Suitable Dose of Long-Term Tolvaptan to Reduce Heart Failure Rehospitalizations.

The short-term effectiveness of tolvaptan (TLV) for heart failure (HF) has been established, but the long-term effects are controversial. We investigated HF patients who could not discontinue both loop diuretics and TLV at discharge from AURORA (Acute Heart Failure Registry in Osaka Rosai Hospital). We compared the following factors at discharge between the RH group, consisting of patients with rehospitalizations due to worsening HF within 1 year after discharge (RH group), and non-RH group: age, gender, blood pressure, history of HF admission, electrocardiogram and echocardiographic parameters, atherosclerotic risk factors, laboratory data, and medications. Furthermore, we compared the effects of long-term low-dose TLV (≤ 7.5 mg/day) and high-dose TLV on HF rehospitalizations. The RH group consisted of 81 patients (58.7%). A multivariate analysis revealed that a history of HF admission and the TLV dose were independently and significantly associated with 1-year HF rehospitalizations. A receiver operating characteristic curve revealed that 7.5 mg of TLV was a suitable cutoff value for 1-year HF rehospitalizations. The Kaplan-Meier curves demonstrated that the HF rehospitalization free ratio was significantly higher in the low-dose TLV group (≤ 7.5 mg/day) than in high-dose TLV group over 1 year.In conclusion, the TLV dose, in addition to a history of HF admission, was associated with 1-year HF rehospitalizations in diuretic-dependent HF patients. In these patients, long-term low-dose TLV (≤ 7.5 mg/day) may be favorable for reducing HF rehospitalizations.

Peak Lag Between Plasma Vasopressin and Urine Aquaporin-2 Following Cardiac Surgery.

Tolvaptan, a vasopressin type-2 receptor antagonist, is utilized to ameliorate fluid retention following cardiac surgery. However, the optimal timing of tolvaptan administration considering novel biomarkers remains unknown. We prospectively included patients who underwent cardiac surgery between 2016 and 2020. We measured perioperative trends of free water reabsorption mediators including plasma arginine vasopressin and urine aquaporin-2. A total of 20 patients (68 [60, 75] years old, 18 men) were included. Urine volume decreased gradually after the initial 3 hours following cardiac surgery. The plasma arginine vasopressin level increased significantly with a peak at postoperative 6 hours, whereas the urine aquaporin-2 level increased later with a delayed peak at postoperative 12 hours. As a result, urine aquaporin-2 relative to the plasma arginine vasopressin level, which represents the activity of the collecting ducts and indicates predicted responses to tolvaptan, was a minimum at postoperative 6 hours. Tolvaptan administration immediately after cardiac surgery might not be recommended given the transient refractoriness to tolvaptan probably due to the stunning of kidney collecting ducts.

A cross-sectional survey of hospitalization and blood tests implementation status in patients who received tolvaptan under 75 years of age using a Japanese claims database.

BACKGROUND: Hypernatremia and liver injury are typical adverse effects of tolvaptan. Therefore, hospitalization and frequent monitoring of serum sodium concentration and liver function are necessary for tolvaptan initiation. We performed a cross-sectional survey to evaluate these situations. RESEARCH DESIGN AND METHODS: We employed the Japanese claims database, which contains data of patients aged < 75 years. Patients who were newly prescribed tolvaptan for fluid accumulation induced by chronic heart failure (FA-CHF) or liver cirrhosis (FA-LC) from January 2011 to June 2017 were included. We evaluated the hospitalization status and implementation of serum sodium and liver function tests in the evaluation period, based on the Japanese package insert. RESULTS: Of 1,173 patients, 347 and 117 were enrolled in FA-CHF and FA-LC groups, respectively. Among them, 10.7% (FA-CHF group) and 5.13% (FA-LC group) were prescribed tolvaptan without hospitalization. In the FA-CHF group, 11.0% and 17.6% did not undergo serum sodium and liver function tests even once in the evaluation period, respectively, compared with 12.0% and 12.8% in the FA-LC group. CONCLUSIONS: Our results highlight the deviation from Japanese package insert recommendations. This approach can be applied to other drugs and provides important perspectives on pharmacovigilance research.

Open-label, multicenter, dose-titration study to determine the efficacy and safety of tolvaptan in Japanese patients with hyponatremia secondary to syndrome of inappropriate secretion of antidiuretic hormone.

The purpose of this study was to determine the efficacy and safety of tolvaptan in Japanese patients with hyponatremia secondary to syndrome of inappropriate secretion of antidiuretic hormone (SIADH). This multicenter, open-label, dose-escalation, phase III study enrolled Japanese patients (20-85 years old) with hyponatremia secondary to SIADH who were unresponsive to fluid restriction. Oral tolvaptan was administered for up to 30 days, initially at 7.5 mg/day, but escalated daily as necessary, based on the serum sodium concentration and safety, over the first 10 days until the optimal maintenance dose was determined for each patient (maximum 60 mg/day). The primary endpoint was the proportion of patients with normalized serum sodium concentration on the day after the final tolvaptan dose. Secondary endpoints included the mean change in serum sodium concentration from baseline on the day after the final dose. Sixteen patients (male, 81.3%; mean ± standard deviation age 71.9 ± 6.1 years) received tolvaptan treatment and 11 patients completed the study with one patient re-administered tolvaptan in the treatment period. Serum sodium concentrations normalized in 13 of 16 (81.3%) patients on the day after the final tolvaptan dose. The mean change in serum sodium concentration from baseline on the day after the final dose was 11.0 ± 4.3 mEq/L. Adverse events considered related to tolvaptan (10 [62.5%] patients) were generally of mild to moderate severity. Oral tolvaptan corrects hyponatremia in Japanese patients with SIADH with a similar efficacy and safety profile as that noted in non-Japanese patients.

Daily Monitoring of Serum Wisteria floribunda Agglutinin-Positive Mac-2 Binding Protein Is Useful for Predicting Therapeutic Effect of Tolvaptan in Cirrhotic Ascites.

Wisteria floribunda agglutinin (WFA) is a lectin that binds to the sugar chain of Mac-2 binding protein (M2BP), and WFA-positive M2BP (WFA+-M2BP) has been reported as a useful marker for assessing liver fibrosis in chronic liver disease. Tolvaptan (TLV), a selective vasopressin V2 receptor antagonist, is used for cirrhotic ascites in Japan, but good predictors of treatment efficacy remain to be established. Our aim was to investigate whether WFA+-M2BP monitoring before and after TLV administration can predict treatment efficacy in patients with cirrhotic ascites. Twenty patients (10 men), with a median age of 72 years, were enrolled. Cirrhosis was caused by hepatitis B virus (n = 3), hepatitis C virus (n = 4), alcohol (n = 8), and others (n = 5). Responders were defined as having a body weight loss of ≥ 1.5 kg/week after TLV administration. Serum WFA+-M2BP levels were measured at baseline and days 1, 3, and 7 after TLV treatment. Twelve patients (60%) were responders. Baseline WFA+-M2BP levels were correlated with serum albumin levels (r = -0.544, P = 0.013). The baseline furosemide dose was lower and platelet count was higher in responders than in non-responders (P < 0.05). The ratio of WFA+-M2BP levels on day 1 after TLV administration to baseline was lower in responders than in non-responders (P < 0.05). The decrease in the ratio discriminated responders from non-responders (AUC = 0.844, P < 0.05). In conclusion, monitoring serum WFA+-M2BP is helpful for predicting the efficacy of TLV treatment in patients with cirrhotic ascites.

Durable response without recurrence to Tolvaptan improves long-term survival.

BACKGROUND: Decompensated liver cirrhosis patients with refractory ascites or pleural effusion have a poor prognosis. Tolvaptan has been used for treating water retention associated with cirrhosis. However, despite the short-term response, water retention recurrence is still observed in some cases. This study aimed to clarify the water retention recurrence rate and the relationship between long-term response without recurrence and prognosis. METHODS: Altogether, 100 patients with decompensated cirrhosis treated with tolvaptan were retrospectively analyzed. Recurrence was evaluated according to the criteria of the EASL clinical practice guideline. The recurrence rate and prognosis of non-responders, patients with recurrence, and long-term responders were analyzed. The baseline factors related to short-term response, recurrence, and long-term response were also evaluated. RESULTS: Approximately 31.0% of the short-term responders had recurrence. Although there was no significant difference in the prognosis by short-term response (p = 0.07), the long-term responders had a significantly better prognosis than those with recurrence and non-responders (p < 0.01). Low CRP levels and high urinary Na/K ratios were significant factors related to short-term response, and the presence of acute kidney injury was also a factor related to non-response. The low CRP level (relapse: < 1.10 mg/dl, long-term response: < 0.94 mg/dl) was identified as a factor related to recurrence and long-term response. CONCLUSION: The long-term responders without recurrence had a significantly better prognosis. CRP was a useful predictor for long-term response, whereas renal function parameters were useful predictors for short-term response. Inflammation control may be important for long-term response and prognosis in cirrhosis patients with water retention.

Pharmacological Dilutional Therapy Using the Vasopressin Antagonist Tolvaptan for Young Patients With Cystinuria: A Pilot Investigation.

OBJECTIVE: To perform a pilot study of short-term safety, tolerability, and impact on urinary stone risk parameters of the vasopressin V2-receptor antagonist tolvaptan (which increases urinary excretion of free water) among adolescents and young adults with cystinuria. MATERIALS AND METHODS: We enrolled cystinuria patients age 12-25 years. Subjects were treated for 4 days at low-dose tolvaptan (0.3 mg/kg/day, maximum 30 mg) and 4 days at high dose (0.6 mg/kg/day, maximum 60 mg). Twenty-four-hour urine collections were done at baseline, day 3-4 of the dosing period, day 7-8 of the dosing period, and 3-6 days after washout. Primary outcome was cystine capacity (mg/L, target capacity > 0). Secondary outcomes included other urinary/serum parameters, tolerability, and thirst response. RESULTS: Two females (17, 23 years) and 2 males (13, 24 years) were enrolled. Cystine capacity respectively went from baseline of -312, -82, -353, and -628 mg/L to 97, 111, 75, and -3 mg/L on high dose (Figure 1). Twenty-four-hour volume went from 1.96, 3.0, 2.1, and 0.91 L to 11.74, 6.5, 9.9, and 2.8 L on high dose (Figure 2). There were no abnormalities in serum electrolytes or liver enzymes. Subjects did experience extreme thirst (9/10 on visual scale), but none discontinued treatment or reduced dose. CONCLUSION: Dilutional therapy with tolvaptan increased both cystine capacity and urinary volumes. This treatment approach has the potential to reduce recurrence of stones in this population. Further investigation should study longer term effects and safety, and determine optimal dosing to improve tolerability.

[The Effect of Increased Free Concentrations of Warfarin Due to Protein-binding Substitution in a Combination of Tolvaptan on the PT-INR].

We previously reported that tolvaptan may influence warfarin pharmacodynamics in vivo; however, the mechanism responsible for this influence was not clear. In this study, we investigated the drug-drug interactions between warfarin and tolvaptan by measuring warfarin blood concentrations in 18 patients who received warfarin therapy and in 24 who received warfarin+tolvaptan therapy. The free warfarin concentrations significantly increased in patients who were also receiving oral tolvaptan (p=0.04). In vitro albumin-binding experiments showed that the free warfarin concentrations significantly increased with the addition of tolvaptan, in a dose-dependent manner, through albumin-binding substitution (approximately 2.5 times). Both clinical and in vitro data showed that tolvaptan increased the unbound warfarin serum concentration. The prothrombin time-international normalized ratio (PT-INR) tended to increase within 2 weeks when tolvaptan was added at clinically used doses (p=0.14). Special attention is warranted in cases with a serum tolvaptan concentration of ≥125 ng/mL (≥7.5 mg/d) for at least 2 weeks following oral tolvaptan administration.

Tolvaptan add-on therapy in patients with acute heart failure: A systematic review and meta-analysis.

This study aimed to investigate the short-term efficacy and safety of tolvaptan as an add-on to traditional diuretics in patients with acute heart failure (AHF). The PubMed, EMBASE, Cochrane Library, and Web of Science databases were comprehensively searched for all randomized controlled trials (RCTs) that examined AHF patients treated with tolvaptan as a combination therapy with traditional diuretics published on or before December 2, 2019. Efficacy indicators such as improved dyspnea, reduced edema, and changes in urine output and body weight were evaluated. In-hospital mortality and worsening renal function (WRF) were measured as safety indicators. Data from the published literature included in this study were independently extracted by two reviewers. The Cochrane risk of bias tool was used to evaluate the quality of the included RCTs. Twelve RCTs involving 5577 patients admitted for AHF were included. Compared with traditional diuretics alone, add-on tolvaptan significantly relieved dyspnea, reduced weight, increased total urine volume and changes in urine volume from baseline, reduced edema, and increased serum sodium concentration in the short term without increasing the mortality. Most importantly, a low dose of tolvaptan (7.5-15 mg/d) significantly reduced the incidence of WRF, while a high dose (30 mg/d) had the opposite effect. Short-term add-on tolvaptan in hospitalized AHF patients could significantly relieve shortness of breath, reduce body weight, improve edema, and increase urine output and serum sodium concentrations without increasing mortality. The protective effects of add-on tolvaptan against WRF, however, were observed at low doses, but not at high doses.

[Tolvaptan in ADPKD: a turning point or an unsustainable therapy? One year of "real life" experience].

Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent monogenic kidney disease, alone responsible for over 10% of patients with end-stage renal disease, and with an important impact on public health. Tolvaptan (TOLV) has recently been approved in many European countries for its ability to slow disease progression in patients that are eligible for treatment. Nevertheless, the doctor's choice to prescribe the drug and the patient's compliance are strongly influenced by the aquaretic effect complications. In a cohort of patients pertaining to the Nephrology clinic of the AOU Federico II of Naples and treated with TOLV, we assessed not only the adherence to the treatment and the safety of the drug, but also the real feasibility of this therapy through specific questionnaires on sleep quality, abdominal-renal pain, quality of life and patients' general satisfaction. Within the limits of preliminary data and on the basis of the responses of our population, followed for a period of at least one year and administered the maximum titration dosage, it can be asserted that the doubts regarding the real compliance of the patients can be overcome.

Vasopressin antagonist efficacy and safety in volume-overloaded critically ill patients: a new therapeutic alternative.

Objectives: To assess tolvaptan's efficacy and safety in critical care patients with volume overload. Methods: Prospective observational study. Twenty-eight patients in the recovery phase from multiple organ failure and with volume overload refractory to conventional therapy treated with tolvaptan were included. Results: Patients received an initial daily dose of 3.75 (n=1), 7.5 (n=8) and 15 (n=19) mg of tolvaptan. Median treatment duration was 2 days (range: 1 to 12). All patients presented an increase in 24 hours diuresis after the first dose (median increase from baseline (IQR)=1114 (285-1943) mL), with a median net daily fluid loss of 1007 mL (456-2380) mL after 24 hours. High diuretic efficacy (daily fluid loss higher than 0.5 L with tolvaptan first dose) was detected in 18 patients (64.3%). Initial hyponatraemia was present in 16 (57.1%) patients, while overly rapid correction with tolvaptan treatment occurred in two patients without clinical consequences. Two patients presented hypophosphataemia after treatment. Conclusion: Tolvaptan is an effective therapeutic option in critically ill patients with volume overload refractory to conventional diuretics. Further studies are required to evaluate its safety profile and its effect on short-term outcomes and mortality.

Long-term administration of Tolvaptan to patients with decompensated cirrhosis.

Aim: Tolvaptan, an oral vasopressin-2 antagonist, sometimes improves hepatic edema including ascites in patients with decompensated cirrhosis. In this study, we examined the effectiveness and survival advantage in patients with the long-term administration of tolvaptan. Methods: A total of 115 patients with refractory ascites who were treated with tolvaptan were retrospectively analyzed based on their clinical records. Patients with a decrease in body weight of ≥1.5 kg from the baseline on day 7 were determined as responders. Re-exacerbation was defined as a return to the baseline BW, dose escalation of conventional diuretics, or abdominal drainage. Results: Of the 115 patients, 84 were included in this analysis. Response to tolvaptan treatment was observed in 55 out of the 84 patients (65.5%), with a mean weight reduction of 2.52 kg. Multivariate analyses demonstrated that body mass index (≥24) and urinary specific gravity (≥1.018) were significant predictors of the response to tolvaptan. However, cumulative re-exacerbation rates in responders at 6 and 12 months were 42.4 and 60.1%, respectively. Child-Pugh (classification C), HCC complication, and serum sodium levels (≥133 mEq/L) were determined as independent prognostic factors impacting overall survival (OS). Although there were no significant differences in OS between tolvaptan responders and non-responders, the responders without re-exacerbation within 3 months showed significantly longer OS than those with re-exacerbation within 3 months. Conclusion: A persistent therapeutic response, but not early response to tolvaptan, was associated with favorable survival of decompensated cirrhotic patients.

Tolvaptan therapy to treat severe hyponatremia in pediatric nephrotic syndrome.

BACKGROUND: Tolvaptan is a selective oral vasopressin V2-receptor antagonist. Some data have implicated stimulation of arginine vasopressin (AVP) as an important factor in oedema formation in a rodent model of nephrotic syndrome (NS) and adult NS patients. We report case of pediatric NS with severe hyponatremia efficiently treated by tolvaptan. CASE/DIAGNOSIS - TREATMENT: A 22-month-old girl presented first with NS. She remained nephrotic after a 30-day course of oral steroids. Tacrolimus was inefficient and there was no response to plasma exchanges (15 sessions on a daily basis). She had severe oedema and ascites. Thus, in addition to immunosuppressive therapy, she received diuretics, furosemide 5 mg/kg/day, and amiloride 1 mg/kg/day, and required water restriction. She was hypertensive and was treated with a full dose of calcium inhibitor (amlodipine 0.5 mg/kg/day). After2 months of treatment, serum sodium reached 116 mmol/L and urinary osmolarity 547 mosmol/L, suggesting an inappropriate AVP secretion. Tolvaptan was introduced at 0.3 mg/kg/day and progressively increased to 3 mg/kg/day on day 4, leading to a partial correction of serum sodium (130 mmol/l) and a urinary osmolarity decrease to 90 mosmol/L. Tolvaptan was then continued at the dose of 3 mg/kg/day with unchanged serum sodium, without hypernatremia or dehydration. Her weight decreased from 14.8 k to 14 k, but oedema still persisted. CONCLUSION: Tolvaptan was very efficient in this case of hyponatremia associated with steroid-resistant NS. Tolvaptan should be considered in the management of therapy-resistant hyponatremia in patients with NS.

Clinical implications with tolvaptan on monitored bioimpedance-defined fluid status in patients with cirrhotic ascites: an observational study.

BACKGROUND: Prognostic value or clinical implications of fluid status monitoring in liver cirrhosis are not fully elucidated. Tolvaptan, an orally available, selective vasopressin V2-receptor antagonist approved for hyponatremia in the United States and European Union. It is also used for cirrhotic ascites at a relatively low dose (3.75 mg to 7.5 mg) in Japan, exerts its diuretic function by excreting electrolyte-free water. We hypothesized that bioimpedance-defined dynamic changes in fluid status allow prediction of response of V2 antagonism and survival in cirrhotic patients. METHODS: In this prospective observational study, 30 patients with decompensated liver cirrhosis who were unresponsive to conventional diuretics were enrolled. Detailed serial changes of body composition that were assessed by using non-invasive bioimpedance analysis (BIA) devices, along with biochemical studies, were monitored at 5 time points. RESULTS: Sixteen patients were classified as short-term responders (53%). Rapid and early decrease of BIA-defined intracellular water, as soon as 6 h after the first dose (ΔICWBIA%-6 h), significantly discriminated responders from non-responders (AUC = 0.97, P < 0.0001). ΔICWBIA%-6 h was highly correlated with the change of BIA-derived phase angle of trunk, e.g. reduced body reactance operated at 50 kHz after 24 h of the first dose of tolvaptan. Lower baseline blood urea nitrogen and lower serum aldosterone were predictive of a rapid and early decrease of ICWBIA. A rapid and early decrease of ICWBIA in response to tolvaptan was also predictive of a better transplant-free survival. CONCLUSIONS: BIA-defined water compartment monitoring may help predict short-term efficacy and survival in decompensated cirrhotic patients treated with tolvaptan.

Tolvaptan can limit postoperative paroxysmal atrial fibrillation occurrence after open-heart surgery.

PURPOSE: Tolvaptan administration in the early postoperative period after cardiac surgery rapidly treats fluid retention without affecting the renal function. Tolvaptan also has the benefit of not stimulating the renin-angiotensin and sympathetic nervous systems, which are risk factors for postoperative paroxysmal atrial fibrillation. In this study, we examined the hypothesis that tolvaptan administration reduces postoperative paroxysmal atrial fibrillation and worsening of the renal function incidence in patients who have undergone open-heart surgery. METHODS: From our previous randomized study, we selected 166 open-heart surgery patients, divided them into 2 groups [tolvaptan group, 83 patients; control (non-tolvaptan) group, 83 patients], and compared the incidence of postoperative paroxysmal atrial fibrillation and worsening of the renal function in the postoperative period between the groups. RESULTS: The incidence of worsening of the renal function was significantly lower in the tolvaptan group than in the control group (4.8% vs. 15.7%; P = 0.04). The incidence of postoperative paroxysmal atrial fibrillation within 14 days was also significantly lower in the tolvaptan group than in the control group (26.5% vs. 42.2%; P = 0.011). CONCLUSION: Tolvaptan administration in the early postoperative period after open-heart surgery may reduce the incidence of postoperative paroxysmal atrial fibrillation and worsening of the renal function.

Analysis of factors associated with the prognosis of cirrhotic patients who were treated with tolvaptan for hepatic edema.

BACKGROUND AND AIM: The prognosis of cirrhotic patients with hepatic edema is poor. Although several short-term predictors of tolvaptan (novel diuretic agent) treatment for such patients have been reported, the factors related to long-term survival are still unclear. METHODS: Among 459 patients with hepatic edema enrolled in a retrospective, multicenter collaborative study, we analyzed 407 patients who received tolvaptan. RESULTS: Patients consisted of 266 men and 141 women, with the median age of 68 years (range, 28-93 years). The frequency of short-term responders to tolvaptan was 59.7% (243/407). In the Cox regression analysis, short-term response to tolvaptan, low average dosages of furosemide and spironolactone during tolvaptan treatment, Child-Pugh classification A and B, and absence of hepatocellular carcinoma were independent factors contributed to 1-year survival. The 1-year and long-term cumulative survival rates in short-term responders were significantly higher than those in non-responders (P = 0.011 and 0.010, respectively). Using a receiver operating characteristic curve analysis, the optimal cut-off values of average daily dosages of furosemide and spironolactone for predicting 1-year survival were 19 and 23 mg/day, respectively. The long-term cumulative survival rates in patients who received a mean dosage of spironolactone < 23 mg/day during tolvaptan treatment were significantly higher than those receiving a mean dosage of ≥ 23 mg/day (P = 0.001). CONCLUSIONS: The present study suggests that the short-term response to tolvaptan and low dosages of conventional diuretics during tolvaptan treatment might improve the 1-year and long-term survival rates in cirrhotic patients with hepatic edema.

Diuretic Strategies for Loop Diuretic Resistance in Acute Heart Failure: The 3T Trial.

OBJECTIVES: This study compared combination diuretic strategies in acute heart failure (AHF) complicated by diuretic resistance (DR). BACKGROUND: Combination diuretic regimens to overcome loop DR are commonly used but with limited evidence. METHODS: This study was a randomized, double-blinded trial in 60 patients hospitalized with AHF and intravenous (IV) loop DR. Patients were randomized to oral metolazone, IV chlorothiazide, or tolvaptan therapy. All patients received concomitant high-dose IV infusions of furosemide. The primary outcome was 48-h weight loss. RESULTS: The cohort exhibited DR prior to enrollment, producing 1,188 ± 476 ml of urine in 12 h during high-dose loop diuretic therapy (IV furosemide: 612 ± 439 mg/day). All 3 interventions significantly improved diuretic efficacy (p < 0.001). Compared to metolazone (4.6 ± 2.7 kg), neither IV chlorothiazide (5.8 ± 2.7 kg; 1.2 kg [95% confidence interval (CI)]: -2.9 to 0.6; p = 0.292) nor tolvaptan (4.1 ± 3.3 kg; 0.5 kg [95% CI: -1.5 to 2.4; p = 0.456) resulted in more weight loss at 48 h. Median (interquartile range [IQR]) cumulative urine output increased significantly and did not differ among those receiving metolazone (7.78 [IQR: 6.59 to 10.10] l) and chlorothiazide (8.77 [IQR: 7.37 to 10.86] l; p = 0.245) or tolvaptan (9.70 [IQR: 6.36 to 13.81] l; p = 0.160). Serum sodium decreased less with tolvaptan than with metolazone (+4 ± 5 vs. -1 ± 3 mEq/l; p = 0.001), but 48-h spot urine sodium was lower with tolvaptan (58 ± 25 mmol/l) than with metolazone (104 ± 16 mmol/l; p = 0.002) and with chlorothiazide (117 ± 14 mmol/l; p < 0.001). CONCLUSIONS: In this moderately sized DR trial, weight loss was excellent with the addition of metolazone, IV chlorothiazide, or tolvaptan to loop diuretics, without a detectable between-group difference. (Comparison of Oral or Intravenous Thiazides vs. tolvaptan in Diuretic Resistant Decompensated Heart Failure [3T]; NCT02606253).

Idiosyncratic hepatic toxicity in autosomal dominant polycystic kidney disease (ADPKD) patient in combined treatment with tolvaptan and amoxicillin/clavulanic acid: a case report.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary disease characterized by the presence of renal cysts. Over time the expanding cysts lead to progressive renal failure. The use of tolvaptan, a V2-receptor antagonist, was recently approved in ADPKD patients. It was demonstrated that tolvaptan get slower decline in Kidney function compared with placebo. Idiosyncratic hepatic toxicity was described in patients receiving tolvaptan, with elevations in aminotransferases levels. We describe the first case reported in the literature in which hepatic toxicity is caused by the association of amoxicillin/clavulanic acid and tolvaptan. CASE PRESENTATION: A 41 years old woman with diagnosis of ADPKD had been in treatment with tolvaptan for 16 weeks when an elevation of liver enzyme levels was detected. She had taken autonomously amoxicillin/clavulanic acid (in doses of 825/175 mg twice a day for 7 days) about 5 weeks before. The timing of the event and the kind of hepatocellular injury could be attributed to the concomitance of medication of tolvaptan and amoxicillin/clavulanic acid. CONCLUSION: We highlight the need to careful monitor hepatic enzyme levels in order to recognize early hepatic side effects in ADPKD patients in treatment with tolvaptan and amoxicillin/clavulanic acid.

A new method of intermittent lower dose of tolvaptan combined with fluid restriction to treat the syndrome of inappropriate antidiuresis: A case report.

RATIONALE: Tolvaptan, an oral vasopressin V2 receptor antagonist, is a new approach for the treatment of adult patients with the syndrome of inappropriate antidiuresis (SIADH). However, dose-dependent side effect including rapid increase in serum sodium levels and liver injury, and the expensive price limit the long-term use of tolvaptan. We report a case of SIADH patient treated with intermittent lower dose of tolvaptan combined with fluid restriction. PATIENT CONCERNS: A 60-year-old woman presented of nausea and vomiting, dizzy and amaurosis, and transient disturbance, after a week of persistent diarrhea. DIAGNOSIS: Diagnosis of SIADH was based on severe persistent hyponatremia, decreased plasma osmolality, raised urinary sodium excretion, and the absence of other causes. INTERVENTIONS: She was given the treatment of tolvaptan 15 mg once daily, and experienced tolvaptan-related side effects including thirst and dry mouth, polyuria, and dizziness. Then, single dose of tolvaptan was reduced from 15 to 7.5 mg, and the interval between medication was gradually prolonged from 24 to 72 hours. Meanwhile, serum sodium was negatively correlated with the amount of daily water intake in interval days, so daily water intake of the patient was restricted to 1500 mL in interval days. OUTCOMES: Serum sodium was maintained within the normal range, 137 to 141 mmol/L without liver damage. LESSONS: For patients with chronic SIADH, the tolvaptan dose should be individualized, and the regimen of intermittent lower dose of tolvaptan combined with fluid restriction maybe an effective choice.