

Eq

/L

Conivaptan 20 mg/d (n=37)

Conivaptan 40 mg/d (n=214)



25

Tolvaptan Clinical Studies(SALT-1, SALT-2, SALTWATER)

� 2 double-blind, randomized, multicenter studies of 448 patients with euvolemic or hypervolemic hyponatremia (serum [Na+] <135 mEq/L) treated with placebo or tolvaptan, 15 mg/d

� For first 4 d, dose could be increased from 15–30 mg or from 30–60 mg

� If serum [Na+] rose above 145 mEq/L or increased too fast (>12 mEq/L in 24 h or >8 mEq/L in 8 h on Day 1), the next dose was withheld or decreased, or fluid intake was increased

� Serum [Na+] increased more in tolvaptan group than in placebo group during first 4 d (P<0.001) and after full 30 d of therapy (P<0.001)

47Schrier RW et al.

N Engl J Med. 2006;

355:2099-2112.

SALT-1 SALT-2

Tolvaptan Placebo Tolvaptan Placebo

Baseline 128.5 ± 4.5 128.7 ± 4.1 129.0 ± 3.5 128.9 ± 4.5

Day 4 133.9 ± 4.8 129.7 ± 4.9 135.3 ± 3.6 129.6 ± 5.2

Day 30 135.7 ± 5.0 131.0 ± 6.2 135.9 ± 5.9 131.5 ± 5.7

Tolvaptan Clinical Studies (SALT-1, SALT-2, SALTWATER continued)

� Increase in serum [Na+] in tolvaptan group sustained 30 d1

� Most common AEs: thirst, dry mouth, polyuria (no ODS)1

� In an open-label study, increases in serum [Na+] were significant and maintained over the long term (mean follow up 701 d)2

481. Schrier RW et al. N Engl J Med. 2006;355:2099-2112. 2. Advisory Committee Meeting of the Cardiovascular and Renal Drugs Division

of the US FDA. June 25, 2008. Available at: www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4373b1-05.pdf. Accessed March 15, 2013.



26

SIADH Cost Analysis

� Cost estimate methods

� HCUP 2009 Nationwide Inpatient Sample database� 21,718 patients hospitalized for SIADH: mean LOS 5.7 d, mean hospital cost $8667

� Used tolvaptan treatment duration of 4 d at $250/dose

� LOS reduction estimate based upon SALT-1 and SALT-2 trials� SIADH patients receiving tolvaptan had shorter hospital LOS (4.98 vs 6.19 d)

� Results

� Cost offset model estimated LOS reduction of 1.11 d and total cost offset of $694 per admission� 95% CI for cost offset using Monte Carlo simulation was $73‒$1405

� Cost-neutral break-even mean duration of tolvaptan inpatient use: 6.78 d

� Use of tolvaptan to treat these 21,718 patients identified in the HCUP population would result in total cost offset >$15 million

CI, confidence interval.Dasta JF et al. Hosp Practice. 2012;40(1):1-8. 49

Bioavailability of Tolvaptan Administered via NG Tube

� Tolvaptan 15 mg crushed and administered via NG tube vs oral tablet swallowed intact (each with 240 mL H20)� Randomized crossover study in 28 healthy fasted adults

� Administration with NG tube compared with oral intact tablet� Cmax ≈10% lower and AUCt and AUC

∞≈25% lower

� No evidence of different aquaresis� 24-h urine output 2.8% lower with NG tube

AUC, area under the curve; Cmax,, maximum concentration; NG, nasogastricMcNeely EB et al. Am J Health Syst Pharm. 2013;70:1230-1237.

Relative Bioavailability

Est. Ratio of Geometric Means With NG vs Oral

Administration, % 90% CI

Cmax (ng/mL) 88.9 80.1–98.6

AUCt (ng � h/mL) 74.3 68.1‒81.0

AUC∞ (ng � h/mL) 74.2 68.1–80.9

50

Mean plasma concentration–

time profiles after oral vs

NG tube administration



27

The Vaptans: Contraindications & Precautions

Conivaptan/tolvaptan1,2

� Do not use with potent CYP3A and P-glycoprotein inhibitors, or in hypovolemic or anuric patients

� Use with caution in patients with hepatic or renal impairment

� Monitor serum [Na+] and neurologic status

Conivaptan1

� Do not use in patients with known allergy to corn or corn products

� May cause significant infusion site reactions

Tolvaptan2

� Do not use in patients unable to respond appropriately to thirst

� Liver injury noted in study of ADPKD patients (incidence of ALT >3x ULN in 4.4% [42/958] of tolvaptan patients vs 1.0% [5/484] of placebo patients)

� Therefore, limit treatment to 30 d, discontinue treatment if hepatic injury suspected, avoid use in patients with underlying liver disease

51

ADPKD, autosomal dominant polycystic kidney disease; ULN, upper limit of normal.

1. Vaprisol (conivaptan hydrochloride injection)[prescribing information]. Deerfield, Ill: Astellas Pharma US, Inc.; October 2012.

2. Samsca (tolvaptan)[prescribing information]. Rockville, MD: Otsuka America Pharmaceutical, Inc.; April 2013.

The Vaptans: Drug–Drug Interactions

Conivaptan1

� Substrate/inhibitor of CYP3A

� Concomitant use of conivaptan

and potent CYP3A inhibitors

(ketoconazole, itraconazole,

clarithromycin, ritonavir, or

indinavir) is contraindicated

� Generally avoid CYP3A

substrates

� Exposure to coadministered

digoxin may be increased and

digoxin levels should be

monitored

Tolvaptan2

� Substrate of CYP3A

� Concomitant use of tolvaptan and potent CYP3A inhibitors (ketoconazole, itraconazole, clarithromycin, ritonavir, or indinavir) is contraindicated

� Avoid use with CYP3A inducers and moderate CYP3A inhibitors

� Does not significantly change pharmacokinetics of other CYP3A substrates

� Coadministration with digoxin results in 1.3-fold increase in digoxin Cmax

� Coadministration with P-gp inhibitors may require dose reduction of tolvaptan

521. Vaprisol (conivaptan hydrochloride injection)[prescribing information]. Deerfield, Ill: Astellas Pharma US, Inc.; October 2012.

2. Samsca (tolvaptan)[prescribing information]. Rockville, MD: Otsuka America Pharmaceutical, Inc.; April 2013.



28

Monitoring Patients on Conivaptan

� Only for use in hospitalized patients

� Administer through large veins, change infusion site every 24 h to minimize risk of vascular irritation

� Monitor serum [Na+] and neurologic status appropriately, as serious neurologic sequelae can result from overly rapid correction (>12 mEq/L in 24 h)

� Discontinue conivaptan if patient develops undesirably rapid rate of rise of serum [Na+], and carefully monitor serum [Na+]and neurologic status

� If serum [Na+] continues to rise, do not resume treatment

� If hyponatremia persists or recurs, and patient has had no evidence of neurologic sequelae of rapid rise in serum [Na+], conivaptan may be resumed at reduced dose

53Vaprisol (conivaptan hydrochloride injection)[prescribing information]. Deerfield, Ill: Astellas Pharma US, Inc.; October 2012.

Monitoring Patients on Tolvaptan

� Medication MUST be started and re-started in the hospital1

� Obtain serum [Na+] every 4-6 h for 48 h2

� In clinical trials, no patients had evidence of ODS1

� In postmarketing surveillance, cases of ODS have been identified in which HTS was administered concomitantly or in close approximation to tolvaptan1

� As many as 35% of patients (especially those with highest Uosm) may need concomitant water restriction to see rise in serum [Na+]1

� After 48 h, vast majority reach steady state and can be safely discharged with outpatient monitoring2

� Check serum [Na+] once a week for the first month2

� Outpatient administration should be limited to ≤30 d per label.1

If administration is continued, [Na+] should be monitored monthly if stable, and patient should be closely monitored for any signs of liver impairment2

541. Samsca (tolvaptan). [prescribing information]. Rockville, MD. Otsuka America Pharmaceutical, Inc.; April 2013.

2. Faculty recommendations.



29

Case StudyTreatment Course

� Patient admitted

� Fluid restriction discontinued

� Tolvaptan therapy initiated at 15 mg/d

� Uptitrated to tolvaptan 30 mg/d after 24 h

55

Case Study Response to Therapy

� Urine volume increased, urine osmolality decreased, and

serum [Na+] increased by 4.5 mEq/L/d over first 48 h

� Patient discharged after 3 d with [Na+] 136 mEq/L

56

121 123126 124

130 132 133 132

100

110

120

130

140

Admission 8 h 16 h 24 h 32 h 40 h 48 h 56 h

Se

rum

[N

a⁺]

,

mE

q/L



30

Treatment Algorithm

Fluid restriction; vaptan under select circumstances:

•Inability to tolerate fluid restriction or failure of fluid restriction

•Prevention of worsened hyponatremia with increased fluid administration

•Unstable gait and/or high fracture risk

•Serum [Na+] <125 mEq/L

•To correct serum [Na+] to safer levels for surgery/procedures or ICU/hospital discharge

• Therapeutic trial for symptom relief

Euvolemic

hyponatremia

Verbalis JG et al. Am J Med. 2007;120:S1-S21.

Hypovolemic

hyponatremia

Level 1:

No or

minimal

symptoms

Hypervolemic

hyponatremia

Saline or

HTS

± fludro-cortisone

Level 2:

Moderate

symptoms

Level 3:

Severe

symptoms

Vaptan ±±±± fluid restriction Vaptan ±±±± fluid restriction

HTS followed by

fluid restriction

±±±± vaptan

HTS followed by

fluid restriction

±±±± vaptan��

Vaptan ±±±± fluid

restriction��

57

Top 10 Take-Aways

1. Role of AVP in pathophysiology of SIADH and hypervolemia

2. Hyponatremia has real impacts on costs and outcomes

3. Chronic consequences of hyponatremia

4. When hyponatremia is present, consider drug-related causes

5. Be vigilant for cognitive dysfunction at any level of hyponatremia

6. Treatment algorithm

7. Vaptans are necessary "tool" in the treatment algorithm

8. Rate of serum [Na+] correction important

9. Monitor, monitor, monitor during [Na+] correction for safety

10. Know vaptan AEs, drug interactions

58



31

Supplemental Slides

Role of AVP in Edematous Disorders

Adapted from Janicic N et al. Endocrinol Metab Clin North Am. 2003;32:459-481. S1

CHF�� Cardiac output

Cirrhosis�� Peripheral resistance dueto splanchnic vasodilation

Arterial underfilling

Stimulation of arterialbaroreceptors

Nonosmotic release of AVP

Impaired H2O excretion

Hypervolemic hyponatremia



32

<100 mOsm/L(maximally dilute)

Polydipsia

≥100 mOsm/L(inappropriately concentrated)

Impaired water excretion

HyperglycemiaMannitol

>295 mOsm/kgHyperosmolar

HypervolemiaIncreased ECF volume

ECF, extracellular fluid.Cole CD et al. Neurosurg Focus. 2004;16:E9. Diringer MN, Zazulia AR. Neurologist. 2006;12(3):117-126.

Schrier RW, ed. Atlas of Diseases of the Kidney. Philadelphia, PA: Current Medicine. 1999:1.1-1.22.

[Na+] <135 mEq/L

<275 mOsm/kgHypo-osmolar

Assess serum osmolality

Assess urine osmolality

Excessive water intake

Assess volume status

EuvolemiaNormal ECF volume

HypovolemiaReduced ECF volume

275-295 mOsm/kgNormo-osmolar

PseudohyponatremiaNa-free irrigant solutions

S2

Classification Algorithm

� Caused by excessive levels of AVP as a result of disease, drug-induced pituitary release of AVP, or ectopic production of AVP

� AVP secretion not suppressed appropriately when Posmfalls below the osmotic threshold1,2

� The inability to suppress AVP secretion results in

� Impaired renal water excretion

� Increased total body water

� Hyponatremia

� “Dilute serum, nondilute urine”

SIADH: Pathophysiology

1. Verbalis JG. J Mol Endocrinol. 2002;29:1-9. 2. Robertson GL et al. Am J Med. 1982;72:339-353. S3



33

� ↓↓↓↓ Effective osmolality of the ECF (Posm <275 mOsm/kg H2O)

� Inappropriate urinary concentration (Uosm >100 mOsm/kg H2O) with normal renal function at some level of hypo-osmolality)

� Clinical euvolemia (no signs of hypovolemia or hypervolemia)

� Elevated urinary Na excretion despite normal salt and H2O intake

� No other potential causes of euvolemic hypo-osmolality

Essential Criteria for Diagnosis of SIADH

Posm, plasma osmolality; Uosm, urinary osmolality.

Janicic N, Verbalis JG. Endocrinol Metab Clin North Am. 2003;32(2):459-481. S4

Most Common Diagnoses in Hospitalized Patients With Hyponatremia

S5Zilberberg MD et al. Curr Med Res Opin. 2008; 24(6):1601-1608.

DiagnosisHyponatremia

Incidence

Pneumonia, organism unspecified 6.0%

Septicemia 5.5%

Disorders of fluid, electrolyte, and acid–base balance (including hyponatremia)

5.3%

Heart failure 5.3%

Diabetes mellitus 5.0%

Acute renal failure 3.9%

Acute myocardial infarction 3.2%



34

� Direct costs estimated at $1.6 to $3.6 billion annually1

� Hospitalization costs account for ≈70% of total cost of illness

� Associated with worse clinical and economic outcomes2

� Patients with hyponatremia have

� 10% to 32% increased risk of requiring ICU stay2,3

� Adjusted mean LOS of 3.06 d longer4

� Adjusted OR of 1.64 for requiring discharge to short- or long-term care facility5

� 41.2% higher cost at 6 mo; 45.7% higher at 1 y6

Costs of Hyponatremia

1. Boscoe A et al. Cost Eff Resour Alloc. 2006;4:1-11. 2. Zilberberg MD et al. BMC Pul Med. 2008;8:16. 3. Callahan MA et al.

Postgrad Med. 2009;121(2):186-191. 4. Cyr PL et al. Am J Health Syst Pharm. 2011;15(68(4):328-333. 5. Wald R et al. Arch Intern Med.

2010;170:294-3024. 6. Shea AM et al. J Am Soc Nephrol. 2008;19:764-770. S6

Moderate-Severe (≤129

mEq/L)

32% ICU admission

Total costs*

$19,519

8-d LOS

Costs of Admission Hyponatremia (adjusted for clinical & demographic variables)

*Per admission.

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

Mild-Moderate (130–134 mEq/L)

26% ICU admission

8-d LOS

Total costs*

$18,054

Normal

(135–145 mEq/L)

22% ICU admission

6-d LOS

Total costs*

$17,085

Difference = $2434

Difference = $969

S7



35

� Retrospective study in 77 medical, surgical, and mixed ICUs in Austria

� 151,486 adults admitted consecutively over 10 y (1998–2007)

� Borderline (130 ≤ [Na+] <135 mEq/L) hyponatremia: 13.8%

� Mild hyponatremia (125 ≤ [Na+] <130 mEq/L): 2.7%

� Severe hyponatremia ([Na+] <125 mEq/L): 1.2%

� Independent mortality risk with increasing severity of hyponatremia

� Borderline: OR, 1.32 (95% CI, 1.25–1.39)

� Mild: OR, 1.89 (95% CI, 1.71–2.09)

� Severe: OR, 1.81 (95% CI, 1.56–2.10)

Hyponatremia Associated with Increased Mortality in Patients in the ICU

Funk GC et al. Intensive Care Med. 2010;36(2):304-311. S8

Change in Serum [Na+] & Mortality

Waikar SS et al. Am J Med. 2009;122:857-865. S9

0

10

20

30

40

50

In-hospital 1-y 5-y

Crude Mortality, %Normonatremia

Resolution of

Hyponatremia

Persistent

Hyponatremia

Acquired

Hyponatremia

Adjusted HR for Mortality

In-hospital 1-y 5-y

Normonatremia (n=42176) 1 (ref) 1 (ref) 1 (ref)

Resolution of hyponatremia (n=3794) 1.26 1.19 1.18

Persistent hyponatremia (n=4524) 2.37 1.55 1.32

Acquired hyponatremia (n=1974) 2.44 1.54 1.40



36

Whyte M et al. Int J Clin Pract. 2009;63:1451-1455.

� 113 patients with severe hyponatremia (serum [Na+] ≤120 mEq/L)

� Relationship between investigation for hyponatremia and mortality

Failure to Measure Plasma & Urinary Osmolalities Associated With Increased Hyponatremia Mortality

S10

14.3 12.79.8

32 3430

0

10

20

30

40

Serum Osmolality Urine Osmolality Paired Osmolality

Mortality, %

Measured

Not measured

� 115,969 patients hospitalized for CHF

� Grouped by serum [Na+]Eq/L

Impact of Hyponatremia on Cost in Hospitalized Patients With HF

Shorr AF et al. Congest Heart Fail. 2011;17(1):1-7. S11

Serum [Na+],

mEq/L

Risk-Adjusted

Attributable Hospital Cost

Hypernatremia >145 $99

Normonatremia (ref) 136–145 0

Hyponatremia 131–135 $509

Severe hyponatremia ≤ 130 $1132



37

� 15 randomized, controlled trials of vaptans with or w/o fluid restriction

� Primary result: Normal or significant increase in serum [Na+] at 3-7 d

� Vaptan treatment significantly increased

� Early response rate (11 trials): RR, 3.15; 95% CI, 2.27–4.37

� Late response rate (4 trials): RR, 2.27; 95% CI 1.79–2.89

� Rates of hypernatremia (5 trials): RR, 2.21; 95% CI, 0.61–7.96

� No cases of ODS

Meta-analysis: Vaptans for Hyponatremia

Rozen-Zvi B et al. Am J Kidney Dis. 2010;56(2):325-337. S12

� Objectives of this post-hoc analysis of EVEREST trial � Compare LOS between normonatremic (n=1789) and

hyponatremic (n=216) patients who were randomized to placebo

� Evaluate the effect of tolvaptan (n=225) compared with placebo (n=216) on LOS in hyponatremic patients

� LOS in hyponatremic vs normonatremic patients � Serum [Na+] <135 mEq/L: LOS + 3.06 d (P<.001)

� More severe hyponatremia: LOS + 5.17 d (P<.001)

� LOS tolvaptan vs placebo� 1.72 d shorter vs placebo (P=NS)

� 2.12 d shorter in patients with more severe hyponatremia (P=NS)

Effect of Serum [Na+] & Tolvaptanon LOS in Hospitalized Patients With HF

Cyr PL et al. Am J Health Syst Pharm. 2011;68(4):328-333. S13



38

S14

Pro

po

rtio

n W

ith

ou

t E

ven

t

Post-hoc Exploratory Analysis EVEREST: CV Mortality & Morbidity

Advisory Committee Meeting of the Cardiovascular and Renal Drugs Division of the US Food and Drug Administration. June 25,

2008. Available at: www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4373b1-05.pdf. Accessed March 15, 2013.

� Hospital cost and LOS for DRG hospitalizations of adult HF patients with

complications, comorbidities estimated from HCUP 2008 NIS database

� Reductions in LOS associated with tolvaptan estimated from EVEREST

trial data for hyponatremic patients

� Cost offset model used to evaluate impact of tolvaptan on LOS and

hospital cost

� LOS reduced 0.81 d among HF hospitalizations

� $265 total cost savings per admission (based on wholesale acquisition cost

of $250/d)

� Supports clinical and economic benefit of tolvaptan use

� Study limitation: Clinical trial patient profiles and relative LOS

reductions may not be applicable to real-world patient populations

Economic Benefits of Tolvaptanin Hyponatremic HF Patients

DRG, diagnosis-related group; HCUP, Healthcare Cost and Utilization Project; NIS, Nationwide Inpatient Sample.

Chiong JR et al. J Med Econ. 2012;15(2):1-9. S15

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