Journal Club: Journal Club Jalandhara Nishant PGY 2


The Article: : 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: 1. Endocrinol Metab Clin North Am 32: 459-481 2. Med Clin North Am 81: 585-609 Hyponatremia 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


Hyponatremia: Role of AVP: 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 urine In hyponatremic patients, regulation of AVP is often altered


Hyponatremia: Treatment Option: Hyponatremia: Treatment Option


Tolvaptan in Hyponatremia: 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 hyponatremia. Gheorghiade M. Circulation 2003;107:2690-2696 Abraham WT. J Am Coll Cardiol 2006;47:1615-1621 Gerbes ALGastroenterology 2003;124:933-939 Saito T. J Clin Endocrinol Metab 1997;82:1054-1057. Gheorghiade M JAMA 2004;291:1963-1971


Phase 3 Clinical Studies : Phase 3 Clinical Studies Phase 3 studies are expanded controlled and uncontrolled trials. 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? : Why this study? Evaluate the efficacy of tolvaptan in treatment of hyponatremia (euvolemic and hypervolemic) Define the adverse effect profile of tolvaptan Assess the outpatient efficacy of tolvaptan


The Study: Salt 1 & 2: The Study: Salt 1 & 2 Q’s ???


Salt 1 & 2: 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:: The Study: Salt 1 US based multicenter study (42 sites) 102 patients to tolvaptan arm and 103 to placebo Salt 2 Europe based multicenter study (50 sites) 123 patients to tolvaptan arm and 120 to placebo


Inclusion Criteria: 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 : 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


Protocol : Protocol The identical study designs of the two trials assessed reproducibility and were intended to ensure comparability IRB approved Written informed consent was obtained from all patients. 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…): 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+] 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…): 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 hyponatremia Absolute serum sodium concentration at each visit


Protocol (Cont…): 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 medication Efficacy analysis: Patients whose serum sodium concentrations were evaluated at baseline and one or more times after baseline


Slide19: Enrollment, Randomization, and Follow-up of Patients in the SALT-1 (Panel A) and SALT-2 (Panel B) Trials


Results : Results Q’s ???


SF-12 Health survey: SF-12 Health survey


Slide27: 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? : Why this study? Evaluate the efficacy of tolvaptan in treatment of hyponatremia (euvolemic and hypervolemic) Define the adverse effect profile of tolvaptan Assess the outpatient efficacy of tolvaptan


Discussion: Discussion 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…): 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.


Conclusion : Conclusion 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 causes.


Limitations of study : 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: 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 Fresenius. 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?: What do authors recommend? Tolvaptan is a safe drug to improve hyponatremia 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…: 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 failure. 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: Thank you


Free water clearance (FWC): 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: 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: 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