RESUMEN
BACKGROUND: Patients with decompensated cirrhosis experience high mortality rates. Current prognostic scores, including the model for end-stage liver disease (MELD), may underperform in settings other than in those they were initially developed. Novel biomarkers have been proposed to improve prognostication accuracy and even to predict development of complications. METHODS: We performed a systematic review and meta-analysis on novel urine and blood biomarkers and their ability to predict 90-day mortality in patients with decompensated cirrhosis. Secondary outcomes included 28-day and 1-year mortality, and development of acute-on-chronic liver failure, acute kidney injury and other complications. To overcome differences in units, temporal changes in assays and reporting heterogeneity, we used the ratio of means (RoM) as measure of association for assessing strength in predicting outcomes. An RoM>1 implies that the mean biomarker level is higher in those that develop the outcome than in those that do not. RESULTS: Of 6629 unique references, 103 were included, reporting on 29 different biomarkers, with a total of 31 362 biomarker patients. Most studies were prospective cohorts of hospitalised patients (median Child-Pugh-Turcotte score of 9 and MELD score of 18). The pooled 90-day mortality rate was 0.27 (95% CI 0.24 to 0.29). The RoM for predicting 90-day mortality was highest for interleukin 6 (IL-6) (2.56, 95% CI 2.39 to 2.74), followed by urinary neutrophil gelatinase-associated lipocalin (uNGAL) (2.42, 95% CI 2.20 to 2.66) and copeptin (2.33, 95% CI 2.17 to 2.50). These RoMs were all higher than for MELD (1.44, 95% CI 1.42 to 1.46). CONCLUSION: Novel biomarkers, including IL-6, uNGAL and copeptin, can probably improve prognostication of patients with decompensated cirrhosis compared with MELD alone.
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Enfermedad Hepática en Estado Terminal , Cirrosis Hepática , Humanos , Pronóstico , Estudios Prospectivos , Cirrosis Hepática/complicaciones , Interleucina-6 , Índice de Severidad de la Enfermedad , BiomarcadoresRESUMEN
BACKGROUND: The risk factors for hepatic hydrothorax are unknown. METHODS: We used data from three randomized trials of satavaptan treatment in patients with cirrhosis and ascites followed for up to 1 year. We excluded patients with previous hepatic hydrothorax or other causes for pleural effusion. The candidate risk factors were age, sex, heart rate, mean arterial pressure, diuretic-resistant ascites, a recurrent need for paracentesis, diabetes, hepatic encephalopathy, International Normalized Ratio, creatinine, bilirubin, albumin, sodium, platelet count, use of non-selective beta-blockers (NSBBs), spironolactone, furosemide, proton pump inhibitors, and insulin. We identified risk factors using a Fine and Gray regression model and backward selection. We reported subdistribution hazard ratios (sHR) for hepatic hydrothorax. Death without hepatic hydrothorax was a competing risk. RESULTS: Our study included 942 patients, of whom 41 developed hepatic hydrothorax and 65 died without having developed it. A recurrent need for paracentesis (sHR: 2.55, 95% CI: 1.28-5.08), bilirubin (sHR: 1.18 per 10 µmol/l increase, 95% CI: 1.09-1.28), diabetes (sHR: 2.49, 95% CI: 1.30-4.77) and non-use of non-selective beta-blockers (sHR: 2.27, 95% CI: 1.13-4.53) were risk factors for hepatic hydrothorax. Development of hepatic hydrothorax was associated with a high mortality-hazard ratio of 4.35 (95% CI: 2.76-6.97). CONCLUSIONS: In patients with cirrhosis and ascites, risk factors for hepatic hydrothorax were a recurrent need for paracentesis, a high bilirubin, diabetes and non-use of NSBBs. Among these patients with cirrhosis and ascites, development of hepatic hydrothorax increased mortality fourfold.
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Diabetes Mellitus , Hidrotórax , Antagonistas Adrenérgicos beta , Ascitis/etiología , Ascitis/terapia , Bilirrubina , Estudios de Cohortes , Humanos , Hidrotórax/etiología , Hidrotórax/terapia , Cirrosis Hepática/complicaciones , Cirrosis Hepática/terapia , Factores de RiesgoRESUMEN
INTRODUCTION AND OBJECTIVES: Spontaneous bacterial peritonitis (SBP) is a frequent complication to cirrhosis with an unclear long-term prognosis. We aimed to examine its effect on mortality in two independent patient cohorts. PATIENTS AND METHODS: We used Danish healthcare data on cirrhosis patients with a first-time paracentesis in 2000-2014 and data from three randomized controlled trials on satavaptan treatment of ascites conducted in 2006-2008. We used the Kaplan-Meier method to estimate cumulative mortality, and Cox regression to compare the confounder-adjusted mortality hazard for patients with vs. without SBP. RESULTS: In the Danish Healthcare Cohort, we included 1.282 patients of whom 133 (10.4%) had SBP. The SBP patients' cumulative 4-month mortality was 51.2% (95% CI: 43.0-59.9%) vs. 34.7% (95% CI: 32.0-37.6) in those without SBP. The SBP patients' confounder-adjusted mortality hazard was 1.54-fold higher (95% CI: 1.18-2.00) in the four months after paracentesis, but was not increased thereafter (confounder-adjusted mortality hazard 1.02, 95% 0.72-1.46). In the satavaptan trial data of 1,198 cirrhosis patients with ascites, the 93 patients with SBP had a cumulative 4-month mortality of 38.6% (95% CI: 29.3-49.7) compared with 11.4% (95% CI: 8.5-15.2) in those without. The SBP patients' confounder-adjusted mortality hazard ratio was 3.86 (95% CI: 2.44-6.12) during the first four months, and was 1.23 (95% CI: 0.54-2.83) thereafter. CONCLUSIONS: In both cohorts of patients with cirrhosis, an SBP episode had a high short-term mortality compared to patients without SBP, and had no lasting effect on the long-term mortality.
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Infecciones Bacterianas , Peritonitis , Ascitis/etiología , Infecciones Bacterianas/diagnóstico , Infecciones Bacterianas/tratamiento farmacológico , Humanos , Cirrosis Hepática/complicaciones , Cirrosis Hepática/diagnóstico , Peritonitis/diagnóstico , Peritonitis/tratamiento farmacológico , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de RiesgoRESUMEN
Management of decompensated cirrhosis is currently geared towards the treatment of complications once they occur. To date there is no established disease-modifying therapy aimed at halting progression of the disease and preventing the development of complications in patients with decompensated cirrhosis. The design of clinical trials to investigate new therapies for patients with decompensated cirrhosis is complex. The population of patients with decompensated cirrhosis is heterogeneous (i.e., different etiologies, comorbidities and disease severity), leading to the inclusion of diverse populations in clinical trials. In addition, primary endpoints selected for trials that include patients with decompensated cirrhosis are not homogeneous and at times may not be appropriate. This leads to difficulties in comparing results obtained from different trials. Against this background, the LiverHope Consortium organized a meeting of experts, the goal of which was to develop recommendations for the design of clinical trials and to define appropriate endpoints, both for trials aimed at modifying the natural history and preventing progression of decompensated cirrhosis, as well as for trials aimed at managing the individual complications of cirrhosis.
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Ascitis , Encefalopatía Hepática , Hipertensión Portal , Cirrosis Hepática , Calidad de Vida , Prevención Secundaria/métodos , Ascitis/etiología , Ascitis/terapia , Ensayos Clínicos como Asunto , Consenso , Manejo de la Enfermedad , Progresión de la Enfermedad , Determinación de Punto Final , Europa (Continente) , Encefalopatía Hepática/etiología , Encefalopatía Hepática/terapia , Humanos , Hipertensión Portal/etiología , Hipertensión Portal/terapia , Cirrosis Hepática/complicaciones , Cirrosis Hepática/fisiopatología , Cirrosis Hepática/psicología , Cirrosis Hepática/terapia , Proyectos de Investigación , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND & AIMS: Many patients with cirrhosis use proton pump inhibitors. We aimed to determine their effects on the risk and prognosis of infections in patients with cirrhosis and ascites. METHODS: We used data from three 1-year trials of satavaptan treatment of ascites (N = 1198) to compare incidence and 90-day mortality of first-time infections between users and nonusers of proton pump inhibitors. With standard and marginal structural Cox models, we adjusted for differences in gender, age, cirrhosis aetiology, Model for End-stage Liver Disease score, serum albumin, lactulose use, severity of ascites, and history of spontaneous bacterial peritonitis or variceal bleeding. RESULTS: During the follow-up, 446 patients had an infection. At inclusion, 524 patients (44%) used proton pump inhibitors, and 645 (54%) used them at some point during the follow-up. Proton pump inhibitor use increased the rate of infections overall (adjusted hazard ratio = 1.43, 95% CI 1.18-1.74), and it also increased the rate of all specific types of infections except upper respiratory tract infections of presumably viral origin. The estimated cumulative risk of infections was 36.4% for proton pump inhibitor users vs 25.1% for nonusers at 6 months (relative risk = 1.45, 95% CI 1.22-1.73), and 45.2% vs 37.7% at 1 year (relative risk = 1.20, 95% 0.97-1.40). Use of proton pump inhibitors did not affect mortality during the 90 days following infection (adjusted hazard ratio = 0.83, 95% CI 0.53-1.31). CONCLUSIONS: Approximately half of patients with cirrhosis and ascites use proton pump inhibitors. This use increases their risk of bacterial infections, but does not affect their prognosis after an infection occurs.
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Ascitis/tratamiento farmacológico , Infecciones Bacterianas/epidemiología , Cirrosis Hepática/tratamiento farmacológico , Peritonitis/epidemiología , Inhibidores de la Bomba de Protones/efectos adversos , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Ascitis/diagnóstico , Ascitis/mortalidad , Infecciones Bacterianas/diagnóstico , Infecciones Bacterianas/microbiología , Infecciones Bacterianas/mortalidad , Femenino , Humanos , Incidencia , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/mortalidad , Masculino , Persona de Mediana Edad , Morfolinas/uso terapéutico , Estudios Multicéntricos como Asunto , Peritonitis/diagnóstico , Peritonitis/microbiología , Peritonitis/mortalidad , Ensayos Clínicos Controlados Aleatorios como Asunto , Medición de Riesgo , Factores de Riesgo , Compuestos de Espiro/uso terapéutico , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND AND AIM: Hyponatremia, a cause of brain dysfunction and risk factor for hepatic encephalopathy, is frequent in patients with advanced cirrhosis and ascites. The interdependence of liver failure and hyponatremia makes it difficult to separate the effects of each on cognitive function. The objective was to assess whether an increase in plasma sodium in patients with cirrhosis and ascites leads to an improvement in cognitive function. METHODS: This is a post-hoc analysis of 250 cirrhosis patients without overt hepatic encephalopathy randomized to receive either placebo or satavaptan, a vasopressin V2 antagonist. The exposure was plasma sodium, and the outcome was the trail-making test (TMT) parts A and B, which assesses speed of information processing, performed before the study starts and after 14 days. The results were analyzed by initial and change to final sodium concentration. RESULTS: At entry, the patients with normonatremia exhibited better results on both the TMT-A (median 56 vs 77.5 s for patients with sodium ≤ 130 mmol/L [P = 0.0059]) and the TMT-B (median 127 vs 170 s for patients with sodium ≤ 130 mmol/L [P = 0.0066]), unrelated to age. Improvement of hyponatremia was more common in patients who received satavaptan (59.7%) than placebo (18.5%). Correction of hyponatremia did not shorten the simple TMT-A but markedly improved the complex TMT-B by an average of 20 s compared with 6.5 s in those with continuing hyponatremia (P = 0.02). Liver status measures remained stable during the period reported. CONCLUSIONS: These data suggest that improvement of hyponatremia in patients with cirrhosis leads to an increase in the speed of complex information processing.
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Hiponatremia/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Morfolinas/uso terapéutico , Compuestos de Espiro/uso terapéutico , Cognición , Humanos , Masculino , Persona de Mediana Edad , Sodio/sangre , Resultado del TratamientoRESUMEN
BACKGROUND AND AIM: Hyponatremia is associated with development of hepatic encephalopathy (HE), but the nature of the relationship between serum sodium and HE incidence is unknown. We examined the association between serum sodium, changes in serum sodium, and HE incidence using data from three randomized trials of satavaptan in cirrhosis patients with ascites. METHODS: During follow-up, patients were examined for HE, and serum sodium was measured regularly. We used fractional polynomials to estimate the nature of the association between current serum sodium and hazard rate of HE (e.g. with a linear, logarithmic, or exponential slope) and Cox regression to adjust for confounders. Moreover, we examined the association between serum sodium at inclusion and 30-day and 1-year cumulative risk of HE. Finally, we examined the effect of "change in serum sodium since inclusion" on the hazard rate of HE. RESULTS: We included 1116 patients of whom 302 developed HE. Median serum sodium at inclusion was 137 (interquartile range, 134-139). The lower the current serum sodium, the higher the rate of HE. Specifically, the confounder-adjusted HE hazard rate increased linearly by 8% (adjusted hazard ratio = 1.08, 95% confidence interval: 1.06-1.10) for every mmol/L decrease in serum sodium over the range of measured values. Current serum sodium had a stronger effect on the HE rate than the changes in serum sodium since inclusion. CONCLUSION: The hazard rate of HE development increased by 8% for every mmol/L decrease in serum sodium. Further, current serum sodium had a stronger effect on the HE rate than changes in serum sodium.
Asunto(s)
Ascitis/complicaciones , Encefalopatía Hepática/etiología , Cirrosis Hepática/complicaciones , Sodio/sangre , Femenino , Encefalopatía Hepática/epidemiología , Humanos , Hiponatremia/complicaciones , Hiponatremia/epidemiología , Masculino , Persona de Mediana Edad , Ensayos Clínicos Controlados Aleatorios como Asunto , Factores de RiesgoRESUMEN
BACKGROUND & AIMS: Acute episodes of renal dysfunction or acute kidney injury (AKI) in cirrhotic patients with ascites are mostly precipitated by an acute event. The prevalence of un-precipitated AKI in stable ascitic cirrhotic patients is unknown. The aims of this study were to determine (i) the prevalence of un-precipitated AKI in stable cirrhotics with ascites and (ii) any predictive factors for its development. METHODS: A total of 1115 stable cirrhotic patients with mild liver and renal dysfunction but varying degrees of ascites severity from 3 previous satavaptan vs placebo randomized controlled trials (Group A, ascites requiring diuretics but not paracentesis; Group B, ascites requiring frequent paracentesis; Group C, refractory ascites) were included. AKI was diagnosed when there was either an increase of ≥0.3 mg/dL in ≤48 hours or a 50% increase in serum creatinine, and staged according to the fold increase of the serum creatinine. Two serum creatinine levels measured maximally 7 days apart at screening and at randomization of the satavaptan studies with no acute intervening events were used. RESULTS: The prevalence of un-precipitated AKI was 1.8% overall, with the prevalence rising with increasing severity of ascites. Ninety-five per cent of cases were stage 1, with 15% progression rate, 3 reaching the severity of type 1 acute hepatorenal syndrome. Ascites severity was the most powerful predictor for un-precipitated AKI development, which did not predict overall mortality. CONCLUSIONS: Increased prevalence of AKI with more severe ascites despite minimal baseline liver and renal dysfunction suggests that frequent monitoring of renal function in these patients is mandatory.
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Lesión Renal Aguda/etiología , Ascitis/complicaciones , Cirrosis Hepática/complicaciones , Lesión Renal Aguda/diagnóstico , Anciano , Ascitis/terapia , Creatinina/sangre , Diuréticos/uso terapéutico , Femenino , Humanos , Internacionalidad , Cirrosis Hepática/terapia , Masculino , Persona de Mediana Edad , Morfolinas/uso terapéutico , Paracentesis , Pronóstico , Modelos de Riesgos Proporcionales , Índice de Severidad de la Enfermedad , Compuestos de Espiro/uso terapéuticoRESUMEN
UNLABELLED: The safety of nonselective ß-blockers (NSBBs) in advanced cirrhosis has been questioned. We used data from three satavaptan trials to examine whether NSBBs increase mortality in cirrhosis patients with ascites. The trials were conducted in 2006-2008 and included 1198 cirrhosis patients with ascites followed for 1 year. We used Cox regression to compare all-cause mortality and cirrhosis-related mortality between patients who did and those who did not use NSBBs at randomization, controlling for age, gender, Model for End-Stage Liver Disease score, Child-Pugh score, serum sodium, previous variceal bleeding, cirrhosis etiology, and ascites severity. Moreover, we identified clinical events predicting that a patient would stop NSBB treatment. At randomization, the 559 NSBB users were more likely than the 629 nonusers to have a history of variceal bleeding but less likely to have Child-Pugh class C cirrhosis, hyponatremia, or refractory ascites. The 52-week cumulative all-cause mortality was similar in the NSBB user and nonuser groups (23.2% versus 25.3%, adjusted hazard ratio = 0.92, 95% confidence interval 0.72-1.18), and NSBBs also did not increase mortality in the subgroup of patients with refractory ascites (588 patients, adjusted hazard ratio = 1.02, 95% confidence interval 0.74-1.40) or in any other subgroup. Similarly, NSBBs did not increase cirrhosis-related mortality (adjusted hazard ratio = 1.00, 95% confidence interval 0.76-1.31). During follow-up, 29% of initial NSBB users stopped taking NSBBs, and the decision to stop NSBB treatment marked a sharp rise in mortality and coincided with hospitalization, variceal bleeding, bacterial infection, and/or development of hepatorenal syndrome. CONCLUSION: This large and detailed data set on worldwide nonprotocol use of NSBBs in cirrhosis patients with ascites shows that NSBBs did not increase mortality; the decision to stop NSBB treatment in relation to stressful events may have added to the safety. (Hepatology 2016;63:1968-1976).
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Antagonistas Adrenérgicos beta/uso terapéutico , Ascitis/mortalidad , Hemorragia Gastrointestinal/prevención & control , Cirrosis Hepática/mortalidad , Antagonistas de los Receptores de Hormonas Antidiuréticas/uso terapéutico , Ascitis/tratamiento farmacológico , Ascitis/etiología , Femenino , Hemorragia Gastrointestinal/etiología , Humanos , Cirrosis Hepática/complicaciones , Masculino , Persona de Mediana Edad , Morfolinas/uso terapéutico , Compuestos de Espiro/uso terapéuticoRESUMEN
UNLABELLED: Proton pump inhibitors (PPIs) may be a risk factor for hepatic encephalopathy (HE) in patients with cirrhosis, possibly through translocation of gut bacteria, which can also lead to spontaneous bacterial peritonitis (SBP). We examined the associations between PPIs and development of HE or SBP in patients with cirrhosis with ascites. We used data from three 1-year trials of satavaptan for ascites control. We used Cox regression to compare HE and SBP rates between users and nonusers of PPIs. At inclusion, 39% of the 865 patients with cirrhosis with ascites used PPIs, 52% used them at some point during the follow-up, and the proportion of current users was always in the 30%-39% range. There were 189 first-time HE episodes during the follow-up, and the cumulative 1-year risk was 31% for those who used PPIs at baseline versus 25% for those who did not. The confounder-adjusted hazard ratio (HR) of HE for current PPI use versus current nonuse was 1.36 (95% confidence interval [CI], 1.01-1.84). The HR for overt HE was higher (adjusted HR = 1.88; 95% CI, 1.21-1.91). During the follow-up, 86 patients developed SBP. The adjusted HR of SBP for current PPI users versus nonusers was 1.72 (95% CI, 1.10-2.69). CONCLUSION: PPIs were used by 52% of this international cirrhosis cohort during a 1-year period and was a risk factor for developing HE and SBP. These findings are consistent with the hypothesis that PPIs may increase translocation of gut bacteria. (Hepatology 2016;64:1265-1272).
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Infecciones Bacterianas/inducido químicamente , Encefalopatía Hepática/inducido químicamente , Peritonitis/inducido químicamente , Peritonitis/microbiología , Inhibidores de la Bomba de Protones/efectos adversos , Anciano , Ascitis/complicaciones , Ascitis/tratamiento farmacológico , Femenino , Humanos , Cirrosis Hepática/complicaciones , Masculino , Persona de Mediana Edad , Inhibidores de la Bomba de Protones/uso terapéutico , Factores de RiesgoRESUMEN
BACKGROUND: Epilepsy is associated with an increased mortality among cirrhosis patients, but the reasons are unknown. We aimed to determine whether epilepsy is a risk factor for developing hepatic encephalopathy (HE), which is a strong predictor of mortality. METHODS: We used data from three randomized 1-year trials of satavaptan in cirrhosis patients with ascites. With Cox regression, we compared the hazard rates of HE grade 1-4 between those cirrhosis patients who did or did not have epilepsy. We adjusted for confounding by gender, age, cirrhosis etiology, diabetes, history of HE, Model for Endstage Liver Disease (MELD) score, serum sodium, albumin, lactulose use, rifaximin use, and benzodiazepine/barbiturate sedation. In a supplementary analysis we examined the association between epilepsy and the hazard rate of HE grade 2-4. RESULTS: Of the 1120 cirrhosis patients with ascites, 21 (1.9 %) were diagnosed with epilepsy. These patients had better liver function at inclusion than the patients without epilepsy (median MELD score 7.9 vs. 11.4), and only one died during the trials. Nevertheless, seven patients with epilepsy had an HE episode during the follow-up, and the adjusted hazard ratio of HE grade 1-4 for patients with epilepsy vs. controls was 2.12 (95 % CI 0.99-4.55). The corresponding hazard ratio of HE grade 2-4 was 3.83 (95 % CI 1.65-8.87). CONCLUSIONS: Our findings suggest that epilepsy is associated with an increased risk of HE in patients with cirrhosis.
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Epilepsia/complicaciones , Encefalopatía Hepática/complicaciones , Cirrosis Hepática/complicaciones , Ascitis/complicaciones , Femenino , Encefalopatía Hepática/etiología , Humanos , Cirrosis Hepática/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Factores de RiesgoRESUMEN
BACKGROUND & AIMS: It remains unclear whether diabetes increases the risk for hepatic encephalopathy (HE) in cirrhotic patients. We examined this question using data from three randomized trials of satavaptan, a vasopressin receptor antagonist that does not affect HE risk, in cirrhotic patients with ascites. METHODS: The trials included 1198 patients, and we excluded those with HE before or at randomization and followed the remaining patients for the one year duration of the trials. They were examined for HE regularly, and we compared rates of first-time overt HE between diabetics and non-diabetic patients using Cox regression, adjusting for gender, age, ascites severity, cirrhosis etiology, Child-Pugh class, creatinine, bilirubin, INR, sodium, potassium, albumin, platelets, lactulose use, benzodiazepine/barbiturate use, spironolactone dose, furosemide dose, potassium-sparing diuretic dose, and CirCom comorbidity score. RESULTS: We included 862 patients of whom 193 (22%) had diabetes. In total, they experienced 115 first-time episodes of overt HE during the follow-up. Fewer diabetics than non-diabetic patients were in Child-Pugh class C at baseline (13% vs. 23%), yet they had higher cumulative risk of first-time overt HE (26.0% vs. 15.8% after 1 year), and their episodes of first-time overt HE were more likely to progress beyond grade 2 (64% vs. 42% of episodes progressed to grade 3 or 4, p=0.01 for independence between diabetes and highest HE grade). After the confounder adjustment, the hazard ratio of first-time overt HE for diabetics vs. non-diabetic patients was 1.86 (95% CI 1.20-2.87). CONCLUSIONS: Diabetes increased the risk of first-time overt HE among cirrhotic patients with ascites.
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Diabetes Mellitus/epidemiología , Encefalopatía Hepática/etiología , Cirrosis Hepática/complicaciones , Morfolinas/administración & dosificación , Medición de Riesgo/métodos , Compuestos de Espiro/administración & dosificación , Anciano , Antagonistas de los Receptores de Hormonas Antidiuréticas/administración & dosificación , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Francia/epidemiología , Encefalopatía Hepática/tratamiento farmacológico , Encefalopatía Hepática/epidemiología , Humanos , Incidencia , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/epidemiología , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Tasa de Supervivencia/tendencias , Factores de TiempoRESUMEN
The aim of this study was to investigate upper body muscle activity during a 30 s Wingate test. Eighteen physically active participants performed a Wingate test while muscle activity was recorded from the brachioradialis (BR), biceps brachii (BB), triceps brachii (TB) and upper trapezius (UT). Measurements were obtained at rest, during a function maximal contraction (FMC) and during the 30 s Wingate test, whilst participants were positioned in a seated position on the cycle ergometer. All muscles were significantly active for the duration of the test. When normalized as a %FMC no differences in activity were found between muscles. Across the 30 s, power output was found to significantly decrease, whereas no changes were found in upper body muscle activity. All muscles investigated were active during the Wingate test and therefore confirmed previous findings that the upper body significantly contributes to power profiles obtained during high intensity cycle ergometry in addition to its role in stabilizing the body.
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Electromiografía , Ergometría/métodos , Contracción Muscular/fisiología , Músculo Esquelético/fisiología , Adulto , Femenino , Humanos , Masculino , Adulto JovenRESUMEN
BACKGROUND: Sodium and water retention is a mainstay of the pathophysiology leading to ascites formation in patients with advanced cirrhosis. Refractory ascites denotes the most severe ascites status with limited treatment options and a poor prognosis. We investigated the efficacy and safety of the natriuretic peptide ularitide in patients with refractory cirrhotic ascites. METHODS: We conducted a randomized placebo-controlled trial investigating ularitide to manage refractory ascites. Until trial termination after interim analyses, we randomized 17 participants in a 2:1 ratio between ularitide (n=11) and placebo (n=6). While hospitalized, the participants received treatment for up to 48 hours. The primary efficacy endpoint was a change in renal water excretion, and secondary end points included changes in renal sodium excretion rate and body weight. The starting dose was 30 ng/kg/min, though later reduced to 20 for safety reasons. RESULTS: In contrast to the study hypothesis, the mean urine production decreased after 24 hours of ularitide treatment compared with the baseline level (22.8 vs. 47.5 mL/h, p=0.04) and decreased more in participants randomized to ularitide than placebo (24.7 vs. -6.2 mL/h, p=0.05). Ularitide did not increase the renal sodium excretion rate or reduce the weight gain. The incidence rate ratio of adverse reactions in ularitide versus placebo was 8.5 (95% CI: 2-35, p=0.003). Participants treated with ularitide developed serious blood pressure reductions, impacting their renal responsiveness. CONCLUSIONS: Ularitide in doses of 20-30 ng/kg/min did not benefit urine production and renal sodium excretion rate in patients with refractory ascites. The participants randomized to ularitide overall developed more adverse reactions than placebo. EudraCT no. 2019-002268-28.
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Ascitis , Cirrosis Hepática , Humanos , Masculino , Ascitis/tratamiento farmacológico , Ascitis/etiología , Cirrosis Hepática/complicaciones , Cirrosis Hepática/tratamiento farmacológico , Femenino , Persona de Mediana Edad , Resultado del Tratamiento , Método Doble Ciego , Anciano , Adulto , Sodio/orinaRESUMEN
Satavaptan, a vasopressin V2-receptor antagonist, has been shown to improve hyponatraemia in patients with cirrhosis. Hyponatraemia has been associated with an increased risk of hepatic encephalopathy. The objective is to evaluate the efficacy of satavaptan in reducing the risk of new episodes of hepatic encephalopathy. 1,200 patients with cirrhosis and uncomplicated ascites were included in three randomised double-blind studies comparing satavaptan (5-10 mg/day) vs placebo over a one-year treatment period. Effects on incidence of hepatic encephalopathy episodes in individual study and pooled databases were determined with analyses adjusted for hyponatraemia and previous episodes of encephalopathy. Hyponatraemia was improved by satavaptan. Three hundred and ninety-five hepatic encephalopathy episodes were recorded. The risk of an episode and the mean number of episodes were not reduced by satavaptan in any of the three studies in the overall population or in patients who were hyponatraemic on entry. These findings were confirmed in analysis of the pooled data. Satavaptan did not reduce the frequency of hepatic encephalopathy in patients with cirrhosis and ascites.
Asunto(s)
Antagonistas de los Receptores de Hormonas Antidiuréticas , Ascitis/tratamiento farmacológico , Encefalopatía Hepática/tratamiento farmacológico , Cirrosis Hepática/tratamiento farmacológico , Morfolinas/uso terapéutico , Compuestos de Espiro/uso terapéutico , Encefalopatía Hepática/etiología , Humanos , Estimación de Kaplan-Meier , Cirrosis Hepática/complicaciones , Estudios Multicéntricos como Asunto , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de Investigación , Análisis de SupervivenciaRESUMEN
OBJECTIVE: Satavaptan, a vasopressin V2 receptor antagonist, has been shown to improve the control of ascites in cirrhosis in short-term phase II studies. The aim of this study was to evaluate the efficacy and safety of satavaptan in three different populations of patients with cirrhosis and ascites. METHODS: 1200 patients were included in three randomised double-blind studies comparing satavaptan with placebo in uncomplicated ascites (study 1: n=463 patients) and difficult-to-treat ascites, with and without concomitant diuretic treatment (studies 2 and 3: n=497 and n=240 patients, respectively). RESULTS: Satavaptan was not more effective than placebo in the control of ascites in any of the populations studied as estimated by the primary efficacy endpoints: worsening of ascites (study 1) and the cumulative number of large-volume paracenteses during 12 weeks (studies 2 and 3). Nevertheless, some of the secondary efficacy endpoints related to the treatment of ascites were met in the three studies, suggesting a slight advantage of satavaptan over placebo in delaying ascites formation. Moreover, satavaptan was more effective than placebo in improving the serum sodium concentration in patients with hyponatraemia. The incidence of major complications of cirrhosis during follow-up did not differ significantly between the satavaptan and placebo groups in the three studies. Overall, the rate of any treatment-related adverse events, serious treatment-related events and treatment-related events leading to permanent discontinuation of treatment did not differ significantly between the treatment groups. However, in study 2 mortality was higher in patients treated with satavaptan compared with placebo (HR 1.47; 95% CI 1.01 to 2.15); no significant differences in mortality between the two groups were observed in the other two studies. No specific cause for the increased mortality was identified. Most deaths were associated with known complications of liver cirrhosis. CONCLUSION: Satavaptan, alone or in combination with diuretics, is not clinically beneficial in the long-term management of ascites in cirrhosis.
Asunto(s)
Antagonistas de los Receptores de Hormonas Antidiuréticas , Ascitis/tratamiento farmacológico , Cirrosis Hepática/complicaciones , Morfolinas/uso terapéutico , Compuestos de Espiro/uso terapéutico , Anciano , Ascitis/etiología , Ascitis/prevención & control , Diuréticos/uso terapéutico , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Estimación de Kaplan-Meier , Cirrosis Hepática/mortalidad , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Prevención Secundaria , Resultado del TratamientoRESUMEN
Background and Aims: Previous studies have not been able to determine whether non-selective beta-blockers (NSBB) reduce the risk of sepsis in cirrhosis. We aimed to examine this question with data from 1198 patients with cirrhosis and ascites included in clinical studies of satavaptan, a vasopressin receptor antagonist with no effect on infection risk. Methods: Risk of sepsis was estimated for NSBB users vs nonusers. Patients were examined every four weeks, or in relation to hospitalization, for the one-year duration of the trials. We computed the cumulative risk of sepsis for patients who did vs did not use NSBB at baseline. We used Cox regression to compare hazard rates of sepsis between current users and nonusers, accounting for changes in NSBB use over time. We adjusted for patient sex and age, MELD-Na score, albumin, use of antibiotics, use of proton pump inhibitors, cirrhosis etiology, history of variceal bleeding or SBP, severity of ascites and HE, HCC, other cancers, and diabetes, while stratifying on geographical region. Results: Of the 1198 patients, 54% used NSBB at some time. There were 56 sepsis episodes. The 1-year risk of sepsis was reduced to 5.7% (95% confidence interval [CI] 2.8-8.6) in baseline NSBB users vs 11.6% (95% CI 7.0-15.9) in baseline nonusers. The hazard ratio of sepsis for current NSBB users vs current nonusers was reduced to 0.5 (95% CI 0.3-0.8) and after adjustment to 0.7 (95% CI 0.4-1.3). Conclusion: NSBB use may reduce the risk of sepsis in patients with cirrhosis and ascites, but the precision of the estimate was limited by the number of episodes of sepsis.