The Critically Ill Hyponatremic Patient: New Insights into Pharmacologic Management

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The Critically Ill Hyponatremic Patient New
Insights into Pharmacologic Management

• Joseph F. Dasta, M.Sc. FCCP, FCCM
• Adjunct Professor University of Texas College of
  Pharmacy
• Professor Emeritus
• The Ohio State University

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Mantra for Hyponatremia

• Hyponatremia is a water problem, not a sodium
  problem

McLlwaine JF, Corwin HL Hypernatremia and
hyponatremia In Grenvik A (Editor) Textbook of
Critical Care, 5th Edition, 2005.
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Traditional Approach

• Add to the numerator of the equation
• Better to subtract from the denominator

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Osmotic Demyelination Syndrome Can Be a
Consequence of Inappropriate Management of
Hyponatremia

• An overly rapid increase in serum Na (gt12
  mEq/L/24 hours) may result in serious sequelae1
• Presence or absence of significant neurologic
  signs and symptoms must guide treatment2
• Acute or chronic hyponatremia impacts the rate at
  which correction should be undertaken3

Image with permission of www.dizziness-and-balance
.com/disorders/central/brainstem20strokes.htm.
1. Vaprisol (conivaptan hydrochloride
injection) Prescribing information. Deerfield,
Ill Astellas Pharma US, Inc. February 2007 2.
Kumar S, Berl T. In Atlas of Diseases of the
Kidney. 19991.1-1.22 3. Adrogué HJ et al. N
Engl J Med. 20003421581-1589.
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Incidence of Hyponatremia

• Hyponatremia is a common electrolyte disorder
  occurring in up to 15 of hospitalized patients1
• Euvolemic hyponatremia, most often caused by
  SIADH, accounts for about 60 of all types of
  chronic hyponatremia1
• If not treated appropriately, hyponatremia may
  lead to significant morbidity and death2,3

1. Baylis PH. Int J Biochem Cell Biol.
2003351495-1499. 2. Adrogué HJ. Am J Nephrol.
200525240-249. 3. Huda MSB et al. Postgrad Med
J. 200682216-219.
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Annual Cost of Hyponatremia in the United States

• Prevalence-based cost of illness study, including
  information from databases, published literature,
  and an expert physician panel
• Low and high scenarios were estimated and
  incorporated in a cost of illness model
• Results
• US prevalence for hyponatremia estimated at 3.2
  to 6.1 million persons annually
• Estimated 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 estimated from 1.6 to 3.6 billion
  annually

Boscoe A et al. Cost Eff Resour Alloc.
200641-11.
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Morbidities in Hospitalized Patients With
Symptomatic Hyponatremia
Symptoms of Hyponatremic Encephalopathy
n89

• Single-center, retrospective review at large US
  hospital over a 4-year period (1997-2001)
• 168 patients with serum Na lt115 mEq/L
• Symptoms of hyponatremic encephalopathy in 89 of
  168 patients (53)
• No documented symptoms in 79 of 168 patients (47)

Nzerue CM et al. J Natl Med Assoc.
200395335-343.
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Admission Serum Sodium in Heart Failure Patients

• Hyponatremia occurs in 20-30 of ADHF patients
• In hospital (6 vs 3.2) and 60-day mortality
  rates are highest in patients with lowest serum
  Na on admission
• Each 5 mmol/L increase in Na associated with a
  25 lower 60-day mortality
• Also, longer LOS (6.4 vs 5.5 days) and post
  discharge mortality (12.4 vs 7.1)

Gheorghiade M et al. Eur Heart J 2007epub Feb. 19
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Diagnostic Algorithm for Hyponatremia
Assessment of volume status

• Hypervolemia
• Total body water ??
• Total body Na ?

• Euvolemia (no edema)
• Total body water ?
• Total body Na ?

• Hypovolemia
• Total body water ?
• Total body Na ??

UNa lt20 mEq/L
UNa gt20 mEq/L
UNa lt20 mEq/L
UNa gt20 mEq/L
UNagt20 mEq/L
Nephrotic syndrome Cirrhosis Cardiac failure
Glucocorticoid deficiency Hypothyroidism Syndrome
of inappropriate ADH secretion -
Drug-induced - Stress
Extrarenal losses Vomiting Diarrhea Third spacing
of fluids Burns Pancreatitis Trauma
Renal losses Diuretic excess Mineralocorticoid
deficiency Salt-losing deficiency Bicarbonaturia
with renal tubal acidosis and metabolic
alkalosis Ketonuria Osmotic diuresis
Acute or chronic renal failure
Legend ? increase ?? greater increase ?
decrease ?? greater decrease ? no change.
Adapted from Kumar S, Berl T. In Atlas of
Diseases of the Kidney. 19991.1-1.22.
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Thiazide-Induced Hyponatremia

• Mechanism1
• Decreased urinary dilution
• Mild volume depletion stimulates AVP, water
  retention, and syndrome of inappropriate
  antidiuretic hormone secretion (SIADH)
• Elderly have impaired renal function and impaired
  ability to excrete excess fluid
• 3-4 times increased risk in women2,3
• One study found that 63 of cases occurred within
  14 days of starting treatment with a thiazide
  diuretic2
• A second study found that 37 of patients
  developed thiazide-induced hyponatremia more than
  1 year after starting the thiazide3

1. Miller M. J Gen Intern Med. 200654345-353
2. Sonnenblick M et al. Chest. 1993103601-606
3. Sharabi Y et al. J Human Hypertension.
200216631-635.
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SSRI-Induced Hyponatremia

• Retrospective case-note study of elderly patients
  in an acute psychiatry ward
• Patients receiving SSRIs and who developed
  hyponatremia due to SIADH were identified
• Of 108 patients admitted over a 1-year period,
  7.7 had a Nalt13 mEq/L
• 32 admitted patients (25) received an SSRI for
  depression
• 4 (12.5) developed symptomatic hyponatremia due
  to SIADH
• 4 (12.5) developed asymptomatic hyponatremia
  following initiation of the SSRI

SSRISelective serotonin reuptake
inhibitor Bouman WP et al. Int J Geriatr
Psychiatry. 19981312-15.
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General Principles in the Treatment of Acute
Hyponatremia

• Neurologic consequences can follow both the
  failure to promptly treat as well as the
  excessively rapid rate of correction of
  hyponatremia
• Presence or absence of significant neurologic
  signs and symptoms must guide treatment
• Acuteness or chronicity of hyponatremia impacts
  the rate at which serum Na is corrected
• If drug-induced SIADH, discontinue the drug
• The half-life or offset of effect of the
  offending drug should be taken into consideration
• Frequent monitoring of serum Na is needed

Kumar S, Berl T. In Atlas of Diseases of the
Kidney. 19991.1-1.21 Adrogue HJ, Madias NE. N
Engl J Med. 20003421581-1589.
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Traditional Treatments for Hyponatremia

• Acute
• Saline infusion
• isotonic
• hypertonic (caution ODS)
• Fluid restriction (slow effect)
• Furosemide NaCl (not in CHF)
• Chronic
• Demeclocycline
• Mineralocorticoids
• Lithium
• Urea

Cawley M. Ann Pharmacother 200741epub DOI
10.1345/aph.1H502
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• There is no clear consensus regarding the
  optimal treatment of symptomatic hyponatremia

Adrogue HJ. Consequences of inadequate management
of hyponatremia. Am J Nephrol. 200525240.
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Ideal Therapy for Acute Hyponatremia

• Prompt but safe correction of Na in 24 to 48
  hr
• 12 mEq/L in the first 24 hr
• 18 mEq/L in the first 48 hr
• Produces increased water excretion without
  electrolyte excretion (Na and K) - AQUARESIS
• Eliminates or decreases need for fluid
  restriction
• Predictable and reliable action
• Quick onset/offset easily titratable
• No unexpected side effects/toxicities
• No drug/disease interactions
• Cost-effective data available

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AVP-Receptor Subtypes
ACTHadrenocorticotropic hormone. Adapted from
Lee CR et al. Am Heart J. 20031469-18 Verbalis
JG. J Mol Endocrinol. 2002291-9.
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Plasma AVP Is Elevated in Patients With SIADH
11
10
9
8
Normalrange
7
6
Plasma AVP (pg/mL)
5
4
3
2
1
0
230
240
250
260
270
280
290
300
310
Plasma Osmolality (mOsm/kg)
Adapted from Robertson GL et al. Am J Med.
198272339-353.
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Aquaresis

• Aquaresis is defined as the solute-free excretion
  of water by the kidney
• Because electrolytes represent a major component
  of urine solutes, aquaresis is also
  electrolyte-sparing
• Measured by increases in EWC and is calculated
  from the urine volume and from the plasma and
  urine Na and K
• Typically accompanied by increased urine output
  and reduced urine osmolality
• Distinguished from diuresis (increased urine
  output accompanied by electrolyte excretion)

EWCeffective water clearance. Vaprisol
(conivaptan hydrochloride injection). Prescribing
information. Deerfield, Ill Astellas Pharma US,
Inc. February 2007 Verbalis JG. J Mol
Endocrinol. 2002291-9.
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VAPRISOL(conivaptan hydrochloride injection)

• Vaprisol is indicated for the treatment of
  euvolemic hyponatremia (eg, SIADH, or in the
  setting of hypothyroidism, adrenal insufficiency,
  pulmonary disorders, etc) in hospitalized
  patients
• Vaprisol is also indicated for the treatment of
  hypervolemic hyponatremia in hospitalized
  patients
• Not indicated for the treatment of congestive
  heart failure (effectiveness and safety have not
  been established in these patients)

Vaprisol (conivaptan hydrochloride injection).
Prescribing information. Deerfield, Ill Astellas
Pharma US, Inc. February 2007 Verbalis JG. J
Mol Endocrinol. 2002291-9.
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Efficacy Endpoints in a Double-Blind Clinical
Trial

• 29 patients receiving 40 mg iv per day (euvolemic
  and hypervolemic)
• Fluid restriction 2 L or less per day
• Primary
• Change in serum Na from baseline during the
  treatment phase, as measured by the serum Na
  AUC (mEqhr/L)
• Secondary
• Time from first dose to a confirmed increase in
  serum Na 4 mEq/L from baseline
• Total time during the treatment phase that serum
  Na was 4 mEq/L above baseline
• Change in serum Na from baseline to end of
  treatment
• Number of patients achieving a confirmed increase
  in serum Na 6 mEq/L or a normal serum Na
  (135 mEq/L)

Astellas Pharma US, Inc. Data on file.
(087-CL-027 Clinical Study Report dated 22 Dec
2003).
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Change From Baseline in Serum Na
Mean (SE) Change from Baseline in Serum Na
With Vaprisol 40 mg/d
10
VAPRISOL 40 mg/d Placebo
8
6
Change in Serum Na (mEq/L)
4
2
0
2
0
96
8
16
24
32
40
48
56
64
72
80
88
Time (hr)
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Evidence of Aquaresis

• By day 4, Vaprisol produced a cumulative increase
  in EWC of more than 2900 mL, compared with
  approximately 1800 mL with placebo.

All values at hour 24 of study day. Vaprisol
(conivaptan hydrochloride injection). Prescribing
information. Deerfield, Ill Astellas Pharma US,
Inc. February 2007 Verbalis JG. J Mol
Endocrinol. 2002291-9.
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Secondary Efficacy Outcomes in Open-Label Study
080
Vaprisol (conivaptan hydrochloride injection).
Prescribing information. Deerfield, Ill Astellas
Pharma US, Inc. February 2007 Verbalis JG. J
Mol Endocrinol. 2002291-9.
26
Secondary Efficacy Outcomes in Patients With
Hypervolemic Hyponatremia
Vaprisol (conivaptan hydrochloride injection).
Prescribing information. Deerfield, Ill Astellas
Pharma US, Inc. February 2007 Verbalis JG. J
Mol Endocrinol. 2002291-9.
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Data on Acute Decompensated Heart Failure
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Vasopressin Antagonists in Heart Failure

• Single dose of conivaptan, dual V1a/V2 receptor
  antagonist
• 142 NYHA FC III-IV patients

PCWP
Urine Output
Udelson JE. Circulation 20011042417-23.
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Pilot Study of Conivaptan in ADHF

• Multicenter RCT ADHF and pulmonary congestion
• Placebo, iv conivaptan 40 mg, 80, 120 mg/d x 2
• Significant increase in urine output and decrease
  in body weight
• No improvement in respiratory symptoms

Goldsmith S et al AHA 2006
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Safety and Efficacy of Conivaptan in
Hypervolemic Hyponatremia

• 62 of patients had CHF
• IV conivaptan 20, 40, and 80 mg/d
• Time to serum Na gt 4 mEq/L was 24 hr (40 mg)
• Overall change in serum Na 7.4 4.8 mEq/L
• ADEs infusion-site reactions, hypokalemia,
  vomiting, hypotension

Goldsmith S et al ACC 2007
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Dosage and AdministrationConivaptan

• Initiate therapy with a loading dose of 20 mg IV
  over 30 minutes
• Follow with 20 mg of conivaptan administered in a
  continuous IV infusion over 24 hours
• Conivaptan may be administered for an additional
  1 to 3 days by continuous infusion of 20 mg/d
• If serum Na is not rising at the desired rate,
  the dosage may be adjusted upward to 40 mg daily
  administered in a continuous IV infusion
• The total duration should not exceed 4 days
• To minimize the risk of vascular irritation
• Administer conivaptan through large veins
• Change the infusion site every 24 hours

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Overview of Pharmacokinetics

• Nonlinear pharmacokinetics
• Conivaptans inhibition of its own metabolism
  seems to be the major factor for nonlinearity
• High intersubject variability in clearance (94
  CV)
• Pharmacokinetics in healthy subjects receiving
  20-mg loading dose of conivaptan followed by a
  40-mg/d infusion for 3 days, the mean clearance
  was 15.2 L/hr, and the mean t1/2 was 5 hours
• In patients with hyponatremia receiving 20-mg
  loading dose of conivaptan followed by a 40-mg/d
  infusion for 4 days, the median clearance was
  9.5 L/hr, and the median t1/2 was 8.6 hours

CVcoefficient of variation t1/2terminal
elimination half-life.
Vaprisol (conivaptan hydrochloride injection).
Prescribing information. Deerfield, Ill Astellas
Pharma US, Inc. February 2007 Verbalis JG. J
Mol Endocrinol. 2002291-9.
33
Distribution, Metabolism, and Excretion

• Conivaptan is extensively bound to human plasma
  proteins (99)
• Mass balance study
• 83 of dose was excreted in feces, 12 in urine
• During the first 24 hours after dosing, about 1
  of IV dose was excreted in urine as intact
  conivaptan
• Conivaptan is a substrate and potent inhibitor of
  CYP3A4. The coadministration of conivaptan with
  potent CYP3A4 inhibitors such as ketoconazole,
  itraconazole, clarithromycin, ritonavir, and
  indinavir is contraindicated
• CYP3A4 is the sole isoenzyme responsible for
  metabolism of conivaptan

CYPcytochrome P450. Vaprisol (conivaptan
hydrochloride injection). Prescribing
information. Deerfield, Ill Astellas Pharma US,
Inc. February 2006.
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Pharmacokinetics in Hepatic and Renal Impairment
and in Geriatric patients

• Use with caution in both populations
• Little data are available

Vaprisol (conivaptan hydrochloride injection).
Prescribing information. Deerfield, Ill Astellas
Pharma US, Inc. February 2007 Verbalis JG. J
Mol Endocrinol. 2002291-9.
35
Precautions Drug Interactions

• Conivaptan is a substrate of CYP3A4, and
  coadministration of conivaptan and CYP3A4
  inhibitors could lead to an increase in
  conivaptan concentration
• Concomitant use of conivaptan and potent CYP3A4
  inhibitors such as ketoconazole, itraconazole,
  clarithromycin, ritonavir, or indinavir is
  contraindicated
• Conivaptan is a potent inhibitor of CYP3A4, and
  conivaptan may increase plasma concentrations of
  coadministered with drugs that are primarily
  metabolized by this isoenzyme

Vaprisol (conivaptan hydrochloride injection).
Prescribing information. Deerfield, Ill Astellas
Pharma US, Inc. February 2007 Verbalis JG. J
Mol Endocrinol. 2002291-9.
36
Preparation Guidelines

• Conivaptan should be diluted only with 5
  Dextrose Injection
• Conivaptan should not be mixed or administered
  with Lactated Ringers Injection or 0.9 Sodium
  Chloride Injection
• Once conivaptan is added to the infusion bag,
  gently invert the bag several times to ensure
  complete mixing
• Compatibility of conivaptan with other drugs has
  not been studied

Vaprisol (conivaptan hydrochloride injection).
Prescribing information. Deerfield, Ill Astellas
Pharma US, Inc. February 2007 Verbalis JG. J
Mol Endocrinol. 2002291-9.
37
Propylene Glycol

• Propylene glycol is an inactive ingredient used
  in the formulation of Vaprisol
• Propylene glycol is an FDA-approved acceptable
  ingredient in food and drug products
• Potency and administration methods vary among
  products
• Maximum potency limits apply

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Where Does Conivapan Fit?

• No safety issues with the entire vasopressin
  receptor antagonist class
• Infusion-site reactions with infusion
• Do not use in hypovolemic patient
• No data in severe hyponatremia (seizure patient)
• Evolving story in CHF patients
• One dosing approach Administer conivaptan 20 mg
  IV over 30 minutes, check serum Na in 4-6 hours,
  along with urine output, and determine if further
  therapy is needed

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EVEREST Results

• Two RCTs of tolvaptan 30 mg qd orally vs placebo
  within 48 hr of admission for ADHF
• Short-term clinical study revealed tolvaptan
  improves many but not all signs and symptoms of
  acute HF.
• Tolvaptan patients lost more weight
• Long-term outcomes study of tolvaptan for at
  least 60 days
• No difference in all-cause mortality or
  cardiovascular death or HF hospitalizations
• No worsening of renal function
• Mean change in serum Na at 7 days 5.6 mEq/l for
  tolvaptan vs 1.8 mEq/l for placebo
• No safety signal was seen
• Do findings affect our thoughts on this drug
  class?

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Summary

• Euvolemic and hypervolemic hyponatremia is a
  common electrolyte abnormality
• The neurohormone arginine vasopressin plays a key
  role in salt and water balance
• Treat the primary condition first (i.e.,
  drug-induced, acute heart failure)
• Conivaptan blocks the V2 receptors in the
  collecting ducts of the kidneys, it gets rid of
  what patients have in excessH2O
• The role of conivaptan in the overall management
  of euvolemic and hypervolemic patient with
  hyponatremia is evolving
• Clinical and economic outcomes data are needed