Nonselective beta-blockers in cirrhotic patients with no or small varices:A meta-analysis

AIM:To explore effects of nonselective beta-blockers(NSBBs) in cirrhotic patients with no or small varices.METHODS:The Pub Med,EMBASE,Science Direct,and Cochrane library databases were searched for relevant papers.A meta-analysis was performed using ORs with 95%CI as the effect sizes.Subgroup analysis was conducted according to the studies including patients without varices and those with small varices.RESULTS:Overall,784 papers were initially retrieved from the database searches,of which six randomized controlled trials were included in the meta-analysis.The incidences of large varices development(OR = 1.05,95%CI:0.25-4.36;P = 0.95),first upper gastrointestinal bleeding(OR = 0.59,95%CI:0.24-1.47;P = 0.26),and death(OR = 0.70,95%CI:0.45-1.10;P = 0.12) were similar between NSBB and placebo groups.However,the incidence of adverse events was significantly higher in the NSBB group compared with the placebo group(OR = 3.47,95%CI:1.45-8.33;P = 0.005).The results of subgroup analyses were similar to those of overall analyses.CONCLUSION:The results of this meta-analysis indicate that NSBBs should not be recommended for cirrhotic patients with no or small varices.

Beta-blockers and physical frailty in patients with endstage liver disease

AIM To investigate beta-blocker(BB) use in patients with cirrhosis and determine their effects on physical frailty and overall survival.METHODS Adult outpatients with cirrhosis listed for liver transplantation underwent testing of physical frailty using the performance-based Liver Frailty Index, comprised of chair stands, grip strength, and balance testing, as well as self-reported assessments of exhaustion and physical activity. BB use was assessed from medical chart review. Univariable and multivariable logistic regression were performed to determine BB use and their association with measures of physical frailty. Competing risk analyses were performed to determine the effect of BB use on wait-list mortality, as defined by death or delisting for being too sick for transplant.RESULTS Of 344 patients, 35% were female, median age was 60, median model for end stage liver disease was 15, and 53% were prescribed a BB. Compared to those not on BB, patients on BB were similar except for percentage female(25% vs 46%; P < 0.001) and BMI(29 vs 28; P = 0.008). With respect to tests of physical frailty, BB use was not associated with increased odds of frailty(by the Liver Frailty Index), exhaustion, or low physical activity. BB use was, however, significantly associated with a decreased adjusted risk of mortality(SHR 0.55; P = 0.005).CONCLUSION In patients with cirrhosis awaiting liver transplantation, BB use is not associated with physical frailty. We confirmed the known survival benefits with BB use, and concerns about adverse effects should not deter their utilization when indicated.

Beta-blockers and 1-year clinical outcomes in hospitalized heart failure patients with atrial fibrillation

OBJECTIVE To assess the association between beta-blockers and 1-year clinical outcomes in heart failure(HF)patients with atrial fibrillation(AF),and further explore this association that differs by left ventricular ejection fraction(LVEF)level.METHODS We enrolled hospitalized HF patients with AF from China Patient-centered Evaluative Assessment of Cardiac Events Prospective Heart Failure Study.COX proportional hazard regression models were employed to calculate hazard ratio of betablockers.The primary outcome was all-cause death.RESULTS Among 1762 HF patients with AF(756 women[41.4%]),1041(56%)received beta-blockers at discharge and 1272(72.2%)had an LVEF>40%.During one year follow up,all-cause death occurred in 305(17.3%),cardiovascular death occurred in203 patients(11.5%),and rehospitalizations for HF occurred in 622 patients(35.2%).After adjusting for demographic characteristics,social economic status,smoking status,medical history,anthropometric characteristics,and medications used at discharge,the use of beta-blockers at discharge was not associated with all-cause death[hazard ratio(HR):0.86;95%Confidence Interval(CI):0.65-1.12;P=0.256],cardiovascular death(HR:0.76,95%CI:0.52-1.11;P=0.160),or the composite outcome of all-cause death and HF rehospitalization(HR:0.97,95%CI:0.82-1.14;P=0.687)in the entire cohort.There were no significant interactions between use of beta-blockers at discharge and LVEF with respect to all-cause death,cardiovascular death,or composite outcome.In the adjusted models,the use of beta-blockers at discharge was not associated with all-cause death,cardiovascular death,or composite outcome across the different levels of LVEF:reduced(<40%),mid-range(40%-49%),or preserved LVEF(≥50%).CONCLUSION Among HF patients with AF,the use of beta-blockers at discharge was not associated with 1-year clinical outcomes,regardless of LVEF.

Minimising non-selective defects in ultrathin reduced graphene oxide membranes with graphene quantum dots for enhanced water and NaCl separation

Reduced graphene oxide(rGO)membranes have been intensively evaluated for desalination and ionic sieving applications,benefiting from their stable and well-confined interlayer channels.However,rGO membranes generally suffer from low permeability due to the high transport resistance resulting from the narrowed two-dimensional(2D)channels.Although high permeability can be realized by reducing membrane thickness,membrane selectivity normally declines because of the formation of nonselective defects,in particular pinholes.In this study,we demonstrate that the non-selective defects in ultrathin rGO membranes can be effectively minimised by a facile posttreatment via surfacedeposition of graphene quantum dots(GQDs).The resultant GQDs/rGO membranes obtained a good trade-off between water permeance(14 L·m^(-2)·h^(-1).MPa^(-1))and NaCl rejection(91%).This work provides new insights into the design of high quality ultrathin 2D laminar membranes for desalination,molecular/ionic sieving and other separation applications.

Analysis of Beta-blockers in Doping Control

A retiabte and sensitive method is developed for the detection of β-blockers which are excreted in free or conjugated forms in human urine.9 β-blockers were derivatized by MSTFA and MBTFA and subjected to GC/MSB analysis.Both chromato- grams and mass spectrometric data were obtained from full scanning mode.This method is suitable for routine screening and confirmation of β-blockers in doping control.

Non-Selective SiGe Graphic Epitaxial by MBE

To handle the thermal budget in SiGe BiCMOS process, a non-selective graphic epitaxial technology using molecular beam epitaxial （MBE） has been developed. SEM, AFM, XRD, and dislocation density measurements are carried out. The SiGe film＇s RMS roughness is 0.45nm, and dislocation density is 0.3×10^3cm^-2-1.2×10^3cm^-2. No dislocation accumulation exists on the boundary of the windows; this indicates the high quality of the SiGe film. The experiment results show that the technology presented in this paper meets the fabrication requirements of SiGe BiCMOS.

Research Progress in Preparation of Oxidized Cellulose

Cellulose is the most abundant natural polymer material in the world.Cellulose is diffi-cult to dissolve because it contains a large number of inter molecular hydrogen bonds.Therefore,the modification of natural cellulose by chemical oxidation can expand its application field.The oxidation process of cellulose is focused on,the oxidation methods and research progress of cellulose are introduced,and further development direction of oxidized cellulose is prospected.

Long-term clinical outcome between beta-blocker with ACEI or ARB in patients with NSTEMI who underwent PCI with drug-eluting stents

Background Because limited comparative data are available,we decided to compare 2-year major clinical outcomes between beta-blockers (BB) with angiotensin converting enzyme inhibitors (ACEI) and BB with angiotensin receptor blockers (ARB) therapy in patients with non-ST-segment elevation myocardial infarction (NSTEMI) after percutaneous coronary intervention (PCI) with drug-eluting stents (DES).Methods A total 11,288 NSTEMI patients who underwent PCI with DES were enrolled and they were divided into two groups,the BB with ACEI group (n = 7600) and the BB with ARB group (n = 3688).The major clinical endpoint was the occurrence of major adverse cardiac events (MACE) defined as all-cause death,recurrent myocardial infarction (re-MI),total revascularization [target lesion revascularization (TLR),target vessel revascularization (TVR),non-TVR] rate during the 2-year follow-up period.Results After propensity score-matched (PSM) analysis,two PSM groups (3317 pairs,n = 6634,C-statistic = 0.695) were generated.Although the cumulative incidences of all-cause death,cardiac death,TLR,and non-TVR were similar between the two groups,MACE (HR = 0.832,95% CI: 0.704?0.982,P = 0.030),total revascularization rate (HR = 0.767,95% CI: 0.598?0.984,P = 0.037),and TVR rate (HR = 0.646,95% CI: 0.470?0.888,P = 0.007) were significantly lower in the BB with ACEI group after PSM.Conclusions In this study,we suggest that the combination of BB with ACEI may be beneficial for reducing the cumulative incidences of MACE,total revascularization rate,and TVR rather than the BB with ARB after PCI with DES in NSTEMI patients.

Beta-blocker therapy in elderly patients with renal dysfunction and heart failure

OBJECTIVE To assess the role of beta-blockers(BB)in patients with chronic kidney disease(CKD)aged≥75 years.METHODS AND RESULTS From January 2008 to July 2014,we included 390 consecutive patients≥75 years of age with ejection fraction≤35%and glomerular filtration rate(GFR)≤60 m L/min per 1.73 m^2.We analyzed the relationship between treatment with BB and mortality or cardiovascular events.The mean age of our population was 82.6±4.1 years.Mean ejection fraction was 27.9%±6.5%.GFR was 60-45 m L/min per 1.73 m^2 in 50.3%of patients,45-30 m L/min per 1.73 m^2 in 37.4%,and<30 m L/min per 1.73 m^2 in 12.3%.At the conclusion of follow-up,67.4%of patients were receiving BB.The median follow-up was28.04(IR:19.41-36.67)months.During the study period,211 patients(54.1%)died and 257(65.9%)had a major cardiovascular event(death or hospitalization for heart failure).BB use was significantly associated with a reduced risk of death(HR=0.51,95%CI:0.35-0.74;P<0.001).Patients receiving BB consistently showed a reduced risk of death across the different stages of CKD:stage IIIa(GFR=30-45 m L/min per 1.73 m^2;HR=0.47,95%CI:0.26-0.86,P<0.0001),stage IIIb(GFR 30-45 m L/min per 1.73 m^2;HR=0.55,95%CI:0.26-1.06,P=0.007),and stages IV and V(GFR<30 m L/min per 1.73 m~2;HR=0.29,95%CI:0.11-0.76;P=0.047).CONCLUSIONS The use of BB in elderly patients with HFr EF and renal impairment was associated with a better prognosis.Use of BB should be encouraged when possible.

Is heart rate reduction more important than target dose in chronic heart failure therapy with a beta-blocker?

1 Introduction Beta-adrenoceptor blocking agents(beta-blockers)are now well established as cornerstone therapy in patients with systolic chronic heart failure(CHF).[1]Clinical data have overwhelmingly proven the beneficial effects of beta-blocker therapy in terms of improving patient prognosis,decreasing requirements for hospitalization,and postponing disease progression.[2-4]However,it remains unclear what the optimal efficacious and safe dose for an individual patient with CHF is,and whether this can simply be inferred from the target dose for each beta-blocking agent as used in the major clinical trials.

Discharge heart rate and future events among Japanese patients with acute heart failure receiving beta-blocker therapy

Background: Randomized trials have demonstrated the efficacy of beta-blockers (BBs) in heart failure (HF) patients. We sought to assess the impact of BBs on long-term outcome;in particular, we assessed the association between outcome and BB dose and discharge heart rate. Methods and Results: Prescriptions for dispensed medication and outcomes were identified from a prospective, single-institution HF registry. Long-term prognosis was compared between users and non-users of BBs. BB users were further divided into 2 groups based on dose (full and non-full dose) and discharge heart rate (70 bpm was significantly associated with impaired long-term outcome (HR = 1.872, P = 0.04). Conclusions: Optimizing heart rate, rather than maximizing BB dose, appears to be an appropriate treatment strategy for the beta-sensitive Japanese population.

Evolution of care in cirrhosis: Preventing hepatic decompensation through pharmacotherapy

Cirrhosis is a leading cause of morbidity and mortality,impacting more than 120 million people worldwide.Although geographic differences exist,etiologic factors such as alcohol use disorder,chronic viral hepatitis infections,and non-alcoholic fatty liver disease are prevalent in nearly every region.Historically,significant effort has been devoted to modifying these risks to prevent disease progression.Nevertheless,more than 11%of patients with compensated cirrhosis experience hepatic decompensation each year.This transition signifies the most important prognostic factor in the natural history of the disease,corresponding to a decline in median survival to below 2 years.Over the past decade,the need for pharmacotherapies aimed at reducing the risk for hepatic decompensation has been emphasized,and non-selective beta-blockers have emerged as the most effective option to date.However,a critical therapeutic gap still exists,and additional therapies have been proposed,including statins,rifaximin,and sodium-glucose cotransporter-2 inhibitors.Based on the results of innovative retrospective analyses and small-scale prospective trials,these pharmacotherapies represent promising options,but further studies,including randomized controlled trials,are necessary before they can be incorporated into clinical use.This report highlights the potential impact of these agents and others in preventing hepatic decompensation and discusses how this paradigm shift may pave the way for guideline-directed medical therapy in cirrhosis.

Is it time to replace propranolol with carvedilol for portal hypertension?

Beta-adrenergic receptor antagonists(β-blockers) have been well established for use in portal hypertension for more than three decades. Different Non-selective β-blockers like propranolol, nadolol, timolol, atenolol, metoprolol and carvedilol have been in clinical practice in patients with cirrhosis. Carvedilol has proven 2-4 times more potent than propranolol as a beta-receptor blocker in trials conducted testing its efficacy for heart failure. Whether the same effect extends to its potency in the reduction of portal venous pressures is a topic of on-going debate. The aim of this review is to compare the hemodynamic and clinical effects of carvedilol with propranolol, and attempt assess whether carvedilol can be used instead of propranolol in patients with cirrhosis. Carvedilol is a promising agent among the beta blockers of recent time that has shown significant effects in portal hypertension hemodynamics. It has also demonstrated an effective profile in its clinical application specifically for the prevention of variceal bleeding. Carvedilol has more potent desired physiological effects when compared to Propranolol. However, it is uncertain at the present juncture whether the improvement in hemodynamics also translates into a decreased rate of disease progression and complications when compared to propranolol. Currently Carvedilol shows promise as a therapy for portal hypertension but more clinical trials need to be carried out before we can consider it as a superior option and a replacement for propranolol.

Current and future pharmacological therapies for managing cirrhosis and its complications

Due to the restrictions of liver transplantation,complication-guided pharmacological therapy has become the mainstay of long-term management of cirrhosis.This article aims to provide a complete overview of pharmacotherapy options that may be commenced in the outpatient setting which are available for managing cirrhosis and its complications,together with discussion of current controversies and potential future directions.PubMed/Medline/Cochrane Library were electronically searched up to December 2018 to identify studies evaluating safety,efficacy and therapeutic mechanisms of pharmacological agents in cirrhotic adults and animal models of cirrhosis.Non-selective betablockers effectively reduce variceal re-bleeding risk in cirrhotic patients with moderate/large varices,but appear ineffective for primary prevention of variceal development and may compromise renal function and haemodynamic stability in advanced decompensation.Recent observational studies suggest protective,haemodynamically-independent effects of beta-blockers relating to reduced bacterial translocation.The gut-selective antibiotic rifaximin is effective for secondary prophylaxis of hepatic encephalopathy;recent small trials also indicate its potential superiority to norfloxacin for secondary prevention of spontaneous bacterial peritonitis.Diuretics remain the mainstay of uncomplicated ascites treatment,and early trials suggest alpha-adrenergic receptor agonists may improve diuretic response in refractory ascites.Vaptans have not demonstrated clinical effectiveness in treating refractory ascites and may cause detrimental complications.Despite initial hepatotoxicity concerns,safety of statin administration has been demonstrated in compensated cirrhosis.Furthermore,statins are suggested to have protective effects upon fibrosis progression,decompensation and mortality.Evidence as to whether proton pump inhibitors cause gut-liver-brain axis dysfunction is conflicting.Emerging evidence indicates that anticoagulation therapy reduces incidence and increases recanalisation rates of non-malignant portal vein thrombosis,and may impede hepatic fibrogenesis and decompensation.Pharmacotherapy for cirrhosis should be implemented in accordance with up-to-date guidelines and in conjunction with aetiology management,nutritional optimisation and patient education.

Nonselective β-blockers may induce development of portal vein thrombosis in cirrhosis

Currently, nonselective β-blockers(NSBBs) are commonly used for the prevention of variceal bleeding in liver cirrhosis. The beneficial effects of NSBBs are primarily attributed to the reduction in cardiac output by blockade of β1 receptors and vasoconstriction of the splanchnic circulation by the blockade of β2 receptors. The prognostic value of occlusive portal vein thrombosis(PVT) in cirrhotic patients has been increasingly recognized. The most important risk factor for the development of PVT in liver cirrhosis is the decreased portal vein inflow velocity. Collectively, we propose that the use of NSBBs potentially increases the development of portal vein thrombosis by reducing portal vein inflow velocity. The hypothesis should be confirmed by prospective cohort studies, in which cirrhotic patients without prior PVT treated with and without NSBBs are enrolled, and the development of PVT during followup is compared between the two groups. Additionally,subgroup analyses should be performed according to the dosage of NSBBs and the reduction of portal inflow velocity after use of NSBBs.

Portal hypertension and gastrointestinal bleeding:Diagnosis,prevention and management

Bleeding from esophageal varices is a life threatening complication of portal hypertension.Primary prevention of bleeding in patients at risk for a first bleeding episode is therefore a major goal.Medical prophylaxis consists of non-selective beta-blockers like propranolol or carvedilol.Variceal endoscopic band ligation is equally effective but procedure related morbidity is a drawback of the method.Therapy of acute bleeding is based on three strategies:vasopressor drugs like terlipressin,antibiotics and endoscopic therapy.In refractory bleeding,self-expandable stents offer an option for bridging to definite treatments like transjugular intrahepatic portosystemic shunt(TIPS).Treatment of bleeding from gastric varices depends on vasopressor drugs and on injection of varices with cyanoacrylate.Strategies for primary or secondary prevention are based on non-selective beta-blockers but data from large clinical trials is lacking.Therapy of refractory bleeding relies on shuntprocedures like TIPS.Bleeding from ectopic varices,portal hypertensive gastropathy and gastric antral vascular ectasia-syndrome is less common.Possible medical and endoscopic treatment options are discussed.

Cardiovascular drugs in the treatment of infantile hemangioma

Since the introduction of propranolol in the treatment of complicated infantile hemangiomas(IH) in 2008, other different beta-blockers, including timolol, acetabutolol, nadolol and atenolol, have been successfully used for the same purpose. Various hypotheses including vasoconstriction, inhibition of angiogenesis and the induction of apoptosis in proliferating endothelial cells have been advanced as the potential beta-blockerinduced effect on the accelerated IH involution, although the exact mechanism of action of beta-blockers remains unknown. This has generated an extraordinary interest in IH research and has led to the discovery of the role of the renin-angiotensin system(RAS) in the biology of IH, providing a plausible explanation for the beta-blocker induced effect on IH involution and the development of new potential indications for RAS drugs such as angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers in the treatment of IH. This review is focused on the current use of cardiovascular drugs in the treatment of IH.

Clinical algorithms for the prevention of variceal bleeding and rebleeding in patients with liver cirrhosis

Portal hypertension(PH),a common complication of liver cirrhosis,results in development of esophageal varices.When esophageal varices rupture,they cause significant upper gastrointestinal bleeding with mortality rates up to 20%despite state-of-the-art treatment.Thus,prophylactic measures are of utmost importance to improve outcomes of patients with PH.Several high-quality studies have demonstrated that non-selective beta blockers(NSBBs)or endoscopic band ligation(EBL)are effective for primary prophylaxis of variceal bleeding.In secondary prophylaxis,a combination of NSBB+EBL should be routinely used.Once esophageal varices develop and variceal bleeding occurs,standardized treatment algorithms should be followed to minimize bleeding-associated mortality.Special attention should be paid to avoidance of overtransfusion,early initiation of vasoconstrictive therapy,prophylactic antibiotics and early endoscopic therapy.Pre-emptive transjugular intrahepatic portosystemic shunt should be used in all Child C10-C13 patients experiencing variceal bleeding,and potentially in Child B patients with active bleeding at endoscopy.The use of carvedilol,safety of NSBBs in advanced cirrhosis(i.e.with refractory ascites)and assessment of hepatic venous pressure gradient response to NSBB is discussed.In the present review,we give an overview on the rationale behind the latest guidelines and summarize key papers that have led to significant advances in the field.

Cirrhotic portal hypertension: From pathophysiology to novel therapeutics

Portal hypertension and bleeding from gastroesophageal varices is the major cause of morbidity and mortality in patients with cirrhosis. Portal hypertension is initiated by increased intrahepatic vascular resistance and a hyperdynamic circulatory state. The latter is characterized by a high cardiac output, increased total blood volume and splanchnic vasodilatation, resulting in increased mesenteric blood flow. Pharmacological manipulation of cirrhotic portal hypertension targets both the splanchnic and hepatic vascular beds. Drugs such as angiotensin converting enzyme inhibitors and angiotensin Ⅱ type receptor 1 blockers, which target the components of the classical renin angiotensin system(RAS), are expected to reduce intrahepatic vascular tone by reducing extracellular matrix deposition and vasoactivity of contractile cells and thereby improve portal hypertension. However, these drugs have been shown to produce significant offtarget effects such as systemic hypotension and renal failure. Therefore, the current pharmacological mainstay in clinical practice to prevent variceal bleeding and improving patient survival by reducing portal pressure is non-selective-blockers(NSBBs). These NSBBs work by reducing cardiac output and splanchnic vasodilatation but most patients do not achieve an optimal therapeutic response and a significant proportion of patients are unable to tolerate these drugs.Although statins, used alone or in combination with NSBBs, have been shown to improve portal pressure and overall mortality in cirrhotic patients, further randomized clinical trials are warranted involving larger patient populations with clear clinical end points. On the other hand, recent findings from studies that have investigated the potential use of the blockers of the components of the alternate RAS provided compelling evidence that could lead to the development of drugs targeting the splanchnic vascular bed to inhibit splanchnic vasodilatation in portal hypertension. This review outlines the mechanisms related to the pathogenesis of portal hypertension and attempts to provide an update on currently available therapeutic approaches in the management of portal hypertension with special emphasis on how the alternate RAS could be manipulated in our search for development of safe, specific and effective novel therapies to treat portal hypertension in cirrhosis.

Primary prophylaxis of variceal bleeding in patients with cirrhosis:A comparison of different strategies

Patients with cirrhosis and esophageal varices bleed at a yearly rate of 5%-15%,and,when variceal hemorrhage develops,mortality reaches 20%.Patients are deemed at high risk of bleeding when they present with medium or large-sized varices,when they have red signs on varices of any size and when they are classified as Child-Pugh C and have varices of any size.In order to avoid variceal bleeding and death,individuals with cirrhosis at high risk of bleeding must undergo primary prophylaxis,for which currently recommended strategies are the use of traditional non-selective beta-blockers(NSBBs)(i.e.,propranolol or nadolol),carvedilol(a NSBB with additional alpha-adrenergic blocking effect)or endoscopic variceal ligation(EVL).The superiority of one of these alternatives over the others is controversial.While EVL might be superior to pharmacological therapy regarding the prevention of the first bleeding episode,either traditional NSBBs or carvedilol seem to play a more prominent role in mortality reduction,probably due to their capacity of preventing other complications of cirrhosis through the decrease in portal hypertension.A sequential strategy,in which patients unresponsive to pharmacological therapy would be submitted to endoscopic treatment,or the combination of pharmacological and endoscopic strategies might be beneficial and deserve further investigation.