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1.
Limited Efficacy of Tolvaptan in Patients with Cirrhosis and Severe Hyponatremia: Real-Life Experience.
Pose, E, Solà, E, Piano, S, Gola, E, Graupera, I, Guevara, M, Cárdenas, A, Angeli, P, Ginès, P
The American journal of medicine. 2017;(3):372-375
Abstract
BACKGROUND Vaptans, vasopressin selective V2-receptor antagonists, represent the first pharmacologic approach to the treatment of hypervolemic hyponatremia in cirrhosis. However, information on the use of vaptans for patients with cirrhosis and hyponatremia in a real-life scenario is limited. Therefore, this study evaluated the effect of tolvaptan on serum sodium in patients with cirrhosis and severe hypervolemic hyponatremia. METHODS Nine patients with cirrhosis and serum sodium ≤125 mEq/L were included. RESULTS Only 2 of the 9 patients (22%) gained an increase in serum sodium >130 mEq/L that persisted throughout treatment. In the remaining patients, serum sodium did not change or increased during the first days but decreased thereafter despite continuation of treatment. Only 1 patient developed hyperkalemia as a side effect. CONCLUSIONS The efficacy of tolvaptan in patients with cirrhosis and severe hypervolemic hyponatremia seems to be limited.
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Health-related quality of life in randomized controlled trials of lorcaserin for obesity management: what mediates improvement?
Kolotkin, RL, Crosby, RD, Wang, Z
Clinical obesity. 2017;(6):347-353
Abstract
Lorcaserin, plus diet and exercise, has demonstrated significant weight loss and improved cardiometabolic parameters vs. placebo in patients with overweight/obesity in three randomized, placebo-controlled trials. We examined whether lorcaserin is also associated with greater improvements in health-related quality of life (HRQOL) and whether these improvements are wholly attributable to weight loss. Pooled data from Behavioral Modification and Lorcaserin for Overweight and Obesity Management (BLOOM), Behavioral Modification and Lorcaserin Second Study for Obesity Management (BLOSSOM) and BLOOM-Diabetes Mellitus (BLOOM-DM) trials were analysed (n = 5624). HRQOL was assessed at baseline and 52 weeks using the Impact of Weight on Quality of Life-Lite (IWQOL-Lite) questionnaire. Multiple mediation analyses were conducted to evaluate the mechanisms underlying improved HRQOL. Greater HRQOL improvements were observed at 52 weeks in lorcaserin vs. placebo (P < 0.0001). A greater percentage of lorcaserin patients (54.1%) experienced meaningful improvements in IWQOL-Lite total score than placebo patients (48.2%) (P < 0.001). Body mass index (BMI) reduction was the primary driver of improved HRQOL (P < 0.0001), with depressive symptoms and total cholesterol also playing a role (P < 0.05). Improved HRQOL varied by gender, age, race and presence of diabetes and other comorbidities. Lorcaserin treatment significantly improves HRQOL compared with placebo. Although BMI reduction accounts for the majority of these improvements, improvement in depressive symptoms and total cholesterol are contributing factors.
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3.
Tolvaptan and Neurocognitive Function in Mild to Moderate Chronic Hyponatremia: A Randomized Trial (INSIGHT).
Verbalis, JG, Ellison, H, Hobart, M, Krasa, H, Ouyang, J, Czerwiec, FS, ,
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2016;(6):893-901
Abstract
BACKGROUND This trial assessed the effect of tolvaptan on cognition, gait, and postural stability in adult patients with mild to moderate asymptomatic hyponatremia. STUDY DESIGN Phase 3b, multicenter, randomized, double-blind, placebo-controlled, parallel-group pilot study. SETTING & PARTICIPANTS 57 men and women 50 years or older with chronic asymptomatic euvolemic or hypervolemic hyponatremia (serum sodium concentration >120-<135 mEq/L) at 16 sites. INTERVENTION Patients were randomly assigned 1:1 to receive tolvaptan or matching placebo beginning at a dose of 15mg/d, with titration to 30 or 60mg/d based on change in serum sodium concentration and tolerance. OUTCOMES Primary: change from baseline in the neurocognitive composite score of speed domains. Secondary: changes from baseline in individual neurocognitive domain scores, overall neurocognitive composite score, gait and postural stability test results, and serum sodium concentrations. RESULTS Mean serum sodium concentration increased from 129 to 136 mEq/L in the tolvaptan group and from 130 to 132 mEq/L in the placebo group (P<0.001). There was no difference in overall neurocognitive composite scores of speed domains between groups, except for the psychomotor speed domain, which was statistically improved following hyponatremia correction with tolvaptan (treatment effect, 0.27; 95% CI, 0.04-0.51; P=0.03). LIMITATIONS There were some imbalances between treatment groups in baseline neurocognitive function scores and some baseline test results were near normal, leaving little opportunity for improvement. Formal sample size calculations were not performed because this was a pilot study. The study population was small (n=57) and treatment was of short duration (3 weeks). The primary end point of the study was not significant; thus, subgroup analyses are subject to errors of multiplicity and should be regarded as hypothesis generating. CONCLUSIONS Tolvaptan was effective in reversing chronic hyponatremia, and this correlated with improvements in results of a variety of neurocognition tests, particularly rapid motor movements, which tended to reverse following return to a low baseline serum sodium concentration after treatment withdrawal.
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4.
Impact of lorcaserin on glycemic control in overweight and obese patients with type 2 diabetes: analysis of week 52 responders and nonresponders.
Pi-Sunyer, X, Shanahan, W, Fain, R, Ma, T, Garvey, WT
Postgraduate medicine. 2016;(6):591-7
Abstract
OBJECTIVES Treatment guidelines for type 2 diabetes mellitus (T2DM) suggest weight loss as a means to maintain glycemic control. Lorcaserin has been approved for chronic weight management in the United States as an adjunct to a reduced-calorie diet and exercise, and the previous phase 3 Behavioral Modification and Lorcaserin for Obesity and Overweight Management in Diabetes Mellitus (BLOOM-DM) study has shown that, in addition to weight loss, lorcaserin is associated with improvements in glycemic parameters. In this post hoc analysis of the BLOOM-DM trial, the relationship between responder status (patients achieving ≥5% weight loss at Week 52) and glycemic and cardiometabolic parameters is evaluated. METHODS Data are presented for patients receiving lorcaserin 10 mg twice daily or placebo for 52 weeks. RESULTS More than twice as many patients receiving lorcaserin plus diet and exercise counseling were classified as Week 52 responders compared to those receiving diet and exercise counseling alone (37.5% vs. 16.1%, respectively; p < 0.001), and lorcaserin Week 52 responders had greater improvements vs. placebo Week 52 responders in FPG (-38.1 mg/dL vs. -26.0 mg/dL) and HbA1c (-1.3% vs. -1.0%). Furthermore, more lorcaserin-treated Week 52 responders decreased the number of concomitant oral antidiabetic medications (OADs) used, and fewer increased the number of OADs used, compared to placebo. Unexpectedly, lorcaserin Week 52 nonresponders also had substantial reductions in glycemic levels, despite very modest weight loss. CONCLUSIONS These data support lorcaserin use in overweight and obese patients with T2DM to promote weight loss and facilitate glycemic control. CLINICAL TRIAL REGISTRATION www.clinicaltrials.gov identifier is NCT00603291.
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5.
Ivabradine in Combination with Metoprolol Improves Symptoms and Quality of Life in Patients with Stable Angina Pectoris: A post hoc Analysis from the ADDITIONS Trial.
Werdan, K, Ebelt, H, Nuding, S, Höpfner, F, Stöckl, G, Müller-Werdan, U, ,
Cardiology. 2016;(2):83-90
Abstract
OBJECTIVES Elevated heart rate can increase myocardial oxygen demand and reduce myocardial perfusion, provoking myocardial ischemia and angina symptoms. We evaluated adding ivabradine to the therapy of patients on metoprolol. METHODS ADDITIONS (prActical Daily efficacy anD safety of Procoralan® In combinaTION with betablockerS) was a multicenter, 4-month, noninterventional, prospective, open-label trial that involved stable-angina patients. Along with metoprolol, patients received ivabradine (5 or 7.5 mg, b.i.d.). We investigated the effect of ivabradine on heart rate, angina attacks, nitrate consumption, quality of life (QoL) and tolerability as well as the influence of baseline heart rate. RESULTS Heart rate fell by 19.7 ± 11.2 bpm, with an 8-fold decrease in weekly angina attacks (1.7 ± 2.2 to 0.2 ± 0.7) and nitrate consumption (2.4 ± 3.4 to 0.3 ± 0.9). Patient numbers in Canadian Cardiovascular Society class I more than doubled (i.e. from 29 to 65%) and QoL improved (the EQ-5D index and visual analog scale scores rose from 0.68 ± 0.27 to 0.84 ± 0.20 and 58.1 ± 18.4 to 72.2 ± 15.5 mm, respectively). The effect of ivabradine was greater in patients with a baseline heart rate ≥70 bpm (mean reduction in heart rate -21.2 ± 10.4 bpm, with a relative reduction in angina attacks and short-acting nitrate consumption of 87.1 and 87.2%, respectively). CONCLUSIONS Ivabradine combined with metoprolol safely and effectively reduces heart rate, angina attacks and nitrate use, and improves QoL in stable-angina patients.
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6.
Correction of hyponatraemia improves cognition, quality of life, and brain oedema in cirrhosis.
Ahluwalia, V, Heuman, DM, Feldman, G, Wade, JB, Thacker, LR, Gavis, E, Gilles, H, Unser, A, White, MB, Bajaj, JS
Journal of hepatology. 2015;(1):75-82
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Abstract
BACKGROUND & AIMS Hyponatraemia in cirrhosis is associated with impaired cognition and poor health-related quality of life (HRQOL). However, the benefit of hyponatraemia correction is unclear. The aim of this study was to evaluate the effect of tolvaptan on serum sodium (Na), cognition, HRQOL, companion burden, and brain MRI (volumetrics, spectroscopy, and diffusion tensor imaging) in cirrhotics with hyponatraemia. METHODS Cirrhotics with Na <130 mEq/L were included for a four-week trial. At screening, patients underwent cognitive and HRQOL testing, serum/urine chemistries and companion burden assessment. Patients then underwent fluid restriction and diuretic withdrawal for two weeks after which cognitive tests were repeated. If Na was still <130 mEq/L, brain magnetic resonance imaging (MRI) was performed and tolvaptan was initiated for 14 days with frequent clinical/laboratory monitoring. After 14 days of tolvaptan, all tests were repeated. Comparisons were made between screen, pre-and post-drug periods Na, urine/serum laboratories, cognition, HRQOL and companion burden. RESULTS 24 cirrhotics were enrolled; seven normalized Na without tolvaptan with improvement in cognition. The remaining 17 received tolvaptan of which 14 completed the study over 13 ± 2 days (age 58 ± 6 years, MELD 17, 55% HCV, median 26 mg/day of tolvaptan). Serum Na and urine free water clearance increased with tolvaptan without changes in mental status or liver function. Cognitive function, HRQOL and companion burden only improved in these 14 patients after tolvaptan, along with reduced total brain and white matter volume, increase in choline on magnetic resonance spectroscopy, and reduced cytotoxic oedema. CONCLUSIONS Short-term tolvaptan therapy is well tolerated in cirrhosis. Hyponatraemia correction is associated with cognitive, HRQOL, brain MRI and companion burden improvement.
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Fixed-dose combination therapy with daclatasvir, asunaprevir, and beclabuvir for noncirrhotic patients with HCV genotype 1 infection.
Poordad, F, Sievert, W, Mollison, L, Bennett, M, Tse, E, Bräu, N, Levin, J, Sepe, T, Lee, SS, Angus, P, et al
JAMA. 2015;(17):1728-35
Abstract
IMPORTANCE The antiviral activity of all-oral, ribavirin-free, direct-acting antiviral regimens requires evaluation in patients with chronic hepatitis C virus (HCV) infection. OBJECTIVE To determine the rates of sustained virologic response (SVR) in patients receiving the 3-drug combination of daclatasvir (a pan-genotypic NS5A inhibitor), asunaprevir (an NS3 protease inhibitor), and beclabuvir (a nonnucleoside NS5B inhibitor). DESIGN, SETTING, AND PARTICIPANTS This was an open-label, single-group, uncontrolled international study (UNITY-1) conducted at 66 sites in the United States, Canada, France, and Australia between December 2013 and August 2014. Patients without cirrhosis who were either treatment-naive (n = 312) or treatment-experienced (n = 103) and had chronic HCV genotype 1 infection were included. INTERVENTIONS Patients received a twice-daily fixed-dose combination of daclatasvir, 30 mg; asunaprevir, 200 mg; and beclabuvir, 75 mg. MAIN OUTCOMES AND MEASURES The primary study outcome was SVR12 (HCV-RNA <25 IU/mL at posttreatment week 12) in patients naive to treatment. A key secondary outcome was SVR12 in the treatment-experienced cohort. RESULTS Baseline characteristics were comparable between the treatment-naive and treatment-experienced cohorts. Patients were 58% male, 26% had IL28B (rs12979860) CC genotype, 73% were infected with genotype 1a, and 27% were infected with genotype 1b. Overall, SVR12 was observed in 379 of 415 patients (91.3%; 95% CI, 88.6%-94.0%): 287 of 312 treatment-naive patients (92.0%; 95% CI, 89.0%-95.0%) and 92 of 103 treatment-experienced patients (89.3%; 95% CI, 83.4%-95.3%). Virologic failure occurred in 34 patients (8%) overall. One patient died at posttreatment week 3; this was not considered related to study medication. There were 7 serious adverse events, all considered unrelated to study treatment, and 3 adverse events (<1%) leading to treatment discontinuation, including 2 grade 4 alanine aminotransferase elevations. The most common adverse events (in ≥10% of patients) were headache, fatigue, diarrhea, and nausea. CONCLUSIONS AND RELEVANCE In this open-label, nonrandomized, uncontrolled study, a high rate of SVR12 was achieved in treatment-naive and treatment-experienced noncirrhotic patients with chronic HCV genotype 1 infection who received 12 weeks of treatment with the oral fixed-dose regimen of daclatasvir, asunaprevir, and beclabuvir. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01979939.
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Immediate administration of tolvaptan prevents the exacerbation of acute kidney injury and improves the mid-term prognosis of patients with severely decompensated acute heart failure.
Shirakabe, A, Hata, N, Yamamoto, M, Kobayashi, N, Shinada, T, Tomita, K, Tsurumi, M, Matsushita, M, Okazaki, H, Yamamoto, Y, et al
Circulation journal : official journal of the Japanese Circulation Society. 2014;(4):911-21
Abstract
BACKGROUND Tolvaptan, an oral selective vasopressin 2 receptor antagonist that acts on the distal nephrons to cause a loss of electrolyte-free water, is rarely used during the acute phase of acute heart failure (AHF). METHODS AND RESULTS We investigated 183 AHF patients admitted to the intensive care unit and administered tolvaptan (7.5mg) with continuous intravenous furosemide, and then additionally at 12-h intervals until HF was compensated. When intravenous furosemide was changed to peroral use, the administration of tolvaptan was stopped. The patients were assigned to tolvaptan (n=52) or conventional treatment (n=131) groups. The amount of intravenous furosemide was significantly lower (35.4 [16.3-56.0] mg vs. 80.0 [30.4-220.0] mg), the urine volume was significantly higher on days 1 and 2 (3,691 [3,109-4,198] ml and 2,953 [2,128-3,592] ml vs. 2,270 [1,535-3,258] ml and 2,129 [1,407-2,906] ml) and the numbers of patients with worsening-AKI (step-up RIFLE Class to I or F) and Class F were significantly fewer (5.8% and 1.9% vs. 19.1% and 16.0%) in the tolvaptan group than in the conventional group, respectively. One of the specific medications indicated worsening-AKI and in-hospital mortality was tolvaptan (odds ratio [OR] 0.155, 95% confidence interval [CI] 0.037-0.657 and OR 0.191, 95% CI 0.037-0.985). The Kaplan-Meier curves showed that the death rate within 6 months was significantly lower in the tolvaptan group. The same result was found after propensity matching of the data. CONCLUSIONS Early administration of tolvaptan could prevent exacerbation of AKI and improve the prognosis for AHF patients.
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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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Novel criteria of urine osmolality effectively predict response to tolvaptan in decompensated heart failure patients--association between non-responders and chronic kidney disease.
Imamura, T, Kinugawa, K, Shiga, T, Kato, N, Muraoka, H, Minatsuki, S, Inaba, T, Maki, H, Hatano, M, Yao, A, et al
Circulation journal : official journal of the Japanese Circulation Society. 2013;(2):397-404
Abstract
BACKGROUND A newly-developed vasopressin type 2 receptor antagonist, tolvaptan (TLV), has a unique feature of diuresis, but the response to this drug can be unpredictable. METHODS AND RESULTS Data were collected from hospitalized patients with decompensated congestive heart failure who were administered TLV at 3.75-15 mg/day (n=61). A responder/non-responder to TLV was determined as having any increase/decrease in urine volume (UV) during the next 24h after TLV treatment on the first day. Logistic regression analyses for increases in UV were performed, and independent predictors of the responder were the following: C1, baseline urine osmolality (U-OSM) >352 mOsm/L; and C2, %decrease in U-OSM >26% at 4-6h after TLV administration. Criteria consisting of C1 and C2 had a good predictability for responders by receiver-operating characteristic analysis (area under the curve=0.960). Kidneys of the non-responders no longer had diluting ability (%decrease of U-OSM at 4-6h=2.7 ± 14.6%*), but also barely kept concentrating ability (baseline U-OSM=296.4 ± 68.7*mOsm/L) with markedly reduced estimated glomerular filtration ratio (35.5 ± 29.4 m l · min(-1) · 1.73 m(-2)*) (*P<0.05 vs. patients who had at least 1 positive condition [n=42]). CONCLUSIONS More than 26% decrease in U-OSM from a baseline >352 mOsm/L for the first 4-6h predicts responders to TLV. Unresponsiveness to TLV is attributable to nephrogenic diabetes insipidus complicated by chronic renal disease.