Safety Of Tolvaptan In Patients Research Articles

Liver safety of tolvaptan in patients with autosomal dominant polycystic kidney disease: interim data from a post-authorization safety study.

After the risk of drug-induced liver injury was detected during tolvaptan clinical development for the treatment of autosomal dominant polycystic kidney disease (ADPKD), a post-marketing pharmacovigilance study was required for European Union regulatory approval. This is an interim analysis from a prospective, observational study enrolling patients prescribed tolvaptan for ADPKD in routine clinical practice. Data were obtained through physician records collected during regular care. Per the prescribing label, liver transaminases were to be monitored monthly for the first 18months of treatment and once every 3months thereafter. Patients and physicians were required to report adverse events suggestive of serious and potentially fatal liver injury. Data collection was from October 2016 to April 2022. Of 2074 patients (median follow-up 528days), alanine aminotransferase (ALT) or aspartate aminotransferase (AST) levels ≥3 times the upper limit of normal (ULN) were reported in 75 (3.6%) patients. At data cut-off, the enzyme elevations were confirmed for 65 patients. Among the 65 confirmed patients, in addition to transaminase elevations, there were 69 adverse events suggestive of liver injury. Tolvaptan was interrupted or withdrawn in 59/65 (90.8%) participants with confirmed ALT or AST ≥3times the ULN, with most transaminase elevations and adverse events resolved or resolving at data cut-off. No liver enzyme elevations met laboratory criteria for Hy's law cases. Transaminase elevations occurred post-marketing in a similar proportion of patients as reported in clinical trials (4.4-5.6%). Regular monitoring per label facilitates prompt detection of liver adverse events and intervention to mitigate the risk of severe injury.

Protocol to evaluate the efficacy and safety of tolvaptan in patients with refractory ascites after liver resection: an open-label, single-arm phase I/II study.

In patients with chronic liver diseases such as cirrhosis, massive ascites after hepatic resection is the cause of prolonged hospitalization and worsening prognosis. Recently, the efficacy of tolvaptan in refractory ascites has been reported; however, there are no reports on the efficacy or safety of tolvaptan for refractory ascites after hepatic resection. This study aims to evaluate the efficacy of early administration of tolvaptan in patients with refractory ascites after hepatic resection. This is an open-label, single-arm phase I/II study. This study subject will comprise patients scheduled for hepatic resection of a liver tumor. Patients with refractory ascites after hepatic resection (drainage volume on postoperative day 1 ≥5ml/body weight 1kg/day) will be treated with tolvaptan. The primary endpoint will include the maximum change in body weight after hepatic resection relative to the preoperative baseline. The secondary endpoints will include drainage volume, abdominal circumference, urine output, postoperative complication rate (heart failure and respiratory failure), number of days required for postoperative weight gain because of ascites to decrease to preoperative weight, change in improvement of postoperative pleural effusion, total amount of albumin or fresh frozen plasma transfusion, type and amount of diuretics used, and postoperative hospitalization days. This trial will evaluate the efficacy and safety of tolvaptan prophylaxis for refractory ascites after hepatic resection. As there are no reports demonstrating the efficacy of tolvaptan prophylaxis for refractory ascites after hepatic resection, the authors expect that these findings will lead to future phase III trials and provide valuable indications for the selection of treatments for refractory postoperative ascites.

Liver Safety of Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD): Interim Data from a European Union Post-Authorization Safety Study (EUPASS)

Liver Safety of Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease (ADPKD): Interim Data from a European Union Post-Authorization Safety Study (EUPASS)

Efficacy and safety of tolvaptan for refractory fluid collection and edema in the terminal cancer patients.

Tolvaptan, a vasopressin V2 receptor antagonist, is an oral diuretic. Patients with terminal cancer develop marked fluid retention, and oral diuretics other than tolvaptan have been used as treatments without clear therapeutic effects. Herein, we aimed to study the efficacy and safety of tolvaptan in patients with terminal cancer. Tolvaptan was administered at a dose of 7.5mg/day to 29 patients (median, 72 years) between August 2017 and February 2020. The duration of tolvaptan treatment ranged from 1 to 85 days (mean, 18.5 days). Median albumin (Alb) and transthyretin (TTR) levels on admission were 2.3g/dL (1.2-4.2g/dL) and 8.9mg/dL (2.1-38.2g/dL), respectively. Median Alb and TTR levels 1 month after treatment initiation remained at 2.3g/dL (0.8-2.9g/dL) and 8.6mg/dL (0.8-23.7mg/dL), respectively. Regarding renal function indicators, median blood urea nitrogen (BUN) and creatinine levels on admission were 19.9mg/dL (8.6-49.3mg/dL) and 0.81mg/dL (0.38-2.25mg/dL), respectively. Median BUN and creatinine levels 1 month after treatment initiation were 23.4mg/dL (13.5-34.0mg/dL) and 0.91mg/dL (0.39-2.41mg/dL), respectively. No patients had hypernatremia on admission, and no effects of tolvaptan on the blood sodium level were found 1 month after treatment initiation. The median potassium level on admission was 4.2mEq/dL (2.9-5.0mEq/dL); tolvaptan treatment had no effects on blood potassium level. Tolvaptan is effective and safe for treating fluid retention refractory to conventional diuretics in patients with terminal cancer.

POS-269 EFFICACY AND SAFETY OF TOLVAPTAN IN TYPE 4 CARDIORENAL SYNDROME Abstract paid for submission 2020-A-WCN21-0618(100985411245)

Cardiorenal syndrome poses great challenges to treating physicians. Diuretic resistance is common and adds to morbidity of these patients. Many patients do need dialysis due to this issue. Combination of diuretics had been used for diuretic resistance. There is paucity of literature on use of tolvaptan in patients with type 4 renal syndrome. Therefore we undertook this study to see for efficacy and safety of tolvaptan in patients those did not respond to maximal dose of torsemide and metolazone

Effectiveness and Safety of Tolvaptan in Patients with Aortic Stenosis.

Heart failure in severe aortic stenosis (AS) before aortic valve has a poor prognosis with high risk. Although the overuse of loop diuretics may induce hypovolemia, cardiac output reduction, and critical hypotension in severe AS, tolvaptan is characterized by its ability to help maintain hemodynamics and seems to be appropriate for use in heart failure caused by AS. Therefore, we retrospectively examined the effects and safety of tolvaptan use in patients with heart failure caused by severe AS. Ten patients with heart failure caused by severe AS were enrolled. Tolvaptan administration did not cause blood pressure decrease significantly, whereas urine volume increased significantly from 896±318 to 1322±502 mL/day (P<0.05). Although there was no statistical significance, functional classes tended to be improved. Blood tests indicated no worsening of kidney function and N-terminal pro-brain natriuretic peptide levels after the use of tolvaptan. Echocardiography also showed no hypovolemia and no worsening of aortic valve flow (18.3±3.8 to 15.5±5.5 cm/s, n.s). Tolvaptan use in AS patients with heart failure is effective and safe before aortic valve intervention.

Short-Term Efficacy and Safety of Tolvaptan in Patients with Left Ventricular Assist Devices.

Tolvaptan is an effective therapy for heart failure patients with symptomatic congestion and hyponatremia. The efficacy of its use in patients with continuous-flow left ventricular assist devices (LVADs) is unknown. The aim of this study was to assess the clinical efficacy and safety of tolvaptan in LVAD patients. We retrospectively reviewed medical records of patients who underwent LVAD implantation between January 2014 and August 2018. Among 217 consecutive LVAD patients, tolvaptan was used in 20 patients. Mean age was 46 ± 14 years old and 14 patients were males. The duration of tolvaptan therapy was 4 (interquartile range 1-8) days. Urine volume significantly increased from 2,623 ± 1,109 ml/day before tolvaptan to 4,308 ± 1,432 ml/day during tolvaptan therapy (p < 0.001). Serum sodium increased from 127 ± 3 to 133 ± 3 mEq/L at the end of tolvaptan therapy (p < 0.001). No patients developed hypernatremia (serum sodium >150 mEq/L). The 90-day overall survival following tolvaptan therapy was 89% in both the tolvaptan group and a propensity score-matched non-tolvaptan group (p = 0.918). Survival free of heart failure readmissions was also comparable between the groups (p = 0.751). In conclusion, short-term use of tolvaptan following LVAD implantation is a safe and effective therapy to augment diuresis and improve hyponatremia.

Short-Term Efficacy and Safety of Tolvaptan in Patients with Left Ventricular Assist Devices

Short-Term Efficacy and Safety of Tolvaptan in Patients with Left Ventricular Assist Devices

Impaired Renal Function May Not Negate the Efficacy of Tolvaptan in the Treatment of Cirrhotic Patients with Refractory Ascites

Background and ObjectiveTolvaptan, an oral vasopressin V2 receptor antagonist, has been widely used for the treatment of patients with cirrhosis and ascites. However, its efficacy in patients with renal dysfunction remains unknown. The objective of this study was to investigate the efficacy and safety of tolvaptan in patients with decompensated cirrhosis and severe chronic kidney disease (s-CKD).MethodsWe studied 43 patients with liver cirrhosis who received tolvaptan (7.5 mg/day) for refractory ascites. s-CKD was defined as an estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m2. Response to tolvaptan was defined as weight loss ≥ 1.5 kg in 7 days of treatment.ResultsEighteen patients (42%) had s-CKD (s-CKD group), while the other 25 patients (58%) did not have s-CKD (n-CKD group). Rates of response to tolvaptan were similar: 68% in the n-CKD group and 56% in the s-CKD group. Urine volumes increased significantly from baseline to day 7 in both groups. Incidences of adverse events were also similar (P = 0.93). Mean eGFR did not decline even in the s-CKD group (27.3 ± 2.2 mL/min/1.73 m2 at baseline vs. 26.6 ± 2.3 mL/min/1.73 m2 on day 7; P = 0.9). The cumulative survival rate did not differ significantly between the n-CKD and s-CKD groups. In the s-CKD group, responders obtained a better prognosis than non-responders.ConclusionsTolvaptan significantly increased urine volumes similarly in patients with s-CKD and n-CKD without affecting renal function. As responders achieved a better prognosis, tolvaptan could be a good option to treat ascites in patients with cirrhosis and s-CKD.Electronic supplementary materialThe online version of this article (10.1007/s40261-018-0714-5) contains supplementary material, which is available to authorized users.

Tolvaptan in Later-Stage Autosomal Dominant Polycystic Kidney Disease

BackgroundIn a previous trial involving patients with early autosomal dominant polycystic kidney disease (ADPKD; estimated creatinine clearance, ≥60 ml per minute), the vasopressin V2-receptor antagonist tolvaptan slowed the growth in total kidney volume and the decline in the estimated glomerular filtration rate (GFR) but also caused more elevations in aminotransferase and bilirubin levels. The efficacy and safety of tolvaptan in patients with later-stage ADPKD are unknown.MethodsWe conducted a phase 3, randomized withdrawal, multicenter, placebo-controlled, double-blind trial. After an 8-week prerandomization period that included sequential placebo and tolvaptan run-in phases, during which each patient’s ability to take tolvaptan without dose-limiting side effects was assessed, 1370 patients with ADPKD who were either 18 to 55 years of age with an estimated GFR of 25 to 65 ml per minute per 1.73 m2 of body-surface area or 56 to 65 years of age with an estimated GFR of 25 to 44 ml per minute per 1.73 m2 were randomly assigned in a 1:1 ratio to receive tolvaptan or placebo for 12 months. The primary end point was the change in the estimated GFR from baseline to follow-up, with adjustment for the exact duration that each patient participated (interpolated to 1 year). Safety assessments were conducted monthly.ResultsThe change from baseline in the estimated GFR was −2.34 ml per minute per 1.73 m2 (95% confidence interval [CI], −2.81 to −1.87) in the tolvaptan group, as compared with −3.61 ml per minute per 1.73 m2 (95% CI, −4.08 to −3.14) in the placebo group (difference, 1.27 ml per minute per 1.73 m2; 95% CI, 0.86 to 1.68; P<0.001). Elevations in the alanine aminotransferase level (to >3 times the upper limit of the normal range) occurred in 38 of 681 patients (5.6%) in the tolvaptan group and in 8 of 685 (1.2%) in the placebo group. Elevations in the aminotransferase level were reversible after stopping tolvaptan. No elevations in the bilirubin level of more than twice the upper limit of the normal range were detected.ConclusionsTolvaptan resulted in a slower decline than placebo in the estimated GFR over a 1-year period in patients with later-stage ADPKD. (Funded by Otsuka Pharmaceuticals and Otsuka Pharmaceutical Development and Commercialization; REPRISE ClinicalTrials.gov number, NCT02160145.)

Erratum to: The Efficacy and Safety of Tolvaptan in Patients with Hyponatremia: A Meta-Analysis of Randomized Controlled Trials.

Erratum to: The Efficacy and Safety of Tolvaptan in Patients with Hyponatremia: A Meta-Analysis of Randomized Controlled Trials.

The Efficacy and Safety of Tolvaptan in Patients with Hyponatremia: A Meta-Analysis of Randomized Controlled Trials.

Comprehensive evaluations regarding the benefits of tolvaptan in the treatment of hyponatremia are lacking. The objective of this meta-analysis was to assess the efficacy and safety of tolvaptan in patients with hyponatremia. Pertinent studies were identified by searching PubMed, EMBASE, Web of Science, and the Cochrane Library for articles published between their respective inception dates and 31April 2016. Summary relative risks (RRs) or weighted mean differences (WMDs) with their 95% confidence intervals (CIs) were calculated using fixed-effects or randomized-effects models, depending on the degree of heterogeneity noted among the studies included in the analysis. Eleven articles comprising 5209 patients were ultimately included in the analysis. Our pooled results showed that tolvaptan was more effective than control with respect to increasing serum sodium concentrations (WMD=3.99mEq/L), 95% CI 2.80-5.19, Z=6.56, P<0.001), improving serum sodium correction rates (RR=3.35, 95% CI 1.93-5.82, Z=4.31, P<0.001), improving 24-h urine output (WMD=987.64mL, 95% CI 850.71-1124.57, Z=14.14, P<0.001), and improving net fluid balance (WMD=795.97mL, 95% CI 418.56-1173.38, Z=4.13, P<0.001). Tolvaptan treatment also resulted in increased incidences of adverse events compared with control treatment (RR=1.05, 95% CI 1.02-1.07, Z=3.83, P<0.001). These events included dry mouth (RR=2.38, 95% CI 1.41-4.04, Z=3.23, P=0.001), thirst (RR=3.85, 95% CI 1.96-7.57, Z=3.92, P<0.001), pollakiuria (RR=2.47, 95% CI 1.41-4.33, Z=3.16, P=0.002), and overly rapid hyponatremia correction (RR=8.43, 95% CI 1.06-66.96, Z=2.02, P=0.04). No significant differences in all-cause mortality (RR=0.99, 95% CI 0.90-1.10, Z=0.17, P=0.86), serious adverse event rate (RR=1.01, 95% CI 0.80-1.29, Z=0.11, P=0.92), systolic blood pressure (WMD=0.1mmHg, 95% CI -1.04 to 1.23, Z=0.17, P=0.87), or heart rate (WMD=-0.16bpm, 95% CI -1.14 to 0.82, Z=0.31, P=0.76) were noted between the two groups, based on the results of our meta-analysis. The results of this meta-analysis suggest that tolvaptan can increase serum sodium concentrations, serum sodium correction rates, 24-h urine output, net fluid balance, and total adverse event rates without significantly decreasing all-cause mortality rates or increasing serious adverse event rates in patients with hyponatremia.

Efficacy and Safety of Tolvaptan in Patients Hospitalized With Acute Heart Failure

BackgroundThe oral vasopressin-2 receptor antagonist tolvaptan causes aquaresis in patients with volume overload, potentially facilitating decongestion and improving the clinical course of patients with acute heart failure (AHF). ObjectivesThe TACTICS-HF (Targeting Acute Congestion with Tolvaptan in Congestive Heart Failure) study was conducted to address the acute use of tolvaptan to improve congestion in AHF. MethodsThe TACTICS-HF study randomized patients (n = 257) within 24 h of AHF presentation in a prospective, double blind, placebo-controlled trial. Patients were eligible regardless of ejection fraction, and were randomized to either 30 mg of tolvaptan or placebo given at 0, 24, and 48 h, with a fixed-dose furosemide regimen as background therapy. The primary endpoint was the proportion of patients considered responders at 24 h. Secondary endpoints included symptom improvement, changes in renal function, and clinical events. ResultsDyspnea relief by Likert scale was similar between groups at 8 h (25% moderately or markedly improved with tolvaptan vs. 28% placebo; p = 0.59) and at 24 h (50% tolvaptan vs. 47% placebo; p = 0.80). Need for rescue therapy was also similar at 24 h (21% tolvaptan, 18% placebo; p = 0.57). The proportion defined as responders at 24 h (primary study endpoint) was 16% for tolvaptan and 20% for placebo (p = 0.32). Tolvaptan resulted in greater weight loss and net fluid loss compared with placebo, but tolvaptan-treated patients were more likely to experience worsening renal function during treatment. There were no differences in in-hospital or post-discharge clinical outcomes. ConclusionsIn patients hospitalized with AHF, dyspnea, and congestion, the addition of tolvaptan to a standardized furosemide regimen did not improve the number of responders at 24 h, despite greater weight loss and fluid loss. (Targeting Acute Congestion With Tolvaptan in Congestive Heart Failure [TACTICS-HF]; NCT01644331)

Evaluation of the Effectiveness and Safety of Tolvaptan in Patients with Heart Failure: - A Multi Center Registry -

Evaluation of the Effectiveness and Safety of Tolvaptan in Patients with Heart Failure: - A Multi Center Registry -

Rationale and Design of the TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes) 3-4 Study

Current management of autosomal dominant polycystic kidney disease (ADPKD) is focused on treating disease complications, not on slowing cyst development or preventing progression to kidney failure. Tolvaptan, a selective vasopressin V2 (vasopressin 2) receptor antagonist, has been proved to inhibit kidney cyst growth and preserve kidney function in multiple animal models of polycystic kidney disease. The TEMPO (Tolvaptan Efficacy and Safety in Management of Autosomal Dominant Polycystic Kidney Disease and Its Outcomes) 3-4 Study will examine the long-term effectiveness and safety of tolvaptan in patients with ADPKD. We report baseline characteristics and revised power calculations for the trial. A prospective, 3-year, multicenter, double-blind, placebo-controlled trial of tolvaptan, a selective V2 receptor antagonist. Primary outcome is total kidney volume percentage of change from baseline for tolvaptan relative to placebo. Secondary outcome parameters include time to ADPKD-associated complications (kidney function decrease, blood pressure control, renal pain, and albuminuria) and safety end points. This trial includes patients with ADPKD with relatively preserved kidney function (baseline estimated creatinine clearance ≥60 mL/min), aged 50 years or younger, and with total kidney volume measured using magnetic resonance imaging ≥750 mL. Administration of placebo or tolvaptan, dose titrated to tolerance. Number of subjects enrolled and baseline characteristics. Total kidney volume, kidney function, albuminuria, kidney pain, and vital signs. 1,445 patients with ADPKD were enrolled between March 2007 and January 2009. Preliminary baseline median total kidney volume was 1.46 L, and estimated creatinine clearance was 105 ± 34 mL/min. A prespecified blinded sample-size recalculation at two-thirds enrollment confirmed the likely power of the study to detect 20% differences from placebo in the primary and key secondary end points at P < 0.05. This is a preselected ADPKD population chosen for its risk of progression to kidney failure and may not represent the general ADPKD population. If study results are positive with regard to the primary end point, positive effects on other secondary clinical outcomes will be required to assess overall benefit. This randomized trial is the largest clinical study of a proposed ADPKD intervention to date. It targets patients with ADPKD with early disease who are projected to have rapid cyst growth and accelerated outcomes. Blockade of vasopressin V2 receptor is hypothesized to inhibit cyst growth, thereby delaying additional adverse clinical outcomes.

Tolvaptan for the Treatment of Hyponatremia and Congestive Heart Failure

Tolvaptan is an oral, once-daily nonpeptide arginine vasopressin V(2)-receptor antagonist under development for the treatment of hyponatremia and congestive heart failure. In Phase II clinical trials, tolvaptan, in addition to standard therapy, increased fluid loss, resulting in decreased body weight and improved edema and serum sodium without affecting blood pressure, heart rate or renal function in patients with heart failure. The compound appeared to be well tolerated and dose-dependent adverse events were generally realated to its pharmacological activity, such as thirst and dry mouth. In patients with hyponatremia, tolvaptan appears to be more effective than fluid restriction at improving sodium levels without an increase in adverse events. An international Phase III outcome study; Efficacy of Vasopressin antagonism in hEaRt failurE outcome Study with Tolvaptan (EVEREST), evaluating the long-term efficacy and safety of tolvaptan in patients hospitalized with worsening heart failure, is currently ongoing.