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What is the role of tolvaptan for management of hyponatremia?

Background
Hyponatremia, a common electrolyte abnormality, is defined as a serum sodium less than 135 mEq/L.¹ The condition is associated with significant morbidity and mortality. The most important complication is transient or permanent brain dysfunction resulting from the acute effects of hypo-osmolality or if the correction of hyponatremia is too fast. Hyponatremia generally occurs due to an excess of extracellular water caused by impaired water excretion. Depending on serum osmolality, hyponatremia is classified as isotonic (~280 mOsm), hypertonic (>280 mOsm), or hypotonic (<280 mOsm). Hypotonic hyponatremia can be further classified as hypovolemic, euvolemic, or hypervolemic hyponatremia based on the fluid status of the patient.

Hypovolemic hyponatremia is associated with a deficit of extracellular fluid (ECF) volume and sodium.² Causes of hypovolemic hyponatremia include: diarrhea, excessive sweating, and thiazide-type diuretics.¹ Euvolemic hyponatremia is associated with a normal or decreased total body sodium content and increases in ECF volume; most commonly due to syndrome of inappropriate antidiuretic hormone (SIADH). Hypervolemic hyponatremia is associated with an elevated total body sodium content and increased ECF volume. Causes include: cirrhosis, heart failure (HF), and nephrotic syndrome.

Arginine vasopressin (AVP or antidiuretic hormone) is released to the systemic circulation in response to increased osmotic pressure, resulting in water retention.³ Both V_1A and V₂ receptors are stimulated when AVP is released. V_1A receptors are located in vascular smooth muscle and cause arterial vasoconstriction to compensate for low arterial pressure. AVP exerts its anti-diuretic effect by stimulating the V₂ receptor on the renal collecting duct. Elevated AVP contributes to total body water excess and hyponatremia. Diuretics and free water restriction have been used to combat this condition, but such strategies may result in electrolyte imbalances, arrhythmias, and renal failure. Desmopressin and lithium have also been used. Vasopressin receptor antagonists (VRAs) target AVP receptors to inhibit free water absorption. Intravenous conivaptan is a nonselective VRA that is approved by the Food and Drug Administration (FDA) for short-term treatment (4 days) of hyponatremia in hospitalized patients. Tolvaptan was recently approved by the FDA in May 2009 for oral management of chronic hyponatremia.

Tolvaptan (Samsca)
Tolvaptan is a selective vasopressin V₂ receptor antagonist approved for the treatment of clinically significant hypervolemic and euvolemic hyponatremia including patients with HF, cirrhosis, and SIADH.⁴ Tolvaptan causes an increase in urine water excretion and decreased urine osmolality, resulting in an increase in serum sodium concentration.

The usual starting dose in adults is 15 mg once daily.⁴ This dose may be increased to 30 mg daily after at least 24 hours and to a maximum of 60 mg daily, as needed to achieve the desired level of serum sodium. Although there is no need to adjust the dose in patients with mild to severe renal impairment (creatinine clearance 10 to 79 mL/min), tolvaptan has not been evaluated in patients with creatinine clearance <10 mL/min or those receiving dialysis.

The onset of effects occur within 2 to 4 hours after the dose.⁴ A peak effect of ~6 mEq increase in serum sodium and ~9 mL/min increase in urine excretion is observed between 4 to 8 hours post-dose. The most common adverse events reported with tolvaptan use are: dry mouth, thirst, constipation, polyuria, hyperglycemia, and asthenia.^4,5

While on tolvaptan, patients should be monitored carefully for any adverse reactions, drug interactions, and fluid status.^3,5 Tolvaptan contains a boxed warning stating that initiation and re-initiation of tolvaptan should be done only in a hospital where serum sodium can be monitored closely.⁴ Too rapid correction of hyponatremia (e.g., > 12 mEq/L in 24 hours) can cause osmotic demyelination resulting in adverse effects including lethargy, seizures, coma, and even death. In patients with severe malnutrition, alcoholism, or advanced liver disease, slower rates of correction may be necessary. In patients with cirrhosis, there may be an increased risk of gastrointestinal bleeding; therefore, use in these patients should only take place if potential benefits outweigh the risk. Tolvaptan is contraindicated in patients who require urgent intervention to raise serum sodium acutely, patients unable to respond to thirst, hypovolemic hyponatremia, or use with strong/moderate cytochrome P450 3A (CYP3A) inhibitors. Tolvaptan is metabolized by CYP3A; therefore, use with strong/moderate CYP3A inhibitors (e.g., ketoconazole) may cause a marked increase in tolvaptan concentration. Tolvaptan is a substrate of P-glycoprotein (P-gp); therefore, use with inhibitors of P-gp (e.g., cyclosporine) may also increase tolvaptan concentration. As a result, a decrease in tolvaptan dose may be necessary when used with P-gp and/or strong/moderate CYP3A inhibitors.

Literature Review
The Study of Ascending Levels of Tolvaptan in Hyponatremia (SALT-1 and SALT-2) trials were designed to focus specifically on changes in serum sodium in patients with hyponatremia from multiple disorders including SIADH, HF, and cirrhosis.⁵ In 2, prospective, multicenter, randomized, double-blind, placebo-controlled trials (published jointly), the efficacy of tolvaptan was evaluated. Eligible patients were 18 years of age or older and had euvolemic or hypervolemic hyponatremia. Patients with uncontrolled hypothyroidism, adrenal insufficiency, or hyponatremia due to medications that could have been safely withdrawn were excluded. There were numerous other exclusion criteria, a few were: hypovolemic hyponatremia, myocardial infarction, systolic blood pressure <90 mmHg, serum creatinine concentration >3.5 mg/dL, serum sodium <120 mEq/L with associated neurologic impairment, and uncontrolled diabetes.

Patients were randomly assigned to oral placebo (n=223) or oral tolvaptan (n=225) at a dose of 15 mg daily (dose increased to 30 mg or 60 mg daily if necessary) for 30 days with sodium level follow-up assessment 7 days post completion.⁵ The 2 primary endpoints were the change in the average daily area under the curve (AUC) for the serum sodium concentration from baseline to day 4 and then to day 30. Secondary endpoints included change in the AUC for the serum sodium concentration in patients with marked hyponatremia, absolute serum sodium concentration at each visit, and the time to normalization of the serum sodium concentration.

The demographic and baseline characteristics of the patients were similar in the study groups in both trials.⁵ The study population in both trials had an average age of about 61 years old. There were slightly more males (~58%) than females (~42%) in both trials; however, they were evenly distributed between study groups. The average baseline serum sodium in both groups was 128 mEq/L.

Patients were evaluated 8 hours after first administration of drug, and on days 2, 3, 4, 11, 18, 25, 30, and 37.⁵ Tolvaptan was associated with a greater increase in average daily AUC for serum sodium compared to placebo at day 4 and day 30 (p<0.001 for all comparisons). At day 4, tolvaptan patients had an average sodium of 134 mEq/L (SALT-1) to 135 mEq/L (SALT-2) vs. 130 mEq/L for placebo recipients (p<0.001 for both trials). Serum sodium increased to an average of 136 mEq/L in the tolvaptan group at day 30, but was unchanged in the placebo group (p<0.001 for both trials). Once tolvaptan was discontinued at day 30, serum sodium levels returned to similar levels or below those of their placebo counterparts at day 37. The most common adverse events in the tolvaptan group were thirst, dry mouth, and increased urination.

Given the above results, the authors concluded that tolvaptan, when added to standard therapy, was superior to placebo in raising and maintaining serum sodium levels in patients with euvolemic or hypervolemic hyponatremia.⁵ It is important to note the limitations of the study. Many patients were excluded from the trial such as those with recent myocardial infarction, multiple strokes, and diabetes; therefore, it may be difficult to extrapolate the data to those patients. Neither outpatient fluid intake nor urine osmolality was measured throughout the study. Maintenance medications and doses were not mentioned. Also, the short study duration does not provide evidence for long-term benefit.

Use in Heart Failure
Tolvaptan has also been studied for use in patients with acute or worsening HF. Vasopressin has antidiuretic properties that contribute to fluid retention and hyponatremia found in heart failure patients. Antagonizing the vasopressin V₂ receptor, tolvaptan may increase diuresis without causing electrolyte imbalances that are observed with the use of other diuretics.⁶ The Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure (ACTIV in CHF) trial was a multicenter, randomized, double-blind, placebo-controlled phase 2 study conducted to evaluate the short- and intermediate-term effects of tolvaptan in patients hospitalized for HF.⁷ This dose-ranging trial evaluated the addition of tolvaptan 30 mg, 60 mg, or 90 mg to standard HF therapy compared to addition of placebo. Tolvaptan was associated with a reduction in body weight due to improved diuresis. The drug did not affect heart rate or blood pressure, lead to hypokalemia, or worsen renal function.

Rossi and colleagues conducted a post-hoc analysis of data from the ACTIV in CHF trial to determine the value of serum sodium (baseline and subsequent change) as a prognostic marker in patients experiencing an acute heart failure exacerbation.⁸ Results revealed that every 1 mEq/L increase in serum sodium at hospital discharge was associated with a reduction in mortality at day 60 (hazard ratio, 0.736, 95% confidence interval 0.569 to 0.952, p=0.0195).

Two identical prospective, randomized, placebo-controlled trials for the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) randomized 4133 patients with worsening heart failure to either tolvaptan 30 mg daily or placebo.⁹ Tolvaptan in addition to standard therapy, such as diuretics, digoxin, angiotensin-converting enzyme inhibitors, beta-blockers, nitrates, improved heart failure signs and symptoms, but did not have an effect on long-term mortality (median follow up of 9.9 months) or HF associated morbidity.^9,10

Conclusion
Tolvaptan is a selective, oral vasopressin V₂ receptor antagonist that causes an increase in urine water excretion resulting in an increase in aquaresis, decrease in urine osmolality, and an increase in serum sodium concentration. The SALT-1 and SALT-2 trials have shown that tolvaptan was superior to placebo in raising and maintaining serum sodium concentration at 30 days of treatment. If initiated and monitored properly, tolvaptan appears to be safe with dry mouth and increased thirst as the most common adverse events. Current outpatient management strategies of diuretics and fluid restriction may not be effective enough (especially with lack of adherence to fluid restriction), and tolvaptan may be beneficial in patients with chronic hyponatremia. Tolvaptan may also improve HF signs and symptoms when given in addition to conventional HF therapy. However, it is prudent to be cautious of contraindications and monitoring parameters associated with tolvaptan, as well as drug interactions and the need for more long-term studies.

References

By Lamies Abuakar, PharmD