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Hannes Hagstrom - One of the best experts on this subject based on the ideXlab platform.
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risk of cancer in biopsy proven alcohol related Liver Disease a population based cohort study of 3410 persons
Clinical Gastroenterology and Hepatology, 2021Co-Authors: Maja Thiele, Hannes Hagstrom, Bjorn Roelstraete, Jonas Soderling, Rajani Sharma, Tracey G Simon, Jonas F LudvigssonAbstract:Abstract Background & Aims Persons with Alcohol-Related Liver Disease (ALD) are at an increased risk of death and Liver-related endpoints, but the association with incident cancer is not well understood, and whether it differs across histopathological subgroups is undefined. Methods We investigated the risk of cancer in 3,410 persons with a diagnosis of ALD and an available Liver biopsy in Sweden between 1969-2016, compared to a matched reference population. Administrative coding from national registers and Liver biopsy data were used to define exposure and outcome status. Competing risk regression, adjusted for available confounders and using non-cancer mortality as the competing risk, was used to estimate subdistribution hazard ratios (sHRs) for incident cancer. Results At baseline, persons with ALD had a median age of 58.2 years, 67% were men, and 2,042 (60%) had cirrhosis. ALD was not associated with cancer in general (sHR=1.01, 95%CI=0.92-1.11), although the risk was increased in persons surviving ≥1 year (sHR=1.19, 95%CI=1.08-1.32). The risk of Liver cancer was elevated sHR=12.80, 95%CI=9.38-17.45). HCC incidence among ALD persons with cirrhosis was 8.6 cases/1,000 person-years, corresponding to a cumulative incidence after 10 years of 5.0%. Conclusions Persons with biopsy-proven ALD that survive the initial time after diagnosis are at an elevated risk for cancer, in particular HCC compared with the general population. Although the risk for HCC was elevated, data do not suggest that routine surveillance for HCC in ALD cirrhosis is cost-effective.
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mortality in biopsy proven alcohol related Liver Disease a population based nationwide cohort study of 3453 patients
Gut, 2021Co-Authors: Maja Thiele, Hannes Hagstrom, Bjorn Roelstraete, Jonas Soderling, Jonas F LudvigssonAbstract:Objective Patients with Alcohol-Related Liver Disease (ALD) are at increased risk of death, but studies have rarely investigated the significance of histological severity or estimated relative risks compared with a general population. We examined mortality in a nationwide cohort of biopsy-proven ALD. Design Population-based cohort study in Sweden comparing 3453 individuals with an International Classification of Disease (ICD) code for ALD and a Liver biopsy from 1969 to 2017 with 16 535 matched general population individuals. Swedish national registers were used to ascertain overall and Disease-specific mortality, starting follow-up at the latest of first ICD diagnosis or Liver biopsy plus 3 months. Cox regression adjusted for relevant confounders was used to estimate HRs in ALD and histopathological subgroups. Results Median age at diagnosis was 58 years, 65% were men and 52% had cirrhosis at baseline. Five-year cumulative mortality was 40.9% in patients with ALD compared with 5.8% in reference individuals. The risk for overall mortality was significantly increased (adjusted HR (aHR)=4.70, 95% CI 4.35 to 5.08). The risk of Liver-related death was particularly high (43% of all deaths, aHR=167.6, 95% CI 101.7 to 276.3). Mortality was significantly increased also in patients with ALD without cirrhosis and was highest in the first year after baseline but persisted after ≥10 years of follow-up (aHR=2.74, 95% CI 2.37 to 3.16). Conclusion Individuals with biopsy-proven ALD have a near fivefold increased risk of death compared with the general population. Individuals with ALD without cirrhosis were also at increased risk of death, reaffirming the need to increase vigilance in the management of these individuals.
Maja Thiele - One of the best experts on this subject based on the ideXlab platform.
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prognostic performance of seven biomarkers compared to Liver biopsy in early alcohol related Liver Disease
Journal of Hepatology, 2021Co-Authors: Maja Thiele, Ditlev Nytoft Rasmussen, Stine Johansen, Maria Kjaergaard, Katrine Lindvig, Mads IsraelsenAbstract:ABSTRACT Background & aims Alcohol is the most common cause of Liver-related mortality and morbidity. We therefore aimed to assess and compare the prognostic performance of elastography and blood-based markers to predict time to the first Liver-related event, severe infection, and all-cause mortality in patients with a history of excess drinking. Methods Prospective cohort study of patients with early, compensated Alcohol-Related Liver Disease. At baseline, we obtained a Liver biopsy, transient elastography (TE), 2-dimensional shear-wave elastography (2D-SWE), enhanced Liver fibrosis test (ELF), FibroTest, fibrosis-4 index (FIB-4), non-alcoholic fatty Liver fibrosis score (NFS) and Forns index. We compared C-statistics and time-dependent area under the receiver operating characteristics curve for prognostication. We used validated cut-points to create three risk groups for each test: low, intermediate and high risk. Results We followed 462 patients for a median of 49 months (IQR 31-70). Median age was 57 years, 76% were males, 20% had advanced fibrosis. Eighty-four patients (18%) developed a Liver-related event after a median of 18 months (7-34). TE had the highest prognostic accuracy, with a C-statistic of 0.876, and time-dependent AUC at 5 years of 0.889, comparable to 2D-SWE and ELF. TE, ELF and 2D-SWE outperformed FibroTest, FIB4, NFS, Forns index and biopsy-verified fibrosis stage. Compared to patients with TE 15 kPa. Periods of excessive drinking during follow-up increased the risk of progressing to Liver-related events, except for patients in the low-risk groups. Conclusion TE, ELF and 2D-SWE are highly accurate prognostic markers in patients with Alcohol-Related Liver Disease. Easy-to-use cut-offs can distinguish between substantially different risk profiles. Lay Summary Alcohol is the leading cause of death and illness due to Liver Disease. Years of excessive drinking cause the Liver to accumulate scar tissue in some people. This scarring, Liver fibrosis, may ultimately lead to cirrhosis, a condition that is associated with poor survival and poor quality of life. We undertook a study to develop biomarkers for predicting the risk of developing symptomatic Liver Disease in patients with early stages of Alcohol-Related Liver Disease. We found that several tests accurately predicted the risk of Liver-related events such as ascites, esophageal varices and hepatic encephalopathy during an average follow-up of 4.1 years. Liver stiffness measurements by ultrasound elastography and the enhanced Liver fibrosis test performed best. By using them, we were able to stratify patients into three groups with significantly different risks.
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risk of cancer in biopsy proven alcohol related Liver Disease a population based cohort study of 3410 persons
Clinical Gastroenterology and Hepatology, 2021Co-Authors: Maja Thiele, Hannes Hagstrom, Bjorn Roelstraete, Jonas Soderling, Rajani Sharma, Tracey G Simon, Jonas F LudvigssonAbstract:Abstract Background & Aims Persons with Alcohol-Related Liver Disease (ALD) are at an increased risk of death and Liver-related endpoints, but the association with incident cancer is not well understood, and whether it differs across histopathological subgroups is undefined. Methods We investigated the risk of cancer in 3,410 persons with a diagnosis of ALD and an available Liver biopsy in Sweden between 1969-2016, compared to a matched reference population. Administrative coding from national registers and Liver biopsy data were used to define exposure and outcome status. Competing risk regression, adjusted for available confounders and using non-cancer mortality as the competing risk, was used to estimate subdistribution hazard ratios (sHRs) for incident cancer. Results At baseline, persons with ALD had a median age of 58.2 years, 67% were men, and 2,042 (60%) had cirrhosis. ALD was not associated with cancer in general (sHR=1.01, 95%CI=0.92-1.11), although the risk was increased in persons surviving ≥1 year (sHR=1.19, 95%CI=1.08-1.32). The risk of Liver cancer was elevated sHR=12.80, 95%CI=9.38-17.45). HCC incidence among ALD persons with cirrhosis was 8.6 cases/1,000 person-years, corresponding to a cumulative incidence after 10 years of 5.0%. Conclusions Persons with biopsy-proven ALD that survive the initial time after diagnosis are at an elevated risk for cancer, in particular HCC compared with the general population. Although the risk for HCC was elevated, data do not suggest that routine surveillance for HCC in ALD cirrhosis is cost-effective.
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mortality in biopsy proven alcohol related Liver Disease a population based nationwide cohort study of 3453 patients
Gut, 2021Co-Authors: Maja Thiele, Hannes Hagstrom, Bjorn Roelstraete, Jonas Soderling, Jonas F LudvigssonAbstract:Objective Patients with Alcohol-Related Liver Disease (ALD) are at increased risk of death, but studies have rarely investigated the significance of histological severity or estimated relative risks compared with a general population. We examined mortality in a nationwide cohort of biopsy-proven ALD. Design Population-based cohort study in Sweden comparing 3453 individuals with an International Classification of Disease (ICD) code for ALD and a Liver biopsy from 1969 to 2017 with 16 535 matched general population individuals. Swedish national registers were used to ascertain overall and Disease-specific mortality, starting follow-up at the latest of first ICD diagnosis or Liver biopsy plus 3 months. Cox regression adjusted for relevant confounders was used to estimate HRs in ALD and histopathological subgroups. Results Median age at diagnosis was 58 years, 65% were men and 52% had cirrhosis at baseline. Five-year cumulative mortality was 40.9% in patients with ALD compared with 5.8% in reference individuals. The risk for overall mortality was significantly increased (adjusted HR (aHR)=4.70, 95% CI 4.35 to 5.08). The risk of Liver-related death was particularly high (43% of all deaths, aHR=167.6, 95% CI 101.7 to 276.3). Mortality was significantly increased also in patients with ALD without cirrhosis and was highest in the first year after baseline but persisted after ≥10 years of follow-up (aHR=2.74, 95% CI 2.37 to 3.16). Conclusion Individuals with biopsy-proven ALD have a near fivefold increased risk of death compared with the general population. Individuals with ALD without cirrhosis were also at increased risk of death, reaffirming the need to increase vigilance in the management of these individuals.
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a paired Liver biopsy and plasma proteomics study reveals circulating biomarkers for alcohol related Liver Disease
bioRxiv, 2020Co-Authors: Maja Thiele, Ditlev Nytoft Rasmussen, Lili Niu, Philipp E Geyer, Henry Webel, Alberto Santos, Rajat Gupta, Florian Meier, Maximilian T StraussAbstract:Existing tests for detecting Liver fibrosis, inflammation and steatosis, three stages of Liver Disease that are still reversible are severely hampered by limited accuracy or invasive nature. Here, we present a paired Liver-plasma proteomics approach to infer molecular pathophysiology and to identify biomarkers in a cross-sectional Alcohol-Related Liver Disease cohort of nearly 600 individuals. Metabolic functions were downregulated whereas fibrosis-associated signaling and novel immune responses were upregulated, but only half of tissue proteome changes were transmitted to the circulation. Machine learning models based on our biomarker panels outperformed existing tests, laying the foundation for a generic proteomic Liver health assessment.
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transient elastography for screening of Liver fibrosis cost effectiveness analysis from six prospective cohorts in europe and asia
Journal of Hepatology, 2019Co-Authors: Miquel Serraburriel, I N Guha, Isabel Graupera, Pere Toran, Maja Thiele, Dominique Roulot, Vincent Waisun Wong, Nuria Fabrellas, A ArslanowAbstract:Background & Aims Non-alcoholic fatty Liver Disease and Alcohol-Related Liver Disease pose an important challenge to current clinical healthcare pathways because of the large number of at-risk patients. Therefore, we aimed to explore the cost-effectiveness of transient elastography (TE) as a screening method to detect Liver fibrosis in a primary care pathway. Methods Cost-effectiveness analysis was performed using real-life individual patient data from 6 independent prospective cohorts (5 from Europe and 1 from Asia). A diagnostic algorithm with conditional inference trees was developed to explore the relationships between Liver stiffness, socio-demographics, comorbidities, and hepatic fibrosis, the latter assessed by fibrosis scores (FIB-4, NFS) and Liver biopsies in a subset of 352 patients. We compared the incremental cost-effectiveness of a screening strategy against standard of care alongside the numbers needed to screen to diagnose a patient with fibrosis stage ≥F2. Results The data set encompassed 6,295 participants (mean age 55 ± 12 years, BMI 27 ± 5 kg/m2, Liver stiffness 5.6 ± 5.0 kPa). A 9.1 kPa TE cut-off provided the best accuracy for the diagnosis of significant fibrosis (≥F2) in general population settings, whereas a threshold of 9.5 kPa was optimal for populations at-risk of Alcohol-Related Liver Disease. TE with the proposed cut-offs outperformed fibrosis scores in terms of accuracy. Screening with TE was cost-effective with mean incremental cost-effectiveness ratios ranging from 2,570 €/QALY (95% CI 2,456–2,683) for a population at-risk of Alcohol-Related Liver Disease (age ≥45 years) to 6,217 €/QALY (95% CI 5,832–6,601) in the general population. Overall, there was a 12% chance of TE screening being cost saving across countries and populations. Conclusions Screening for Liver fibrosis with TE in primary care is a cost-effective intervention for European and Asian populations and may even be cost saving. Lay summary The lack of optimized public health screening strategies for the detection of Liver fibrosis in adults without known Liver Disease presents a major healthcare challenge. Analyses from 6 independent international cohorts, with transient elastography measurements, show that a community-based risk-stratification strategy for Alcohol-Related and non-alcoholic fatty Liver Diseases is cost-effective and potentially cost saving for our healthcare systems, as it leads to earlier identification of patients.
Jonas F Ludvigsson - One of the best experts on this subject based on the ideXlab platform.
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risk of cancer in biopsy proven alcohol related Liver Disease a population based cohort study of 3410 persons
Clinical Gastroenterology and Hepatology, 2021Co-Authors: Maja Thiele, Hannes Hagstrom, Bjorn Roelstraete, Jonas Soderling, Rajani Sharma, Tracey G Simon, Jonas F LudvigssonAbstract:Abstract Background & Aims Persons with Alcohol-Related Liver Disease (ALD) are at an increased risk of death and Liver-related endpoints, but the association with incident cancer is not well understood, and whether it differs across histopathological subgroups is undefined. Methods We investigated the risk of cancer in 3,410 persons with a diagnosis of ALD and an available Liver biopsy in Sweden between 1969-2016, compared to a matched reference population. Administrative coding from national registers and Liver biopsy data were used to define exposure and outcome status. Competing risk regression, adjusted for available confounders and using non-cancer mortality as the competing risk, was used to estimate subdistribution hazard ratios (sHRs) for incident cancer. Results At baseline, persons with ALD had a median age of 58.2 years, 67% were men, and 2,042 (60%) had cirrhosis. ALD was not associated with cancer in general (sHR=1.01, 95%CI=0.92-1.11), although the risk was increased in persons surviving ≥1 year (sHR=1.19, 95%CI=1.08-1.32). The risk of Liver cancer was elevated sHR=12.80, 95%CI=9.38-17.45). HCC incidence among ALD persons with cirrhosis was 8.6 cases/1,000 person-years, corresponding to a cumulative incidence after 10 years of 5.0%. Conclusions Persons with biopsy-proven ALD that survive the initial time after diagnosis are at an elevated risk for cancer, in particular HCC compared with the general population. Although the risk for HCC was elevated, data do not suggest that routine surveillance for HCC in ALD cirrhosis is cost-effective.
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mortality in biopsy proven alcohol related Liver Disease a population based nationwide cohort study of 3453 patients
Gut, 2021Co-Authors: Maja Thiele, Hannes Hagstrom, Bjorn Roelstraete, Jonas Soderling, Jonas F LudvigssonAbstract:Objective Patients with Alcohol-Related Liver Disease (ALD) are at increased risk of death, but studies have rarely investigated the significance of histological severity or estimated relative risks compared with a general population. We examined mortality in a nationwide cohort of biopsy-proven ALD. Design Population-based cohort study in Sweden comparing 3453 individuals with an International Classification of Disease (ICD) code for ALD and a Liver biopsy from 1969 to 2017 with 16 535 matched general population individuals. Swedish national registers were used to ascertain overall and Disease-specific mortality, starting follow-up at the latest of first ICD diagnosis or Liver biopsy plus 3 months. Cox regression adjusted for relevant confounders was used to estimate HRs in ALD and histopathological subgroups. Results Median age at diagnosis was 58 years, 65% were men and 52% had cirrhosis at baseline. Five-year cumulative mortality was 40.9% in patients with ALD compared with 5.8% in reference individuals. The risk for overall mortality was significantly increased (adjusted HR (aHR)=4.70, 95% CI 4.35 to 5.08). The risk of Liver-related death was particularly high (43% of all deaths, aHR=167.6, 95% CI 101.7 to 276.3). Mortality was significantly increased also in patients with ALD without cirrhosis and was highest in the first year after baseline but persisted after ≥10 years of follow-up (aHR=2.74, 95% CI 2.37 to 3.16). Conclusion Individuals with biopsy-proven ALD have a near fivefold increased risk of death compared with the general population. Individuals with ALD without cirrhosis were also at increased risk of death, reaffirming the need to increase vigilance in the management of these individuals.
Suzanne M. De La Monte - One of the best experts on this subject based on the ideXlab platform.
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therapeutic reversal of chronic alcohol related steatohepatitis with the ceramide inhibitor myriocin
International Journal of Experimental Pathology, 2014Co-Authors: Ming Tong, Lisa Longato, Teresa Ramirez, Valerie Zabala, Jack R. Wands, Suzanne M. De La MonteAbstract:Alcohol-Related Liver Disease (ALD) is associated with steatohepatitis and insulin resistance. Insulin resistance impairs growth and disrupts lipid metabolism in hepatocytes. Dysregulated lipid metabolism promotes ceramide accumulation and oxidative stress, leading to lipotoxic states that activate endoplasmic reticulum (ER) stress pathways and worsen inflammation and insulin resistance. In a rat model of chronic alcohol feeding, we characterized the effects of a ceramide inhibitor, myriocin, on the histopathological and ultrastructural features of steatohepatitis, and the biochemical and molecular indices of hepatic steatosis, insulin resistance and ER stress. Myriocin reduced the severity of Alcohol-Related steatohepatitis including the abundance and sizes of lipid droplets and mitochondria, inflammation and architectural disruption of the ER. In addition, myriocin-mediated reductions in hepatic lipid and ceramide levels were associated with constitutive enhancement of insulin signalling through the insulin receptor and IRS-2, reduced hepatic oxidative stress and modulation of ER stress signalling mechanisms. In conclusion, ceramide accumulation in Liver mediates tissue injury, insulin resistance and lipotoxicity in ALD. Reducing hepatic ceramide levels can help restore the structural and functional integrity of the Liver in chronic ALD due to amelioration of insulin resistance and ER stress. However, additional measures are needed to protect the Liver from alcohol-induced necroinflammatory responses vis-a-vis continued alcohol abuse.
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ceramide inhibitor myriocin restores insulin insulin growth factor signaling for Liver remodeling in experimental alcohol related steatohepatitis
Journal of Gastroenterology and Hepatology, 2013Co-Authors: Diana Lizarazo, Ming Tong, Lisa Longato, Valerie Zabala, Suzanne M. De La MonteAbstract:Background and Aim Alcohol-Related Liver Disease (ALD) is mediated in part by insulin resistance. Attendant dysregulation of lipid metabolism increases accumulation of hepatic ceramides that worsen insulin resistance and compromise the structural and functional integrity of the Liver. Insulin and insulin growth factor (IGF) stimulate aspartyl-asparaginyl-β-hydroxylase (AAH), which promotes cell motility needed for structural maintenance and remodeling of the Liver. AAH mediates its effects by activating Notch, and in ALD, insulin/IGF signaling, AAH, and Notch are inhibited. Method To test the hypothesis that in ALD, hepatic ceramide load contributes to impairments in insulin, AAH, and Notch signaling, control and chronic ethanol-fed adult Long–Evans rats were treated with myriocin, an inhibitor of serine palmitoyl transferase. Livers were used to assess steatohepatitis, insulin/IGF pathway activation, and expression of AAH–Notch signaling molecules. Results Chronic ethanol-fed rats had steatohepatitis with increased ceramide levels; impairments in signaling through the insulin receptor, insulin receptor substrate, and Akt; and decreased expression of AAH, Notch, Jagged, Hairy–Enhancer of Split-1, hypoxia-inducible factor 1α, and proliferating cell nuclear antigen. Myriocin abrogated many of these adverse effects of ethanol, particularly hepatic ceramide accumulation, steatohepatitis, and impairments of insulin signaling through Akt, AAH, and Notch. Conclusions In ALD, the histopathology and impairments in insulin/IGF responsiveness can be substantially resolved by ceramide inhibitor treatments, even in the context of continued chronic ethanol exposure.
Thierry Gustot - One of the best experts on this subject based on the ideXlab platform.
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long term outcomes in patients with decompensated alcohol related Liver Disease steatohepatitis and maddrey s discriminant function 32
Journal of Hepatology, 2020Co-Authors: Delphine Degre, Rudolf E Stauber, Gael Englebert, Francesca Sarocchi, Laurine Verset, F Rainer, Walter Spindelboeck, Hassane Njimi, Eric Trepo, Thierry GustotAbstract:Background & Aims Patients with alcoholic hepatitis and a modified Maddrey's discriminant function (mDF) Methods We studied patients from 2 centers who were admitted for hepatic decompensation (ascites, hepatic encephalopathy, or jaundice) and who had histological findings of steatohepatitis and an mDF Results One hundred and twenty-one patients were included (male: 64%, mean age: 51.5 ± 10.3 years, presence of cirrhosis: 84%). The median model for end-stage Liver Disease and mDF scores were 14 (IQR 11.7–16.1) and 19 (IQR 11.1–24), respectively. During follow-up, 30% of the patients remained abstinent. Survival rates at 1, 6, 12, 24, and 60 months were 96.7 ± 1.6%, 90.1 ± 2.7%, 80.8 ± 3.6%, 69.9 ± 4.3%, and 50.7 ± 4.9%, respectively. The majority of deaths (80%) were Liver related. In multivariable analysis, encephalopathy at baseline and alcohol abstinence were predictive of 5-year survival. The 5-year survival rates of patients without and with encephalopathy at baseline were 60.5 ± 5.8% and 29.7 ± 8.0%, respectively, and the 5-year survival rates of abstinent and non-abstinent patients were 74.0 ± 8.0% and 40.9 ± 5.8%, respectively. Conclusions The mortality rate of patients with alcoholic hepatitis and an mDF Lay summary Patients with alcoholic hepatitis that is of intermediate severity have a low risk of short-term mortality but not much is known regarding long-term outcomes for these patients. This study clearly indicates that patients with intermediate Disease characteristics have poor long-term outcomes. The presence of hepatic encephalopathy at the time of diagnosis and the absence of alcohol abstinence during follow-up are factors that predict poor long-term mortality.
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acute on chronic Liver failure in patients with alcohol related Liver Disease
Journal of Hepatology, 2019Co-Authors: Thierry Gustot, Rajiv JalanAbstract:The spectrum of Alcohol-Related Liver Diseases (ALD) includes steatosis, steatohepatitis, progressive Liver fibrosis, and cirrhosis. Acute-on-chronic Liver failure (ACLF) is a recently defined entity that occurs in patients with chronic Liver Diseases and is characterised by acute decompensation, organ failures and a high risk of short-term mortality. Active alcohol consumption, alcoholic hepatitis and bacterial infections are the most frequent events precipitating the development of ACLF in the context of ALD (ALD-ACLF). The specific management of this entity remains unknown and the place of salvage Liver transplantation controversial. This overview details the current knowledge on specific aspects of epidemiology, pathophysiology, prognosis and management of ALD-ACLF.
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sepsis in alcohol related Liver Disease
Journal of Hepatology, 2017Co-Authors: Thierry Gustot, Alexandre Louvet, Javier J M Fernandez, Gyongyi Szabo, Agustin Albillos, Rajiv Jalan, Richard Moreau, Christophe MorenoAbstract:Alcohol-Related Liver Disease (ALD) remains the most important cause of death due to alcohol. Infections, particularly bacterial infections, are one of the most frequent and severe complications of advanced ALDs, such as alcoholic cirrhosis and severe alcoholic hepatitis (sAH). The specific mechanisms responsible for this altered host defence are yet to be deciphered. The aim of the present study is to review the current knowledge of infectious complications in ALD and its pathophysiological mechanisms, distinguishing the role of alcohol consumption and the contribution of different forms of ALD. To date, corticosteroids are the only treatment with proven efficacy in sAH, but their impact on the occurrence of infections remains controversial. The combination of an altered host defence and corticosteroid treatment in sAH has been suggested as a cause of opportunistic fungal and viral infections. A high level of suspicion with systematic screening and prompt, adequate treatment are warranted to improve outcomes in these patients. Prophylactic or preemptive strategies in this high-risk population might be a preferable option, because of the high short-term mortality rate despite adequate therapies. However, these strategies should be assessed in well-designed trials before clinical implementation.