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A systematic review of known interventions for the treatment of chronic nonhypovolaemic hypotonic hyponatraemia and a meta-analysis of the vaptans.
Bhandari, S, Peri, A, Cranston, I, McCool, R, Shaw, A, Glanville, J, Petrakova, L, O'Reilly, K
Clinical endocrinology. 2017;(6):761-771
Abstract
International and national guidelines on the treatment of chronic nonhypovolaemic hypotonic hyponatraemia differ; therefore, we have undertaken this systematic review and meta-analysis to investigate the efficacy and safety of interventions for the treatment of chronic nonhypovolaemic hypotonic hyponatraemia. Following registration of the review protocol with PROSPERO, systematic literature searches were conducted to identify randomized and quasi-randomized controlled trials assessing any degree of fluid restriction or any drug treatment with the aim of increasing serum sodium concentration in patients with chronic nonhypovolaemic hypotonic hyponatraemia. Where appropriate, outcome data were synthesized in a meta-analysis. A total of 45 716 bibliographic records were identified from the searches and 18 trials (assessing conivaptan, lixivaptan, tolvaptan and satavaptan) met the eligibility criteria. Results suggest that all four vasopressin receptor agonists ("vaptans") significantly improve serum sodium concentration. Lixivaptan, satavaptan and tolvaptan were associated with greater rates of response versus placebo. There was no evidence of a difference between each of the vaptans compared with placebo for mortality, discontinuation and rates of hypernatraemia. No RCT evidence of treatments other than the vaptans for hyponatraemia such as oral urea, salt tablets, mannitol, loop diuretics demeclocycline or lithium was identified. Vaptans demonstrated superiority over placebo for outcomes relating to serum sodium correction. Few trials documented the potential benefit of vaptans on change in health-related quality of life as a result of treatment. There was also a lack of high-quality RCT evidence on the comparative efficacy of the vaptans and other treatment strategies for the treatment of chronic nonhypovolaemic hypotonic hyponatraemia.
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The Efficacy and Safety of Tolvaptan in Patients with Hyponatremia: A Meta-Analysis of Randomized Controlled Trials.
Li, B, Fang, D, Qian, C, Feng, H, Wang, Y
Clinical drug investigation. 2017;(4):327-342
Abstract
BACKGROUND AND OBJECTIVES 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. METHODS Pertinent studies were identified by searching PubMed, EMBASE, Web of Science, and the Cochrane Library for articles published between their respective inception dates and 31 April 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. RESULTS 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 = 3.99 mEq/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 = 987.64 mL, 95 % CI 850.71-1124.57, Z = 14.14, P < 0.001), and improving net fluid balance (WMD = 795.97 mL, 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 = 0.1 mmHg, 95 % CI -1.04 to 1.23, Z = 0.17, P = 0.87), or heart rate (WMD = -0.16 bpm, 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. CONCLUSION 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.
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Mineralocorticoid responsive hyponatremia of the elderly: A systematic review.
Katayama, K, Tokuda, Y
Medicine. 2017;(27):e7154
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Abstract
BACKGROUND Mineralocorticoid responsive hyponatremia of the elderly (MRHE) is an emerging concept of hyponatremia in aged people. Diagnosis of MRHE requires exclusion of syndrome of inappropriate antidiuresis and adrenal dysfunction. Thus we aimed to evaluate the characteristics of all patients with suspected MRHE available for a review. METHODS We conducted a systematic review using MEDLINE and Google scholar. We included published case reports of adult patients diagnosed as MRHE, written by English and Japanese language. Serum and urine electrolytes as well as the levels of antidiuretic hormone (ADH), cortisol, plasma renin activity (PRA), and aldosterone were analyzed. RESULTS A total of 27 MRHE patients were identified in 9 reports. In these patients, average age was 79 years, median serum sodium was 117 mEq/L. The median levels of ADH, cortisol, PRA, and aldosterone were 0.9 pg/mL, 18.7 μg/dL, 0.37 ng/mL/h, and 39.6 pg/mL, respectively. Water restriction test was conducted in 7 patients. Random sample cortisol measurements did not exceed satisfactory levels to rule out adrenal dysfunction in four cases. No cases underwent low-dose adrenocorticotropic hormone stimulation test. Only 27 patients from 9 case reports in Japanese were eligible for inclusion in our study. CONCLUSION All published cases of MRHE as a cause of hyponatremia are described for the first time. In these cases, latent adrenal sufficiency might have been hidden and should have been excluded.
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The Economic Burden of Hyponatremia: Systematic Review and Meta-Analysis.
Corona, G, Giuliani, C, Parenti, G, Colombo, GL, Sforza, A, Maggi, M, Forti, G, Peri, A
The American journal of medicine. 2016;(8):823-835.e4
Abstract
BACKGROUND Hyponatremia is the most common electrolyte abnormality observed in clinical practice. Several studies have demonstrated that hyponatremia is associated with an increased length of hospital stay and of hospital resource utilization. To clarify the impact of hyponatremia on the length of hospitalization and costs, we performed a meta-analysis based on published studies that compared hospital length of stay and cost between patients with and without hyponatremia. METHODS An extensive Medline, Embase, and Cochrane search was performed to retrieve all studies published up to April 1, 2015 using the following words: "hyponatremia" or "hyponatraemia" AND "hospitalization" or "hospitalisation." A meta-analysis was performed including all studies comparing duration of hospitalization and hospital readmission rate in subjects with and without hyponatremia. RESULTS Of 444 retrieved articles, 46 studies satisfied the inclusion criteria, encompassing a total of 3,940,042 patients; among these, 757,763 (19.2%) were hyponatremic. Across all studies, hyponatremia was associated with a significantly longer duration of hospitalization (3.30 [2.90-3.71; 95% CIs] mean days; P < .000). Similar results were obtained when patients with associated morbidities were analyzed separately. Furthermore, hyponatremic patients had a higher risk of readmission after the first hospitalization (odds ratio 1.32 [1.18-1.48; 95% CIs]; P < .000). A meta-regression analysis showed that the hyponatremia-related length of hospital stay was higher in males (Slope = 0.09 [0.05-0.12; 95% CIs]; P = .000 and Intercept = -1.36 [-3.03-0.32; 95% CIs]; P = .11) and in elderly patients (Slope = 0.002 [0.001-0.003; 95% CIs]; P < .000 and Intercept = 0.89 [0.83-0.97; 95% CIs]; P < .001). A negative association between serum [Na(+)] cutoff and duration of hospitalization was detected. No association between duration of hospitalization, serum [Na(+)], and associated morbidities was observed. Finally, when only US studies (n = 8) were considered, hyponatremia was associated with up to around $3000 higher hospital costs/patient when compared with the cost of normonatremic subjects. CONCLUSIONS This meta-analysis confirms that hyponatremia is associated with a prolonged hospital length of stay and higher risk of readmission. These observations suggest that hyponatremia may represent one important determinant of the hospitalization costs.
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Association Between Hyponatremia, Osteoporosis, and Fracture: A Systematic Review and Meta-analysis.
Upala, S, Sanguankeo, A
The Journal of clinical endocrinology and metabolism. 2016;(4):1880-6
Abstract
CONTEXT Hyponatremia is the most common electrolyte disorder. Recent research shows that it may associate with osteoporosis and fracture. However, whether it directly associates or is a surrogate marker of other causes is still unclear. OBJECTIVES To explore the hypothesis of an association of osteoporosis or fracture with hyponatremia. DATA SOURCES MEDLINE and EMBASE databases from inception to October 2015. STUDY SELECTION The inclusion criteria were published studies evaluating bone mineral density, risk or prevalence of osteoporosis or fracture in patients with hyponatremia. DATA EXTRACTION Both authors independently reviewed titles and abstracts of all citations that were identified. DATA SYNTHESIS A meta-analysis using a random-effects model comparing between hyponatremia and normal serum sodium groups was performed. We calculated pooled mean difference in bone mineral density, pooled hazard ratio (HR) or odds ratio (OR) of fracture and osteoporosis. Factors that may predict these associations were evaluated in subgroup analysis and meta-regression. From 29 full-text articles, 15 observational studies involving 212 889 participants met our inclusion criteria. Twelve studies were included in the meta-analysis. There was a significant association with fracture and osteoporosis in patients with hyponatremia with OR of fracture = 1.99 (95% confidence interval, 1.50–2.63; p < .001) for studies that reported OR, and increase risk of fracture with HR = 1.62 (95% confidence interval, 1.28–2.05; P < .001) for studies that reported HR. CONCLUSIONS Hyponatremia significantly associates with osteoporosis and fracture. More prospective studies evaluating osteoporosis and fracture risk reduction after hyponatremia correction should be performed.
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Short-term efficacy and safety of vasopressin receptor antagonists for treatment of hyponatremia.
Jaber, BL, Almarzouqi, L, Borgi, L, Seabra, VF, Balk, EM, Madias, NE
The American journal of medicine. 2011;(10):977.e1-9
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Abstract
BACKGROUND We performed a meta-analysis to systematically measure efficacy and safety of vasopressin receptor antagonists (VRAs) tested in randomized controlled trials for treatment of hyponatremia. METHODS MEDLINE, ClinicalTrials.gov, and scientific abstracts were searched without language restriction. Two authors independently screened citations and extracted data on patient characteristics, quality of reports, and efficacy and safety endpoints. RESULTS Eleven trials were identified (1094 patients). By meta-analysis, VRAs achieved a net increase in serum sodium concentration ([Na(+)](serum)) relative to placebo of 3.3 mEq/L at day 1 (95% confidence interval [CI], 2.7-3.8), and 4.2 mEq/L at day 2 (95% CI, 3.6-4.8), persisting at days 3-5. Larger net increases in [Na(+)](serum) at days 1-4 were observed in euvolemic hyponatremia and with higher doses. VRAs induced a net increase in effective water clearance relative to placebo of 1244 mL at day 1 (95% CI, 920-1567), persisting at days 2 and 4. VRAs were associated with odds ratios of 3.0 for overly rapid correction of [Na(+)](serum) (P <.001), 7.8 for development of hypernatremia (P <.001), 3.3 for thirst development (P <.001), and 2.2 for postural hypotension (P=.04). CONCLUSIONS Short-term use of VRAs in treating hyponatremia was successful at raising [Na(+)](serum). Additional experience is required to guide their optimal use and minimize safety concerns.
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Vasopressin receptor antagonists for the treatment of hyponatremia: systematic review and meta-analysis.
Rozen-Zvi, B, Yahav, D, Gheorghiade, M, Korzets, A, Leibovici, L, Gafter, U
American journal of kidney diseases : the official journal of the National Kidney Foundation. 2010;(2):325-37
Abstract
BACKGROUND In patients with euvolemic and hypervolemic hyponatremia, the effect of vasopressin antagonists is yet undefined. STUDY DESIGN Systematic review and meta-analysis of randomized controlled trials (RCTs). SETTING & POPULATION In- and outpatients with euvolemic or hypervolemic hyponatremia. SELECTION CRITERIA FOR STUDIES We included all RCTs regardless of publication status or language. INTERVENTION Vasopressin antagonists with or without fluid restriction versus placebo or no treatment with or without fluid restriction. OUTCOMES Response rate defined as normalization of serum sodium level or significant increase in serum sodium level at 3-7 days (primary) and later, change from baseline serum sodium level at 3-7 days and later, adverse events, rate of rapid sodium level correction, and rate of hypernatremia. RESULTS 15 RCTs were identified. Vasopressin antagonist treatment significantly increased response rate both early (RR, 3.15; 95% CI, 2.27-4.37; 11 trials) and late (RR, 2.27; 95% CI, 1.79-2.89; 4 trials). Response rates were high in trials assessing mostly euvolemic patients and those assessing mostly hypervolemic patients, with greater effect estimate in the former. Change from baseline serum sodium level was significantly increased both early (weighted mean difference, 5.27 mEq/L; 95% CI, 4.27-6.26, 13 trials) and late (weighted mean difference, 3.49 mEq/L; 95% CI, 2.56-4.41, 8 trials). Although there was an increased rate of rapid sodium correction (RR, 2.52; 95% CI, 1.26-5.08, 8 trials) with vasopressin antagonists, hypernatremia rates were not significantly higher (RR, 2.21; 95% CI, 0.61-7.96; 5 trials), adverse events were not increased, and there were no reports of osmotic demyelination syndrome. LIMITATIONS Significant heterogeneity in the primary outcome. CONCLUSIONS Vasopressin antagonists are effective for the treatment of hypervolemic and euvolemic hyponatremia.