Carvedilol versus traditional, non-selective beta-blockers for adults with cirrhosis and gastroesophageal varices

Zacharias, Antony P; Jeyaraj, Rebecca; Hobolth, Lise; Bendtsen, Flemming; Gluud, Lise Lotte; Morgan, Marsha Y.

doi:10.1002/14651858.cd011510.pub2

Cited by 46 publications

(44 citation statements)

References 85 publications

(38 reference statements)

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“…This could be attributed to the inclusion of 2 additional trials assessing secondary prophylaxis [27,28] that had better precision. In addition, a recently published Cochrane meta-analysis evaluated the effects of carvedilol compared with the conventionally used NSBBs in patients with cirrhosis [34]. Our findings were in line with the results of the aforementioned meta-analysis in terms of both efficacy and safety-related outcomes.…”

Section: Discussionsupporting

confidence: 86%

Carvedilol for prevention of variceal bleeding: a systematic review and meta analysis

Malandris¹,

Paschos²,

Katsoula³

et al. 2019

aog

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Background Beta-blockers are used for prophylaxis of variceal bleeding. Our aim was to assess the efficacy and safety of carvedilol for primary or secondary prevention of variceal bleeding in patients with cirrhosis. Methods We searched Medline, Embase, CENTRAL and gray literature sources for randomized controlled trials (RCTs) comparing carvedilol with placebo or any active intervention. We synthesized data using random effects models. We summarized the strength of evidence using GRADE criteria. Results We included 13 trials with 1598 patients. Carvedilol was as efficacious as endoscopic variceal ligation (EVL) (4 RCTs, risk ratio [RR] 0.74, 95% confidence interval [CI] 0.37-1.49) or propranolol (3 RCTs, RR 0.76, 95%CI 0.27-2.14) for primary prevention of variceal bleeding. Likewise, carvedilol was as efficacious as EVL (3 RCTs, RR 1.10, 95%CI 0.75-1.61), non-selective beta-blockers (NSBBs) plus isosorbide-5-mononitrate (2 RCTs, RR 1.02, 95%CI 0.70-1.51) or propranolol (2 RCTs, RR 0.39, 95%CI 0.15-1.03) for secondary prevention of variceal bleeding. Carvedilol was associated with lower all-cause mortality compared to EVL (3 RCTs, RR 0.51, 95%CI 0.33-0.79). There was no difference in any other efficacy outcome. Finally, there were no significant differences in the safety profiles compared with EVL and NSBBs. Our confidence in the effect estimates for all outcomes was very low. Conclusion Carvedilol is as efficacious and safe as standard-of-care interventions for the primary and secondary prevention of variceal bleeding.

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Section: Discussionsupporting

confidence: 86%

Carvedilol for prevention of variceal bleeding: a systematic review and meta analysis

Malandris¹,

Paschos²,

Katsoula³

et al. 2019

aog

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“…However, labetalol, another NSBB with similar anti-1 adrenergic activity failed to reduce HVPG in patients with cirrhosis[ 140 ]. Although individual studies demonstrated that carvedilol may be more effective than traditional NSBBs such as propranolol in preventing variceal bleeding in cirrhotic patients, a recent meta-analysis which systematically analysed ten randomized clinical trials using carvedilol, propranolol and nadolol, concluded that carvedilol is not as effective as traditional NSBBs in reducing mortality, variceal bleeding and serious adverse events[ 141 ]. Thus, the authors concluded that additional evidence is required from adequately powered, long-term, double-blind, randomised clinical trials, evaluating both clinical and haemodynamic outcomes.…”

Section: Therapies Targeting Splanchnic Vasodilatationmentioning

confidence: 99%

Cirrhotic portal hypertension: From pathophysiology to novel therapeutics

Gunarathne¹,

Rajapaksha²,

Shackel³

et al. 2020

WJG

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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 off-target 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.

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“…After a median follow-up of 2.3 years, carvedilol therapy was associated with a hazard ratio of 0.47 (95% CI 0.29-0.77) in patients with mild ascites and was not associated with increased mortality in patients with moderate to severe ascites[30]. Zacharias et al[34] recently conducted a Cochrane systematic review of 10 RCTs and 810 patients comparing the safety and efficacy of carvedilol versus traditional NSBBs in the primary and secondary prevention of variceal haemorrhage; they identified no differences in the incidence of mortality, variceal haemorrhage and serious adverse events between both groups despite greater reductions in HVPG for the carvedilol group. Due to the low quality of assessed evidence, these findings were associated with substantial uncertainty.…”

Section: Currently-used Medicationsmentioning

confidence: 99%

Current and future pharmacological therapies for managing cirrhosis and its complications

Kockerling

Nathwani

Forlano

et al. 2019

WJG

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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 beta-blockers 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.

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Carvedilol versus traditional, non-selective beta-blockers for adults with cirrhosis and gastroesophageal varices

Abstract: Analysis 1.10. Comparison 1 Carvedilol versus non-selective beta-blockers, Outcome 10 Non-serious adverse events (overall).... Analysis 1.11. Comparison 1 Carvedilol versus non-selective beta-blockers, Outcome 11 Non-serious adverse events

Cited by 46 publications

References 85 publications

Carvedilol for prevention of variceal bleeding: a systematic review and meta analysis

Carvedilol for prevention of variceal bleeding: a systematic review and meta analysis

Cirrhotic portal hypertension: From pathophysiology to novel therapeutics

Current and future pharmacological therapies for managing cirrhosis and its complications

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