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 PMH: CAD (s/p 1 stent placement 2001) DM type 2 (2001) Hypertension Lisinopril 5mg Daily Prazosin 1mg Daily Hyperlipidemia Simvastatin 40mg Daily FH 1 sister with cervical CA & hepatitis Micafungin 50mg Once Daily Acyclovir 400mg BID Bactrim DS 800/160mg 1 tab BID on Sat/Sun SH: 1 ppd x 40 yr, quit 2000 Limited alcohol use No history of Illicit drug use Married, good family support wife at bedside 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 7/19 131 131 7/20 7/21

127 126

7/22 7/23 7/24 7/25 7/26 7/27 7/28 7/29

128

129 130 131 132 132 130 131 Diarrhea Episode: intermittently, started on 16 th ~1600 ml 20 th ~1800ml loose stool 17 th ~1500 ml loose stool 21 st no diarrhea 18 th started solu-medrol

 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)

 From renal/extra renal loss exceeding intake 

Common in hospitalized patients ~15-30%

 Setting also allows for diagnosis 

Clinical complication of wide pathophysiology

 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:  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:  Hyperglycemia (Translational Hyponatremia)    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,

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:

hyponatremia” (278 295 mOsm/Kg): 287 mOsm/Kg H2O = “isotonic  Protein levels: Low protein levels (5.5-5.7)  Lipid Levels: TG high: (7/19) 212 (7/26) 277

Hyperglycemia:

 Glucose levels: Na: Glu: Corrected Na: TG 7/16 7/17 138 133 206 184 7/18 7/19 7/20 7/21 7/22 7/23 7/24 7/25 7/26 7/27 7/28 7/29 131 131

127 126 128

129 130 131 132 132 130 131 180 248 201 260 172 123 147 127 203 114 151 152

128 128 129

212 277

…

    

Acute fluid loss:

  Diarrhea: stool volume Diuretics: Lasix 40mg IV daily X 2

Iatrogenic:

 IVF:   TPN: Pharmacological Agents:  Lisinopril

Hypothyroidism:

 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

 Fluid Balance:  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



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  Normal Saline  Hypertonic Saline Diuretic Therapy

Aquaretic Therapy



Conivaptan



Tolvaptan

Other Agents    Lithium Demeclocycline Urea

RM

Na: Glu: Corrected Na: 7/16 7/17 138 133 206 184 7/18 7/19 7/20 7/21 7/22 7/23 7/24 7/25 7/26 7/27 7/28 7/29 131 131

127 126 128

129 130 131 132 132 130 131 180 248 201 260 172 123 147 127 203 114 151 152

128 128 129

   Fluid Restriction (Free Water)  7/22: <1L/day Lasix 40mg QD x 2 days  7/21  7/22 Na repletion:  Na Phosphate   Na Acetate Na Chloride 7/20 25 85 85 Lasix 40mg IV 7/21 25 85 85 Fluid Restriction <1L/day TPN w/ Insulin & Na repletion  7/22 7/23 25 25 85 105 85 105 Hyperglycemia:  Insulin in TPN:  58u/L  64u/L (7/20-7/23)  +Lispro 5u SC AC/QHS  +SSI

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  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



3 receptor sub-types:

   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         Astellas IV formulation, v1/v2 receptor antagonist FDA approval in 2004 Treatment of Euvolemic/Hypervolemic Hyponatremia  Multi-center, double-blind, placebo controlled, randomly assigned (4days)  

Conivaptan

30min LD (20mg diluted to 100ml D5W) infusion  4 (diluted to 250ml) 

40mg/day



80 mg/day Placebo

100ml D5W as LD  250 ml D5W 96hr CIV days 1 Important Exclusion Criteria:      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) 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     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:    Conivaptan 80mg/day: 54% Conivaptan 40mg/day: 38% PBO: 21% Endpoints used were useful Baseline Na levels were ~124mEq/L         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): 2099 112.

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)  Tolvaptan 15mg tab 1 tab PO Daily x 30 days OR PBO Important Patient Population Criteria:   Inclusion  Etiologies: CHF, cirrhosis or SIADH Exclusion Criteria:  Other etiologies   Hypovolemic hyponatremia Other cardiac diseases (post-MI, SVT, SBP<90)   Serum Na <120 mmol/L w/ neurological impairment 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

Completed Follow-up @ 7-days & 30-days: 

Tolvaptan: N=171 (76%)

 Rash, ARF, increased SCr, decreased Na, aggravated hyponatremia, vomiting

PBO: N=154 (69%)

Study Withdrawal:  Total: N= 123   Tolvaptan: 54 (24%) 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

           

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

“The Vaptans” Convenience MOA Efficacy/Onset Safety DDI

Conivaptan VS Tolvaptan

Conivaptan IV non-selective 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 Infusion site reactions, phlebitis, cardiac effects Strong CYP3A4 Inhibitor/substrate Tolvaptan PO selective 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 Limited to v2 antagonism Rash P-glycoprotein Substrate

Tolvaptan VS Fluid Restriction

Vasopressin V2 Receptor Blockade with Tolvaptan Versus Fluid Restriction in the Treatment of Hyponatremia

    

prospective, multicenter, randomized, active-controlled, open-label trial N=28 patients (euvolemic/hypervolemic hyponatremia) with Na <135 mmol/L

 

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.

Arms:



Tolvaptan 10mg/day



60mg/day x ~27days (n=17)



Fluid restriction 1200ml/day + PBO x ~27days (n=11) Follow-up: 65 days Endpoints:

  

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 067.

Tolvaptan VS Fluid Restriction

Vasopressin V2 Receptor Blockade with Tolvaptan Versus Fluid Restriction in the Treatment of Hyponatremia

  

Results: (p 0.0065)

 Increase in Serum Na by:   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:    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

 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?