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Jalandhara Nishant
The Article:
Tolvaptan, a Selective Oral
Vasopressin V2-Receptor
Antagonist, for Hyponatremia

N Engl J Med 2006; 355:2099-2112

               Otsuka Maryland Research Institute
          Hyponatremia is a disorder of impaired water excretion.
          Definition: Serum [Na+] less than 135 mEq/l
          The incidence of hyponatremia among hospitalized
           patients ranges from 15% to 22% 1
          Hyponatremia is reportedly associated with a 7- to 60-
           fold increase in mortality 2
          Hyponatremia contributes to illness, even in patients with
           mild chronic hyponatremia, increasing the risk of falls
           and cognitive dysfunction

1. Endocrinol Metab Clin North Am 32: 459-481 2. Med Clin North Am 81: 585-609
Hyponatremia: Role of AVP
   The pituitary hormone arginine vasopressin (AVP), also
    referred to as antidiuretic hormone, has a key role in
    regulating water balance by increasing reabsorption of
    solute-free water from filtrate in the distal and collecting
    tubules of the kidney
   The main effects of AVP on water balance are mediated
    through V2 receptors in the renal collecting ducts
   Under the influence of AVP, the renal collecting duct
    system accounts for absorption of 15–20% of filtered
    water, which determines the concentration of voided
   In hyponatremic patients, regulation of AVP is often
       Hyponatremia: Treatment Option
Therapy                        Advantages                         Disadvantages

Fluid restriction              Generally effective; inexpensive   Noncompliance

Demeclocycline                 Consistently effective             Reversible azotemia and nephrotoxicity;

Lithium                        Effective in some patients         Inconsistent effectiveness; significant
                                                                        adverse effects

Loop diuretics (e.g.           Effective in some patients         Imbalance between diuretic action and
     furosemide) plus                                                  salt ingestion can lead to volume
     increased salt intake                                             depletion or overload

Urea                           Consistently effective             Poor palatability; gastrointestinal adverse
                                                                        effects; development of azotemia at
                                                                        higher doses

Hypertonic (3% or 5%) saline   Corrects serum [Na+]               Rate of correction is variable and difficult
     with or without co-                                                to control; overly rapid correction is
     administration of loop                                             associated with myelinolysis
Tolvaptan in Hyponatremia
    Short-term studies have shown that vasopressin V2-
     antagonists correct hyponatremia in patients with chronic
     heart failure,1,2 cirrhosis,3 or SIADH.4
    A long-term study examined the effects of tolvaptan in
     patients with chronic heart failure,5 but the primary end
     point was the change in body weight, not correction of

1.   Gheorghiade M. Circulation 2003;107:2690-2696
2.   Abraham WT. J Am Coll Cardiol 2006;47:1615-1621
3.   Gerbes ALGastroenterology 2003;124:933-939
4.   Saito T. J Clin Endocrinol Metab 1997;82:1054-1057.
5.   Gheorghiade M JAMA 2004;291:1963-1971
Phase 3 Clinical Studies
   Phase 3 studies are expanded controlled and uncontrolled
   They are performed after preliminary evidence
    suggesting effectiveness of the drug has been obtained in
    Phase 2, and are intended to gather the additional
    information about effectiveness and safety that is
    needed to evaluate the overall benefit-risk relationship of
    the drug.
   Phase 3 studies also provide an adequate basis for
    extrapolating the results to the general population and
    transmitting that information in the physician labeling.
   Phase 3 studies usually include several hundred to
    several thousand people.
Why this study?

   Evaluate the efficacy of tolvaptan in
    treatment of hyponatremia (euvolemic and
   Define the adverse effect profile of
   Assess the outpatient efficacy of tolvaptan
The Study: Salt 1 & 2

        Q’s ???
Salt 1 & 2
   Study of Ascending Levels of Tolvaptan in
    Hyponatremia 1 and 2 (15,30 and 60 mg)
   Multicenter, prospective, randomized, placebo-
    controlled, double-blind phase 3 studies
   Intention was to examine the effect of tolvaptan
    on hypervolemic and euvolemic hyponatremia of
    diverse causes
   Assessed the outpatient use tolvaptan, including
    assessments of reversibility and safety
                  The Study:

         Salt 1                      Salt 2

   US based multicenter      Europe based
    study (42 sites)           multicenter study (50
   102 patients to            sites)
    tolvaptan arm and         123 patients to
    103 to placebo             tolvaptan arm and
                               120 to placebo
Inclusion Criteria
   Patients with euvolemic or hypervolemic hyponatremia
    ([Na+] <135 mmol/l)
   Patients with CHF, cirrhosis, or SIADH in association
    with the hyponatremia
   18 years of age or older
   The study protocols also required a serum sodium
    concentration of less than 130 mmol per liter at baseline
    in 50% of those enrolled and also required that no single
    disease entity be represented in more than half the total
    study population
   Mild hyponatremia: [Na+] 130 to 134 mmol/l and
    marked hyponatremia [Na+] <130 mmol/l
Exclusion criteria
   Patients with psychogenic polydipsia, head trauma, postoperative
    conditions, uncontrolled hypothyroidism or adrenal insufficiency, or any
    hyponatremic condition associated with the use of medications that could
    have been safely withdrawn were ineligible
   Hypovolemic hyponatremia
   Recent cardiac surgery, myocardial infarction, sustained ventricular
    tachycardia or fibrillation, severe angina, cerebrovascular accident, or
    multiple strokes; systolic blood pressure of less than 90 mm Hg, central
    venous pressure of less than 5 cm of water, pulmonary-capillary wedge
    pressure of less than 5 mm Hg, a serum creatinine concentration of more
    than 3.5 mg per deciliter (309 µmol per liter), a Child–Pugh score of more
    than 10 (unless approved by the study's medical monitor), or a serum
    sodium concentration less than 120 mmol per liter in association with
    neurologic impairment; and the presence of severe pulmonary hypertension,
    urinary tract obstruction, uncontrolled diabetes mellitus, or progressive or
    episodic neurologic disease. Patients who were judged to have little chance
    of short-term survival or who might not tolerate sudden shifts in fluid
    volumes or pressures were ineligible
   The identical study designs of the two trials assessed
    reproducibility and were intended to ensure
   IRB approved
   Written informed consent was obtained from all
   Fluid restriction was not mandatory according to
    the study protocol. Treatment of hyponatremia with
    demeclocycline, lithium chloride, or urea was not
    permitted but other adjunct therapy continued.
Protocol (Cont…)
   Patients were randomized to receive oral
    tolvaptan (15mg PO) or matching placebo once
    daily for up to 30 days.
   Dose was titrated as follows:
     [Na+] < 136 and Δ by < 5 /24hrs: Increase
     [Na+] > 145 or Δ > 12/24hrs or >8/8hrs: stop
       drug or decrease dose and/or increase PO
       fluid intake
     Hospitalized on D1 and most discharged on
       D4 of study
Protocol (Cont…)
   Follow up: Patients were evaluated at baseline, 8 hours after the
    first administration of the study drug (tolvaptan or placebo), and on
    days 2, 3, 4, 11, 18, 25, 30, and 37. Study drugs were withheld after
    day 30, and the effect of discontinuation of the study drug was
    assessed on day 37
   Primary end points:
       The change in the average daily area under the curve (AUC) for
        the [Na+] from baseline to day 4
       The change in the average daily AUC for the [Na+] from
        baseline to day 30
   Secondary end points:
       Change in the AUC for the [Na+] in patients with marked
       Absolute serum sodium concentration at each visit
Protocol (Cont…)
       Time to normalization of the serum sodium concentration
       The percentages of patients with [Na+] that had normalized at
        day 4 and day 30
       Categorical [Na+] on day 4 and day 30 for patients with mild or
        marked hyponatremia at baseline
       Other Secondary end points: I/O on day 1, change in body
        weight in patients with hypervolemic hyponatremia on day 1,
        fluid restriction or use of intravenous saline as rescue therapy,
        and the change from baseline in scores on the SF-12 General
        Health Survey
   Safety analysis: Patients who received at least one dose of the study
   Efficacy analysis: Patients whose serum sodium concentrations were
    evaluated at baseline and one or more times after baseline
SF 12 health survey
Physical component (5-69): Assesses physical functioning, bodily pain,
physically limited accomplishment, and general Health
Mental component (8-73): Assesses vitality, social functioning,
emotionally limited accomplishment, calmness, and sadness.
Enrollment, Randomization,
and Follow-up of Patients in
the SALT-1 (Panel A) and
SALT-2 (Panel B) Trials

    Q’s ???
Hyponatremia resolved in treatment arm = X = 40%
Hyponatremia resolved in control arm = Y = 13 %
Absolute risk reduction (ARR) = X-Y = 0.27

NNT = 1/ARR = 1/0.27 = 3.7
SF-12 Health survey
                In only 4 of the 223 patients in the tolvaptan
                group were desirable rates of sodium correction
                exceeded during the first 24 hours of the study
                (>0.5 mmol per liter per hour; maximum observed
                rate, 0.61 mmol per liter per hour). In only four
                patients (1.8%) was the predefined, potentially
                clinically important serum sodium concentration
                (>146 mmol per liter) exceeded.
                Are these the same 4 patients ??
                CPM ??

Serious adverse events occurred in eight patients on
tolvaptan, including hypotension, dizziness, and syncope
Why this study?

   Evaluate the efficacy of tolvaptan in
    treatment of hyponatremia (euvolemic and
   Define the adverse effect profile of
   Assess the outpatient efficacy of tolvaptan
   Tolvaptan was superior to placebo with respect to
    several measures
       Change in the average daily AUC for serum sodium
        concentrations from baseline to day 4 and from baseline to
        day 30
       Mean serum sodium concentration at each visit
       Time to normalized serum sodium concentrations
       Percentage of patients with serum sodium concentrations
        that were normal on day 4 and on day 30
       Categorical change in the serum sodium concentration
        from baseline to day 4 and from baseline to day 30.
Discussion (Cont…)
During the 7-day follow-up period, serum sodium
concentrations reverted to degrees of hyponatremia
that were equivalent to those associated with the use
of placebo, indicating that the aquaretic effect of
tolvaptan (excretion of electrolyte-free water) was
required to maintain normal sodium concentrations
in patients with chronic hyponatremia.

  Tolvaptan was superior to placebo from
  the first observation point (8 hours) after
  administration of the first dose until the last
  treatment day (day 30) in patients with either
  mild or marked hyponatremia and among
  patients with hyponatremia from all major
Limitations of study

   The SALT trials were not powered to
    look at clinical end points
   Did not mention how many patient were
    hospitalized secondary to treatment or AE
   Central pontine myelinosis ??
   Hyponatremia: Acute vs chronic and
    symptomatic vs asymptomatic
   No subgroup analysis
Limitations of study: Disclosure
   Dr. Schrier reports having served as a consultant to
    Otsuka, Astellas, Bayer, and Amgen.
   Dr. Gross reports having served as a consultant to
    Sanofi-Synthelabo, having received lecture fees from
    Astellas, and having received grant support from
    GlaxoSmithKline, Takeda, Amgen, Roche, and
   Dr. Gheorghiade reports having served as a consultant to
    Otsuka, PDL, Sigma Tau, Medtronic, and
    GlaxoSmithKline and having received honoraria from
    Medtronic, Astra Zeneca, Scios, GlaxoSmithKline,
    Otsuka, PDL, Abbott, and Sigma Tau.
What do authors recommend?

   Tolvaptan is a safe drug to improve
   It has no effect on renal function, heart rate, or
    blood pressure
   “Careful oversight of the use of this agent is
    required, not only by means of frequent clinic
    visits and measurement of serum sodium, but
    also through daily measurements of body weight
    by patients." – Dr Hays
What next…
     EVEREST:
         Efficacy of Vasopressin Antagonism in Heart Failure: Outcome
          Study with Tolvaptan
         A large, multicenter, placebo-controlled trial that is being
          designed to evaluate the long-term efficacy and safety of
          tolvaptan in subjects hospitalized with decompensated heart
         The target is to enroll about 3,000 patients
         Endpoints: All-cause mortality, cardiovascular mortality,
          hospitalizations, serum sodium concentration, and improvement
          of edema.

Gheorghiade M. J Card Fail 11(4): 260-269
Thank you
Free water clearance (FWC)
   FWC equals the volume of urinary water (over a
    period of time) that exceeds the virtual volume
    that would be required to excrete the solute load
    in an iso-osmolar fashion
   In other words, the excess of pure water excreted
   Urea freely cross cell membranes and therefore
    do not influence the movement of water between
    extracellular and intracellular compartments
   Tonically active particles: sodium, potassium,
    chloride, bicarbonate, and glucose
Calculating FWC
   Over 24 h, a patient collects 4 l of urine with a solute concentration of 70
    mOsm/l. Concurrently measured serum osmolarity is 280 mOsm/l
    (osmolality would be roughly 280 mOsm/kg H2O), four times as
    concentrated as the urine. If the urinary solutes (total = 70 mOsm/l  4 l)
    were dissolved in just one-quarter of the actual volume of urine, then the
    urine osmolarity would match the serum osmolarity of 280 mOsm/l. The
    other 3 l of urine would be pure water. Therefore, the FWC is the actual
    urine volume (4 l) minus the ‘iso-osmolar urine volume’ (1 l), which equals
    3 l. More correctly, because clearance is a volume per unit time, the FWC is
    3 l per 24 h (the period during which the urine was collected).

    FWC = actual urine volume (V) – iso-osmolar urine volume (Viso)

   To generalize this example into mathematical terms, the virtual volume of
    iso-osmolar urine can be calculated by determining how dilute or
    concentrated the urine is compared with serum:

                          Viso = V  (Uosm / Sosm)
Calculating eFWC
   After calculating iso-osmolar urine volume (1 l in the example), the remainder of the
    total urine volume should be composed of osmole-free water, quantified in the
    following equation:
           FWC       = V – Viso
                     = V – V  (Uosm / Sosm)
                     = V  (1 – Uosm / Sosm)
   Finally, divide FWC by the time during which the urine was collected, or V  (1 –
    Uosm / Sosm) / time. This becomes the general formula for FWC (CH2O):
           FWC (CH2O) = V  (1 – Uosm / Sosm) / time

   When re-formulating the equation for FWC on the basis of tonicity Uosm / Sosm
    becomes (UNa + UK) / SNa, Serum potassium is usually ignored because it
    represents an insignificant fraction of the total serum cationic tonicity. By contrast,
    potassium in the urine must be taken into account because it often constitutes a
    sizeable portion of the total urinary cationic tonicity. Incorporating all of these
    tonicity modifications, the FWC equation becomes:
                     V  [1 – (UNa + UK) / SNa] / time

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