Carvedilol versus traditional, non-selective beta-blockers for adults with cirrhosis and gastroesophageal varices.
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ABSTRACT:
SUBMITTER: Zacharias AP
PROVIDER: S-EPMC6517039 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Recent evidence suggests that binding of agonist to its cognate receptor initiates not only classical G protein-mediated signaling, but also beta-arrestin-dependent signaling. One such beta-arrestin-mediated pathway uses the beta(1)-adrenergic receptor (beta(1)AR) to transactivate the EGFR. To determine whether beta-adrenergic ligands that do not activate G protein signaling (i.e., beta-blockers) can stabilize the beta(1)AR in a signaling conformation, we screened 20 beta-blockers for their ability to stimulate beta-arrestin-mediated EGFR transactivation. Here we show that only alprenolol (Alp) and carvedilol (Car) induce beta(1)AR-mediated transactivation of the EGFR and downstream ERK activation. By using mutants of the beta(1)AR lacking G protein-coupled receptor kinase phosphorylation sites and siRNA directed against beta-arrestin, we show that Alp- and Car-stimulated EGFR transactivation requires beta(1)AR phosphorylation at consensus G protein-coupled receptor kinase sites and beta-arrestin recruitment to the ligand-occupied receptor. Moreover, pharmacological inhibition of Src and EGFR blocked Alp- and Car-stimulated EGFR transactivation. Our findings demonstrate that Alp and Car are ligands that not only act as classical receptor antagonists, but can also stimulate signaling pathways in a G protein-independent, beta-arrestin-dependent fashion.
| S-EPMC2567217 | biostudies-literature
Project description:Background and aimsWe aimed to perform a network meta-analysis (NWM) to examine comparative effectiveness of non-selective beta blockers (NSBBs) on prophylaxis of gastroesophageal variceal bleeding (GVB) and mortality benefit.MethodsMEDLINE (OVID) and EMBASE databases were searched for eligible randomized clinical trials (RCTs) from inception to July 3, 2021. Outcomes of interest included primary/secondary prophylaxis of GVB, failure to achieve hepatic venous pressure gradient (HVPG) decremental response, liver-related and all-cause mortality. A Bayesian NWM was performed to derive relative risk (RR) with 95% credible intervals (CrIs). The ranking probability of each NSBB was assessed by surface under cumulative ranking curve (SUCRA).ResultsThirty-three RCTs including 3,188 cirrhosis patients with gastroesophageal varices were included. Compared with placebo, nadolol ranked first for reducing variceal bleeding [RR:0.25, (95% CrI:0.11-0.51); SUCRA:0.898], followed by carvedilol [RR:0.33, (95% CrI: 0.11-0.88); SUCRA:0.692] and propranolol [RR:0.52, (95% CrI:0.37-0.75); SUCRA:0.405]. Carvedilol was more effective than propranolol in achieving HVPG decremental response [RR:0.43, (95% CrI: 0.26-0.69)]. Carvedilol ranked first for reducing all-cause mortality [RR: 0.32, (95% CrI:0.17-0.57); SUCRA:0.963), followed by nadolol [RR:0.48, (95% CI:0.29-0.77); SUCRA:0.688], and propranolol [RR:0.77, (95% CI:0.58-1.02); SUCRA: 0.337]. Similar findings were observed for liver-related mortality. Carvedilol ranked the safest. The RR of adverse events was 4.38, (95% CrI:0.33-161.4); SUCRA:0.530, followed by propranolol [RR: 7.54, (95% CrI:1.90-47.89); SUCRA:0.360], and nadolol [RR: 18.24, (95% CrI:91.51-390.90); SUCRA:0.158].ConclusionsCarvedilol is the preferred NSBB with better survival benefit and lower occurrence of adverse events among patients with gastroesophageal varices.
| S-EPMC10412710 | biostudies-literature
Project description:Non-selective beta-blockers (NSBBs) are the mainstay of treatment for portal hypertension in the setting of liver cirrhosis. Randomised controlled trials demonstrated their efficacy in preventing initial variceal bleeding and subsequent rebleeding. Recent evidence indicates that NSBBs could prevent liver decompensation in patients with compensated cirrhosis. Despite solid data favouring NSBB use in cirrhosis, some studies have highlighted relevant safety issues in patients with end-stage liver disease, particularly with refractory ascites and infection. This review summarises the evidence supporting current recommendations and restrictions of NSBB use in patients with cirrhosis.
| S-EPMC7005550 | biostudies-literature
Project description:Purpose To assess the feasibility of four-dimensional (4D) flow MRI as a noninvasive imaging marker for stratifying the risk of variceal bleeding in patients with liver cirrhosis. Materials and Methods This study recruited participants scheduled for both liver MRI and gastroesophageal endoscopy. Risk of variceal bleeding was assessed at endoscopy by using a three-point scale: no varices, low risk, and high risk requiring treatment. Four-dimensional flow MRI was used to create angiograms for evaluating visibility of varices and to measure flow volumes in main portal vein (PV), superior mesenteric vein, splenic vein (SV), and azygos vein. Fractional flow changes in PV and SV were calculated to quantify shunting (outflow) from PV and SV into varices. Logistic analysis was used to identify the independent indicator of high-risk varices. Results There were 23 participants (mean age, 52.3 years; age range, 25-75 years), including 14 men (mean age, 51.7 years; age range, 25-75 years) and nine women (mean age, 53.2 years; age range, 31-72 years) with no varices (n = 8), low-risk varices (n = 8), and high-risk varices (n = 7) determined at endoscopy. Four-dimensional flow MRI-based angiography helped radiologists to view varices in four of 15 participants with varices. Independent indicators of high-risk varices were flow volume in the azygos vein greater than 0.1 L/min (P = .034; 100% sensitivity [seven of seven] and 62% specificity [10 of 16]) and fractional flow change in PV of less than 0 (P < .001; 100% sensitivity [seven of seven] and 94% specificity [15 of 16]). Conclusion Azygos flow greater than 0.1 L/min and portal venous flow less than the sum of splenic and superior mesenteric vein flow are useful markers to stratify the risk of gastroesophageal varices bleeding in patients with liver cirrhosis. © RSNA, 2018 Online supplemental material is available for this article.
| S-EPMC6312435 | biostudies-literature
Project description:Background and Aims:Liver fibrosis blood tests, platelet count/spleen diameter ratio (PSR), and contrast-enhanced CT are diagnostic alternatives for gastroesophageal varices, but they have heterogeneous diagnostic performance among different study populations. Our study is aimed at evaluating their diagnostic accuracy for esophageal varices (EVs) and gastric varices (GVs) in cirrhotic patients with and without previous endoscopic variceal therapy. Methods:Patients with liver cirrhosis who underwent blood tests and contrast-enhanced CT scans as well as endoscopic surveillance should be potentially eligible. EVs needing treatment (EVNTs) and GVs needing treatment (GVNTs) were recorded according to the endoscopic results. Area under the curves (AUCs) were calculated. Results:Overall, 279 patients were included. In 175 patients without previous endoscopic variceal therapy, including primary prophylaxis population (n = 70), acute bleeding population (n = 38), and previous bleeding population (n = 67), the diagnostic accuracy of contrast-enhanced CT for EVNTs was higher (AUCs = 0.816-0.876) as compared to blood tests and PSR; by comparison, the diagnostic accuracy of contrast-enhanced CT for GVNTs was statistically significant among primary prophylaxis population (AUC = 0.731, P = 0.0316), but not acute or previous bleeding population. In 104 patients with previous endoscopic variceal therapy (i.e., secondary prophylaxis population), contrast-enhanced CT was the only statistically significant alternative for diagnosing EVNTs and GVNTs but with modest accuracy (AUCs = 0.673?and?0.661, respectively). Conclusions:Contrast-enhanced CT might be a diagnostic alternative for EVNTs in cirrhotic patients, but its diagnostic performance was slightly weakened in secondary prophylaxis population. Additionally, contrast-enhanced CT may be considered for diagnosis of GVNTs in primary prophylaxis population without previous endoscopic variceal therapy and secondary prophylaxis population.
| S-EPMC6855090 | biostudies-literature
Project description:Platelet count to spleen diameter ratio (PSR) was studied extensively as a noninvasive method of diagnosis for varices. The present study aimed to systematically assess the performance of PSR in the diagnosis of varices. PubMed, EMBASE, and article references were searched. The summary receiver operating characteristic curves (AUSROCs), sensitivities, specificities, positive and negative likelihood ratio, and diagnostic odds ratio were calculated. The heterogeneity, quality, and publication bias of studies were evaluated. Subgroup and sensitivity analyses were performed. A total of 49 papers were included. The AUSROCs of PSR for any varices and high-risk varices were 0.8719 and 0.8132, respectively. The summary sensitivities of PSR for any varices and high-risk varices were 0.84 and 0.78, respectively. The summary specificities of PSR for any varices and high-risk varices were 0.78 and 0.67, respectively. The AUSROC of PSR for any varices at the threshold of 909 was 0.8867. The AUSROC of PSR for any varices in viral liver cirrhosis was 0.8675. The overall quality of studies was moderate. Significant heterogeneity and publication bias existed in the study. In conclusion, PSR can be used to identify varices in liver cirrhosis. PSR had a high sensitivity in viral liver cirrhosis.
| S-EPMC5320338 | biostudies-literature
Project description:BACKGROUND:The mortality rate of bleeding esophageal varices in cirrhosis is highest during the period of acute bleeding. This is a report of a randomized trial that compared endoscopic sclerotherapy (EST) with emergency portacaval shunt (EPCS) in cirrhotic patients with acute variceal hemorrhage. STUDY DESIGN:A total of 211 unselected consecutive patients with cirrhosis and acutely bleeding esophageal varices who required at least 2 U of blood transfusion were randomized to EST (n=106) or EPCS (n=105). Diagnostic workup was completed within 6 hours and EST or EPCS was initiated within 8 hours of initial contact. Longterm EST was performed according to a deliberate schedule. Ninety-six percent of patients underwent more than 10 years of followup, or until death. RESULTS:The percent of patients in Child's risk classes were A, 27.5; B, 45.0; and C, 27.5. EST achieved permanent control of bleeding in only 20% of patients; EPCS permanently controlled bleeding in every patient (p< or =0.001). Requirement for blood transfusions was greater in the EST group than in the EPCS patients. Compared with EST, survival after EPCS was significantly higher at all time intervals and in all Child's classes (p< or =0.001). Recurrent episodes of portal-systemic encephalopathy developed in 35% of EST patients and 15% of EPCS patients (p< or =0.01). CONCLUSIONS:EPCS permanently stopped variceal bleeding, rarely became occluded, was accomplished with a low incidence of portal-systemic encephalopathy, and compared with EST, produced greater longterm survival. The widespread practice of using surgical procedures mainly as salvage for failure of endoscopic therapy is not supported by the results of this trial (clinicaltrials.gov #NCT00690027).
| S-EPMC6420230 | biostudies-literature
Project description:BackgroundLiver disease is within the top five causes of premature death in adults. Deaths caused by complications of cirrhosis continue to rise, whilst deaths related to other non-liver disease areas are declining. Portal hypertension is the primary sequelae of cirrhosis and is associated with the development of variceal haemorrhage, ascites, hepatic encephalopathy and infection, collectively termed hepatic decompensation, which leads to hospitalisation and mortality. It remains uncertain whether administering a non-selective beta-blocker (NSBB), specifically carvedilol, at an earlier stage, i.e. when oesophageal varices are small, can prevent VH and reduce all-cause decompensation (ACD).Methods/designThe BOPPP trial is a pragmatic, multicentre, placebo-controlled, triple-blinded, randomised controlled trial (RCT) in England, Scotland, Wales and Northern Ireland. Patients aged 18 years or older with cirrhosis and small oesophageal varices that have never bled will be recruited, subject to exclusion criteria. The trial aims to enrol 740 patients across 55 hospitals in the UK. Patients are allocated randomly on a 1:1 ratio to receive either carvedilol 6.25 mg (a NSBB) or a matched placebo, once or twice daily, for 36 months, to attain adequate power to determine the effectiveness of carvedilol in preventing or reducing ACD. The primary outcome is the time to first decompensating event. It is a composite primary outcome made up of variceal haemorrhage (VH, new or worsening ascites, new or worsening hepatic encephalopathy (HE), spontaneous bacterial peritonitis (SBP), hepatorenal syndrome, an increase in Child-Pugh grade by 1 grade or MELD score by 5 points, and liver-related mortality. Secondary outcomes include progression to medium or large oesophageal varices, development of gastric, duodenal, or ectopic varices, participant quality of life, healthcare costs and transplant-free survival.DiscussionThe BOPPP trial aims to investigate the clinical and cost-effectiveness of carvedilol in patients with cirrhosis and small oesophageal varices to determine whether this non-selective beta-blocker can prevent or reduce hepatic decompensation. There is clinical equipoise on whether intervening in cirrhosis, at an earlier stage of portal hypertension, with NSBB therapy is beneficial. Should the trial yield a positive result, we anticipate that the administration and use of carvedilol will become widespread with pathways developed to standardise the administration of the medication in primary care.Ethics and disseminationThe trial has been approved by the National Health Service (NHS) Research Ethics Committee (REC) (reference number: 19/YH/0015). The results of the trial will be submitted for publication in a peer-reviewed scientific journal. Participants will be informed of the results via the BOPPP website ( www.boppp-trial.org ) and partners in the British Liver Trust (BLT) organisation.Trial registrationEUDRACT reference number: 2018-002509-78. ISRCTN reference number: ISRCTN10324656. Registered on April 24 2019.
| S-EPMC11022376 | biostudies-literature
Project description:AimsPatients with cirrhosis and portal hypertension are at high risk of developing complications such as variceal hemorrhage, ascites, and cardiac dysfunction, the latter of which is known as cirrhotic cardiomyopathy. Since non-selective beta-blockers (NSBB) may aggravate hemodynamic complications we investigated the effect of real-time propranolol infusion on cardiac function in patients with varying degrees of cirrhosis.MethodsThirty-eight patients with Child-Pugh A (n = 17), B (n = 17) and C (n = 4) underwent liver vein catheterization and cardiac magnetic resonance imaging. We assessed the effect of real-time propranolol infusion on the hepatic venous pressure gradient, cardiac index, stroke volume, ejection fraction, heart rate, and contractility.ResultsNineteen patients were classified as responders to beta-blocker therapy. In pooling Child-Pugh B and C patients, the reduction in cardiac index by beta-blockade was weaker than in Child-Pugh A patients (-8.5% vs. -20.5%, p = 0.043). The effect of NSBB on portal pressure was inversely correlated to changes in the left atrium where the left atrial volume changed by 4 mL±18 in responders compared to 15 mL±11 in non-responders (p = 0.03). Finally, the baseline ejection fraction correlated inversely with the reduction in portal pressure (r = -0.39, p = 0.02).ConclusionWe found the effect of beta-blockade on cardiac index in patients with advanced cirrhosis to be less potent than in patients with early cirrhosis, indicating that underlying cirrhotic cardiomyopathy increases, and the cardiac compensatory reserve becomes more compromised, with disease progression. The differential effects of beta-blockade in the left atrium may be used to predict the effect of beta-blockers on portal pressure, but further studies are needed to investigate this possibility.
| S-EPMC9239488 | biostudies-literature
Project description:Background and aimsLittle is known about the effectiveness of nonselective beta blockers (NSBBs) in preventing hepatic decompensation in routine clinical settings. We investigated whether NSBBs are associated with hepatic decompensation or liver-related mortality in a national cohort of veterans with Child-Turcotte-Pugh (CTP) A cirrhosis with no prior decompensations.Approach and resultsIn an active comparator, new user (ACNU) design, we created a cohort of new users of carvedilol ( n = 123) versus new users of selective beta blockers (SBBs) ( n = 561) and followed patients for up to 3 years. An inverse probability treatment weighting (IPTW) approach balanced demographic and clinical confounders. The primary analysis simulated intention-to-treat ("pseudo-ITT") with IPTW-adjusted Cox models; secondary analyses were pseudo-as-treated, and both were adjusted for baseline and time-updating drug confounders. Subgroup analyses evaluated NSBB effects by HCV viremia status, CTP class, platelet count, alcohol-associated liver disease (ALD) etiology, and age. In pseudo-ITT analyses of carvedilol versus SBBs, carvedilol was associated with a lower hazard of any hepatic decompensation (HR 0.59, 95% CI 0.42-0.83) and the composite outcome of hepatic decompensation/liver-related mortality (HR 0.56, 95% CI 0.41-0.76). Results were similar in pseudo-as-treated analyses (hepatic decompensation: HR 0.55, 95% CI 0.33-0.94; composite outcome: HR 0.62, 95% 0.38-1.01). In subgroup analyses, carvedilol was associated with lower hazard of primary outcomes in the absence of HCV viremia, higher CTP class and platelet count, younger age, and ALD etiology.ConclusionsThere is an ongoing need to noninvasively identify patients who may benefit from NSBBs for the prevention of hepatic decompensation.
| S-EPMC9877112 | biostudies-literature