Administration Of Tolvaptan Research Articles

Effects of Low-Dose Tolvaptan for Fluid Management After Cardiovascular Surgery.

Background: Perioperative management of body fluid levels after cardiovascular surgery with cardiopulmonary bypass is essential. Fluid management using tolvaptan with conventional diuretics is effective in maintaining urine output without worsening renal function. This study aimed to improve the in-out balance in the early perioperative phase using low-dose tolvaptan (3.75 mg/day). Methods and Results: This prospective, single-center, randomized, open-label study included 199 patients who underwent cardiovascular surgery with cardiopulmonary bypass in Kobe City Medical Center General Hospital between September 2018 and December 2020. Treatment with tolvaptan and loop diuretics (tolvaptan group; 99 patients) was compared with treatment with loop diuretics alone (control group; 100 patients) to evaluate achievement of preoperative body weight as the primary outcome. Secondary outcomes were urine volume, the incidence of worsening renal function (WRF), and postoperative paroxysmal atrial fibrillation (POAF). There was no significant difference between groups in the return to preoperative body weight on postoperative Day 6. The tolvaptan group had significantly increased urine volume (2,530 vs. 2,150 mL/day) and decreased total furosemide dose (24 vs. 32 mg) compared with the control group. No significant differences were observed in the development of WRF and POAF between the 2 groups. Conclusions: Although low-dose tolvaptan administration did not shorten the time to achieving preoperative body weight, it did significantly increase urine volume without WRF and POAF.

Effect of vasopressin V2-receptor antagonist tolvaptan on syndrome of inappropriate antidiuresis (SIAD) after transsphenoidal pituitary surgery: recovery of measured osmolality

BackgroundDelayed hyponatremia after pituitary surgery can be treated with the V2-receptor antagonist, oral tolvaptan. We investigated the pharmacological effect of oral tolvaptan against SIAD in patients with hyponatremia after pituitary surgery. MethodsThirty-nine patients with pituitary adenoma treated by endoscopic transsphenoidal surgery developed SIAD according to the major guidelines, and 7 patients (17.9%) were treated with tolvaptan. Tolvaptan was administrated orally half a tablet (3.75 mg) once in the first two cases, and half a tablet twice in the other five cases. Serum osmolality, urinary osmolality, urinary sodium concentration, urinary volume, and serum sodium and potassium concentration were evaluated before administration, and after the last oral administration of tolvaptan. Serum osmolality and urine osmolality were physically measured. ResultsSerum sodium concentration was significantly increased from 132.1 ± 4.0 to 143.0 ± 2.9 mmol/L (mean ± standard deviation, n = 7, P < 0.001). Serum osmolality was significantly increased from 266.3 ± 7.7 to 289.6 ± 6.7 mOsm/kg (n = 7, P < 0.001). Urine osmolality was significantly reduced from 607.1 ± 240.4 to 262.7 ± 115.6 mOsm/kg (n = 7, P = 0.01). Urinary sodium concentration was significantly decreased from 121.3 ± 48.4 to 36.9 ± 35.0 mOsm/kg (n = 7, P = 0.001). Urine output (24-hour including the first administration) was significantly increased from 1384.2 ± 550.7 to 3291.3 ± 1710.9 mL/day (n = 6, P = 0.026). ConclusionsOral tolvaptan administration corrects SIAD after pituitary surgery. Hyponatremia after pituitary surgery was confirmed to be due to SIAD.

Effect of Tolvaptan in Patients with Chronic Kidney Disease Stage G5, and Impact of Concomitant Use of Thiazide Diuretics: A Retrospective Cohort Study.

The diuretic effect of tolvaptan, a vasopressin V2 receptor antagonist, in patients with severe renal dysfunction remains poorly characterized. Thiazide diuretics reduce urinary volume (UV) in patients with nephrogenic diabetes insipidus, which lacks V2 receptor function. This retrospective study investigated the acute urinary effects of tolvaptan in patients with stage G5 chronic kidney disease and congestive heart failure (CHF), and the impact of thiazide diuretics on the urinary effects of tolvaptan. UVs 24h before and after tolvaptan administration and 30-day dialysis initiation rate were compared between patients with and without thiazide diuretic administration. Thiazide diuretics were used in 26 of the 106 recruited patients (age 73.4±13.0 years; estimated glomerular filtration rate 8.07±3.13 mL/min/1.73 m2). The pre- and post-tolvaptan 24-h UVs were significantly higher in patients not administered thiazide diuretics (1043.4±645.6 vs. 1422.2±774.0 mL/day; p<0.001) than in those administered thiazide diuretics (1177.3±686.5 vs. 1173.1±629.1 mL/day; p=0.93). In a multivariate regression model, thiazide diuretic use was significantly associated with decreased 24-h UV (β coefficient -486.7, 95% confidence interval [CI] -674.5 to -298.8); increased urine osmolality (β coefficient 37.7, 95% CI 17.1-58.4); increased body weight (β coefficient 0.62, 95% CI 0.31-0.92); and increased 30-day dialysis initiation rate (odds ratio 3.40, 95% CI 1.18-9.82) after tolvaptan administration. Tolvaptan exhibited significant diuretic effects in patients with CHF, including those with severe renal dysfunction, which were diminished with concomitant thiazide diuretic use.

Long-Term Benefits of Treatment with Tolvaptan in Patients with Autosomal Dominant Polycystic Kidney Disease.

Tolvaptan is the first effective drug treatment for autosomal dominant polycystic kidney disease (ADPKD) patients, but few long-term observations of the effects of tolvaptan have been reported. In this single center, retrospective cohort study, we investigated nine patients who participated in a phase 3 trial of tolvaptan for ADPKD patients at our hospital between 2008 and 2014. Six of the patients discontinued tolvaptan at the end of the clinical trial and were defined as the discontinuation group, and three continued to take it; these were defined as the continuation group. The observation period was 3 years before and after the end of the tolvaptan trial, and we compared the following data in each group: serum creatinine, estimated glomerular filtration rate (eGFR), total kidney volume, serum sodium concentration, and urine specific gravity. eGFR was significantly improved after the end of the trial in the continuation group (P = 0.0446), but there was no significant change in the regression line before and after the end of the trial in the discontinuation group. The increases in mean total kidney volume rates over the 3 years before and after the trial were 0.01%/year vs. 0.067%/year in the discontinuation group (P = 0.0247). On the other hand, serum sodium concentration and urine specific gravity showed no change during the observation period. This study suggested that long-term administration of tolvaptan may improve renal function and inhibit total kidney volume growth.

FC032: Copeptin as a Potential Biomarker in Patients with Autosomal-Dominant Polycystic Kidney Disease (ADPKD)—Update from the AD(H)PKD Study

Abstract BACKGROUND Prediction of disease progression is one of the main challenges in the treatment of Autosomal-Dominant Polycystic Kidney Disease (ADPKD). In addition to already established biomarkers such as total kidney volume (TKV), further biomarkers that are feasible and easy to collect would be important to allow conclusions on prognosis as well as, in the best case, on long-term treatment response. Post-hoc analyses of the TEMPO 3:4 study showed that copeptin could serve as such a biomarker [1, 2]. In this study, we investigated copeptin over a multi-year course in participants of the AD(H)PKD study. METHOD Copeptin was measure from serum samples of 486 patients in the AD(H)PKD study at both initial and follow-up presentations. A total of 95 patients were on tolvaptan therapy at least at one of the measurement time points. We examined the measured values with respect to their distribution in different patient groups (e.g. age, Mayo class) and their changes on tolvaptan administration. Baseline eGFR values were developed using historic creatinine measurements up to 8000 days prior and 1500 days after copeptin measurements. For each patient with at least 5 creatinine measurements an eGFR slope was calculated. The models were developed using a robust linear modelling approach. Slopes were extracted to be the parameter associated to date and multiplied by 365 to retrieve an annual eGFR slope. eGFRs predicted for the specific dates at which copeptin has been measured were then calculated and used in subsequent modelling approaches. To develop a model predictive of eGFR, we used a stepwise regression approach, removing insignificant coefficients at each step. RESULTS As expected, copeptin was significantly lower in 391 tolvaptan naive patients than in 95 patients on therapy (9.95 pmol/L versus 19.78 pmol/L; P &amp;lt; 0.0001). More advanced CKD stages showed higher copeptin levels, both with and without tolvaptan, than at lower stages. Independent from kidney function, copeptin levels were consistently higher on tolvaptan than without therapy. Also, larger TKV showed higher copeptin levels in both groups. In 40 patients, copeptin measurements before the start of tolvaptan therapy and follow-up measurements under tolvaptan at the target dose (90/30 mg) were available, and a significant increase in copeptin levels on tolvaptan (copeptin before tolvaptan therapy: 9.798 pmol/L, copeptin on tolvaptan 23.83 pmol/L; P &amp;lt; 0.0001) could be traced during the course. Linear regression models showed that copeptin is an independent variable for the prediction of eGFR slope when added to age, height-adjusted total kidney volume (htTKV) and baseline eGFR. Besides, correlation of predicted future eGFR based on Mayo Classification is slightly but significantly improved by adding copeptin to the model (R2 Mayo 0.9244 and R2 Mayo + copeptin 0.9446). CONCLUSION Our data obtained from the real-life setting should again be reconciled with the results from the TEMPO 3:4 cohort. Our findings show that copeptin levels are both associated with kidney function and with future eGFR loss. Adding copeptin to the model of the Mayo Classification indeed improves the prediction of future eGFR. However, it is not clear yet whether this mild effect will have an impact in routine clinical care. Copeptin has the potential to facilitate prognostic assessment as a biomarker and thus could be helpful in deciding on therapy initiation and possibly more patient-specific dosing. Future analyses of outcome in relation to copeptin will provide further data and might enable implementation in clinical practice.

Early initiation of tolvaptan is associated with early discharge in patients with heart failure regardless of age

BackgroundElderly patients with heart failure (HF) have been observed to decrease activities of daily living (ADL) during hospitalization. Prevention of ADL decline from shortening of hospital stays is especially important in the elderly, because decreasing ADL is associated with poor prognosis. We investigated the relationship between the early initiation of tolvaptan (TLV) after hospitalization and the length of hospital stay in patients with HF aged younger than 80 years and aged 80 years and older.MethodsWe analyzed 146 patients younger than 80 years (< 80) and 101 patients aged 80 years and older (≥ 80) who were hospitalized with HF from February 2011 to June 2016 and had initiated TLV. The relationship between the time until commencement of TLV and the length of hospital stay was assessed. Additionally, a comparison made between the TLV early start group (within the median) and the delayed start group (over the median) for both groups. Multivariate analysis was also performed on factors that required hospital stays below the median.ResultsA significant correlation was observed between time to TLV initiation and the length of hospital stay (< 80: r = 0.382, P < 0.001; ≥ 80: r = 0.395, P < 0.001). The length of hospital stay in the early group was significantly longer than that in the delayed group for both groups (< 80: early 21.0 ± 13.0 days and 33.0 ± 22.7 days, respectively, P < 0.001; ≥ 80: early 21.3 ± 12.5 days and 32.9 ± 17.9 days, respectively, P < 0.001). Conversely, no statistically significant difference found in the length of hospital stay after initiation of TLV. Moreover, no increase in adverse events in the elderly observed. A multivariate analysis revealed that a predictive factor for short-term hospitalization was early administration of TLV regardless of age.ConclusionsThe early initiation of TLV after hospitalization was associated with a shorter length of hospital stay in patients with HF regardless of age.

Relationship between the efficacy of tolvaptan and hemoglobin levels in acute decompensated heart failure

Objective: The purpose of this study is to investigate the factors that influence the effectiveness of tolvaptan treatment for acute decompensated heart failure. Methods and patients: This retrospective study included 102 patients with acute decompensated heart failure who were considered to require tolvaptan. We investigated whether tolvaptan administration was completed within 7 days or more and divided patients into two groups accordingly (responders, n = 35, non-responders, n = 67). Univariate, multivariate analysis and structural equation modeling were used to investigate the various clinical features involved in the success or failure of tolvaptan administration within 7 days. Among the investigation of various factors, changes in blood urea nitrogen, creatinine, and hemoglobin before and after tolvaptan administration were associated with the completion of tolvaptan administration. In order to proceed with further examination, we examined using a path diagram based on structural equation modeling. Results: It was found that low hemoglobin before treatment and high hemoglobin after treatment are related to the success of the completion of tolvaptan. Other factors were not related to the success of tolvaptan administration. The effectiveness of tolvaptan in pretreatment patients with low hemoglobin is especially important and hemoglobin level will be a valuable marker. Conclusion: This study showed that tolvaptan may be more effective at low hemoglobin in acute decompensated heart failure, which is generally difficult to treat. In that case, active use of tolvaptan is recommended.

Long-Term Outcomes of Longitudinal Efficacy Study With Tolvaptan in ADPKD

IntroductionThe effects of long-term and uninterrupted tolvaptan treatment on autosomal dominant polycystic kidney disease (ADPKD) are unclear. Therefore, a more than 3-year continuous treatment study was performed.MethodsFrom the Kyorin University cohort, 299 patients were surveyed and 179 patients were indicated for tolvaptan having a total kidney volume (TKV) ≥750 ml, TKV slope ≥5%/yr, and estimated glomerular filtration rate (eGFR) ≥15 ml/min per 1.73 m2. Among 179 patients, 118 patients consented to the study.ResultsRetrospective pretreatment and prospective on-treatment periods had a median of 1.8 and 4.0 years, respectively. During the 5 treatment-years, the log10(TKV) slope/yr decreased from the pretreatment period (P < 0.0001) and the estimated height-adjusted TKV growth rate α (eHTKV-α, %/yr) decreased from baseline (P < 0.0001). The decline in eGFR improved in female patients (P < 0.0001), but not in males (P = 0.6321). Furthermore, during the 5 treatment-years, eGFR remained significantly better in the group with a percent decrease in eHTKV-α from baseline to the first treatment-year ≥ the median (2.94%) than in the group with a decrease <2.94%. The free-water clearance was higher in males than in females irrespective of treatment.ConclusionThe TKV growth rate decreased in 4 years with tolvaptan in both sexes. The insignificant effects of tolvaptan on the eGFR slope in males were likely due to androgen stimulation of cystogenesis and analytical difficulty of longitudinal changes in nonlinear trajectories of eGFR. The larger decrease in eHTKV-α in the first year was related to a better renal prognosis. The vasopressin-mediated water reabsorption was activated more in females than males irrespective of tolvaptan administration.

Cost-Effectiveness of long-term tolvaptan administration for chronic heart failure treatment in Japan

BackgroundTolvaptan (TLV) is effective for acute heart failure (HF) with congestion, but its long-term administration in patients with chronic HF (CHF) remains controversial. Moreover, the cost-effectiveness of TLV for CHF treatment has not yet been investigated. Thus, we sought to validate the cost-effectiveness of TLV for CHF treatment in Japan. MethodsA Markov model was developed to compare total costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratio (ICER) between long-term TLV strategy and the standard strategy using furosemide for CHF. The target population included 75-year-old patients with CHF. The effectiveness of the TLV strategy for CHF treatment was determined based on a systematic review and meta-analysis. We used a 10-year horizon, with sensitivity analyses for significant variables and a scenario analysis for patients with CHF receiving high-dose furosemide (≥60 mg per day). ResultsIn the base case analysis, the total cost of the long-term TLV strategy was higher than that of the standard strategy (¥3,243,779 vs. ¥1,179,964). The total QALYs of the long-term TLV strategy were lower than those of the standard strategy (4.52 vs 4.59). Thus, a standard TLV prescription for CHF treatment has no clinical or economic benefit. In the scenario analysis (i.e. in patients with CHF receiving high-dose furosemide), the long-term TLV strategy was more effective (total QALYs, 5.10 vs. 4.41) but more expensive (total costs, ¥3,540,558 vs. ¥1,272,208) than the standard strategy. The ICER of the TLV strategy against the standard strategy (¥3,289,579/QALY) was below the willingness-to-pay of ¥5,000,000, which suggests that the long-term TLV strategy is cost-effective relative to the standard strategy in patients with CHF receiving high-dose furosemide. ConclusionsLong-term TLV administration did not provide a clear benefit for all patients with CHF. However, this treatment strategy may be a cost-effective therapeutic option for patients who require high-dose furosemide.

Right ventricular contractility affects the clinical efficacy of add-on tolvaptan following hospitalization for heart failure in patients with significant tricuspid regurgitation.

Tricuspid regurgitation (TR) is a common condition that is independently associated with high mortality rates in patients with heart failure (HF). Several studies have demonstrated the clinical efficacy of add-on tolvaptan in patients hospitalized for HF. However, the effects of add-on tolvaptan in patients with significant TR are less well understood. Among the patients with moderate-to-severe TR assessed by transthoracic echocardiography during hospitalization for congestive HF, 39 patients who could complete the clinical course after starting add-on tolvaptan were included in the study. Rehospitalization due to HF and cardiac death were defined as adverse cardiac events in this study. We investigated the presence or absence of cardiac events within 2years following the introduction of tolvaptan and evaluated echocardiographic functional parameters associated with cardiac events. The average patient age was 75 ± 14years, and 23 patients (59%) experienced adverse cardiac events within 2years after add-on tolvaptan administration. Serum creatinine (mg/dL) and brain natriuretic peptide (pg/mL) concentrations at discharge were significantly higher in patients with cardiac events than in those without cardiac events {1.48 [1.02-1.58] vs. 1.07 [0.79-1.41], p = 0.03; 526 [414-1044] vs. 185 [104-476], p = 0.01, respectively}. The presence or absence of past hospitalization for HF was also significantly higher in the event-positive group compared to event-free group (78 vs. 44%, p = 0.04). Comparison of echocardiographic parameters revealed that patients with cardiac events had a significantly lower left ventricular ejection fraction (40 ± 16 vs. 49 ± 15%, p = 0.049) and lower right ventricular fractional area change (RVFAC) (35 ± 12 vs. 45 ± 10%, p = 0.008) than those without cardiac events. Multiple logistic regression analysis revealed that RVFAC and past hospitalization for HF were independently associated with cardiac events following the introduction of tolvaptan (odds ratio, 0.934 and 4.992; p = 0.048 and 0.04, respectively). Right ventricular contractility as well as past history of admission for HF, left ventricular ejection fraction, renal function, and brain natriuretic peptide level at discharge may reflect the clinical outcomes after HF hospitalization in patients with significant TR who were treated with tolvaptan.

Clinical features and long-term prognosis of patients with congestive heart failure taking tolvaptan: a comparison of patients with preserved and reduced left ventricular ejection fraction

Few studies have investigated the clinical benefit of the long-term use of tolvaptan (TLV) for heart failure (HF). This study evaluated the long-term prognosis of patients administered TLV for > 1 year among patients who had HF with preserved ejection fraction (HFpEF) and those who had HF with reduced ejection fraction (HFrEF). Overall, 591 consecutive patients were admitted to our hospital and administered TLV for HF between 2011 and 2018. We retrospectively enrolled 147 patients who were administered TLV for > 1 year. We divided them into the HFpEF group (n = 77, 52.4%) and the HFrEF group (n = 70; 47.6%). Their clinical backgrounds and long-term prognosis were examined. Compared with the patients in the HFrEF group, the patients in the HFpEF group were significantly older and included more women. Moreover, the HFpEF group showed significantly lower all-cause mortality (38.6% vs. 24.7%; log-rank, P = 0.014) and cardiovascular mortality during the average 2.7-year follow-up. Univariate analysis revealed that all-cause mortality was correlated with male sex, HFpEF, and changes in serum creatinine levels from baseline. Multivariate analysis revealed that HFpEF was an independent influencing factor for all-cause mortality (hazard ratio, 0.44; 95% confidence interval, 0.23–0.86; P = 0.017). Long-term administration of TLV may be more beneficial for HFpEF than for HFrEF.

Examination of the acute efficacy and safety about aggressive use of tolvaptan for early rising after admission in super-elder patients with congestive heart failure

Abstract Background From August 2015, for shortening of hospitalization period through efficient medical care in acute phase, we had introduced a unique clinical pathway (PATH) for congestive heart failure (CHF) cases. In PATH, since immediate taking of Tolvaptan, which is an strong oral diuretic and approver for use in the treatment of CHF cases since 2010 in Japan, after admission is specified, early diuresis makes it possible to achieve early rising from bed and streamline each medical care such as oxygen inhalation, continuous infusion, and urethral catheterization. Early rising from bed is particularly important for super-elder CHF patients who merge often frail. On the other hand, for super-elder CHF patients, it is feared that aggressive use of Tolvaptan may frequently cause dehydration, renal damage caused by it, or hypernatremia, which is a peculiar side effect about the drug. Purpose In this study, we examined the usefulness and safety of active use of Tolvaptan by introducing PATH in patients with super-elder CHF patients. Methods We set up three groups, NE group consist of 37 CHF cases (90 years old or over) who admitted in our hospital before (without) introduction of PATH between April 2014 and July 2015, PE group consist of 130 CHF cases (90 years old or over) and PY group consist of 466 CHF cases (under 90 years old) who ware admitted with introduction of PATH between August 2015 and July 2020. And in each group, we investigated various medical conditions in their acute phase after admission and the incidence of adverse events related to oral administration of tolvaptan, and examined the differences between three groups. Results Between NE group and PE group, there were no significant differences in mean age, pre-hospital living status, or clinical status at admission (Figure 1). But due to lean and efficient CHF care, the average length of hospitalization period was significantly shorter in PE group. And, in PE group, each medical care was performed as efficiently as in PY group, but the progression of renal damage or hypernatremia that required unscheduled discontinuation of tolvaptan use occurred more frequently in PE group (Figure 2). Conclusions Aggressive Tolvaptan use through our unique clinical pathway for congestive heart failure cases seemed to be useful even in super-elder patients. Although we thought that the safety of active use of tolvaptan for super-elder patients was well tolerated considering the results of this study, the incidence of adverse events such as hypernatremia was clearly higher in super-elder patients than in non-super-elder patients. It seemed that we should pay close attention to the clinical data of super-elder patients after introduction of tolvaptan. Funding Acknowledgement Type of funding sources: None. Figure 1Figure 2

Clinical features and long-term prognosis of patients with congestive heart failure taking tolvaptan: a comparison between preserved and reduced left ventricular ejection fraction

Abstract Background There were few reports which investigated the clinical benefit of long-term use of tolvaptan (TLV) for heart failure (HF). The purpose of this study was to evaluate the long-term prognosis of patients administrated TLV for more than 1 year in the HF patients with preserved ejection fraction (HFpEF) and reduced ejection fraction (HFrEF). Method In a total of 591 consecutive patients who were admitted to our hospital and administered TLV for HF between 2011 and 2018, we retrospectively enrolled 147 patients who were administered TLV for more than 1 year. The patients were classified into 2 groups, the HFpEF group (n=77, 52.4%) and the HFrEF group (n=70, 47.6%), and clinical backgrounds and long-term prognosis were examined. Furthermore, we performed stratified analysis based on the response to TLV defined by urine osmolality (The responder group n=40, the non-responder group n=52). Results The HFpEF group was significantly older (77.7±9.2 vs. 71.3±11.5 years, P&amp;lt;0.01) and included more female (41.6 vs. 21.4%, P&amp;lt;0.01) compared with the HFrEF group. Other baseline characteristics were not different between the two groups. During the average 2.7 years follow up, the HFpEF group showed significantly lower all-cause mortality and cardiovascular mortality compared to the HFrEF group (24.7 vs. 38.6%, Log-Rank P=0.014, 13.0 vs. 25.7%, Log-Rank P=0.007, respectively). Univariate analysis revealed that male, HFpEF, serum creatinine changes from baseline (ΔCre) were the factors correlated with all-cause mortality (HR 2.12, 95% CI 1.02 – 4.40, P=0.045, HR 0.48, 95% CI 0.26 - 0.87, P=0.016 and HR 1.50, 95% CI 1.00 - 2.24, P=0.049, respectively). According to multivariate analysis, HFpEF was the independent influencing factor of all-cause mortality (HR 0.44, 95% CI 0.23 - 0.86, P=0.017). Stratified analysis revealed that in the non-responder group all-cause mortality was significantly lower in the HFpEF group than in the HFrEF group (24.2% vs 48.3%, P=0.049). Conclusion Long-term administration of TLV maybe more beneficial for HFpEF compared with HFrEF. This tendency was remarkable at non-responder group. Funding Acknowledgement Type of funding sources: None.

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.

Effect of oral tolvaptan for 1 year in patients with functional mitral regurgitation.

The effect of the oral selective vasopressin V2-receptor antagonist tolvaptan for chronic phase therapy on patients with FMR remains unclear. We aimed to determine the efficacy of oral tolvaptan in patients with significant functional mitral regurgitation (FMR) to reduce the mortality and rehospitalization due to worsening heart failure (HF). We enrolled 219 patients (mean age 76 ± 9years, 59.4% men) who were admitted at our hospital due to congestive HF during different two 1-year periods. The patients were divided into 2 groups: those who had significant FMR (MR ≥ grade 2 [n = 76]) and those who did not (MR < grade 2 [n = 143]) at discharge. The patients were further divided into a study group that received tolvaptan during follow-up and a control group that did not receive tolvaptan. We used an inverse probability of treatment weighting method with the primary end point defined as overall all-cause mortality and rehospitalization due to worsening HF within 1year. Of the 76 patients with significant FMR at discharge, 2 of 20 (10%) who were administered tolvaptan died and 8 (40%) were readmitted to a hospital. Of the 56 patients who did not receive tolvaptan, 2 (3.5%) died and 18 (27.5%) required rehospitalization. After multiple adjustments, there were no significant differences for overall survival and rehospitalization between the groups (log-rank p = 0.700 and 0.510, respectively). Our results suggest that oral tolvaptan administration in addition to conventional diuretics had less impact on outcomes in patients with significant FMR.

Clinical Effects of Early and Short-Term Tolvaptan Administration in Patients Hospitalized for Acute Decompensated Heart Failure

Introduction: Previous trials showed that tolvaptan improves acute heart failure (HF). However, the optimal timing for administering tolvaptan to achieve the best outcome remains unclear. Therefore, the current study investigated the relationship between the timing of tolvaptan treatment initiation and clinical outcomes in patients with acute decompensated HF. Methods: We prospectively evaluated 201 patients with acute decompensated HF, randomly divided into 2 groups based on the timing of tolvaptan initiation. The early group was administered tolvaptan approximately 1 week after day 1 or 2 (n = 104), whereas the late group was administered the same drug 1 week after the early group (n = 97). Results: All-cause mortality, cardiovascular death, and hospitalization during the follow-up period were comparable between both groups. The early group had shorter durations of oxygenation, carperitide infusion, and hospitalization than the late group (p = 0.013, 0.003, 0.006, respectively). The early group demonstrated a significantly faster decrease in pleural effusion than the late group (p = 0.001). The 2 groups had comparable maximum and minimum serum sodium and potassium levels and minimum estimated glomerular filtration rates during hospitalization. The early group spent significantly less money on all diuretics administered over the first 2 weeks and on tolvaptan and carperitide administered during the hospitalization period than the late group (p < 0.001). Conclusions: Early and short-term administration of tolvaptan was feasible, contributed to a more rapid improvement in patients with acute decompensated HF, and reduced health-care costs.

Initiation and long-term use of tolvaptan for patients with worsening heart failure through hospital and clinic cooperation.

ABSTRACTWorsening heart failure (WHF) has a negative impact on the prognosis of patients with heart failure. Adequate management of non-hospitalized episodes of WHF, regarded as “outpatient WHF”, may reduce the frequency of emergent/urgent hospitalization for acute heart failure; thus, the patients’ cardiac parameters return to their clinical baseline. This study aimed to investigate the efficacy of tolvaptan initiation during planned hospitalization of patients with “outpatient WHF” through hospital and clinic cooperation. The data from 28 patients with outpatient WHF referred by general practitioners to hospital were assessed. Tolvaptan administration was initiated during planned hospitalization and continued in the clinics. Patients were followed-up for 12 months. None of the patients required withdrawal of tolvaptan due to adverse effects. During the follow-up period, the loop diuretic dosage significantly decreased. There were significant favorable changes in the levels of serum creatinine, estimated glomerular filtration rate, natriuretic peptide and body weight. Kaplan-Meier survival analysis revealed that the cardiac death- and HF-related hospitalization-free survival rates were significantly higher among the patients who were administered tolvaptan for the outpatient WHF than the propensity score-matched patients who were administered tolvaptan for acute heart failure requiring emergent/urgent hospitalization. In conclusion, tolvaptan may be safe and effective for the long-term management of outpatient WHF through hospital and clinic cooperation.

Tolvaptan in Hyponatremia – A Pharmacologic approach

Tolvaptan is the first orally active vasopressin receptor 2 antagonist approved by FDA in 2009 for the treatment of clinically significant hypervolemic and euvolemic hyponatremia associated with heart failure, syndrome of inappropriate antidiuretic hormone secretion, liver cirrhosis. Binding of vasopressin to V2 receptors which are located on renal collecting duct cells were competitively inhibited by Tolvaptan thus prevents vasopressin-mediated activation of these receptors and leads to an increase in the water permeability of the collecting duct causing an increase in the concentration of urine, results in an increase in free water clearance, a decrease in urine osmolality and a fall in serum sodium concentration. Tolvaptan is different from other conventional diuretics because it does not stimulate the sodium channel and increases free water excretion without affecting urinary sodium and potassium excretion. It is metabolized principally via the cytochrome P 450 (CYP 3A) isoenzymes and is eliminated by routes other than renal. Concurrent administration of tolvaptan with ketoconazole or other strong CYP 3A inhibitor decrease the total clearance of tolvaptan and increases tolvaptan concentrations. Urine sodium potassium ratio, weight loss, soluble CD14, urinary aquaporin 2 levels are known predictors of tolvaptan response. Tolvaptan is associated with decreased cost and high effectiveness.

Safety Profile of Tolvaptan in the Treatment of Autosomal Dominant Polycystic Kidney Disease.

Autosomal dominant polycystic kidney disease constitutes the most prevalent hereditary kidney disease, associated with high rates of morbidity leading eventually to end-stage renal disease. Tolvaptan is a selective vasopressin antagonist and has emerged as a promising therapeutic option for patients with autosomal dominant polycystic kidney disease. The present review summarized current evidence regarding the safety profile of tolvaptan in patients with the disease. Consistent with its pharmacological action, aquaretic adverse events represent the most common side effects of tolvaptan, consisting of polyuria, pollakiuria and polydipsia. Gradual dose titration based on urinary osmolality, as well as dietary interventions aiming to reduce solute excretion, have been proposed as potential strategies to mitigate polyuria. In addition, tolvaptan administration may be complicated by liver injury, characterized by alanine aminotransferase and bilirubin elevations. Hepatotoxicity has been suggested to be triggered by impaired biliary clearance, activation of innate immunity and increased oxidative stress. Frequent monitoring of liver function tests has been shown to be effective in preventing Hy’s Law and liver failure cases. Uric acid elevation due to reduced renal excretion may lead to hyperuricemia and gout, although no drug discontinuations have been linked to these events. Future studies should confirm the safety profile of tolvaptan in large-scale real-world studies, clarify the pathogenetic pathways leading to hepatotoxicity and define its role in special populations, especially pediatric patients.

Management of Cirrhotic Ascites under the Add-on Administration of Tolvaptan.

Tolvaptan is a recently available diuretic that blocks arginine vasopressin receptor 2 in the renal collecting duct. Its diuretic mechanism involves selective water reabsorption by affecting the water reabsorption receptor aquaporin 2. Given that liver cirrhosis patients exhibit hyponatremia due to their pseudo-aldosteronism and usage of natriuretic agents, a sodium maintaining agent, such as tolvaptan, is physiologically preferable. However, large scale studies indicating the patients for whom this would be effective and describing management under its use have been insufficient. The appropriate management of cirrhosis patients treated with tolvaptan should be investigated. In the present review, we collected articles investigating the effectiveness of tolvaptan and factors associated with survival and summarized their management reports. Earlier administration of tolvaptan before increasing the doses of natriuretic agents is recommended because this may preserve effective arterial blood volume.