Transcript Hyponatremia in SIADH: Role of the Vaptans

Hyponatremia in
SIADH:
Role of the Vaptans
Mary Joana Co
Pharm.D Candidate 2011
Western University
COH Medicine Rotation Student
Case: R.M.
66 yo Male, diagnosed with AML in ‘09
s/p Allo-HSCT MUD (day 0 -7/1/10)
Complications: GI GVHD Stage III
Tacrolimus 1.5mg BID
Sirolimus 4mg Once Daily
Prednisone 30mg Once Daily
Budesonide 3mg TID
Allergy: Cefazolin/Ceftazidime – Rash
FH
1 sister with cervical CA & hepatitis
SH:
1 ppd x 40 yr, quit 2000
Limited alcohol use
No history of Illicit drug use
Married, good family support wife at bedside
PMH:
CAD (s/p 1 stent placement 2001)
DM type 2 (2001)
Hypertension
Lisinopril 5mg Daily
Prazosin 1mg Daily
Hyperlipidemia
Simvastatin 40mg Daily
Micafungin 50mg Once Daily
Acyclovir 400mg BID
Bactrim DS 800/160mg 1 tab BID on Sat/Sun
Supportive Care:
Lasix 40 mg Daily x 2 days
Zolpidem 10mg QHS prn insomnia
Lorazepam 1mg q6hr prn nausea
Famotidine 20mg BID
Magnesium + Protein 1 tab BID
Chief Complaint
CC: Diarrhea, Low Serum Na w/ TPN
(Lomotil 2.5mg prn diarrhea)
Na:
7/16 7/17
138 133
7/18
131
7/19
131
7/20
127
7/21 7/22
126
128
7/23 7/24
129 130
7/25
131
7/26 7/27 7/28 7/29
132 132 130 131
Diarrhea Episode: intermittently, started on
16th ~1600 ml
20th ~1800ml loose stool
17th ~1500 ml loose stool 21st no diarrhea
18th started solu-medrol
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
Is having a low Na an urgent matter?
What are the various causes of
having this electrolyte abnormality?

Does RM require immediate
treatment?

If so, what are the options
available to him?
Low Sodium Levels
 HYPONATREMIA

Total body Na deficit (Na <135mEq/L)

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Common in hospitalized patients ~15-30%
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From renal/extra renal loss exceeding intake
Setting also allows for diagnosis
Clinical complication of wide pathophysiology

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

Associated with many underlying disease states
Multiple etiologies
Differing pathophysiologic mechanisms
Results in confusion in management
Verbalis, Joseph G., Stephen R. Goldsmith, Arthur Greenberg, Robert W. Schrier, and Richard H. Sterns. "Hyponatremia
Treatment Guidelines 2007: Expert Panel Recommendations." The American Journal of Medicine 120 (2007): S1-S21.
Why is Na important?
 Osmotic Equilibrium
Osmolality: 280-295 mOsm/Kg H20
 85-95% Na is extracellular
 Cell function relies on maintenance of body fluid tonicity
 Present as disorders of water balance:
 Altered Na and Water content: Regulation of volume and osmolality
 Alterations in Na levels manifest as:
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
ECF volume depletion
 Hypotension
 Tachycardia

ECF volume overload
 Peripheral edema
 Pulmonary Edema
 Water balance regulated through
 ADH (AVP; vasopressin)
 Hypothalamus: Thirst Control Center
Palmer, Biff F., John R. Gates, and Malcolm Lader. "Causes and Management of Hyponatremia." The Annals of
Pharmacotherapy 37 (2003): 1694-701.
Washington Manual of Therapeutics
http://www.accessmedicine.com.proxy.westernu.edu/content.aspx?aID=10935&searchStr=hyponatremia
 Isotonic Hyponatremia:
 Hyperproteinemia
 Hyperlipidemia
http://www.accessmedicine.com.proxy.westernu.edu/content.aspx?aID=10935&searchStr=hyponatremia
Washington Manual of Therapeutics
 Hypertonic Hyponatremia:
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Hyperglycemia (Translational Hyponatremia)
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
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Corrected Na=Na + 0.016 x (Glu-100)
Mannitol, sorbitol, glycerol, maltose
Radiocontrast dye agents
http://www.accessmedicine.com.proxy.westernu.edu/content.aspx?aID=10935&searchStr=hyponatremia
Washington Manual of Therapeutics
 Hypotonic Hyponatremia

Volume status dependent
Hypovolemic, Hypervolemic, Euvolemic,
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http://www.accessmedicine.com.proxy.westernu.edu/content.aspx?aID=10935&searchStr=hyponatremia
Washington Manual of Therapeutics
Other etiologies
 Iatrogenic:
 Pharmacologic Agents:
 Via stimulation of AVP release:
 Nicotine, carbamazepine, antidepressants, narcotics,
antipsychotics, antineoplastics

Potentiation of antidiuretic action:
 Chlorpropramide, methylxanthines, NSAIDs

Vasopressin analogs:
 Oxytocin, desmopressin acetate (dDAVP)

Exogenous sources of free water:
 Maintenance IVF
 TPN
Washington Manual of Therapeutics
Symptoms
Symptoms related to degree of Na insufficiency:
ACUTE:
121-130 mEq/L
Nausea, malaise, headache, lethargy, muscle
cramps, disorientation, restlessness
<120 mEq/L
Obtundation, seizures, respiratory arrest, coma,
death
CHRONIC: (developed over days)
Usually Asymptomatic / Non-Specific
Nausea, fatigue, gait disturbance, forgetfulness,
muscle cramps confusion, lethargy
Palmer, Biff F., John R. Gates, and Malcolm Lader. "Causes and Management of Hyponatremia." The Annals of
Pharmacotherapy 37 (2003): 1694-701.
Back to our case…
Mr. RM:
 CNS: Asymptomatic
 Serum Na: levels were lowest on 7/21: 126mEq/L
 Serum Osmolality: (278-295 mOsm/Kg): 287 mOsm/Kg H2O = “isotonic
hyponatremia”
 Protein levels: Low protein levels (5.5-5.7)
 Lipid Levels: TG high: (7/19) 212 (7/26) 277
 Hyperglycemia:
 Glucose levels:
Na:
Glu:
7/16 7/17
138 133
206 184
7/18
131
180
7/19
131
248
Corrected Na:
TG
212
7/20
127
201
128
7/21 7/22
126
128
260
172
128
129
7/23 7/24 7/25 7/26 7/27 7/28 7/29
129 130 131 132 132 130 131
123 147 127 203 114 151 152
277
…
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Acute fluid loss:
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Iatrogenic:
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IVF:
TPN:
Pharmacological Agents:
 Lisinopril
Hypothyroidism:
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Diarrhea: stool volume
Diuretics: Lasix 40mg IV daily X 2
TSH (0.35-5.5 mIU/L): 0.897
Adrenal Insufficiency:
Cortisol: 9.2 @ 1215h
(@0800h: 6-23 ug/dL)
(@2000h: 0-9 ug/dL)
Possible SIADH due to GVHD….
SIADH
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Fluid Balance:
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Water Intake, Renal Function (reabsorption; secretion), ADH
 ADH (anti-diuretic hormone)/AVP (arginine vasopressin)
 Anterior hypothalamus
 Responsible for retention of solute-free water
Affected by:
 Increased POsm = Increased AVP = Water retention
 Decreased BP = Increased AVP = Water retention
In SIADH:
 Decreased Posm = Inappropriate AVP secretion = Water
retention/Hyponatremia
 “Inappropriate secretion of ADH”
 What happens to the electrolytes when there is increased
ADH?
Sherlock, Mark, and Chris J. Thompson. "The Syndrome of Inappropriate Antidiuretic Hormone: Current and Future Management Options."
European Journal of Endocrinology 162 (2010): S13-18.
SIADH
Diagnostic Criteria for SIADH:
A) Essential:
Plasma Osmolality <270 mOsmol/Kg H2O
Urine Osmolality >100mOsmol/Kg H2O
Euvolemia
Urinary Sodium >40 mmol/L, with normal salt and water intake
Excluding Hypothyroidism & Glucocorticoid deficiency
B) Supplemental:
Abnormal Water Load Test
Elevated plasma AVP levels
Compare to RM:
Plasma Osmolality (278-295 mOsm/Kg): 287 mOsm/Kg
Urine Osmolality (250-1200 mOsm/Kg): 711 mOsm/Kg
Determined to be clinically euvolemic per PE
Urine Na: 159 mmol/L
Excluded Hypothyroidism & Glucocorticoid Deficiency
Other:
History of GVHD due to Inflammation
Sherlock, Mark, and Chris J. Thompson. "The Syndrome of Inappropriate Antidiuretic Hormone: Current and Future Management Options."
European Journal of Endocrinology 162 (2010): S13-18.
RM
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Hyperglycemia
Hypertriglyceridemia
Acute Fluid Loss
Exogenous Water Sources
Possible SIADH
…..We’ve ID’d possible causes, what do we
do now???
Treatment Options
 ID cause & remove it!
 Fluid Restriction
 Saline Infusions
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Normal Saline
Hypertonic Saline
 Diuretic Therapy
 Aquaretic Therapy
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Conivaptan
Tolvaptan
 Other Agents
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Lithium
Demeclocycline
Urea
RM
Na:
Glu:
7/16 7/17
138 133
206 184
7/18
131
180
7/19
131
248
Corrected Na:
7/20
127
201
128
7/21 7/22
126
128
260
172
128
129
Lasix
40mg IV
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Fluid Restriction (Free Water)
 7/22: <1L/day
Lasix 40mg QD x 2 days
 7/21
 7/22
Na repletion:
7/20
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Na Phosphate
Na Acetate
Na Chloride
25
85
85
7/23 7/24 7/25 7/26 7/27 7/28 7/29
129 130 131 132 132 130 131
123 147 127 203 114 151 152
TPN w/ Insulin &
Na repletion
Fluid
Restriction
<1L/day
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7/21
7/22
25
85
85
25
85
105
Hyperglycemia:
 Insulin in TPN:
 58u/L  64u/L (7/20-7/23)
 +Lispro 5u SC AC/QHS
 +SSI
7/23
25
85
105
Treatment
 ACUTE vs. CHRONIC

Affects management of treatment
 Low Na=cells can swell or extrude solutes
 Capacity of “adaptation”-brain may extrude solutes
 Acute Hyponatremia = Cerebral Edema= Brain Herniation


Goal/Recommendation: Increase Na not to exceed 10-12 mmol/L over
24h or <18 mmol/l over 48h
Methods:

ID source remove cause
 Mild-moderate symptoms:
 No further Intervention needed
 Severe symptoms:
 Hypertonic (3%) Saline
 3% NaCl
 Careful infusion rates due to risk of Central Pontine
Myelinolysis
 Requires monitoring ~q2hr
 <12mEq/L change over 24hr, serial Chem 7
Verbalis, Joseph G., Stephen R. Goldsmith, Arthur Greenberg, Robert W. Schrier, and Richard H. Sterns. "Hyponatremia Treatment Guidelines
.
2007: Expert Panel Recommendations." The American Journal of Medicine 120 (2007): S1-S21
Treatment
 Chronic Hyponatremia = Brain Adaptation
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Rate of correction is important Brain adapts and may
extrude solutes
Brain is vulnerable to injury if Na is rapidly corrected
due to this compensation…Brain can “shrink” due to
inability to recapture lost solutes

“Central Pontine Myelinolysis” / “Osmotic
Demyelenation”
 Most important in the brain due to the confines of the skull
 Dysarthria, dysphagia, seizures, altered mental status,
quadriparesis, hypotension
 1-3 days after correction of serum sodium
 <12mEq/L change over 24hr, serial Chem 7
Verbalis, Joseph G., Stephen R. Goldsmith, Arthur Greenberg, Robert W. Schrier, and Richard H. Sterns. "Hyponatremia Treatment Guidelines
.
2007: Expert Panel Recommendations." The American Journal of Medicine 120 (2007): S1-S21
Treatment

Chronic Hyponatremia cont..
 Hypovolemic:
 Normal Saline- Restores tissue perfusion
 Euvolemic/Hypervolemic
 Na & H20 restriction
 Loop diuretic w/ Salt tablets – Loops also loose electrolytes!
 Vasopressin Receptor Antagonist
 Other
 Demeclocycline
 Cause Nephrogenic Diabetes Insipidus
 Onset 2-5 days
 Profound Polyuria  Hypernatremia
 Nephrotoxicity, photosensitivity, skin rash
 Urea
 Long-term treatment may be effective (5 years)
 Animal model showed benefit
 Lithium
 Downregulates vasopressin-stimulates aquaporin-2 expression
 Unpredictable efficacy
 Cause Nephrogenic Diabetes Insipidus
Verbalis, Joseph G., Stephen R. Goldsmith, Arthur Greenberg, Robert W. Schrier, and Richard H. Sterns. "Hyponatremia Treatment Guidelines
.
2007: Expert Panel Recommendations." The American Journal of Medicine 120 (2007): S1-S21
Vaptan Therapy
 Class of drugs affecting AVP, thus play an
important role in circulatory & water
homeostsis
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3 receptor sub-types:
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V1a vascular smooth
musclevasoconstriction/cardiac hypertrophy
V1blimbic systemstimulates ACTH &
endorphins
V2renal collecting duct systemresorption of
free water
Conivaptan (Vaprisol)
"Assessment of the Efficacy and Safety of Intravenous
Conivaptan in Euvolemic and Hypervolemic Hyponatremia."
Zeltser, David, Steven Rosansky, Hannes Van Rensburg, Joseph G. Verbalis, and
Neila Smith. "Assessment of the Efficacy and Safety of Intravenous Conivaptan
in Euvolemic and Hypervolemic Hyponatremia." American Journal of Nephrology
27 (2007): 447-57
Conivaptan (Vaprisol)
"Assessment of the Efficacy and Safety of Intravenous Conivaptan in
Euvolemic and Hypervolemic Hyponatremia
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
Treatment of Euvolemic/Hypervolemic Hyponatremia
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Astellas
IV formulation, v1/v2 receptor antagonist
FDA approval in 2004
Multi-center, double-blind, placebo controlled, randomly assigned (4days)
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Conivaptan 30min LD (20mg diluted to 100ml D5W) infusion  96hr CIV days 14 (diluted to 250ml)
 40mg/day
 80 mg/day
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Placebo 100ml D5W as LD  250 ml D5W
Important Exclusion Criteria:
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Hypovolemic hyponatremia
Cardiac problems: SBP <85mmHg, orthostatic hypotension, uncontrolled HTN or
tachyarrhythmia needing pacemaker
Hyponatremia requiring immediate treatment
Medications interacting with CYP4503A4
Other medications: AVP, oxytocin, desmopressin, lithium, urea, demeclocycline

Co-intervention: instructed to maintain 24hr Na intake, calorie consumption,
caffeine intake, and had limited daily fluid intake <2L/day (excluding food)
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Modified ITT
Similar Baseline Characteristics across study groups, Mean baseline Na: ~124 mEq/L
Zeltser, David, Steven Rosansky, Hannes Van Rensburg, Joseph G. Verbalis, and Neila Smith. "Assessment of the Efficacy and Safety of Intravenous
Conivaptan in Euvolemic and Hypervolemic Hyponatremia." American Journal of Nephrology 27 (2007): 447-57
Conivaptan (Vaprisol)
"Assessment of the Efficacy and Safety of Intravenous Conivaptan in
Euvolemic and Hypervolemic Hyponatremia
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Time to increase >/= 4mEq/L :
 Conivaptan 40mg/day: 24 hours
 Conivaptan 80mg/day: 10 hours
 PBO: no increase within 4 day infusion
Change in serum Na from baseline to end of treatment
 Conivaptan 40mg/day: 6.3 mEq/L
 Conivaptan 80mg/day: 9.4 mEq/L
 PBO: 0.8 mEq/L
Patients with increase in Na >/=6mEq/L or Na >/=135 mEq/L
 Conivaptan 40mg/day: 69% (6.3)
 Conivaptan 80mg/day: 88.5% (23)
 PBO: 20.7% (6)
Change in serum Na from Baseline to 6-9days post treatment :
 Conivaptan 40mg/day: 8.1mEq/L (n=13)
 Conivaptan 80mg/day: 4.7 mEq/L (n=26)
 PBO: 5.2 mEq/L (n=17)
Conivaptan (Vaprisol)
"Assessment of the Efficacy and Safety of Intravenous Conivaptan in
Euvolemic and Hypervolemic Hyponatremia
 Discontinuation was mainly due to Infusion
site reactions
 Other ADRs: hypotension, postural
hypotension, pyrexia, hyperkalemia, infusion
site thrombosis
Conivaptan (Vaprisol)
"Assessment of the Efficacy and Safety of Intravenous Conivaptan in
Euvolemic and Hypervolemic Hyponatremia

Baseline characteristics
were matched
 ADRs due to drug were
evaluated and recorded
 Able to monitor patients
levels often, setting was
inpatient
 Fluid restriction carried
out & recorded violations:
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
Conivaptan 80mg/day:
54%
Conivaptan 40mg/day:
38%
PBO: 21%
Endpoints used were
useful
 Baseline Na levels were
~124mEq/L
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1/3 of patients were
hypervolemic and were
infused with D5W
Length of treatment was only
4 days
Follow-up was done for only
6-9days post treatment
Outcomes were not assessed
by symptoms
Baseline symptoms not
recorded, if any
Drop-out rate was high
Target Na levels not specified
Did not address long term
benefit of correctiong
hyponatremia
Tolvaptan (Samsca)
 Tolvaptan, a Selective Oral Vasopressin V2-
Receptor Antagonist, for Hyponatremia
Schrier, Robert G., Peter Gross, Mihai Gheorghiade, Tomas Berl, Joseph
G. Verbalis, Frank Czerwiec, and Cesare Orlandi. "Tolvaptan, a
Selective Oral Vasopressin V2-Receptor Antagonist, for
Hyponatremia." New England Journal of Medicine 355 (2006): 2099112.
Tolvaptan (Samsca)
"Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for
Hyponatremia."
Otsuka Pharmaceutical
 Orally active V2RA  selectively excretes electrolyte-free water
 FDA approval in 2009
Treatment of Euvolemic/Hypervolemic Hyponatremia
Prospective, multi-center, randomized centrally, double-blind, placebo controlled
Conducted 2 trials to assess reproducibility (SALT-1 & SALT-2)
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Important Patient Population Criteria:
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Tolvaptan 15mg tab 1 tab PO Daily x 30 days OR PBO
Inclusion
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Etiologies: CHF, cirrhosis or SIADH
Exclusion Criteria:
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Other etiologies

Hypovolemic hyponatremia
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Other cardiac diseases (post-MI, SVT, SBP<90)
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Serum Na <120 mmol/L w/ neurological impairment
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Poor prognosis not tolerating fluid shifts: short-term survival
Similar Baseline Characteristics across study groups (except height in SALT-2),
Mean baseline Na: ~128 mEq/L
Co-Administration/Co-intervention: Fluid restriction was not mandatory;
treatment with other agents were not allowed (demeclocycline, lithium, urea)
Dose adjustments were made at the discretion of the investigator at Day 4
Drug was administered until day 30, final assessments done at day 37
Schrier, Robert G., Peter Gross, Mihai Gheorghiade, Tomas Berl, Joseph G. Verbalis, Frank Czerwiec, and Cesare Orlandi. "Tolvaptan, a Selective
Oral Vasopressin V2-Receptor Antagonist, for Hyponatremia." New England Journal of Medicine 355 (2006): 2099-112.
Tolvaptan (Samsca)
"Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for
Hyponatremia."



Values were statistically significant
Increases in Na were greater in Tolvaptan group than PBO in both trials and in both
stratifications at Day 4 and much more at Day 30
Increases were more rapid (by day 4) and greater (marked hyponatremia)
Schrier, Robert G., Peter Gross, Mihai Gheorghiade, Tomas Berl, Joseph G. Verbalis, Frank Czerwiec, and Cesare Orlandi. "Tolvaptan, a Selective
Oral Vasopressin V2-Receptor Antagonist, for Hyponatremia." New England Journal of Medicine 355 (2006): 2099-112.
Tolvaptan (Samsca)
"Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for
Hyponatremia."
 Tolvaptan patients reached normal Na levels on day 4 and 30 more
than PBO
 Day 4: SALT-1 (40% vs 13%) SALT-2 (55% vs11%)
 Day 30: SALT-1 (53% vs 25%) SALT-2 (58% vs25%)
 Less “marked” hyponatremia
 Day 4: SALT-1 (13% vs 49%) SALT-2 (10% vs 40%)
 Day 30: SALT-1 (7% vs 35%) SALT-2 (15% vs 32%) not sig
 SF-12 scores
 Showed difference in “mental component summary” in “marked
hyponatremia” patients, but not overall
 Vitality, social functioning, calmness, sadness
 No difference in physical component summary
 OTHER:
 Day 37 analysis: Na concentrations showed no difference between
each arm
Schrier, Robert G., Peter Gross, Mihai Gheorghiade, Tomas Berl, Joseph G. Verbalis, Frank Czerwiec, and Cesare Orlandi. "Tolvaptan, a Selective
Oral Vasopressin V2-Receptor Antagonist, for Hyponatremia." New England Journal of Medicine 355 (2006): 2099-112.
Tolvaptan (Samsca)
"Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for
Hyponatremia."

ADR
 Most common: Thirst (14%;5%); Dry mouth (13%;4%)

Incidence: Tolvaptan: 171 patients PBO: 176, not all ADRs were deemed to be related
to study drug

weakness, nausea, constipation, peripheral edema, ascites, diarrhea, fatigue,
vomiting

Tolvaptan:
 8 patients withdrew due to ADR
Rash, dysguesia, nocturia, urinary frequency, exanthema, muscle weakness,
hypernatremia



PBO:
 8 patients withdrew due to ADR
Rash, ARF, increased SCr, decreased Na, aggravated hyponatremia, vomiting
Completed Follow-up @ 7-days & 30-days:
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Tolvaptan: N=171 (76%)
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PBO: N=154 (69%)
Study Withdrawal:
 Total: N= 123
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Tolvaptan: 54 (24%)
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PBO: 69 (31%)
Schrier, Robert G., Peter Gross, Mihai Gheorghiade, Tomas Berl, Joseph G. Verbalis, Frank Czerwiec, and Cesare Orlandi. "Tolvaptan, a Selective
Oral Vasopressin V2-Receptor Antagonist, for Hyponatremia." New England Journal of Medicine 355 (2006): 2099-112.
Tolvaptan (Samsca)
"Tolvaptan, a Selective Oral Vasopressin V2-Receptor Antagonist, for
Hyponatremia."
 Reproducible results
 SALT-1
 SALT-2


 Baseline characteristics
were matched
 Endpoints were
measured at Day 4 & 30
 ADRs due to drug were
evaluated and recorded



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




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OP setting primarily:
 No mandated fluid restriction, but
co-intervention possible
No mandated change in patients
medication regimen (diuretic use) if for
primary disease
 CHF patients
Other etiologies excluded
No severe Hyponatremia w/
Neurological ADRs were allowed
Serum Na baseline ~128 mmol/L
Outcomes were assessed via AUC, not
by symptoms
Baseline symptoms not recorded, if any
Subjective safety assessments
Drop-out rate was high
Target Na levels not specified
Did not state Na levels of 4 patients who
exceeded target levels
Did not address long term benefit of
hyponatremia
Conivaptan VS Tolvaptan
“The Vaptans”
Conivaptan
Tolvaptan
Convenience
MOA
IV
non-selective
PO
selective
Efficacy/Onset
Mean Increases:
40 mg/day: 6.3mEq/L
80 mg/day: 9.4 mEq/L
Lost effect at end of tx
As early as 10 hr in the 80mg
arm, increase >=4mEq/L
Mean increases
~6.2 mEq/L
(end of 30 day treatment)
Lost effect at end of tx
At day 4,~4mEq/L increase
was achieved
Safety
Infusion site reactions,
phlebitis, cardiac effects
Limited to v2 antagonism
Rash
DDI
Strong CYP3A4
Inhibitor/substrate
P-glycoprotein Substrate
Tolvaptan VS Fluid Restriction
Vasopressin V2 Receptor Blockade with Tolvaptan Versus Fluid Restriction
in the Treatment of Hyponatremia
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prospective, multicenter, randomized, active-controlled, open-label trial
N=28 patients (euvolemic/hypervolemic hyponatremia) with Na <135 mmol/L
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Arms:
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Inclusion Criteria: age 18 years, serum sodium 135 mmol/L for 2 consecutive
days, and normovolemia or signs of fluid overload
Exclusion Criteria: acute coronary ischemic events 60 days after
randomization, a history of sustained ventricular tachycardia or ventricular
fibrillation, or serum creatinine 2.8 mg/dl.
Tolvaptan 10mg/day60mg/day x ~27days (n=17)
Fluid restriction 1200ml/day + PBO x ~27days (n=11)
Follow-up: 65 days
Endpoints:
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Primary: Normalization of Serum Na: Na >135 mmol/L or >=10% increase in
baseline
Secondary: urine osmolality, urine volume, urine sodium concentration, body
weight, total fluid intake, free-water clearance, and thirst score.
 Thirst score: via visual analog scale
Safety: adverse events, vital signs, laboratory tests, electrocardiograms, and the
rate of sodium correction.
Gheorghiade, Mihai, Stephen G. Goulieb, James Udelson, Marvin Konstam, Frank Czerwiec, John Ouyang, and Cesare Orlandi. "Vasopressin V2
Receptor Blockade with Tolvaptan Versus Fluid Restriction in the Treatment of Hyponatremia." American Journal of Cardiology 97 (2006): 1064-
Tolvaptan VS Fluid Restriction
Vasopressin V2 Receptor Blockade with Tolvaptan Versus Fluid Restriction in the
Treatment of Hyponatremia
 Results: (p 0.0065)
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Increase in Serum Na by:
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5.7 +/- 3.2 mmol/L in the tolvaptan group and
1.0 +/- 4.7 mmol/L in the fluid restriction group
 ADR:
No differences in serum potassium, blood pressure, or heart
rate were observed between treatment groups. No
differences in thirst score or adverse events requiring drug
discontinuation were observed between treatment groups.
 Drop out rates were high
 Therapy completion:
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6/17 Tolvaptan vs 2/28 PBO
At 14 days, patients can withdraw if no benefit has been seen
Used LOCF method
What happens next?
 …data are limited in comparing
effectiveness/toxicities of the vasopressin antagonists
with other therapeutic options for hyponatremia
 Chronic Hyponatremia
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Mild hyponatremia is associated with reversible
attention deficit and gait instability which can cause a
high rate of falls & admissions for bone fractures
Studies only go as far as 30 days
 What is the role in acute setting?
 Limited data to show that it is effective in acute
situations
RM
 What else can we do for Mr. RM
 Na levels are still low after interventions, although seems like it
is trending up (8/3) = 133mEq/L
 Hypertriglyceridemia may need to be adressed
 Continue to treat Hyperglycemia
 V2RA: May be beneficial if RM presents with Na levels that have
been continually low for consecutive days
 QUESTIONS?