The Treatment of Acute Hyponatremia with Tolvaptan

Clinical Medicine Insights: Therapeutics, 2011

Hyponatremia is a very common electrolyte disorder and is a significant independent predictor of medical prognosis and costs. Tolvaptan is a vasopressin receptor antagonist developed for the treatment of hyponatremia. It has its principal application in the treatment of euvolemic and hypervolemic hyponatremia. Its major role is in the treatment of heart failure (HF), cirrhosis and the syndrome of inappropriate antidiuretic hormone secretion (SIADH). While at present tolvaptan has not demonstrated long term survival benefit with its use, it clearly has proven short term efficacy in the management of hyponatremia by demonstrating improvement in serum sodium levels at an acceptable rate without evidence of over-correction.

Journal of the American Society of Nephrology, 2010

Vasopressin antagonists increase the serum sodium concentration in patients who have euvolemia and hypervolemia with hyponatremia in the short term (Յ30 days), but their safety and efficacy with longer term administration is unknown. SALTWATER was a multicenter, open-label extension of the Study of Ascending Levels of Tolvaptan in Hyponatremia (SALT-1 and SALT-2). In total, 111 patients with hyponatremia received oral tolvaptan for a mean follow-up of 701 days, providing 77,369 patient-days of exposure. All patients had hyponatremia at randomization in SALT-1 and SALT-2, and 85% continued to have hyponatremia at entry in SALTWATER. The most common adverse effects attributed to tolvaptan were pollakiuria, thirst, fatigue, dry mouth, polydipsia, and polyuria. Six drug-related adverse effects led to study discontinuation. The increase in serum sodium exceeded the desired 1 mmol/L per h at initiation in five patients. Hypernatremia (Ͼ145 mmol/L) led to discontinuation in one patient. Mean serum sodium increased from 130.8 mmol/L at baseline to Ͼ135 mmol/L throughout the observation period (P Ͻ 0.001 versus baseline at most points). Responses were comparable between patients with euvolemia and those with heart failure but more modest in patients with cirrhosis. In conclusion, prolonged administration of tolvaptan maintains an increased serum sodium with an acceptable margin of safety.

Turkish journal of internal medicine, 2020

Introduction. Non-peptide vasopressin receptor antagonists (vaptans) are effective at increasing sodium in euvolemic and hypervolemic states and appear safe. We aimed to evaluate the efficacy of tolvaptan in euvolemic or hypervolemic hyponatremic patients. Methods. The study included 9 hyponatremic (serum sodium level <125 mmol/L) patients. Serum potassium levels of all patients were normal and there was no acid-base disturbance. Patients with hypovolemic status and hepatic dysfunction were excluded from the study. Clinical and laboratory data of patients were obtained before and after tolvaptan treatment. Results. The median age of patients (6 females, 3 males) was 66.63 years (range, 56-82). The mean sodium levels before tolvaptan treatment were 120.5 mEq/L (SD 2.2, range, 116-124). The mean sodium levels increased significantly to 132.6±4.0 mEq/L (range, 125-140) after tolvaptan treatment at 2.7±1.3 days (range, 2-6) (p<0.001). Hyponatremia did not recur after tolvaptan treatment. We did not observe serious adverse event related with tolvaptan treatment. Conclusion. Hyponatremia was a common problem, and tolvaptan can treat hyponatremia effectively and safely in patients with euvolemic or hypervolemic hyponatremia.

The American Journal of Cardiology, 2006

Hyponatremia is common and is associated with a poor prognosis. Traditional management with fluid restriction is difficult to maintain, and it is often ineffective. The objective of this study was to determine the effect of tolvaptan versus fluid restriction on serum sodium concentration. The study was a prospective, multicenter, randomized, active-controlled, open-label trial. Twenty-eight hospitalized subjects with serum sodium <135 mmol/L were enrolled in the study. After a 2-day run-in period, subjects were randomized 2:1 to tolvaptan alone (n ‫؍‬ 17) or fluid restriction (1,200 ml/day) plus placebo (n ‫؍‬ 11). Oral tolvaptan was started at 10 mg/day and increased to 60 mg/day as needed. Treatment was continued for up to 27 days, and follow-up continued for up to 65 days. The primary end point was the normalization of serum sodium, defined as >135 mmol/L or a >10% increase from baseline. At the last inpatient visit, serum sodium had increased by 5.7 ؎ 3.2 mmol/L in the tolvaptan group and 1.0 ؎ 4.7 mmol/L in the fluid restriction group (p ‫؍‬ 0.0065). No differences in adverse events were observed between the groups. In conclusion, tolvaptan appears to be more effective than fluid restriction at correcting hyponatremia in hospitalized subjects, without an increase in adverse events.

Annals of Intensive Care, 2016

Background: Hyponatremia is the most common electrolyte disturbance in hospitalized patients, and it represents a well-established risk factor for ICU/hospital mortality. The majority of hyponatremic states are associated with elevated arginine vasopressin levels and a preserved sodium pool. Conventional treatment is either not pathophysiologically oriented or of limited effectiveness. The aim of the present study is to investigate the use of enteral Tolvaptan in critically ill hyponatremic patients. Methods: This is a retrospective observational study in a general ICU. Patients with preserved sodium pool hyponatremia refractory to conventional therapy were enrolled. The hemodynamic, renal, and hepatic functions, together with sodium and water balance as close as possible to the drug administration and up to 72 h thereafter, were analyzed. The main outcome was a serum sodium increase of ≥ 4 mmol/L in 24 h; secondary endpoints were the ability to maintain serum sodium at 24 and 72 h, a decrease in urine sodium concentration and an increase in sodium-free diuresis. Results: 38 patients were enrolled. The average dose of enteral Tolvaptan was 7.5 mg. 31 patients (81.6 %) increased their serum sodium >4 mmol/l/24 h; the average increase was 6.7 ± 3.4 mmol/l during the first 24 h (p < 0.001 vs baseline), and this was sustained at 72 h. No adverse effects were reported. Plasma sodium (R = -0.622, p < 0.001), urine sodium (R = -0.345, p < 0.001), central venous oxygen saturation (R = 0.401, p = 0.013), and BUN (R = -0.416, p = 0.031) before Tolvaptan were all significantly correlated with the absolute increase in serum sodium after the administration. Conclusions: Enteral administration of Tolvaptan seems effective in the treatment of hyponatremia with preserved sodium pool in critically ill patients. Even if the study was underpowered to detect significant side effects or complications of unwarranted fast corrections of hyponatremia, we report no complications.

The Open Urology & Nephrology Journal, 2014

Hyponatremia is associated with increased morbidity and mortality. Water restriction is usually the prescribed treatment for most forms of asymptomatic hyponatremia. An oral vasopressin V2-receptor antagonist, tolvaptan has been successfully used in the treatment of asymptomatic hyponatremia. In this retrospective study, tolvaptan (n=40) and a control group (n=40) were compared for asymptomatic hyponatremia etiology and response to treatment. The syndrome of inappropriate anti-diuretic hormone (SIADH) and congestive heart failure (CHF) were the most common causes of asymptomatic hyponatremia that were treated with tolvaptan. Of note, the cause of hyponatremia was not clarified in 50% of the control and 10% of the tolvaptan group. In the tolvaptan group, serum sodium concentration increased from 125±4.2 to 136±2.1 mEq/L (mean±SD, P<0.001) over 5±2 days while the control group did not show any change from its baseline value of 129.9±3 vs 128±4 mEq/L. SIADH and CHF were the most common disorders associated with asymptomatic hyponatremia and treated with tolvaptan. Importantly, 50% of the asymptomatic hyponatremia patients in the control group were labeled as unclear etiology and did not receive tolvaptan. Increased awareness of the etiology and mechanisms of asymptomatic hyponatremia development can identify individuals who benefit from tolvaptan therapy.

International Journal of Nephrology and Renovascular Disease, 2010

Hyponatremia is an electrolyte disorder frequently observed in several clinical settings and common in hospitalized patients with decompensated heart failure (HF). It is caused by deregulation of arginine vasopressin (AVP) homeostasis associated with water retention in hypervolemic or in euvolemic states. While hypervolemic hypotonic hyponatremia is also seen in advanced liver cirrhosis, renal failure, and nephrotic syndrome, the bulk of evidence associating this electrolyte disorder to increasing morbidity and mortality can be found in the HF literature. Hospitalized HF patients with low serum sodium concentration have lower short-term and long-term survival, longer hospital stay and increased readmission rates. Conventional therapeutic approaches, ie, restriction of fluid intake, saline and diuretics, can be effective, but often the results are unpredictable. Recent clinical trials have demonstrated the effectiveness of nonpeptide AVP receptor antagonists (vaptans) in the treatment of hyponatremia. The vaptans induce aquaresis, an electrolyte-sparing excretion of free water resulting in the correction of serum sodium concentrations and plasma osmolality, without activation of the renin-angiotensin-aldosterone system (RAAS) or changes in renal function and blood pressure. Further prospective studies in a selected congestive HF population with hyponatremia, using clinical-status titrated dose of tolvaptan, are needed to determine whether serum sodium normalization will be translated into a better long-term prognosis. This review will focus on recent clinical trials with tolvaptan, an oral V 2 receptor antagonist, in HF patients. The ability of tolvaptan to safely increase serum sodium concentration without activating the RAAS or compromising renal function and electrolyte balance makes it an attractive agent for treating hyponatremic HF patients.

Cancer management and research, 2016

Hyponatremia is the most frequently observed electrolyte abnormality in clinical practice, and its frequency is almost double in hospitalized cancer patients. As a subset of cancer, hyponatremia is quite common in lung cancer patients, and it is often coupled with the diagnosis of syndrome of inappropriate antidiuretic hormone secretion. The presence of hyponatremia is consequential in that its presence adversely affects cancer patients&#39; prognosis and outcomes. Limited data suggest that correcting hyponatremia in lung cancer patients can increase response to anticancer treatment, may help reduce length of hospital stay and cost, and reduce morbidity and mortality. The type of treatment for hyponatremia depends on several factors; the key factors are the duration and severity of neurological symptoms of hyponatremia and the status of extracellular volume. When hyponatremia is caused by syndrome of inappropriate antidiuretic hormone, hypertonic saline is indicated for acute sympto...

Cancer medicine, 2017

Hyponatremia is a common electrolyte disorder in cancer patients and has been associated with poor prognosis. A frequent cause of cancer-related hyponatremia is the syndrome of inappropriate antidiuretic hormone (SIADH). This study was a post hoc subgroup analysis of the SALT-1 (Study of Ascending Levels of Tolvaptan in Hyponatremia) and SALT-2 clinical trials. Hyponatremic subjects with SIADH and cancer received the oral selective vasopressin V2-receptor antagonist tolvaptan (n = 12) or matching placebo (n = 16) once-daily for 30 days. The initial tolvaptan dose (15 mg) was titrated over 4 days to 30 or 60 mg per day, as needed, according to serum sodium level and tolerability. Baseline serum sodium levels in the SIADH/cancer cohort of the SALT trials was 130 and 128 mEq/L for tolvaptan and placebo, respectively. Mean change from baseline in average daily serum sodium AUC for tolvaptan relative to placebo was 5.0 versus -0.3 mEq/L (P &lt; 0.0001) at day 4, and 6.9 versus 1.0 mEq/L ...

Eurasian Journal of Medical Investigation, 2020

Objectives: This study aimed to reveal the therapeutic efficacy and side effects of tolvaptan use in patients with hypotonic euvolemic hyponatremia caused by syndrome of inappropriate anti-diuretic hormone (SIADH) in our oncology clinic. Herein is presented the first real-life data on the use of tolvaptan in hyponatremia observed in cancer patients in Turkey to the researchers' knowledge. Methods: Clinically euvolemic patients who had serum osmolality <275 mOsm/kg, urine osmolality >100 mOsm/kg, urine sodium concentration >40 mmol/L and were diagnosed with SIADH, were scanned via electronic data. In treatment, tolvaptan 15 mg/day was administered for 3 days. Results: Hypotonic euvolemic hyponatremia due to SIADH was diagnosed in 24 patients (16 males, 8 females) who followed up for malignancy. The median sodium value of the patients before tolvaptan treatment was 121.5 mEq/L. The median sodium concentrations in the 3 days of treatment were 126.0 mEq/L, 132.0 mEq/L and 137.0 mEq/L, respectively. In 6 patients, adverse effects were observed; none of them stopped or paused treatment, however. Only 2 patients were discharged, while the other patients died. The use of tolvaptan in the treatment of SIADH-induced hypotonic euvolemic hyponatremia provided an effective correction in serum sodium concentration, and improved the symptoms associated with hyponatremia.