Safety of two different doses of simvastatin plus rifaximin in decompensated cirrhosis (LIVERHOPE-SAFETY): a randomised, double-blind, placebo-controlled, phase 2 trial

Pose, Elisa; Napoleone, Laura; Amin, Ahmed Adel; Campion, Daniela; Jimenez, César; Piano, Salvatore; Roux, Olivier; Uschner, Frank Erhard; Wit, Koos de; Zaccherini, Giacomo; Alessandria, Carlo; Angeli, Paolo; Bernardi, Mauro; Beuers, Ulrich; Caraceni, Paolo; Durand, François; Mookerjee, R.; Trebicka, Jonel; Vargas, Vı́ctor; Andrade, Raúl J.; Carol, Marta; Pich, Judit; Ferrero, Juan Pablo; Doménech, Gema; Llopis, Marta; Torres, Ferrán; Kamath, Patrick S.; Abraldes, Juan G.; Solà, Elsa; Ginès, Pere

doi:10.1016/s2468-1253(19)30320-6

Cited by 107 publications

(80 citation statements)

References 27 publications

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“…Several additional steps in simvastatin liver metabolism and bile excretion might be altered with impaired liver function. Finally, very recent data from a double-blind dose-finding trial conducted in patients with decompensated cirrhosis showed that a dose of 20 mg OD was associated with no muscle toxicity,101 whereas the rate of muscle toxicity with simvastatin 40 mg OD was even higher than in the BLEPS study. This is likely due to the fact that the BLEPS study included patients with less advanced liver disease, and further suggests that patients with decompensated cirrhosis should not be treated with >20 mg OD of simvastatin.…”

Section: Problems With Statin Use In Patients With Advanced Liver Dismentioning

confidence: 97%

Cirrhosis as new indication for statins

Bosch

Gracia‐Sancho

Abraldes

2020

Gut

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In the recent years, there have been an increasing number of reports on favourable effects of statins in patients with advanced chronic liver disease. These include reduction in portal pressure, improved liver sinusoidal endothelial and hepatic microvascular dysfunction, decreased fibrogenesis, protection against ischaemia/reperfusion injury, safe prolongation of ex vivo liver graft preservation, reduced sensitivity to endotoxin-mediated liver damage, protection from acute-on-chronic liver failure, prevention of liver injury following hypovolaemic shock and preventing/delaying progression of cirrhosis of any aetiology. Moreover, statins have been shown to have potential beneficial effects in the progression of other liver diseases, such as chronic sclerosing cholangitis and in preventing hepatocellular carcinoma. Because of these many theoretically favourable effects, statins have evolved from being considered a risk to kind of wonder drugs for patients with chronic liver diseases. The present article reviews the current knowledge on the potential applications of statins in chronic liver diseases, from its mechanistic background to objective evidence from clinical studies.

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Section: Problems With Statin Use In Patients With Advanced Liver Dismentioning

confidence: 97%

Cirrhosis as new indication for statins

Bosch

Gracia‐Sancho

Abraldes

2020

Gut

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“…Moreover, considering drug-induced hepatotoxicity as a rare, though well-described side effect of statin as well as increased risk of rhabdomyolysis in patients with chronic liver disease due to impaired CYP3A4 metabolism in the liver, the safety profile of statins in patients with chronic liver disease and liver cirrhosis needs to be evaluated in detail. Thus, just recently Pose et al reported rhabdomyolysis requiring treatment discontinuation in 19% (3/18) of patients with decompensated liver cirrhosis and treatment with 40mg simvastatin per day compared to 14% in 20mg simvastatin or placebo treated patients, respectively [291]. Another study reported severe rhabdomyolysis in 3% of patients with liver cirrhosis and statin use [289].…”

Section: Hepatic Protection Via Lipid-lowering Agentsmentioning

confidence: 99%

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

Roehlen

Crouchet

Baumert

2020

Cells

747

440

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Liver fibrosis due to viral or metabolic chronic liver diseases is a major challenge of global health. Correlating with liver disease progression, fibrosis is a key factor for liver disease outcome and risk of hepatocellular carcinoma (HCC). Despite different mechanism of primary liver injury and disease-specific cell responses, the progression of fibrotic liver disease follows shared patterns across the main liver disease etiologies. Scientific discoveries within the last decade have transformed the understanding of the mechanisms of liver fibrosis. Removal or elimination of the causative agent such as control or cure of viral infection has shown that liver fibrosis is reversible. However, reversal often occurs too slowly or too infrequent to avoid life-threatening complications particularly in advanced fibrosis. Thus, there is a huge unmet medical need for anti-fibrotic therapies to prevent liver disease progression and HCC development. However, while many anti-fibrotic candidate agents have shown robust effects in experimental animal models, their anti-fibrotic effects in clinical trials have been limited or absent. Thus, no approved therapy exists for liver fibrosis. In this review we summarize cellular drivers and molecular mechanisms of fibrogenesis in chronic liver diseases and discuss their impact for the development of urgently needed anti-fibrotic therapies.

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“…In another recent clinical trial, addition of simvastatin to the NSBB treatment decreased overall mortality in patients although it failed to reduce the rate of re-bleeding from varices[ 164 ]. Whilst this study showed that 3% of the patients treated with simvastatin developed severe adverse side effects such as rhabdomyolysis, a more recent clinical trial suggested that statins-associated risks appear to be dose-related[ 165 ]. The above clinical evidence suggests that statins possess a clear potential for the treatment of portal hypertension in cirrhotic patients, however, further randomized clinical trials are warranted involving larger patient populations with clear clinical end points.…”

Section: Therapies Targeting Increased Intrahepatic Vascular Tonementioning

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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Safety of two different doses of simvastatin plus rifaximin in decompensated cirrhosis (LIVERHOPE-SAFETY): a randomised, double-blind, placebo-controlled, phase 2 trial

Abstract: Grant support and Acknowledgements: This work has been supported by funding from EU H2020 Research & Innovation programme, No. 731875 (LIVERHOPE).We acknowledge Nicola Van Berckel for her administrative support and her valuable collaboration with the development of the Liverhope Project.

Cited by 107 publications

References 27 publications

Cirrhosis as new indication for statins

Cirrhosis as new indication for statins

Liver Fibrosis: Mechanistic Concepts and Therapeutic Perspectives

Cirrhotic portal hypertension: From pathophysiology to novel therapeutics

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