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Tolvaptan treatment improves survival of cirrhotic patients with ascites and hyponatremia.
Wang, S, Zhang, X, Han, T, Xie, W, Li, Y, Ma, H, Liebe, R, Weng, H, Ding, HG
BMC gastroenterology. 2018;(1):137
Abstract
BACKGROUND Although tolvaptan treatment improves hyponatremia, only few studies have investigated whether tolvaptan actually benefits the survival of cirrhotic patients. This study evaluated the impact of tolvaptan on six-month survival of decompensated cirrhotic patients with and without hyponatremia. METHODS Two hundred forty-nine decompensated cirrhotic patients with or without hyponatremia were enrolled in a multicenter cohort study. Patients were divided into two groups according to receiving either tolvaptan or placebo treatment for 7-day. Subsequently, the patients were followed up for 6 months. RESULTS Two hundred thirty patients, including 98 with hyponatremia (tolvaptan vs. placebo: 69 vs. 29) finished the study. Tolvaptan did not alter serum sodium levels and survival outcome of decompensated cirrhotic patients without hyponatremia. However, tolvaptan treatment remarkably improved serum sodium levels and six-month survival in patients with hyponatremia. Following tolvaptan treatment, serum sodium levels were restored to normal in 63.8% of patients, whereas in patients receiving placebo, only 36.2% showed the same effect (P < 0.05). Compared to a six-month survival rate of 68.97% in patients receiving placebo, the survival rate in tolvapatan-treated patients was 89.94% (P < 0.05). Furthermore, six-month survival rate in the tolvaptan-treated hyponatremia patients with resolved serum sodium was 81.32%, whereas the survival in those with unresolved serum sodium was only 24% (P < 0.05). CONCLUSIONS Tolvaptan improves short term survival in most decompensated cirrhotic hyponatremia patients with resolved serum sodium. TRIALS REGISTRATION Clinical trial one: ClinicalTrials.gov ID: NCT00664014 , Registered on April 14, 2008. Clinical trial two: ClinicalTrials.gov ID: NCT01349335 , Registered on March 5, 2010. Clinical trial three: ClinicalTrials.gov ID: NCT01349348 , Registered on May 4, 2011.
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Short-Term Effects of Tolvaptan in Patients With Acute Heart Failure and Volume Overload.
Konstam, MA, Kiernan, M, Chandler, A, Dhingra, R, Mody, FV, Eisen, H, Haught, WH, Wagoner, L, Gupta, D, Patten, R, et al
Journal of the American College of Cardiology. 2017;(11):1409-1419
Abstract
BACKGROUND In patients with acute heart failure (AHF), dyspnea relief is the most immediate goal. Renal dysfunction, diuretic resistance, and hyponatremia represent treatment impediments. OBJECTIVES It was hypothesized that the addition of tolvaptan to a background diuretic improved dyspnea early in patients selected for an enhanced vasopressin antagonism response. METHODS In a double-blind trial, patients were randomized to tolvaptan 30 mg/day or placebo. Study entry required hospitalization within the previous 36 h, active dyspnea, and any of the following: 1) estimated glomerular filtration rate <60 ml/min/1.73 m2; 2) hyponatremia; or 3) diuretic resistance (urine output ≤125 ml/h following intravenous furosemide ≥40 mg). The primary endpoint was a 7-point change in self-assessed dyspnea at 8 and 16 h, using a novel standardized approach. RESULTS We randomized 250 patients. There was no difference in the primary endpoint of day 1 dyspnea reduction, despite significantly greater weight reduction with tolvaptan (-2.4 ± 2.1 kg vs. -0.9 ± 1.8 kg; p < 0.001). At day 3, dyspnea reduction was greater with tolvaptan (p = 0.01). There were 2 significant treatment-by-subgroup interactions: patients without elevated jugular venous pressure and those without ascites showed directional favorability of tolvaptan over placebo for the primary endpoint compared with patients with these findings. CONCLUSIONS Despite rapid and persistent weight loss with tolvaptan compared with placebo, in patients with AHF who were selected for greater potential benefit from vasopressin receptor inhibition, tolvaptan was not associated with greater early improvement in dyspnea. Apparent subsequent differences in dyspnea warrant further exploration of the temporal relationship between diuresis and dyspnea relief and a possible clinical role for tolvaptan. (Randomized, Double-Blind, Placebo Controlled Study of the Short Term Clinical Effects of Tolvaptan in Patients Hospitalized for Worsening Heart Failure With Challenging Volume Management [SECRET of CHF]; NCT01584557).
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Effect of tolvaptan on acute heart failure with hyponatremia--a randomized, double blind, controlled clinical trial.
Shanmugam, E, Doss, CR, George, M, Jena, A, Rajaram, M, Ramaraj, B, Anjaneyan, K, Kanagesh, B
Indian heart journal. 2016;(Suppl 1):S15-21
Abstract
OBJECTIVES To assess the efficacy of tolvaptan in acute heart failure with hyponatremia using a randomized double-blinded placebo-controlled study design. BACKGROUND Tolvaptan is a selective vasopressin receptor 2 antagonist. There are no published clinical trials on the utility of tolvaptan in acute heart failure with hyponatremia in the Indian population. METHODS After screening and informed consent, 51 HF patients with hyponatremia were randomized using computer-generated randomization sequence to receive placebo or 15mg of tolvaptan for 5 days along with conventional medical therapy. The patient's perception of dyspnea using Likert score and the plasma sodium was measured at baseline and for the next 4 days. RESULTS There was a mean improvement in sodium concentration by 5mEq/L (p=0.001) in patients receiving tolvaptan, whereas no significant improvement was seen in the placebo group (p=0.33). Significant improvement in Likert score was observed in both the groups (p=0.001), even though there was no difference between both the groups. Dry mouth and thirst were the most commonly occurring adverse effects observed in both the groups. There were no significant hemodynamic changes with tolvaptan therapy. CONCLUSION Tolvaptan at a dose of 15mg is effective in reversing hyponatremia in acute heart failure and may be a suitable option in these patients.
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Effectiveness and adverse events of tolvaptan in octogenarians with heart failure. Interim analyses of Samsca Post-Marketing Surveillance In Heart faiLurE (SMILE study).
Kinugawa, K, Inomata, T, Sato, N, Yasuda, M, Shimakawa, T, Bando, K, Mizuguchi, K
International heart journal. 2015;(2):137-43
Abstract
The vasopressin receptor 2 (V2) receptor antagonist tolvaptan is an aquaretic agent that has been found to improve symptoms in patients with congestive heart failure. In this study (SMILE study), we administered tolvaptan to patients aged ≥ 80 years with heart failure accompanied by congestive symptoms and compared its effectiveness and safety profiles in this group with those in patients < 80 years (U-80). The results showed that the effectiveness of tolvaptan in the aged patients was similar to that in U-80 patients. In the safety profile, the incidence rate of thirst was lower in the aged patients than that in U-80 patients (9.6% versus 11.6%, P = 0.0023). Furthermore, the incidence of hypernatremia, defined as ≥ 150 mEq/L in aged patients, was comparable with that in U-80 patients (2.9% versus 3.6%, respectively, P = 0.3657). Based on these findings, tolvaptan has similar effectiveness and safety profiles in aged patients compared with U-80 patients. In addition, we found that a higher starting dose of tolvaptan was markedly associated with the occurrence of hypernatremia exclusively in the aged population; therefore, we recommend that tolvaptan should be started at lower doses in aged patients.
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Efficacy and safety of ivabradine in patients with chronic systolic heart failure according to blood pressure level in SHIFT.
Komajda, M, Böhm, M, Borer, JS, Ford, I, Robertson, M, Manolis, AJ, Tavazzi, L, Swedberg, K, ,
European journal of heart failure. 2014;(7):810-6
Abstract
AIMS: Low systolic blood pressure (SBP) is associated with poor outcomes in heart failure and complicates management. In a post hoc analysis, we investigated the efficacy and safety of ivabradine in the SHIFT population divided by tertiles of baseline SBP. METHODS AND RESULTS The analysis comprised 2110 patients with SBP <115 mmHg, 1968 with 115≤ SBP <130 mmHg, and 2427 with SBP ≥130 mmHg. Patients with low SBP were younger, had lower ejection fraction, and were less likely to be at target beta-blocker dose than patients in the other SBP groups. Ivabradine was associated with a similar relative risk reduction of the composite outcome in the three SBP groups [SBP <115 mmHg, hazard ratio (HR) = 0.84, 95% confidence interval (CI) 0.72-0.98; 115≤ SBP <130 mmHg, HR = 0.86, 95% CI 0.72 to 1.03; SBP ≥130 mmHg, HR = 0.77, 95% CI 0.66 to 0.92; P interaction = 0.68]. Similar results were found for cardiovascular mortality (P interaction = 0.91), hospitalization because of heart failure (P interaction = 0.79), all-cause mortality (P interaction = 0.90), and heart failure mortality (P interaction = 0.18). There was no evidence for a difference in safety profile according to SBP group. CONCLUSION The efficacy and safety of ivabradine is independent of SBP. This may have implications for the management of HF patients with low SBP and elevated heart rate.
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Efficacy and safety of a 14-day administration of tolvaptan in the treatment of patients with ascites in hepatic oedema.
Sakaida, I, Yamashita, S, Kobayashi, T, Komatsu, M, Sakai, T, Komorizono, Y, Okada, M, Okita, K, ,
The Journal of international medical research. 2013;(3):835-47
Abstract
OBJECTIVE To investigate the efficacy and safety of 14 days' orally administered tolvaptan as adjunctive treatment for hepatic oedema in Japanese liver cirrhosis patients with insufficient response to conventional diuretics, with the option to increase dose in those who did not respond initially. METHODS This multicentre, single-arm, phase 3 study allocated patients with liver cirrhosis and persistent ascites to 7-day treatment with 7.5 mg/day tolvaptan followed by an additional 7 days' treatment. Responders at day 7 (achieving ≥ 1 kg body-weight reduction) continued on 7.5 mg/day tolvaptan; nonresponders (<1 kg body-weight reduction) received 15 mg/day tolvaptan. Conventional diuretic treatment continued throughout. The primary endpoint was change in body weight from baseline, as a marker of ascites volume. RESULTS A total of 51 patients received 7.5 mg/day tolvaptan for 7 days, which caused a significant reduction in mean body weight (55% response rate). During the second 7-day treatment period, 30 patients received 7.5 mg/day tolvaptan and 13 patients received tolvaptan 15 mg/day: response rates were 43% and 23%, respectively. Two serious adverse events were observed. Serum sodium was within normal range. CONCLUSIONS Tolvaptan therapy for 14 days (with possible dose increase as necessary), in combination with conventional diuretics, effectively reduced body weight in patients with hepatic oedema.
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Association of low body temperature and poor outcomes in patients admitted with worsening heart failure: a substudy of the Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial.
Payvar, S, Spertus, JA, Miller, AB, Casscells, SW, Pang, PS, Zannad, F, Swedberg, K, Maggioni, AP, Reid, KJ, Gheorghiade, M, et al
European journal of heart failure. 2013;(12):1382-9
Abstract
AIMS: Risk stratification in patients admitted with worsening heart failure (HF) is essential for tailoring therapy and counselling. Risk models are available but rarely used, in part because many require laboratory and imaging results that are not routinely available. Body temperature is associated with prognosis in other illnesses, and we hypothesized that low body temperature would be associated with worse outcomes in patients admitted with worsening HF. METHODS AND RESULTS The Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) trial was an event-driven, randomized, double-blind, placebo-controlled study of tolvaptan in 4133 patients hospitalized for worsening HF with an EF <40%. Co-primary endpoints were all-cause mortality and cardiovascular (CV) death or HF rehospitalization. Body temperature was measured orally at randomization and entered in analyses both as a continuous variable and categorized into three groups (<36 °C, 36-36.5 °C, and >36.5 °C) using Cox regression models. The composite of CV death or HF rehospitalization occurred in 1544 patients within 1 year. For every 1 °C decrease in body temperature, the risk of adverse outcomes increased by 16% [hazard raio (HR) 1.16, 95% confidence interval (CI) 1.04-1.28], after adjustment for age, gender, race, systolic blood pressure, EF, blood urea nitrogen, and serum sodium. In fully adjusted analysis, the risk of adverse outcomes in the lowest body temperature group (<36 °C) was 51% higher than that of the index group (>36.5 °C) (HR 1.35, 95% CI 1.15-1.58). CONCLUSIONS Low body temperature is an independent marker of poor cardiovascular outcomes in patients admitted with worsening HF and reduced EF.
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Acute heart failure volume control multicenter randomized (AVCMA) trial: comparison of tolvaptan and carperitide.
Suzuki, S, Yoshihisa, A, Yamaki, T, Sugimoto, K, Kunii, H, Nakazato, K, Abe, Y, Saito, T, Ohwada, T, Suzuki, H, et al
Journal of clinical pharmacology. 2013;(12):1277-85
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Abstract
BACKGROUND [corrected] Acute decompensated heart failure (ADHF) is a common and highly morbid cardiovascular disorder. Diuresis is a major therapy for the reduction of congestive symptoms. However, most diuretics cause hyponatremia, which is a worsening factor of ADHF patients prognosis. The purpose of this study was to examine the efficacy and safety of tolvaptan, which is a selective vasopressin V2 receptor antagonist and produces water excretion without changes in sodium excretion, compared with carperitide. METHODS AND RESULTS One hundred and nine hospitalized ADHF patients were enrolled and randomly assigned to tolvaptan or carperitide treatment groups. Subjective symptoms and plasma BNP level were similarly improved by treatment in both groups. Urine volume was significantly higher in the tolvaptan group (P < .05), but volume of water intake was also higher in the tolvaptan group (P < .05). Blood pressure was significantly lower in the carperitide group than in the tolvaptan group after treatment (P < .05). Less adverse events such as worsening heart failure and hypotension requiring drug discontinuation were observed in the tolvaptan group (P = .027). The average drug cost of tolvaptan was lower than that of carperitide (P < .001). CONCLUSIONS Tolvaptan might be a novel promising agent for ADHF in terms of efficacy and safety compared to carperitide.
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Oral tolvaptan is safe and effective in chronic hyponatremia.
Berl, T, Quittnat-Pelletier, F, Verbalis, JG, Schrier, RW, Bichet, DG, Ouyang, J, Czerwiec, FS, ,
Journal of the American Society of Nephrology : JASN. 2010;(4):705-12
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Vasopressin antagonists increase the serum sodium concentration in patients who have euvolemia and hypervolemia with hyponatremia in the short term (≤30 days), but their safety and efficacy with longer term administration is unknown. SALTWATER was a multicenter, open-label extension of the Study of Ascending Levels of Tolvaptan in Hyponatremia (SALT-1 and SALT-2). In total, 111 patients with hyponatremia received oral tolvaptan for a mean follow-up of 701 days, providing 77,369 patient-days of exposure. All patients had hyponatremia at randomization in SALT-1 and SALT-2, and 85% continued to have hyponatremia at entry in SALTWATER. The most common adverse effects attributed to tolvaptan were pollakiuria, thirst, fatigue, dry mouth, polydipsia, and polyuria. Six drug-related adverse effects led to study discontinuation. The increase in serum sodium exceeded the desired 1 mmol/L per h at initiation in five patients. Hypernatremia (>145 mmol/L) led to discontinuation in one patient. Mean serum sodium increased from 130.8 mmol/L at baseline to >135 mmol/L throughout the observation period (P < 0.001 versus baseline at most points). Responses were comparable between patients with euvolemia and those with heart failure but more modest in patients with cirrhosis. In conclusion, prolonged administration of tolvaptan maintains an increased serum sodium with an acceptable margin of safety.